Chemically induced reprogramming to reverse aging

Abstract

Provided herein are methods of rejuvenating, restoring cellular function to, decreasing the biological age of, decreasing the apparent chronological age of, and reprogramming cells, organs, and tissues, using chemical cocktails comprising two or more compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof. Also provided herein are methods of treating a disease, methods of monitoring cellular aging, and pharmaceutical compositions and kits using two or more compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof.

Description

CHEMICALLY INDUCED REPROGRAMMING TO REVERSE AGING RELATEDAPPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N.63 / 511,601, filed June 30, 2023, which is incorporated herein by reference. GOVERNMENT SUPPORT

[0002] This invention was made with government support under AG019719 and AG058605 and AG028730 and HG011850 awarded by National Institutes of Health (NIH). The government has certain rights in this invention. BACKGROUND OF THE INVENTION

[0003] In many animals, including vertebrates, vital organs have a limited intrinsic capacity for regeneration and repair. Acute injury and chronic disorders can damage vital organs and tissues, including the brain. Mature somatic cells, however, often cannot survive these insults, and even if they do, they are unable to self-renew and transdifferentiate to replace damaged cells. Furthermore, cells that are capable of self-renewal can be limited in quantity, have limited capacity and are susceptible to damage, especially with age. In contrast to somatic cells from adults, cells from individuals that are chronologically closer to fertilization, such as those from embryos and infants, display cellular youthfulness and have a greater capacity to resist injury and stress, heal, renew, and regenerate organs and tissues. Thus, compositions and methods directed at rejuvenating cells, thereby restoring them from an aged, mature state to a younger, more vital state, have long been sought to treat certain injuries and diseases, as well as generally reverse and prevent aging in entire organisms.

[0004] There are two types of information in the body: digital and analog. DNA is digital information and the epigenome is analog information. Analog information typically does not last as long as digital, nor can analog information generally be copied with high fidelity compared to digital information. This has consequences for how long organisms live and thrive.

[0005] Several “hallmarks of aging” are cited as key contributors to the systemic deterioration of tissue function over time [1,2]. Of the aging hallmarks, there is strong evidence that a loss of epigenetic information and a smoothening of the epigenetic landscape, leading to changes in gene expression and a loss of cell identity, are among the main causes of aging [3–7]. The Information Theory of Aging states that a loss of information, particularly epigenetic information, causes a cascade of events that instigate the emergence of additional aging hallmarks, including mitochondrial dysfunction, inflammation, and cellular senescence [5,7,8]. The breakdown of these processes leads to a progressive decline in cell and tissue function, which manifests as aging and age-related diseases. It has previously been shown that DNA double-strand breaks and cellular injury are a major cause of1 / 240 12591029. H0824.70430WO00epigenetic information loss, leading to a decline in health of the organism, with increased frailty and vulnerability to disease [5].

[0006] Cellular senescence is a state of permanent cell cycle arrest that facilitates wound repair, tissue remodeling, and avoidance of cancer by halting proliferation in aged and damaged cells [9]. Senescence is associated with alterations in cell morphology, chromatin architecture, and the release of inflammatory factors in a process referred to as the senescence associated secretory phenotype (SASP). The transition to cellular senescence can be initiated by telomere shortening, DNA damage, cytoplasmic DNA, or a loss of epigenetic information [7,10]. The accumulation of senescent cells with age increases inflammation and reactive oxygen species both locally and across the organism, contributing to a broad range of age-related diseases, from macular degeneration to increased blood pressure

[0011] .

[0007] Starting in 1962, Gurdon and others demonstrated that the nuclei of adult cells, such as those from intestinal cells, contain the necessary information to generate new individuals with normal lifespans

[0012] . Then in 2006, Takahashi and Yamanaka showed that by expressing four transcription factors – OCT3 / 4, SOX2, KLF4 and c-MYC(OSKM) – it is possible to epigenetically reset adult cells in vitro to erase cellular identity then coax them into myriad cell types [12–15]. These findings began the field of stem cell reprogramming, with a string of publications in the 2000s showing that, through transient expression or varying the cocktail of Yamanaka factors in vitro, the identities of adult cells could be erased back to a pluripotent stem cell stage [8,16–18].

[0008] The remarkable potency of the Yamanaka factors raised a significant question: is it possible to reverse cellular aging safely without compromising cellular identity, as the latter is known to lead to uncontrolled cell growth and tumorigenesis, which can swiftly endanger the life of the individual

[0016] . It has been confirmed that it is possible to improve the function of tissues in vivo by pulsing the expression of OSKM, or expressing only OSK continuously [8,16,17]. In the optic nerve, the expression of Yamanaka factors has been shown to reset youthful DNA methylomes and gene expression patterns, restoring vision in old and glaucomatous mice [8]. Numerous tissues, including brain tissue, kidney, and muscle, have now been safely reprogrammed, and the expression of OSK throughout the entire body of mice is known to extend their lifespan

[0019] . Together, these results suggest the existence of a “back-up copy” of a youthful epigenome, one that can be reset via partial reprogramming to regain tissue function without erasing cellular identity or causing tumorigenesis [7,8,16].

[0009] Despite the promise of partial reprogramming to reverse aging and treat age-related diseases in humans, translational applications heavily rely on the delivery of genetic material via either adeno- associated viruses (AAV) or lipid nanoparticles [8,20]. These approaches, however, face barriers, especially for whole-body rejuvenation, including high-cost, regulatory stipulations, and unanswered questions about safety and long-term effectiveness.2 / 240 12591029. H0824.70430WO00

[0010] Aging was once thought of as a process driven by mutations in the genetic material of a cell. This has largely been abandoned as an explanation. A major cause of aging is now thought to be due to epigenetic changes that cause cells to transcribe the wrong genes at the wrong time, a process that becomes more dysfunctional over time, leading to diseases, an inability to heal and eventually to death. The Yamanaka factors (OCT4, SOX2, c-Myc, and KLF4) have previously been shown to induce pluripotency in vitro (Takahashi et al., Cell.2006 Aug 25;126(4):663-76) and reverse the DNA methlylation clock of aging (Horvath, Genome Biol.2013). Nanog and Lin28 can help induce pluripotency together with Yamanaka factors. And Tet1, NR5A-2, Sall4, and NKX3-1 can replace Oct4 (Gao et al., Cell Stem Cell 12, 1–17, April 4, 2013; and Mai et al., Nature Cell Biology 20, 900–908, 2018). Expression of the original four transcription factors in transgenic mice, however, induces teratomas in vivo, along with other acute toxicities like dysplasia in the intestinal epithelium, that can kill an animal in a few days (Abad et al., Nature.2013 Oct 17;502(7471):340-5). Therefore, non-toxic and efficient methods of cellular reprogramming are needed. SUMMARY OF THEINVENTION

[0011] The inventors have unexpectedly discovered that it is possible to reverse aspects of aging using chemicals, such as small molecules, rather than genetic means. In connection with this discovery, disclosed herein are a variety of novel chemical cocktails capable of rejuvenating cells and reversing transcriptomic age to a similar extent as OSK overexpression, and methods and uses of the same, as well as novel screening methods, including a quantitative nucleocytoplasmic compartmentalization assay (NCC) that can readily distinguish between young, old, and senescent cells

[0024] . An advantage of the present disclosure is that the compositions, methods, uses allow for the safe mimicking of OSK’s rejuvenating effects, which can allow for reduction of the cost and timelines for the development of regenerative medicines. [21–23].

[0012] The cellular aging process has been postulated to be caused by the loss of both genetic and epigenetic information. While previous studies have hypothesized that aging is caused primarily by the loss of genetic information (most commonly in the form of genetic mutations such as substitutions and deletions in an organism’s genome), the systems, compositions, uses, kits, and methods of the present disclosure are informed by the unexpected finding that aging in the central nervous system is primarily driven by a loss in the particular epigenetic information that is established closer to fertilization and final differentiation of particular cells. Epigenetic information, which commonly takes the form of covalent modifications to DNA, such as 5-methylcytosine(5mC), hydroxymethylcytosine (5hmeC), 5-formylcytosine (fC), 5-carboxylcytosine (caC), and adenine methylation, and to certain proteins, such as lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation of histone proteins, is sometimes referred to as the “analog” information of the cell. The loss of this analog information can3 / 240 12591029. H0824.70430WO00result in dysregulation of vital cellular processes, such as the processes that maintain cell identity, causing cells to exhibit traits that are typically associated with aging, such as senescence.

[0013] The present disclosure stems from the unexpected discovery that, in some embodiments, chemical cocktails comprising two or more compounds can reverse the age of human fibroblasts and restore genome-wide transcript profiles. Surprisingly, in some embodiments, as described herein, this rejuvenation can occur in less than a week and without erasing cellular identity, a crucial aspect of partial epigenetic reprogramming. Thus, reversal of cellular aging by partial reprogramming and the restoration of youth, similar to the effect of the Yamanaka factors, Oct4, Sox2, and Klf4 (OSK), can be achieved by chemical means. See, e.g., International Publication No. WO 2020 / 069373, the contents of which are incorporated herein by reference.

[0014] Aspects of the present disclosure provide several methods, compositions, uses, and kits, that may be useful for efficient rejuvenation of a cell, tissue, and / or organ. In some embodiments, the cell, tissue, and / or organ is the skin. In some embodiments, the cell, tissue, and / or organ is in the central nervous system. In some embodiments, the organ is the eye. In some embodiments, the organ is the ear. In some embodiments, the central nervous system does not include the retina. In some embodiments, the cell, tissue, and / or organ in the central nervous system is a brain cell, brain tissue, and / or the brain. In come embodiments, the cell, tissue, and / or organ is in a human subject. In some embodiments, the cell, tissue, and / or organ is in a non-human subject. In some embodiments, the use is for a nutraceutical. In some embodiments, the use is for improvement of cosmetic beauty.

[0015] In one aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;4 / 240 12591029. H0824.70430WO00basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0016] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;5 / 240 12591029. H0824.70430WO00Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0017] In another aspect, the present disclosure provides methods of decreasing the biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;6 / 240 12591029. H0824.70430WO00linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0018] In another aspect, the present disclosure provides methods of decreasing the apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and7 / 240 12591029. H0824.70430WO00lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0019] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).8 / 240 12591029. H0824.70430WO00

[0020] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0021] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;9 / 240 12591029. H0824.70430WO00ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0022] In another aspect, the present disclosure provides methods of decreasing the biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;10 / 240 12591029. H0824.70430WO00butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0023] In another aspect, the present disclosure provides methods of decreasing the apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;11 / 240 12591029. H0824.70430WO00smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0024] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.12 / 240 12591029. H0824.70430WO00

[0025] In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium ascorbate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium chloride. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium orotate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium carbonate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium citrate.

[0026] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0027] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0028] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0029] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0030] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0031] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

[0032] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

[0033] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.13 / 240 12591029. H0824.70430WO00

[0034] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

[0035] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

[0036] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).14 / 240 12591029. H0824.70430WO00

[0037] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0038] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0039] In another aspect, the present disclosure provides methods of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof lithium ascorbate.

[0040] In another aspect, the present disclosure provides a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and15 / 240 12591029. H0824.70430WO00a second reporter gene linked to nuclear export signal.

[0041] In another aspect, the present disclosure provides a method of monitoring cellular aging, the method comprising: (a) providing a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal; (b) contacting the cell with at least one test agent; (c) measuring a first signal from a first protein produced by the first reporter gene; (d) measuring a second signal from a second protein produced by the second reporter gene; (e) comparing the first signal and the second signal to assess the distribution of the first protein and the second protein in the cell.

[0042] In another aspect, the present disclosure provides a pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;16 / 240 12591029. H0824.70430WO00linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0043] In another aspect, the present disclosure provides a pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0044] In another aspect, the present disclosure provides a kit comprising (a) a container housing a pharmaceutical composition comprising two or more compounds described herein (e.g., laduviglusib,17 / 240 12591029. H0824.70430WO00RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof); and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof.

[0045] In another aspect, the present disclosure provides a pharmaceutical composition for use in rejuvenating a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and18 / 240 12591029. H0824.70430WO00lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0046] In another aspect, the present disclosure provides a pharmaceutical composition for use in rejuvenating a cell, tissue, or organ, the pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0047] The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, Examples, Figures, and Claims.

[0048] 19 / 240 12591029. H0824.70430WO00DEFINITIONS

[0049] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0050] Compounds described herein may comprise one or more asymmetric centers, and thus may exist as stereoisomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Compounds may exist as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0051] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,20 / 240 12591029. H0824.70430WO00glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1–4alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0052] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0053] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R⋅x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R⋅0.5 H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H2O) and hexahydrates (R⋅6 H2O)).

[0054] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0055] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain21 / 240 12591029. H0824.70430WO00embodiments, at least one of the components is a solvent. A co-crystal of a compound and an acid is different from a salt formed from a compound and the acid. In the salt, a compound is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound easily occurs at room temperature. In the co-crystal, however, a compound is complexed with the acid in a way that proton transfer from the acid to a herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is substantially no proton transfer from the acid to a compound. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound.

[0056] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0057] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

[0058] Stereoisomers that are not mirror images of one another are termed “diastereomers,” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”

[0059] The term “isotopically labeled compound” refers to a derivative of a compound that only structurally differs from the compound in that at least one atom of the derivative includes at least one isotope enriched above (e.g., enriched 3-, 10-, 30-, 100-, 300-, 1,000-, 3,000- or 10,000-fold above) its natural abundance, whereas each atom of the compound includes isotopes at their natural abundances. In certain embodiments, the isotope enriched above its natural abundance is2H. In certain embodiments, the isotope enriched above its natural abundance is13C,15N, or18O.

[0060] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include choline ester derivatives and the like, N-22 / 240 12591029. H0824.70430WO00alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.

[0061] The term “small molecule” refers to molecules, whether naturally-occurring or artificially created (e.g., via chemical synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (e.g.., it contains carbon). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, hydroxyl, carbonyls, and heterocyclic rings, etc.). In certain embodiments, the molecular weight of a small molecule is not more than about 1,000 g / mol, not more than about 900 g / mol, not more than about 800 g / mol, not more than about 700 g / mol, not more than about 600 g / mol, not more than about 500 g / mol, not more than about 400 g / mol, not more than about 300 g / mol, not more than about 200 g / mol, or not more than about 100 g / mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g / mol, at least about 200 g / mol, at least about 300 g / mol, at least about 400 g / mol, at least about 500 g / mol, at least about 600 g / mol, at least about 700 g / mol, at least about 800 g / mol, or at least about 900 g / mol, or at least about 1,000 g / mol. Combinations of the above ranges (e.g., at least about 200 g / mol and not more than about 500 g / mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (C.F.R.)). The small molecule may also be complexed with one or more metal atoms and / or metal ions. In this instance, the small molecule is also referred to as a “small organometallic molecule.” Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more preferably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or regulatory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present disclosure.

[0062] The terms “pharmaceutical composition,” “composition,” and “formulation” are used interchangeably.

[0063] The terms “administer,” “administering,” or “administration,” as used herein, refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described23 / 240 12591029. H0824.70430WO00herein, or a composition thereof, alone, or in combination to any cell, tissue, organ, and / or subject. Any of the compounds described herein, or a composition thereof, alone, or in combination may be administered intravenously, intradermally, intraarterially, intralesionally, intratumorally, intracranially, intraarticularly, intraprostaticaly, intrapleurally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally, topically, locally, systemically, injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, in creams, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art (see, for example, Remington’s Pharmaceutical Sciences (1990), incorporated herein by reference).

[0064] The term “epigenome” or “epigenetics” refers to the modification and structural changes within a cell that control the expression of nucleic acids (e.g., engineered nucleic acids) or genomic information in a cell. Changes to the epigenome occur during, and drive the processes of embryonic development, disease progression, and aging.

[0065] The term “epigenetic clock” may refer to an age estimator or an innate biological process. In some embodiments, rejuvenating or reversing the epigenetic clock refers to reducing the estimated age of a cell, tissue, organ, or a subject. The epigenetic clock may be partially or fully reversed or rejuvenated by any of the methods described herein. In some embodiments, an age estimator is an epigenetic age estimator. For example, an epigenetic age estimator may be sets of CpG dinucleotides that when used in combination with a mathematical algorithm may be used to estimate age of a DNA source, including cells, organs, or tissues. In some embodiments, an age estimator is a DNA methylation-based (DNAm) age estimator. In some embodiments, a DNAm age estimator is calculated as an age correlation using Pearson correlation coefficient r, between DNA methylation- based (DNam) age (also known as estimated age) and chronological age. In some embodiments, the DNA methylation-based (DNAm) age estimator is a single-tissue DNA methylation-based age estimator. In some embodiments, the DNA methylation-based age estimator is a multi-tissue DNA methylation-based age estimator. In some embodiments, the DNAm age estimator is DNAm PhenoAge. See, e.g., Horvath and Raj, Nat Rev Genet.2018 Jun;19(6):371-384 and Levine et al., Aging (Albany NY).2018 Apr 18;10(4):573-591.

[0066] “Epigenetic information” as used herein includes covalent modifications to DNA, such as 5- methylcytosine(5mC), hydroxymethylcytosine (5hmeC), 5-formylcytosine (fC), 5-carboxylcytosine (caC), and adenine methylation and to certain proteins, such as lysine acetylation, lysine and arginine methylation, serine and threonine phosphorylation, and lysine ubiquitination and sumoylation of histone proteins, and the 3D architecture of cells, including TADs (topologically associated domains) and compartments. Epigenetic information is sometimes referred to as the “analog” information of the cell.24 / 240 12591029. H0824.70430WO00

[0067] “Restoring the expression” of at least one gene to youthful levels is meant to include increasing the expression of a downregulated gene or decreasing the expression of an upregulated gene that changes during aging. In some embodiments, the at least one gene is at least one gene selected from the group consisting of CDKN1A, IL6, CCL2, MMP3, LMNB1, and EZH2.

[0068] As used herein, the term “cell” is meant not only to include an individual cell but refers also to the particular tissue or organ from which it originates.

[0069] The term “cellular senescence” or “senescent cell” refers to a cell that has exited the cell cycle, displays epigenetic markers consistent with senescence, or expressing senescence cell markers (e.g., senescence-associated beta-galactosidase, or inflammatory cytokines). Cellular senescence may be partial or complete.

[0070] The term “gene expression” refers to the degree to which certain genes or all genes in a cell or tissue are transcribed into RNA. In some instances, the RNA is translated by the cell into a protein. The epigenome dictates gene expression patterns.

[0071] The term “cellular reprogramming” refers to the process of altering the epigenome of a cell using reprogramming factors (e.g., reversing or preventing epigenetic changes in cells that are causes of dysfunction, deterioration, cell death, senescence, or aging). Cellular reprogramming may be complete reprogramming, such that a differentiated cell (e.g., somatic cell) is reprogrammed to a pluripotent stem cell. Cellular reprogramming may be incomplete, such that a differentiated cell (e.g., somatic cell) retains its cellular identity (e.g., lineage-specific stem cell). Cellular reprogramming may be incomplete, e.g., a stem cell is not created, such that a cell is rejuvenated, or takes on more youthful attributes (e.g., increased survival, reduced inflammation, or ability to divide). Cellular reprogramming may provide additional cellular functions, or prevent cellular aging (e.g., transdifferentiation, or transition into cellular senescence). Cellular reprogramming may induce temporary or permanent gene expression changes. In some embodiments, incomplete cellular reprogramming is shown by the lack of Nanog expression. In some embodiments, cellular reprogramming prevents senescence from occurring.

[0072] The term “rejuvenating a cell” as used herein is meant to include preventing or reversing the cellular causes of aging without inducing a pluripotent state. A rejuvenated cell as used herein includes for example a cell that is not a diseased cell.

[0073] A “pluripotent state” as used herein is meant to include a state in which the cell expresses at least one stem cell marker, such as, but not limited to, Esrrb, Nanog, Lin28, TRA-1-60 / TRA-1- 81 / TRA-2-54, SSEA1, or SSEA4. Methods of measuring the expression of stem cell markers on the cell are known in the art and include the methods described herein.

[0074] The term “transdifferentiation” refers to a process in which one cell type is changed into another cell type without entering a pluripotent state. Transdifferentiation may also be referred to as lineage reprogramming or lineage conversion. See, e.g., Cieślar-Pobuda et al., Biochim Biophys Acta Mol Cell Res.2017 Jul;1864(7):1359-1369, which is incorporated herein by reference in its entirety.25 / 240 12591029. H0824.70430WO00

[0075] The term “central nervous system” refers to the part of the nervous system that includes the brain, cochlea, the spinal cord, the medulla, the pons, the cerebellum, the midbrain, the diencephalon, and the cerebral hemispheres. In some embodiments, the central nervous system includes the cranial nerves. In some embodiments, the central nervous system excludes the eye. In some embodiments, the central nervous system excludes the retina, uvea, pupil, lens, cornea, and / or sclera. In some embodiments, a cell or tissue is derived from the central nervous system. Non-limiting examples of cells from the central nervous system include neurons and glial cells. In some embodiments, a neuron is an excitatory neuron. In some embodiments, a cell from the central nervous system is a brain cell. In some embodiments, a brain cell is a neuron or a glial cell. In some embodiments, a cell from the central nervous system is a neuron, glial cell, or choroid plexus cell. In some embodiments, a glial cell is an astrocyte, oligodendrocyte, ependymal cell, or microglia cell. In some embodiments, a neuron is a sensory neuron, a motor neuron or an interneuron.

[0076] The terms “condition,” “disease,” and “disorder” are used interchangeably. Non-limiting examples of conditions, diseases, and disorders include acute injuries, neurodegenerative diseases, chronic diseases, proliferative diseases, cardiovascular diseases, genetic diseases, inflammatory diseases, autoimmune diseases, neurological diseases, hematological diseases, painful conditions, psychiatric disorders, metabolic disorders, chronic diseases, cancers, aging, age-related diseases, and diseases affecting any tissue in a subject. For example, age-related conditions include, heart failure, stroke, heart disease, atherosclerosis, neurodegenerative diseases (e.g., FTO, ALS, Alzheimer’s Disease, Parkinson’s Disease, dementia, Friedreich ataxia, amyotrophic lateral sclerosis, or vascular dementia), cognitive decline, memory loss, diabetes, osteoporosis, arthritis, muscle loss, hearing loss (partial or total), eye-related conditions (e.g., poor eye sight or retinal disease), glaucoma, a progeroid syndrome (e.g., Hutchinson-Gilford progeria syndrome), and cancer. In some embodiments, an age- related condition is senescence. As a non-limiting example, senescence of glial cells may be a cause of Alzheimer’s disease. See e.g., Bussian, et al., Nature.2018 Oct;562(7728):578-582. In some instances, the disease is nerve damage.

[0077] In some instances, a condition increases the DNA methylation-based age of a cell, a tissue, an organ, and / or a subject relative to a control. In some embodiments, the cell is a cell of the central nervous system. In some instances, a condition increases the DNA methylation-based age of a cell, a tissue, an organ, and / or a subject by at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1,000% relative to a control. In some instances, the control is a cell, a tissue, an organ, and / or a subject that does not have the condition. In some instances, the control is the same cell, tissue, organ, and / or subject prior to having the condition. Without being bound by a particular theory, any of the methods described herein may be useful in decreasing the DNA methylation-based age of a diseased cell, a diseased tissue, a diseased organ, and / or a subject who has, is at risk for, or is26 / 240 12591029. H0824.70430WO00suspected of having a disease. In some instances, the disease increases the DNA-methylation-based age of the cell, tissue, organ, and / or subject. In some instances, the disease is an injury.

[0078] In some instances, the condition is aging. In some instances, aging is driven by epigenetic noise. See, e.g., Oberdoerffer and Sinclair. Nat Rev Mol Cell Biol 8, 692-702, doi:10.1038 / nrm2238 (2007); Oberdoerffer et al. Cell 135, 907-918, doi:10.1016 / j.cell.2008.10.025 (2008). Without being bound by a particular theory, mammalian cells may retain a faithful copy of epigenetic information from earlier in life, analogous to Shannon’s “observer” system in Information Theory, essentially a back-up copy of the original signal to allow for its reconstitution at the receiving end if information is lost or noise is introduced during transmission. See, e.g., Shannon, The Bell System Technical Journal 27, 379-423 (1948) for a description of the observer system.

[0079] As used herein, an “ocular disease” or “eye disease” is a disease or condition of the eye. Non- limiting examples of conditions that affect the eye include Ectropion, Lagophthalmos, Blepharochalasis, Ptosis, Stye, Xanthelasma, Dermatitis, Demodex, leishmaniasis, loiasis, onchocerciasis, phthiriasis, (herpes simplex), leprosy, molluscum contagiosum, tuberculosis, yaws, zoster, impetigo, Dacryoadenitis, Epiphora, exophthalmos, Conjunctivitis, Scleritis, Keratitis, Corneal ulcer / Corneal abrasion, Snow blindness / Arc eye, Thygeson's superficial punctate keratopathy, Corneal neovascularization, Fuchs’ dystrophy, Keratoconus, Keratoconjunctivitis sicca, Iritis, iris, Uveitis, Sympathetic ophthalmia, Cataract, lens, Chorioretinal inflammation, Focal chorioretinal inflammation, chorioretinitis, choroiditis, retinitis, retinochoroiditis, Disseminated chorioretinal inflammation, exudative retinopathy, Posterior cyclitis, Pars planitis, chorioretinal inflammations, Harada’s disease, Chorioretinal inflammation, choroid, Chorioretinal scars, Macula scars, posterior pole (postinflammatory) (post-traumatic), Solar retinopathy, Choroidal degeneration, Atrophy, Sclerosis, angioid streaks, choroidal dystrophy, Choroideremia, choroidal, areolar, (peripapillary), Gyrate atrophy, choroid, ornithinaemia, Choroidal haemorrhage, Choroidal detachment, Chorioretinal, Chorioretinal inflammation, infectious and parasitic diseases, Chorioretinitis, syphilitic, toxoplasma, tuberculosis, chorioretinal, Retinal detachment, retina, choroid, distorted vision, Retinoschisis, Hypertensive retinopathy, Diabetic retinopathy, Retinopathy, Retinopathy of prematurity, Age-related macular degeneration, macula, Macular degeneration, Bull's Eye Maculopathy, Epiretinal membrane, Peripheral retinal degeneration, Hereditary retinal dystrophy, Retinitis pigmentosa, Retinal haemorrhage, retinal layers, Central serous retinopathy, Retinal detachment, retinal disorders, Macular edema, macula, Retinal disorder, Diabetic retinopathy, Glaucoma, optic neuropathy, ocular hypertension, open-angle glaucoma, angle-closure glaucoma, Normal Tension glaucoma, open-angle glaucoma, angle-closure glaucoma, Floaters, Leber’s hereditary optic neuropathy, Optic disc drusen, Strabismus, Ophthalmoparesis, eye muscles, Progressive external ophthaloplegia, Esotropia, Exotropia, Disorders of refraction, accommodation, Hypermetropia, Myopia, Astigmatism, Anisometropia, Presbyopia, ophthalmoplegia, Amblyopia, Leber's congenital amaurosis, Scotoma, Anopsia, Color blindness, Achromatopsia / Maskun, cone27 / 240 12591029. H0824.70430WO00cells, Nyctalopia, Blindness, River blindness, Micropthalmia / coloboma, optic nerve, brain, spinal cord, Red eye, Argyll Robertson pupil, pupils, Keratomycosis, Xerophthalmia, and Aniridia. In some embodiments, the ocular disease is acute or chronic eye injury.

[0080] In some embodiments, the ocular disease is a scratched cornea.

[0081] In some embodiments, the ocular disease is glaucoma.

[0082] In some embodiments, an ocular disease is a corneal disease (e.g., a disease affecting the cornea or corneal cells). In some embodiments, an ocular disease is acanthamoeba keratitis, ectropion, lagoph amblyopia, anisocoria, astigmatism, Bell’s Palsy, blepharitis, blurry vision, burning eyes, cataracts, macular degeneration, age-related macular degeneration, diabetic eye disease, glaucoma, dry eye, poor vision (e.g., low vision), astigmatism, blepharitis, cataract, chalazion, conjunctivitis, diabetic retinopathy, dry eye, glaucoma, keratitis, keratonconus, macular degeneration, ocular hypertension, pinquecula, pterygium, retinitis pigmentosa, or ocular cancer (e.g., retinoblastoma, melanoma of the eye, lymphoma of the eye, medulloepithelioma, squamous cell cancer of the conjunctiva). Examples of corneal diseases include, but are not limited to, corneal neovascularization (NV), corneal dystrophy, corneal inflammation, corneal abrasion, and corneal fibrosis. In some embodiments, the ocular disease is Keritaconus. In some embodiments, an ocular disease is macular degeneration. Additional non-limiting examples of eye diseases may be found in the International Statistical Classification of Diseases and Related Health Problems (e.g., VII Diseases of the eye and adnexa).

[0083] An ocular disease may affect any part of the eye and / or adnexa. In some embodiments, the ocular disease is a disorder of the eyelid, lacrimal system and / or orbit. In some embodiments, the ocular disease is a disorders of conjunctiva. In some embodiments, the ocular disease is a disorder of sclera, cornea, iris, and / or ciliary body. In some embodiments, the ocular disease is a disorder of the lens. In some embodiments, the ocular disease is a disorder of choroid and / or retina. In some embodiments, the ocular disease is glaucoma. In some embodiments, the ocular disease is a disorder of vitreous body and / or globe. In some embodiments, the ocular disease is a disorder of optic nerve and / or visual pathways. In some embodiments, the ocular disease is a disorder of ocular muscles, binocular movement, accommodation, and / or refraction. In some embodiments, the ocular disease is a visual disturbance and / or blindness. In some embodiments, the ocular disease is associated with aging, for example, vision loss associated with aging, decline in visual acuity associated with aging, and / or decline in retinal function.

[0084] Any suitable method may be used to measure ocular function. Non-limiting examples include visual acuity tests, pattern electroretinograms, and pathology.

[0085] The term “genetic disease” refers to a disease caused by one or more abnormalities in the genome of a subject, such as a disease that is present from birth of the subject. Genetic diseases may be heritable and may be passed down from the parents’ genes. A genetic disease may also be caused by mutations or changes of the DNAs and / or RNAs of the subject. In such cases, the genetic disease28 / 240 12591029. H0824.70430WO00will be heritable if it occurs in the germline. Exemplary genetic diseases include, but are not limited to, Aarskog-Scott syndrome, Aase syndrome, achondroplasia, acrodysostosis, addiction, adreno- leukodystrophy, albinism, ablepharon-macrostomia syndrome, alagille syndrome, alkaptonuria, alpha- 1 antitrypsin deficiency, Alport’s syndrome, Alzheimer’s disease, asthma, autoimmune polyglandular syndrome, androgen insensitivity syndrome, Angelman syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention deficit hyperactivity disorder (ADHD), autism, baldness, Batten disease, Beckwith-Wiedemann syndrome, Best disease, bipolar disorder, brachydactyl), breast cancer, Burkitt lymphoma, chronic myeloid leukemia, Charcot-Marie-Tooth disease, Crohn’s disease, cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer, congenital adrenal hyperplasia, Cornelia de Lange syndrome, Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia, Crigler- Najjar syndrome, Creutzfeldt-Jakob disease, cystic fibrosis, deafness, depression, diabetes, diastrophic dysplasia, DiGeorge syndrome, Down’s syndrome, dyslexia, Duchenne muscular dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van Creveld syndrome, Ehlers-Danlos, epidermolysis bullosa, epilepsy, essential tremor, familial hypercholesterolemia, familial Mediterranean fever, fragile X syndrome, Friedreich’s ataxia, Gaucher disease, glaucoma, glucose galactose malabsorption, glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome (velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey disease, hemihypertrophy, hemochromatosis, hemophilia, hereditary motor and sensory neuropathy (HMSN), hereditary non polyposis colorectal cancer (HNPCC), Huntington’s disease, immunodeficiency with hyper-IgM, juvenile onset diabetes, Klinefelter’s syndrome, Kabuki syndrome, Leigh’s disease, long QT syndrome, lung cancer, malignant melanoma, manic depression, Marfan syndrome, Menkes syndrome, miscarriage, mucopolysaccharide disease, multiple endocrine neoplasia, multiple sclerosis, muscular dystrophy, myotrophic lateral sclerosis, myotonic dystrophy, neurofibromatosis, Niemann-Pick disease, Noonan syndrome, obesity, ovarian cancer, pancreatic cancer, Parkinson’s disease, paroxysmal nocturnal hemoglobinuria, Pendred syndrome, peroneal muscular atrophy, phenylketonuria (PKU), polycystic kidney disease, Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer, REAR syndrome, Refsum disease, retinitis pigmentosa, retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia, severe combined immunodeficiency, sickle cell anemia, spina bifida, spinal muscular atrophy, spinocerebellar atrophy, sudden adult death syndrome, Tangier disease, Tay-Sachs disease, thrombocytopenia absent radius syndrome, Townes-Brocks syndrome, tuberous sclerosis, Turner syndrome, Usher syndrome, von Hippel-Lindau syndrome, Waardenburg syndrome, Weaver syndrome, Werner syndrome, Williams syndrome, Wilson’s disease, xeroderma piginentosum, a progeroid syndrome (e.g., Hutchinson- Gilford progeria syndrome), and Zellweger syndrome.

[0086] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal29 / 240 12591029. H0824.70430WO00location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0087] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. For example, a prostate cancer that has migrated to bone is said to be metastasized prostate cancer and includes cancerous prostate cancer cells growing in bone tissue.

[0088] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal30 / 240 12591029. H0824.70430WO00adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non- Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T- cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian31 / 240 12591029. H0824.70430WO00embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0089] The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,32 / 240 12591029. H0824.70430WO00epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation. In some embodiments, the inflammatory disease is inflammaging (e.g., inflammation that is a side effect of aging).

[0090] An “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture’s disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture’s syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener’s granulomatosis, microscopic polyangiitis), uveitis, Sjogren’s syndrome, Crohn’s disease, Reiter’s syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto’s thyroiditis, and cardiomyopathy.

[0091] The term “skin” refers to the external tissue layer in humans and animals. Typically, the skin forms a protective barrier against water, UV light, pathogens, physical injury, and chemical agents. Skin comprises the epidermis, dermis, subcutaneous tissue layer, and associated cells, glands, mucous membranes, and connective tissue. The epidermis is the outermost layer of the skin, comprising five sub-layers: stratum corneum, transparent layer, granular layer, visible layer, and an embryonic (base) layer. The dermis is the inner layer between the epidermis and the subcutaneous tissue layer. The dermis comprises the papillary dermis and the reticular dermis and may include connective tissue, blood vessels, oil and sweat glands, nerves, and hair follicles. The subcutaneous tissue layer (hypodermis) is the innermost layer of the skin, comprising fat and a loose meshwork of connective tissue (e.g., collagen and elastic fibers). In certain embodiments, the term “skin” refers to the stratum corneum. In another embodiment, the term “skin” refers to the dermis. Skin is described in detail in Anatomy, Skin (Integument), H. Yousef, M. Alhajj, and S. Sharma, StatPearls, StatPearls Publishing, 2020.

[0092] A “skin condition” refers to a disease or condition affecting the skin. Exemplary skin conditions include skin cancer, lupus, seborrheic dermatitis, tinea, psoriasis, acne, rosacea,33 / 240 12591029. H0824.70430WO00hyperseborrhea, xerosis, atopic dermatitis (eczema), sebaceous hyperplasia, sunburn, an open wound, burns, bed sores, skin ulcers, pruritus (itch), dehydration, or wrinkles.

[0093] The term “liver disease” or “hepatic disease” refers to damage to or a disease of the liver. Non- limiting examples of liver disease include intrahepatic cholestasis (e.g., alagille syndrome, biliary liver cirrhosis), fatty liver (e.g., alcoholic fatty liver, Reye’s syndrome), hepatic vein thrombosis, hepatolenticular degeneration (i.e., Wilson’s disease), hepatomegaly, liver abscess (e.g., amebic liver abscess), liver cirrhosis (e.g., alcoholic, biliary, and experimental liver cirrhosis), alcoholic liver diseases (e.g., fatty liver, hepatitis, cirrhosis), parasitic liver disease (e.g., hepatic echinococcosis, fascioliasis, amebic liver abscess), jaundice (e.g., hemolytic, hepatocellular, cholestatic jaundice), cholestasis, portal hypertension, liver enlargement, ascites, hepatitis (e.g., alcoholic hepatitis, animal hepatitis, chronic hepatitis (e.g., autoimmune, hepatitis B, hepatitis C, hepatitis D, drug induced chronic hepatitis), toxic hepatitis, viral human hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), granulomatous hepatitis, secondary biliary cirrhosis, hepatic encephalopathy, varices, primary biliary cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma, hemangiomas, bile stones, liver failure (e.g., hepatic encephalopathy, acute liver failure), angiomyolipoma, calcified liver metastases, cystic liver metastases, fibrolamellar hepatocarcinoma, hepatic adenoma, hepatoma, hepatic cysts (e.g., simple cysts, polycystic liver disease, hepatobiliary cystadenoma, choledochal cyst), mesenchymal tumors (mesenchymal hamartoma, infantile hemangioendothelioma, hemangioma, peliosis hepatis, lipomas, inflammatory pseudotumor), epithelial tumors (e.g., bile duct hamartoma, bile duct adenoma), focal nodular hyperplasia, nodular regenerative hyperplasia, hepatoblastoma, hepatocellular carcinoma, cholangiocarcinoma, cystadenocarcinoma, tumors of blood vessels, angiosarcoma, Karposi’s sarcoma, hemangioendothelioma, embryonal sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary lymphoma, peliosis hepatis, erythrohepatic porphyria, hepatic porphyria (e.g., acute intermittent porphyria, porphyria cutanea tarda), and Zellweger syndrome.

[0094] The term “spleen disease” refers to a disease of the spleen. Example of spleen diseases include, but are not limited to, splenomegaly, spleen cancer, asplenia, spleen trauma, idiopathic purpura, Felty’s syndrome, Hodgkin’s disease, and immune-mediated destruction of the spleen.

[0095] The term “lung disease” or “pulmonary disease” refers to a disease of the lung. Examples of lung diseases include, but are not limited to, bronchiectasis, bronchitis, bronchopulmonary dysplasia, interstitial lung disease, occupational lung disease, emphysema, cystic fibrosis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), asthma (e.g., intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma), chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, interstitial lung disease, sarcoidosis, asbestosis, aspergilloma, aspergillosis, pneumonia (e.g., lobar pneumonia, multilobar pneumonia, bronchial pneumonia, interstitial pneumonia), pulmonary fibrosis, pulmonary34 / 240 12591029. H0824.70430WO00tuberculosis, rheumatoid lung disease, pulmonary embolism, and lung cancer (e.g., non-small-cell lung carcinoma (e.g., adenocarcinoma, squamous-cell lung carcinoma, large-cell lung carcinoma), small-cell lung carcinoma).

[0096] A “hematological disease” includes a disease which affects a hematopoietic cell or tissue. Hematological diseases include diseases associated with aberrant hematological content and / or function. Examples of hematological diseases include diseases resulting from bone marrow irradiation or chemotherapy treatments for cancer, diseases such as pernicious anemia, hemorrhagic anemia, hemolytic anemia, aplastic anemia, sickle cell anemia, sideroblastic anemia, anemia associated with chronic infections such as malaria, trypanosomiasis, HTV, hepatitis virus or other viruses, myelophthisic anemias caused by marrow deficiencies, renal failure resulting from anemia, anemia, polycythemia, infectious mononucleosis (EVI), acute non-lymphocytic leukemia (ANLL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), polycythemia vera, lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilm’s tumor, Ewing’s sarcoma, retinoblastoma, hemophilia, disorders associated with an increased risk of thrombosis, herpes, thalassemia, antibody-mediated disorders such as transfusion reactions and erythroblastosis, mechanical trauma to red blood cells such as micro-angiopathic hemolytic anemias, thrombotic thrombocytopenic purpura and disseminated intravascular coagulation, infections by parasites such as Plasmodium, chemical injuries from, e.g., lead poisoning, and hypersplenism.

[0097] The term “neurological disease” refers to any disease of the nervous system, including diseases and injuries that involve the central nervous system (brain, brainstem and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of which are located in both central and peripheral nervous system). Neurodegenerative diseases refer to a type of neurological disease marked by the loss of nerve cells, including, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia, Friedreich ataxia, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington’s disease. Examples of neurological diseases include, but are not limited to, vascular dementias, stroke, headache, stupor and coma, dementia, seizure, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of peripheral nerves, muscle and neuromuscular junctions. Addiction and mental illnesses include, but are not limited to, bipolar disorder and schizophrenia, are also included in the definition of neurological diseases. Further examples of neurological diseases include acquired epileptiform aphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardi syndrome; Alexander disease; Alpers’ disease; alternating hemiplegia; Alzheimer’s disease; amyotrophic lateral sclerosis; anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari malformation; arteriovenous malformation; Asperger syndrome; ataxia telangiectasia; attention deficit hyperactivity disorder; autism; autonomic35 / 240 12591029. H0824.70430WO00dysfunction; back pain; Batten disease; Behcet’s disease; Bell’s palsy; benign essential blepharospasm; benign focal; amyotrophy; benign intracranial hypertension; Binswanger’s disease; blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury; brain abscess; brain injury; brain tumors (including glioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia; central pain syndrome; central pontine myelinolysis; cephalic disorder; cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism; cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced neuropathy and neuropathic pain; Chiari malformation; chorea; chronic inflammatory demyelinating polyneuropathy (CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma, including persistent vegetative state; congenital facial diplegia; corticobasal degeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing’s syndrome; cytomegalic inclusion body disease (CIBD); cytomegalovirus infection; dancing eyes- dancing feet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier’s syndrome; Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; early infantile epileptic encephalopathy; empty sella syndrome; encephalitis; encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb’s palsy; essential tremor; Fabry’s disease; Fahr’s syndrome; fainting; familial spastic paralysis; febrile seizures; Fisher syndrome; Friedreich’s ataxia; frontotemporal dementia and other “tauopathies”; Gaucher’s disease; Gerstmann’s syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome; HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury; headache; hemifacial spasm; hereditary spastic paraplegia; heredopathia atactica polyneuritiformis; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also neurological manifestations of AIDS); holoprosencephaly; Huntington’s disease and other polyglutamine repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia; immune-mediated encephalomyelitis; inclusion body myositis; incontinentia pigmenti; infantile; phytanic acid storage disease; Infantile Refsum disease; infantile spasms; inflammatory myopathy; intracranial cyst; intracranial hypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg- Welander disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh’s disease; Lennox- Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia; lissencephaly; locked-in syndrome; Lou Gehrig’s disease (aka motor neuron disease or amyotrophic lateral sclerosis); lumbar disc disease; Lyme disease-neurological sequelae; Machado-Joseph disease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieres disease; meningitis; Menkes disease; metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motor neurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarct dementia; multifocal motor36 / 240 12591029. H0824.70430WO00neuropathy; multiple sclerosis and other demyelinating disorders; multiple system atrophy with postural hypotension; muscular dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia congenital; narcolepsy; neurofibromatosis; neuroleptic malignant syndrome; neurological manifestations of AIDS; neurological sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migration disorders; Niemann-Pick disease; O’Sullivan-McLeod syndrome; occipital neuralgia; occult spinal dysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overuse syndrome; paresthesia; Parkinson’s disease; paramyotonia congenita; paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy; painful neuropathy and neuropathic pain; persistent vegetative state; pervasive developmental disorders; photic sneeze reflex; phytanic acid storage disease; Pick’s disease; pinched nerve; pituitary tumors; polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia (PHN); postinfectious encephalomyelitis; postural hypotension; Prader-Willi syndrome; primary lateral sclerosis; prion diseases; progressive; hemifacial atrophy; progressive multifocal leukoencephalopathy; progressive sclerosing poliodystrophy; progressive supranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen’s Encephalitis; reflex sympathetic dystrophy syndrome; Refsum disease; repetitive motion disorders; repetitive stress injuries; restless legs syndrome; retrovirus-associated myelopathy; Rett syndrome; Reye’s syndrome; Saint Vitus Dance; Sandhoff disease; Schilder’s disease; schizencephaly; septo-optic dysplasia; shaken baby syndrome; shingles; Shy-Drager syndrome; Sjogren’s syndrome; sleep apnea; Soto’s syndrome; spasticity; spina bifida; spinal cord injury; spinal cord tumors; spinal muscular atrophy; stiff-person syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis; subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy; sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic outlet syndrome; tic douloureux; Todd’s paralysis; Tourette syndrome; transient ischemic attack; transmissible spongiform encephalopathies; transverse myelitis; traumatic brain injury; tremor; trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg’s syndrome; Werdnig- Hoffman disease; West syndrome; whiplash; Williams syndrome; Wilson’s disease; and Zellweger syndrome. In some embodiments, a neurological disorder affects the central nervous system, which includes the brain and the spinal cord. In some embodiments, a neurological disorder affects neurons. In some embodiments, a neurological disorder affects nerves. In some embodiments, a neurological disorder affects the spinal cord. In some embodiments, a neurological disorder is a brain disease (i.e., a disease affecting the brain).

[0098] The term “musculoskeletal disease” or “MSD” refers to an injury and / or pain in a subject’s joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck, and back. In37 / 240 12591029. H0824.70430WO00certain embodiments, an MSD is a degenerative disease. In certain embodiments, an MSD includes an inflammatory condition. Body parts of a subject that may be associated with MSDs include upper and lower back, neck, shoulders, and extremities (arms, legs, feet, and hands). In certain embodiments, an MSD is a bone disease, such as achondroplasia, acromegaly, bone callus, bone demineralization, bone fracture, bone marrow disease, bone marrow neoplasm, dyskeratosis congenita, leukemia (e.g., hairy cell leukemia, lymphocytic leukemia, myeloid leukemia, Philadelphia chromosome-positive leukemia, plasma cell leukemia, stem cell leukemia), systemic mastocytosis, myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, myeloid sarcoma, myeloproliferative disorders, multiple myeloma, polycythemia vera, pearson marrow-pancreas syndrome, bone neoplasm, bone marrow neoplasm, Ewing sarcoma, osteochondroma, osteoclastoma, osteosarcoma, brachydactyly, Camurati-Engelmann syndrome, Craniosynostosis, Crouzon craniofacial dysostosis, dwarfism, achondroplasia, bloom syndrome, Cockayne syndrome, Ellis-van Creveld syndrome, Seckel syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, Werner syndrome, hyperostosis, osteophyte, Klippel-Trenaunay-Weber syndrome, Marfan syndrome, McCune-Albright syndrome, osteitis, osteoarthritis, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, Leri- Weill dyschondrosteosis, osteochondrosis, osteodystrophy, osteogenesis imperfecta, osteolysis, Gorham-Stout syndrome, osteomalacia, osteomyelitis, osteonecrosis, osteopenia, osteopetrosis, osteoporosis, osteosclerosis, otospondylomegaepiphyseal dysplasia, pachydermoperiostosis, Paget disease of bone, Polydactyly, Meckel syndrome, rickets, Rothmund-Thomson syndrome, Sotos syndrome, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, syndactyly, Apert syndrome, syndactyly type II, or Werner syndrome. In certain embodiments, an MSD is a cartilage disease, such as cartilage neoplasm, osteochondritis, osteochondrodysplasia, Kashin-Beck disease, or Leri-Weill dyschondrosteosis. In certain embodiments, an MSD is hernia, such as intervertebral disk hernia. In certain embodiments, an MSD is a joint disease, such as arthralgia, arthritis (e.g., gout (e.g., Kelley-Seegmiller syndrome, Lesch-Nyhan syndrome), Lyme disease, osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid arthritis, Felty syndrome, synovitis, Blau syndrome, nail-patella syndrome, spondyloarthropathy, reactive arthritis, Stickler syndrome, synovial membrane disease, synovitis, or Blau syndrome. In certain embodiments, an MSD is Langer-Giedion syndrome. In certain embodiments, an MSD is a muscle disease, such as Barth syndrome, mitochondrial encephalomyopathy, MELAS syndrome, MERRF syndrome, MNGIE syndrome, mitochondrial myopathy, Kearns-Sayre syndrome, myalgia, fibromyalgia, polymyalgia rheumatica, myoma, myositis, dermatomyositis, neuromuscular disease, Kearns-Sayre syndrome, muscular dystrophy, myasthenia, congenital myasthenic syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis, myotonia, myotonia congenita, spinal muscular atrophy, tetany, ophthalmoplegia, or rhabdomyolysis. In certain embodiments, an MSD is Proteus syndrome. In certain embodiments, an MSD is a rheumatic diseases, such as arthritis (e.g., gout (e.g., Kelley-Seegmiller syndrome, Lesch- Nyhan Lyme disease)), osteoarthritis, psoriatic arthritis, reactive arthritis, rheumatic fever, rheumatoid38 / 240 12591029. H0824.70430WO00arthritis, Felty syndrome, synovitis, Blau syndrome, gout (e.g., Kelley-Seegmiller syndrome, Lesch- Nyhan syndrome), polymyalgia rheumatica, rheumatic fever, rheumatic heart disease, or Sjogren syndrome. In certain embodiments, an MSD is Schwartz-Jampel syndrome. In certain embodiments, an MSD is a skeleton disease, such as Leri-Weill dyschondrosteosis, skeleton malformations, Melnick-Needles syndrome, pachydermoperiostosis, Rieger syndrome, spinal column disease, intervertebral disk hernia, scoliosis, spina bifida, spondylitis, ankylosing spondylitis, spondyloarthropathy, reactive arthritis, spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, or spondylosis. In some embodiments, the disease is a musculoskeletal disease.

[0099] A “painful condition” includes, but is not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post–operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre–operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre–term labor, pain associated with withdrawal symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter’s arthritis), lumbosacral pain, musculo–skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental / maxillofacial pain, visceral pain and the like. One or more of the painful conditions contemplated herein can comprise mixtures of various types of pain provided above and herein (e.g., nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain can dominate. In other embodiments, the painful condition comprises two or more types of pains without one dominating. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0100] The term “psychiatric disorder” refers to a disease of the mind and includes diseases and disorders listed in the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM- IV), published by the American Psychiatric Association, Washington D.C. (1994). Psychiatric disorders include, but are not limited to, anxiety disorders (e.g., acute stress disorder agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, and specific phobia), childhood disorders, (e.g., attention-deficit / hyperactivity disorder, conduct disorder, and oppositional defiant disorder), eating disorders (e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar disorder, cyclothymic disorder, dysthymic disorder, and major depressive disorder), personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality39 / 240 12591029. H0824.70430WO00disorder, obsessive-compulsive personality disorder, paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, and shared psychotic disorder), substance-related disorders (e.g., alcohol dependence, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence), adjustment disorder, autism, delirium, dementia, multi-infarct dementia, learning and memory disorders (e.g., amnesia and age-related memory loss), and Tourette’s disorder.

[0101] The term “metabolic disorder” refers to any disorder that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders include, but are not limited to, diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[0102] In some embodiments, a disease is characterized by cellular dysfunction. For example, a disease may be a mitochondrial disease. Non-limiting mitochondrial diseases include Freidrich’s ataxia, alphers disease, barth syndrome, beta-oxidation defects, carnitine deficiency, CPT I deficiency, and mitochondrial DNA depletion. Cellular dysfunction may include mitochondria dysfunction, RNA replication dysfunction, DNA replication dysfunction, translation dysfunction, and / or protein folding dysfunction.

[0103] In some embodiments, the disease or condition is caused by a wound, bleeding out, injuries (e.g., broken bones, gunshot wound, cut, scarring during surgery (e.g., cesarean). In some embodiments, the disease or condition is caused by a spinal cord injury. In some embodiments, the disease or condition is caused by a brain injury.

[0104] In some embodiments, the disease is an infectious disease (e.g., a disease caused by a pathogen and / or virus). Non-limiting examples of infectious diseases include tuberculosis, HIV / AIDS, rabies, plague, cholera, dengue fever, measles, malaria, meningitis, whooping cough, Lyme disease, influenza, hepatitis C, typhoid fever, and poliomyelitis.

[0105] “Cellular causes of aging” as used herein include loss or modification of epigenetic information.

[0106] The term “Nanog” refers to a DNA binding homeobox transcription factor that has been implicated in embryonic stem (ES) cell proliferation, renewal, and pluripotency. Non-limiting examples of amino acid sequences encoding Nanog include the amino acid sequences under UniProtKB Accession Nos. Q9H9S0, Q4JM65, Q80Z64, and A7Y7W3.40 / 240 12591029. H0824.70430WO00

[0107] The terms “c-Myc” or “Myc” refer to a nuclear phosphoprotein that has been implicated in cell cycle progression. C-Myc is capable of forming a heterodimer with the transcription factor MAX and the heterodimer is capable of binding to an E box consequence sequence on nucleic acids (e.g., engineered nucleic acids) to regulate transcription of target genes.

[0108] The terms “effective amount” and “therapeutically effective amount,” as used herein, refer to the amount or concentration of an agent, small molecule, protein, composition, chemical cocktail, or a composition or chemical cocktail comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof), or combination thereof, that, when administered to a cell, tissue, organ, and / or subject, is effective to at least partially treat a condition from which the cell, tissue, organ, and / or subject is suffering.

[0109] As used herein, a protein that is “functional” or “active” is one that retains its biological activity (e.g., capable of acting as a transcription factor or as an inducing agent). Conversely, a protein that is not functional or is inactive is one that is not capable of performing one or more of its wild-type functions.

[0110] The term “gene” refers to a nucleic acid (e.g., engineered nucleic acid) fragment that expresses a protein, including regulatory sequences preceding (5' non-coding sequences) and following (3' non-coding sequences) the coding sequence. “Native gene” refers to a gene as found in nature with its own regulatory sequences. “Chimeric gene” or “chimeric construct” refers to any gene or a construct, not a native gene, comprising regulatory and coding sequences that are not found together in nature. Accordingly, a chimeric gene or chimeric construct may comprise regulatory sequences and coding sequences that are derived from different sources, or regulatory sequences and coding sequences derived from the same source, but arranged in a manner different than that found in nature. “Endogenous gene” refers to a native gene in its natural location in the genome of an organism. A “foreign” gene refers to a gene not normally found in the host organism, but which is introduced into the host organism by gene transfer. Foreign genes can comprise native genes inserted into a non-native organism, or chimeric genes. A “transgene” is a gene that has been introduced into the genome by a transformation procedure.

[0111] “Homolog” or “homologous” refers to sequences (e.g., nucleic acid (e.g., engineered nucleic acid) or amino acid sequences) that share a certain percent identity (e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 71%, at least 72%, at least73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least41 / 240 12591029. H0824.70430WO0097%, at least 98%, at least 99%, or 100% percent identity). Homologous sequences include but are not limited to paralogous or orthologous sequences. Paralogous sequences arise from duplication of a gene within a genome of a species, while orthologous sequences diverge after a speciation event. A functional homolog retains one or more biological activities of a wild-type protein

[0112] “KLF4” may also be referred to as Kruppel-like factor 4, EZF, or GKLF and is a zinc-finger transcription factor. KLF4 has been implicated in regulation of differentiation and proliferation and is capable of interacting with co-activators, including members of the p300-CBP coactivator family. A KLF4 transcription factor, homolog (e.g., functional homolog), or variant thereof, as used herein, may be derived from any species, including humans. In certain embodiments, the nucleic acid (e.g., engineered nucleic acid) encoding human KLF4 comprises a sequence that is at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a nucleic acid (e.g., engineered nucleic acid) described in the NCBI RefSeq database under accession number NM_004235.5 or NM_001314052.1.

[0113] The terms “nucleic acid,” “polynucleotide”, “nucleotide sequence”, “nucleic acid (e.g., engineered nucleic acid) molecule”, “nucleic acid (e.g., engineered nucleic acid) sequence”, and “oligonucleotide” refer to a series of nucleotide bases (also called “nucleotides”) in DNA and RNA, and mean any chain of two or more nucleotides. The terms “nucleic acid” or “nucleic acid (e.g., engineered nucleic acid) sequence”, “nucleic acid (e.g., engineered nucleic acid) molecule”, “nucleic acid (e.g., engineered nucleic acid) fragment” or “polynucleotide” may be used interchangeably with “gene,” “mRNA encoded by a gene,” and “cDNA”.

[0114] “OCT4” may also be referred to as Octamer-binding transcription factor 4, OCT3, OCT3 / 4, POU5F1, or POU class 5 homeobox 1 and is a transcription factor that has been implicated in embryonic development and determination of cell fate. Similar to other OCT transcription factors, OCT4 is characterized by a bipartite DNA binding domain called a POU domain. An OCT4 transcription factor, homolog, or variant thereof, as used herein, may be derived from any species, including humans. In certain embodiments, the nucleic acid (e.g., engineered nucleic acid) encoding human OCT4 is at least 70% (e.g., at least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a nucleic acid (e.g., engineered nucleic acid) described in the NCBI RefSeq under accession number NM_002701, NM_203289, NM_001173531, NM_001285986, or NM_001285987.

[0115] “SRY-box 2” or “SOX2” is a member of the SRY-related HMG-box (SOX) family of transcription factors. SOX2 has been implicated in promoting embryonic development. Members of the SOX (SRY-related HMG-box) family of transcription factors are characterized by a high mobility group 5 (HMG)-box DNA sequence. This HMG box is a DNA binding domain that is highly conserved throughout eukaryotic species. A SOX2 transcription factor, homolog or variant thereof, as used herein, may be derived from any species, including humans. In certain embodiments, the nucleic acid (e.g., engineered nucleic acid) encoding SOX2 comprises a sequence that is at least 70% (e.g., at42 / 240 12591029. H0824.70430WO00least 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100%) identical to a nucleic acid (e.g., engineered nucleic acid) described in the NCBI RefSeq under accession number NM_011443.4.

[0116] “Reversing aging” or “reversing ageing” as used herein refers to modifying the physical characteristics associated with aging. All animals typically go through a period of growth and maturation followed by a period of progressive and irreversible physiological decline ending in death. The length of time from birth to death is known as the life span of an organism, and each organism has a characteristic average life span. Aging is a physical manifestation of the changes underlying the passage of time as measured by percent of average life span.

[0117] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle–aged adult, or senior adult)) and / or other non–human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals, such as cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds, such as chickens, ducks, geese, and / or turkeys). In certain embodiments, the animal is a mammal. The animal may be a male or female and at any stage of development. A non–human animal may be a transgenic animal.

[0118] One of ordinary skill in the art would recognize that the biological age of a pediatric subject or adult subject may vary depending on the type of animal. As a non-limiting example, an adult mouse may be 1 year of age, while an adult human may be more than 21 years of age. In some embodiments, a pediatric subject is less than 21 years of age, less than 20 years of age, less than 15 years of age, less than 10 years of age, less than 9 years of age, less than 8 years of age, less than 7 years of age, less than 6 years of age, less than 5 years of age, less than 4 years of age, less than 3 years of age, less than 2 years of age, less than 1 year of age, less than 10 months of age, less than 9 months of age, less than 8 months of age, less than 7 months of age, less than 6 months of age, less than 5 months of age, less than 4 months of age, less than 2 months of age, or less than 1 month of age. In some embodiments, an adult subject is at least 3 weeks of age, 1 month of age, at least 2 months of age, at least 3 months of age, at least 4 months of age, at least 5 months of age, at least 6 months of age, at least 7 months of age, at least 8 months of age, at least 9 months of age, at least 10 months of age, at least 11 months of age, at least 1 year of age, at least 2 years of age, at least 3 years of age, at least 5 years of age, at least 10 years of age, at least 15 years of age, at least 20 years of age, at least 25 years of age, at least 30 years of age, at least 40 years of age, at least 50 years of age, at least 55 years of age, at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 90 years of age, or at least 100 years of age. In some embodiments, an adult subject is at least 10 years of age, at least 15 years of age, at least 20 years of age, at least 25 years of age, at least 30 years of age, at least 40 years of age, at least 50 years of age, at least 55 years of age, at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 90 years of age, or at least 100 years of age. In43 / 240 12591029. H0824.70430WO00some embodiments, a middle-aged adult subject is between 1 and 6 months of age, between 6 and 12 months of age, between 1 year and 5 years of age, between 5 years and 10 years of age, between 10 and 20 years of age, between 20 and 30 years of age, between 30 and 50 years of age, between 50 and 60 years of age, between 40 and 60 years of age, between 40 and 50 years of age, or between 45 and 65 years of age. In some embodiments, a middle-aged adult subject is between 30 and 50 years of age, between 50 and 60 years of age, between 40 and 60 years of age, between 40 and 50 years of age, or between 45 and 65 years of age. In some embodiments, a senior adult subject is at least 1 month of age, at least 2 months of age, at least 3 months of age, at least 4 months of age, at least 5 months of age, at least 6 months of age, at least 7 months of age, at least 8 months of age, at least 9 months of age, at least 10 months of age, at least 11 months of age, at least 1 year of age, at least 2 years of age, at least 3 years of age, at least 5 years of age, at least 10 years of age, at least 15 years of age, at least 20 years of age, at least 25 years of age, at least 30 years of age, at least 40 years of age, at least 50 years of age, at least 55 years of age, at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 90 years of age, or at least 100 years of age. In some embodiments, a senior adult subject is at least 50 years of age, at least 55 years of age, at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, at least 80 years of age, at least 90 years of age, or at least 100 years of age.

[0119] The term “tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound, particle, and / or composition of the invention is delivered. A tissue may be an abnormal, damaged, or unhealthy tissue, which may need to be treated. A tissue may also be a normal or healthy tissue that is under a higher-than-normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the tissue is considered healthy but suboptimal for performance or survival in current or future conditions. For example, in agricultural practice, environmental conditions including weather and growing conditions (e.g., nutrition) may benefit from any of the methods described herein. In certain embodiments, the tissue is the central nervous system, e.g., the brain. In some embodiments, the cell or tissue is a neuronal cell or nervous tissue. In some embodiments, the cell is a neuron. In some embodiments, the neuron is an excitatory neuron. In some embodiments, the tissue is not eye tissue.

[0120] The term “tissue repair” in the context of damaged tissue refers to restoration of tissue architecture, function following tissue damage, or a combination thereof. Tissue repair includes tissue regeneration, cell growth, tissue replacement, and / or rewiring of existing tissue (reprogramming).

[0121] The term “tissue regeneration” refers to production of new tissue or cells within a tissue that are the same type as the tissue of interest (e.g., same type as the damaged tissue or cell). In some embodiments, the methods provided herein promote organ regeneration.

[0122] The term “tissue replacement” refers to production of a different type of tissue compared to the tissue of interest (e.g., connective tissue to replace damaged tissue).44 / 240 12591029. H0824.70430WO00

[0123] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In certain embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms or may be treated with another damaging agent (e.g., in light of a history of symptoms, in light of genetic or other susceptibility factors, a disease therapy, or any combination thereof). Treatment may also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[0124] The term “variant” refers to a sequence that comprises a modification relative to a wild-type sequence. Non-limiting modifications in an amino acid sequence include insertions, deletions, and point mutations. Non-limiting modifications to nucleic acid (e.g., engineered nucleic acid) sequences include frameshift mutations, nucleotide insertions, and nucleotide deletions.

[0125] The terms “laduviglusib,” “CHIR-99021,” and “CHIR99021” refer to 6-[2-[[4-(2,4- dichlorophenyl)-5-(5-methyl-1H-imidazol-2-yl)pyrimidin-2-yl]amino]ethylamino]pyridine-3- carbonitrile, of the structure:, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “C” refers to laduviglusib.

[0126] The terms “RepSox,” “Repsox,” and “E-616452” refer to 2-(3-(6-methylpyridin-2-yl)-1H- pyrazol-4-yl)-1,5-naphthyridine, of the structure:,45 / 240 12591029. H0824.70430WO00and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the numeral “6” refers to RepSox.

[0127] The term “ascorbic acid” refers to L-ascorbic acid, or vitamin C, of the structure:, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof.

[0128] The term “valproic acid” refers to 2-propylvaleric acid, of the structure:, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “V” refers to valproic acid.

[0129] The term “tranylcypromine” refers to trans-2-phenylcyclopropylamine, with either or both of the structures:, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “T” refers to tranylcypromine.

[0130] The term “forskolin” refers to (3R,4aR,5S,6S,6aS,10S,10aR,10bS)-3-Ethenyl-6,10,10b- trihydroxy-3,4a,7,7,10a-pentamethyl-1-oxododecahydro-1H-naphtho[2,1-b]pyran-5-yl acetate, of the structure:46 / 240 12591029. H0824.70430WO00, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “F” refers to forskolin.

[0131] The term “butyric acid” refers to butanoic acid, with structure:, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof.

[0132] The terms “basic fibroblast growth factor” and “bFGF” refer to the amino acid sequence under UniProtKB Accession No. Q07659, or any other suitable form of basic fibroblast growth factor. In certain embodiments, the terms “basic fibroblast growth factor” and “bFGF” refer to the amino acid sequence under UniProtKB Accession No. Q07659.

[0133] The terms “arotinoid acid” and “TTNPB” refer to 4-[(E)-2-(5,5,8,8-tetramethyl-6,7- dihydronaphthalen-2-yl)prop-1-enyl]benzoic acid, with structure:, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “N” refers to arotinoid acid.

[0134] The term “Y-27632” refers to 4-[(1R)-1-aminoethyl]-N-pyridin-4-ylcyclohexane-1- carboxamide, with structure:47 / 240 12591029. H0824.70430WO00, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “Y” refers to Y-27632.

[0135] The terms “smoothened agonist” and “SAG” refer to 3-chloro-N-[4- (methylamino)cyclohexyl]-N-[(3-pyridin-4-ylphenyl)methyl]-1-benzothiophene-2-carboxamide, with structure:, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “S” refers to smoothened agonist.

[0136] The terms “linifanib” and “ABT-869” refer to 1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2- fluoro-5-methylphenyl)urea, with structure:, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof. In the single character nomenclature used to describe chemical cocktails herein, the letter “A” refers to linifanib.

[0137] The terms “alpha-ketoglutaric acid” and “α-KG” refer to 2-oxopentanedioic acid, with structure:48 / 240 12591029. H0824.70430WO00, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof.

[0138] The terms “chemical reprogramming cocktail,” “chemical reprogramming cocktails,” “chemical cocktail” or “chemical cocktails” refer to a combination of two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In some embodiments, “chemical cocktail” refers to a combination of two or more small molecules.

[0139] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents. BRIEF DESCRIPTION OF THE DRAWINGS

[0140] FIGs.1A-1H show the NCC reporter system to monitor cellular senescence. FIG.1A shows schematics of the NCC reporter system integrated in human fibroblasts. FIG.1B shows NCC signals in quiescent fibroblasts. FIG.1C shows fluorescence intensity profiles corresponding to the arrow in FIG.1B. FIG.1D shows the colocalization of mCherry and eGFP signals in quiescent fibroblasts by Pearson correlation. FIG.1E shows NCC signals in senescent fibroblasts. FIG.1F shows fluorescence intensity profiles corresponding to the arrow in FIG.1E. FIG.1G shows the colocalization of mCherry and eGFP signals in senescent fibroblasts by Pearson correlation. FIG.1H shows Pearson correlation of quiescent and senescent fibroblasts. Data are mean ± SD. ****p < 0.0001.

[0141] FIGs.2A-2J show OSK-mediated partial reprogramming ameliorates features of cellular senescence. FIG.2A shows heatmaps for mRNA levels of genes upregulated by senescence (padj > 0.01, FC > 2). FIG.2B shows the percentage of genes changed by OSK (padj > 0.05) among those upregulated by senescence. FIG.2C shows heatmaps for mRNA levels of genes downregulated by senescence (padj>0.01, FC>2). FIG.2D shows the percentage of genes changed by OSK (padj>0.05) among those downregulated by senescence. FIG.2E shows Top 20 GO processes of genes upregulated by senescence. The red and blue bars indicate upregulation or downregulation by OSK, respectively. FIG.2F shows Top 20 GO processes of genes downregulated by senescence. The red and blue bars indicate upregulation or downregulation by OSK, respectively. FIG.2G shows49 / 240 12591029. H0824.70430WO00schematics of the Tet-On OSK system integrated in NCC reporter system fibroblasts. FIG.2H shows NCC signals and track of the arrows in quiescent, senescent or senescent+OSK fibroblasts. Scale bar, 50 µm. FIG.2I shows fluorescence intensity profiles corresponding to the arrow in FIG.2H. FIG.2J shows EGFP intensities in the cytoplasm. Data are mean ± SD. *p < 0.05; ***p < 0.001.

[0142] FIGs.3A-3D show chemical reprogramming cocktails restore NCC alterations in senescent cells. FIG.3A shows chemical structures of compounds of basal cocktails used to generate induced pluripotent stem cells (iPSCs) from mouse (left) or human (right) somatic cells. FIG.3B shows Correlation heatmaps showing eGFP and mCherry colocalization in human senescent fibroblasts demonstrate the effects of 80 different compounds. FIGs.3C-3D show validation of six selected cocktails through independent experiments, showing colocalization (FIG.3C) and representative images (FIG.3D) of eGFP and mCherry signals. Scale bar, 50 µm.

[0143] FIGs.4A-4F show transcriptomic rejuvenation by chemical reprogramming cocktails. FIGs. 4A-4B show Delta ages measured by a biological transcriptomic clock built on rodents and humans (FIG.4A), or rodents alone (FIG.4B). FIG.4C shows Delta ages measured by a chronological transcriptomic clock built on humans. n.s.: p > 0.05; *p < 0.05; **p < 0.01; ***p < 0.001. FIG.4D shows correlation matrix of transcriptomic differences by cocktail treatment, iPSC reprogramming or aging. FIG.4E shows enrichment of pathways by cocktail treatment, iPSC reprogramming or aging. Normalized Enrichment Score (NES) FIG.4F shows summary of observations showing that both induction of OSK and treatment with C1-6 are capable of restoring NCC integrity and reversing biomarkers of health. It was created using Biorenderer.

[0144] FIG.5 shows NCC signals in fibroblasts from young, old, and HGPG individuals. mCherry (Red) and eGFP (Green) signals in 22y, 94y or HGPS fibroblasts. The cell nuclei were counterstained with Hoechst33342 to define the nuclear compartment.

[0145] FIGs.6A-6C show mRNA levels of senescence-associated genes. FIGs.6A-6C show the levels of OSK in quiescent, senescent cells as well as senescent cells treated with OSK. FIG.6B shows expression of senescence associated genes in all three cell types. FIG.6C shows expression of P16 in all three cell types. P-values shown, adjusted significance threshold of 5x10-2.

[0146] FIGs.7A-7D indicate transcriptome analysis shows cocktail treatments affect mostly similar gene groups and do not promote pluripotency. FIG.7A shows Venn diagrams of gene groups affected mouse chemical cocktails (C1-3), human chemical cocktails (C4-6) or the transition from quiescence to senescence. FIG.7B shows a Heat-map depicting relative scores of each RNA-seq library condition for each of the gene expression modules as described by SEQUIN for cocktail (C1-6) and DMSO treated senescent cells with quiescent cells (None). FIG.7C shows principal component analysis of modules for pluripotency, cocktail treatments. FIG.7D shows pluripotency module scores for each RNA-seq library condition based on iPSC Profiler (SEQUIN) comparing cocktail and DMSO control treatments in senescent cells with quiescent cells.50 / 240 12591029. H0824.70430WO00

[0147] FIG.8 shows the effect of inhibition of key heterochromatin regulators on reprogramming. IF of either control cells or senescent cells treated with cocktail 1 or 4, markers of pluripotency (NANOG, EPCM, & SSEA1) or marker of fibroblast identity THY1.

[0148] FIG.9 shows AGi Reverses nuclear leakage in human cells comparable to 5+ factor chemical cocktails. Human dermal fibroblasts integrated with the nuclear cytoplasmic compartmentalization (NCC) reporter were passaged until they were at or near replicative senescence to the point where a striking NCC defect was observable. Cells were then treated with either cocktail 1 (VPA, 250 µM; CHIR99021, 1 µM; Repsox-616452, 10 µM; Forskolin, 50 µM; and Tranylcypromine, 5 µM) or AGi (50 µg / mL Ascorbic acid + 1 µM CHIR99021) for four days followed by confocal microscopy analysis of the NCC signal. Representative images are shown on the left with blue indicating DAPI (Nucleus), red indicating RFP-NLS (should be nuclear) and green indicating eGFP-NES (should be cytoplasmic). AGi significantly restored nuclear integrity measured by the NCC assay to the same extent as cocktail 1.

[0149] FIG.10 shows AGi Reverses senescence growth arrest. Mouse ear fibroblasts (n=5) were treated with doxorubicin to produce DNA damage-induced senescence or DMSO as a vehicle control for 24 hrs followed by 9 days to allow the cells to reach full senescence. The cells were then treated with AGi (50 µg / mL Ascorbic acid + 3 µM CHIR99021) or DMSO as a control for an additional five days. EdU was added 24 hrs prior to isolation to label newly synthesized DNA in actively dividing cells. EdU was detected using the Invitrogen Click-IT detection system which covalently attaches a green fluorophore to the EdU. Representative images are shown on the left with blue indicating DAPI (Nucleus) and green indicating EdU (growth). Treatment with AGi significantly reversed senescence associated growth arrest up to ~20% compared to <1% growing in the untreated senescent controls.

[0150] FIG.11 shows AGi Reverses senescence-associated reduction in LaminB1. LaminB1 plays a significant role in regulating heterochromatin and its dysregulation is causal in senescence-associated epigenetic and transcriptomic changes. To determine if AGi reduces senescence associated LaminB1 defects, mouse ear fibroblasts (n=5) were treated with the chemotherapeutic doxorubicin (DXR) to induce senescence, followed by incubation with AGi as described in in Figure 2. Immunofluorescence staining was performed on cells following treatment to detect LaminB1. Treatment with AGi entirely reversed levels of LaminB1 in senescent cells back to the levels of healthy cells (p<0.05). This indicates a striking recovery of nuclear health. Based on these findings, it is likely that the recovery of LaminB1 will cause (or at least reflect) epigenomic and transcriptomic rejuvenation in these AGi- treated senescent cells.

[0151] FIGs.12A-12B show that treatment of senescent cells with chemical cocktail 1 (C1) (VC6FT) reduced standard inflammatory cytokine levels and increased anti-inflammatory Il-10. FIG. 12A shows that senescence associated inflammatory cytokines are decreased upon treatment of senescent cells with C1 and C4. Treatment with either C1 or C4 produced a statistically significant difference compared to the untreated senescent cells. FIG.12B shows that anti-inflammatory factor51 / 240 12591029. H0824.70430WO00IL-10, repressed in senescent cells, is increased upon treatment of senescent cells with C1 (>4 fold increase) and C4 (>100 fold increase).

[0152] FIG.13 shows an NCC based assay of chemical combinations show that valproic acid (VPA), laduviglusib (CIHR), tranylcypromine (TCP), and forskolin (FSK) produced significant effects on NCC integrity.

[0153] FIGs.14A and 14B show a DNA-Cytoplasmic based assay of chemical combinations. FIG. 14A shows that valproic acid (VPA), laduviglusib (CIHR), tranylcypromine (TCP), and forskolin (FSK) have the cleanest separation of Nuclear and Cytoplasmic domains. FIG.14B shows combinations of small molecule chemicals used in FIG.14A.

[0154] FIG.15 shows results of a stress test assay for varied chemical concentrations. Boxplots show cell survival of human retinal cells (ARPE19 cells) treated with dilutions of the chemical cocktails. Differences in cell numbers arise from variability in plating. Chemicals were tested at various concentration either alone, or in combination with the other components of chemical cocktail 1 (C1, see Table 3). Relative doses are based on dilution factors and shown in Table 6 for specific doses.

[0155] FIG.16 shows the results of a stress test assay for varied chemical concentrations. Boxplots show human fibroblasts (HF8) survival following treatments with the chemicals. Differences in cell numbers arise from variability in plating. Chemicals were tested at various concentration either alone, or in combination with the other components of chemical cocktail 1 (C1). Relative doses are based on dilution factors and shown in Table 6 for specific doses.

[0156] FIGs.17A-17C show that characterization of combinations of reprogramming small molecules identifies the specific combination of three compounds C6F (laduviglusib, Repsox, and forskolin) as a potent rejuvenative combination from the five compounds of VC6FT (Cocktail 1, see Table 3). FIG.17A shows the Pearson correlation of nucleocytoplasmic compartmentalization (NCC) signal of quiescent fibroblasts or senescent fibroblasts treated with combinations of 250 µM valproic acid (V), 1 µM CHIR-99021 (C), 10 µM E-616452 / RepSox (6), 50 µM forskolin (F), and 5 µM tranylcypromine (n=3). Activation of the OSK cassette with 2 µg / mL doxycycline or treatment with AGi (1 µM CHIR-99021 + 50 µg / mL ascorbic acid) in senescent cells was also performed for benchmarking purposes. FIG.17B shows representative images of NCC signal in senescent cells treated with a minimal reprogramming cocktail C6F in an independent validation experiment (n=4). FIG.17C shows the Pearson correlation of NCC signal in FIG.17B. Data are mean ± SD. One-way ANOVA-Bonferroni.

[0157] FIGs.18A-18B show that formulations of lithium and ascorbic acid potently restore nuclear integrity assayed by NCC. FIG.18A shows the Pearson correlation of NCC signal of senescent fibroblasts treated with lithium chloride (LiCl) and ascorbic acid (AA) either at a 1:1 stoichiometry or with ascorbic acid held constant at 50 µg / mL (to mimic AGi).10 mM lithium chloride with 50 µg / mL ascorbic acid, but no other combination, significantly reset NCC. These data evidence that the52 / 240 12591029. H0824.70430WO00rejuvenative effects of the two-factor AGi can be achieved even when CHIR-99021 is replaced by other GSK3B inhibitors, such as lithium salts.1:1 LiCl + AA was attempted at 10 µM, but this dose exceeded the solubility limit of the media. FIG.18B shows the Pearson correlation of NCC signal of senescent fibroblasts treated with LiCl, lithium ascorbate (LiAA), or LiCl + LiCl + AA at a 1:1 stoichiometry to mimic lithium ascorbate. LiAA but not equivalent doses of LiCl or LiCl + AA was capable of significantly resetting NCC. This finding indicates that a single compound mimicking the activity of AGi is sufficient for substantial amelioration of nuclear health of human senescent cells. Data are mean ± SD. One-way ANOVA-Bonferroni. * p < 0.05; ** p < 0.01.

[0158] FIG.19 shows levels of reactive oxygen species (ROS) in cells treated with chemical cocktails containing different doses of the constituent chemicals. Reduced CHIR (64nM) concentration in combination with V6TF (valproic acid, Repsox, tranylcypromine, and forskolin) leads to decreased levels of ROS in cells following treatments (left arrow). Reduced Repsox concentration from 10 µM to 0.64 µM in combination with V6TF leads to decreased levels of ROS in cells, though not in combination with other drugs (middle two arrows). Reduced Forskolin to 8 µM concentration alone and in combination with VC6T leads to decreased levels of ROS in cells following treatments, and the lowest relative level is reached (right two arrows). All chemical treatments were performed in senescent cells, quiescent cells were included in column 12 as a control.

[0159] FIGs.20A-20H show the viability of SY5Y human cell line treated with single reprogramming chemicals. Cell viability of undifferentiated SY5Y human neuroblastoma cell line after four days of treatment with doses of single chemicals was assessed via calcein-AM staining followed by live cell-microscopy for valproic acid (VPA) (FIG.20A), CHIR-99021 (FIG.20B), forskolin (FIG.20C), tranylcypromine (TCP) (FIG.20D), RepSox (FIG.20E), ascorbic acid (AA) (FIG.20F), lithium ascorbate (LiAA)( FIG.20G), and lithium chloride (LiCl) (FIG.20H). Cell viability is represented as a value relative to the untreated control cells. n=3 error bares are mean + / - STD.

[0160] FIGs.21A-21C show the viability of SY5Y human cell line treated with reprogramming chemical cocktails. Cell viability of undifferentiated SY5Y human neuroblastoma cell line after four days of treatment with doses of chemical cocktails was assessed via calcein-AM staining followed by live cell-microscopy for C1 (VC6FT) (FIG.21A), CHIR-99021, RepSox, and Forskolin (C6F) (FIG. 21B), or AGi (FIG.21C) with variable doses of CHIR-99021. All other chemical components were kept at constant dose typically used for their respective cocktails: 250 µM VPA, 50 µM forskolin, 10 µM RepSox, 5 µM TCP, and 50 µg / ml ascorbic acid. Cell viability is represented as a value relative to the untreated control cells. n=3 error bares are mean + / - STD.

[0161] FIGs.22A-22L show the viability of primary mouse fibroblasts treated with single reprogramming chemicals. Cell viability of primary mouse ear fibroblasts after five days of treatment with doses of single small molecule chemicals was assessed via calcein-AM staining followed by live cell-microscopy for valproic acid (VPA) (FIG.22A), CHIR-99021 (FIG.22B), forskolin (FIG.22C),53 / 240 12591029. H0824.70430WO00tranylcypromine (TCP) (FIG.22D), RepSox (FIG.22E), ABT869 (FIG.22F), smoothend agonist (SAG) (FIG.22G), basic fibroblast growth factor (b-FGF) (FIG.22H), sodium butyrate (FIG.22I), TTNBP (FIG.22J), Y-27632 (FIG.22K), and alpha-ketoglutarate (FIG.22L).Cell viability is represented as a value relative to the untreated control cells. Cell viability is represented as a value relative to the untreated control cells. n=3 error bares are mean + / - STD.

[0162] FIG.23 shows the viability of primary mouse fibroblasts treated with AGi cocktail. Cell viability of primary mouse ear fibroblasts after five days of treatment with AGi Cocktail (CHIR- 99021 with ascorbic acid) was assessed via calcein-AM staining followed by live cell-microscopy for AGi with variable doses of CHIR-99021 and 50 µg / ml ascorbic acid. Cell viability is represented as a value relative to the untreated control cells. n=3 error bares are mean + / - STD. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

[0163] The present disclosure is based, at least in part, on the unexpected results demonstrating that chemical cocktails comprising two or more compounds can reverse the age of human fibroblasts and restore genome-wide transcript profiles. Surprisingly, in some embodiments, as described herein, this rejuvenation can occur in less than a week and without erasing cellular identity, a crucial aspect of partial epigenetic reprogramming. Thus, reversal of cellular aging by partial reprogramming and the restoration of youth, similar to the effect of the Yamanaka factors, Oct4, Sox2, and Klf4 (OSK), can be achieved by chemical means.

[0164] The methods, compositions, uses, and kits of the present disclosure are in part informed by the surprising and unexpected discovery that chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), lithium salts, or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof) can rejuvenate a cell in the absence of OSK without reprogramming the cell to a pluripotent state.

[0165] Aspects of the present disclosure provide several systems, compositions, uses, kits, and methods that may be useful for efficient rejuvenation of a cell, tissue, and / or organ.

[0166] In some embodiments, the results disclosed herein suggest that treatment with chemical cocktails can reprogram cells and reverse the age of the transcriptome. Without being bound by a particular theory, the results disclosed herein suggest that cells maintain a backup epigenome that can be restored using the methods described herein.

[0167] Thus, in various embodiments the methods and uses of the invention rejuvenate a cell by restoring the cellular identity of the cell by reversing the effects of or by preventing the effects of age, or of one or more dysregulated developmental pathways. For example, in certain embodiments, the methods may:54 / 240 12591029. H0824.70430WO00(i) increase the abundance of at least one of histone H2A, histone H2B, histone H3, histone H4, or any combination thereof in the cell; (ii) increase the abundance of at least one of CHAF1a, CHAF1b, HP1α, NuRD, or any combination thereof in the cell; (iii) increase at least one heterochromatin mark in the cell, such as, for example, H3K9me3, H3K27me3, or any combination thereof; or decrease one heterochromatin mark, such as H4K20me3 or euchromatin mark H3K4me3; (iv) increase / decrease DNA methylation of at least one age-related CpG site in the cell towards a younger level; (v) increase the abundance of lamin B1 in the cell; (vi) increase acetylation of histone H3 at lysine 27 (H3K27ac), increase acetylation of histone H3 at lysine 56 (H3K56ac), or any combination thereof in the cell; (vii) decrease acetylation of histone H3 at lysine 122 (H3K122Ac) or histone H4 at lysine 16 (H4K16ac), or any combination thereof in the cell (viii) decrease the abundance of IL6, Ccl2, Ccl20, Apob, p16, LINE-1 repeats, Sat III repeats, Alu elements, IAP, or any combination thereof; (ix) restore the balance between euchromatin epigenetic marks, such as H3K4me3, and heterochromatin epigenetic marks, such as H3K9me3 or H3K27me3; (x) induce the formation of euchromatin; (xi) restore youthful levels of at least one repressive heterochromatin epigenetic mark; (xii) restore the expression of at least one gene to youthful levels. In some embodiments, a youthful level is the level of expression of the gene in a subject who is between 1-5, 1-10, 1-20, 1-30, or 1-40 years old; (xiii) decrease the abundance of senescence-associated inflammatory cytokines, such as, for example, IFNγ, IL-1B, IL-6, IL-8, MCP-1, or TNFα, or any combination thereof; and / or (xiv) increase the abundance of cytokines repressed in senescent cells, such as, for example, IL-10.

[0168] In some embodiments, the at least one gene that is restored to youthful levels is at least one gene selected from the group consisting of CDKN1A, IL6, CCL2, MMP3, LMNB1, and EZH2.

[0169] In some embodiments, the methods disclosed herein alleviate one or more hallmarks of aging, including deterioration of nucleocytoplasmic compartmentalization (NCC), genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. See, e.g., Kennedy et al., Cell.2013 Jun 6; 153(6): 1194–1217.

[0170] In some embodiments, methods disclosed herein increase the expression of one or more of the following gene sets: KEGG PPAR signaling pathway, REACTOME Activation of gene expression by SREBF / SREBP, REACTOME Mitochondrial translation, REACTOME Respiratory55 / 240 12591029. H0824.70430WO00electron transport, HALLMARK Oxidative phosphorylation, HALLMARK MYC targets v1, REACTOME Base excision repair, REACTOME DNA repair, REACTOME Extension of telomeres, KEGG Ribosome, or REACTOME Metabolism of amino acids and derivatives. See, e.g., Molecular Signatures Database (MSigDB) for gene sets. In some embodiments, a gene set is determined using the Biological Process terms of the Gene Ontology (GOBP). In some embodiments, the methods disclosed herein increase expression of one or more of these gene sets by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% relative to a control. In some embodiments, a control is the level of expression of one or more gene sets in the absence of treatment with a chemical cocktail comprising two or more compounds. In some embodiments, gene expression is measured at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 20 weeks, at least 30 weeks, at least 40 weeks, or at least 50 weeks after treatment with the chemical cocktail has stopped.

[0171] Without being bound by a particular theory, more specifically, the methods, compositions, uses, and kits of the present disclosure rejuvenate cells by restoring epigenetic information that has been lost due to the aging process, injury, or disease. The methods, compositions, uses, and kits of the present disclosure comprise chemical cocktails comprising two or more compounds described herein (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT- 869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). The Yamanaka factors have traditionally been used to reprogram cells to a pluripotent state. However, the induction of expression of the four transcription factors in transgenic mice resulted in the formation of teratomas in vivo, along with other acute toxicities like dysplasia in the intestinal epithelium, which can kill the animal in a few days. Moreover, the fact that the four Yamanaka factors are typically used to reprogram cells to a completely pluripotent state, wherein the cell loses its pre-established cellular identity, can be dangerous for in vivo applications where the cellular identity of target cells must be maintained for tissue and / or organ integrity. In contrast, in some embodiments, the methods described herein, allow controlled reprogramming and do not result in global changes in demethylation. In some embodiments, the methods described herein do not require complete de- differentiation of cells.

[0172] Cellular reprograming allows for the production of numerous cell types from existing somatic cells. Although the Yamanaka factors (OCT4, SOX2, KLF4 and c-Myc, also known collectively as OSKM) have been shown to induce pluripotency in differentiated cells, administration of these factors may induce teratomas or other cancers in vivo (Takahashi et al., Cell 2006 Aug 25;126(4):663-76; Abad et al., Nature 2013 Oct 17;502(7471):340-5). As a result of these safety concerns, use of the56 / 240 12591029. H0824.70430WO00Yamanaka factors has largely been limited to in vitro applications. Furthermore, existing methods of gene therapy are plagued by inefficient and inconsistent gene transduction of target cells. The compounds, pharmaceutical compositions thereof, methods, uses, and kits provided herein overcome many of these limitations. Methods of Rejuvenating, Restoring Cellular Function, Decreasing Biological Age, Decreasing Apparent Chronological Age, and Reprogramming

[0173] In one aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and57 / 240 12591029. H0824.70430WO00lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0174] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0175] In another aspect, the present disclosure provides methods of decreasing the biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of:58 / 240 12591029. H0824.70430WO00laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0176] In another aspect, the present disclosure provides methods of decreasing the apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;59 / 240 12591029. H0824.70430WO00ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0177] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;60 / 240 12591029. H0824.70430WO00tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0178] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;61 / 240 12591029. H0824.70430WO00butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0179] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;62 / 240 12591029. H0824.70430WO00smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0180] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.63 / 240 12591029. H0824.70430WO00

[0181] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0182] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;64 / 240 12591029. H0824.70430WO00ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0183] In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. For example, in certain embodiments, the terms “laduviglusib” and “CHIR99021” refer to laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, or stereoisomer thereof. In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, the name of a chemical compound may refer to the compound, or a pharmaceutically acceptable salt thereof. In certain embodiments, the name of a chemical compound may refer to the compound.

[0184] In certain embodiments, the method comprises treating the cell, tissue, or organ with 3 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632,65 / 240 12591029. H0824.70430WO00smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 4 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha- ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co– crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 5 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 6 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 7 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 8 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 9 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 10 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid,66 / 240 12591029. H0824.70430WO00tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 11 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 12 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof). In certain embodiments, the method comprises treating the cell, tissue, or organ with 13 or more compounds selected from the group (e.g., laduviglusib, RepSox, ascorbic acid, tranylcypromine, forskolin, butyric acid, basic fibroblast growth factor (bFGF), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co–crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof).

[0185] In certain embodiments, the method comprises treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and67 / 240 12591029. H0824.70430WO00basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0186] In certain embodiments, the method comprises treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

[0187] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and RepSox (E-616452). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and ascorbic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021)68 / 240 12591029. H0824.70430WO00and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and ascorbic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E- 616452) and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E- 616452) and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and Y- 27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with69 / 240 12591029. H0824.70430WO00valproic acid and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and alpha-ketoglutaric acid (α- KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and linifanib (ABT-869). In certain embodiments, the method comprises treating the70 / 240 12591029. H0824.70430WO00cell, tissue, or organ with basic fibroblast growth factor (bFGF) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and linifanib (ABT- 869). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y-27632 and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y-27632 and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y- 27632 and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with smoothened agonist (SAG) and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with smoothened agonist (SAG) and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with linifanib (ABT-869) and alpha-ketoglutaric acid (α-KG).

[0188] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and ascorbic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and basic fibroblast growth factor (bFGF).

[0189] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and valproic acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-71 / 240 12591029. H0824.70430WO00616452), ascorbic acid, valproic acid, and tranylcypromine. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, and forskolin. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, and forskolin.

[0190] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), tranylcypromine, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, tranylcypromine, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, forskolin, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, forskolin, and butyric acid.

[0191] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with72 / 240 12591029. H0824.70430WO00laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), tranylcypromine, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, valproic acid, tranylcypromine, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, valproic acid, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, tranylcypromine, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), valproic acid, tranylcypromine, forskolin, and basic fibroblast growth factor (bFGF). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), butyric acid, and basic fibroblast growth factor (bFGF).

[0192] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and linifanib (ABT-869). In certain73 / 240 12591029. H0824.70430WO00embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), and alpha-ketoglutaric acid (α-KG).

[0193] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and arotinoid acid (TTNPB). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and Y-27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), arotinoid acid (TTNPB), and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), arotinoid acid (TTNPB), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y- 27632, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), linifanib (ABT-869), and butyric acid. In certain74 / 240 12591029. H0824.70430WO00embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), butyric acid, and alpha-ketoglutaric acid (α-KG).

[0194] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and Y- 27632. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), and linifanib (ABT- 869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT- 869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y- 27632, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the75 / 240 12591029. H0824.70430WO00cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y- 27632, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), linifanib (ABT-869), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, linifanib (ABT-869), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method76 / 240 12591029. H0824.70430WO00comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG).

[0195] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and smoothened agonist (SAG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452),77 / 240 12591029. H0824.70430WO00ascorbic acid, Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y- 27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y- 27632, linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating78 / 240 12591029. H0824.70430WO00the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, linifanib (ABT- 869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y-27632, linifanib (ABT-869), butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG).

[0196] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and linifanib (ABT-869). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened79 / 240 12591029. H0824.70430WO00agonist (SAG), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), butyric acid, and alpha- ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, Y-27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG),80 / 240 12591029. H0824.70430WO00butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), Y- 27632, smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α- KG).

[0197] In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and butyric acid. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), linifanib (ABT-869), and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, smoothened agonist (SAG), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E-616452), ascorbic acid, arotinoid acid (TTNPB), Y-27632, linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG). In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021), RepSox (E- 616452), ascorbic acid, arotinoid acid (TTNPB), smoothened agonist (SAG), linifanib (ABT-869), butyric acid, and alpha-ketoglutaric acid (α-KG).

[0198] In certain embodiments, the pharmaceutically acceptable salt of butyric acid is sodium butyrate. In certain embodiments, the pharmaceutically acceptable salt of butyric acid is lithium butyrate. In certain embodiments, the pharmaceutically acceptable salt of butyric acid is potassium butyrate.

[0199] In certain embodiments, the pharmaceutically acceptable salt of valproic acid is lithium valproate. In certain embodiments, the pharmaceutically acceptable salt of ascorbic acid is lithium ascorbate. In certain embodiments, the pharmaceutically acceptable salt of forskolin is a lithium salt of forskolin. In certain embodiments, the pharmaceutically acceptable salt of TTNPB is a lithium salt of TTNPB. In certain embodiments, the pharmaceutically acceptable salt of α-KG is a lithium salt of α-KG.

[0200] In certain embodiments, the group further comprises a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the group further comprises lithium ascorbate. In certain embodiments, the group further comprises lithium chloride. In certain embodiments, the81 / 240 12591029. H0824.70430WO00group further comprises lithium orotate. In certain embodiments, the group further comprises lithium carbonate. In certain embodiments, the group further comprises lithium citrate. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co– crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y-27632 and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with smoothened agonist (SAG) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with linifanib (ABT-869) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with alpha-ketoglutaric acid (α-KG) and a lithium salt, or a solvate, hydrate,82 / 240 12591029. H0824.70430WO00polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0201] In certain embodiments, one or more of the compounds in the group are replaced with a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, one or more of the compounds in the group are replaced with lithium ascorbate. In certain embodiments, one or more of the compounds in the group are replaced with lithium chloride. In certain embodiments, one or more of the compounds in the group are replaced with lithium orotate. In certain embodiments, the method comprises treating the cell, tissue, or organ with laduviglusib (CHIR99021) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with RepSox (E-616452) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with valproic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with tranylcypromine and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with forskolin and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with butyric acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with basic fibroblast growth factor (bFGF) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with arotinoid acid (TTNPB) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with Y-27632 and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with smoothened agonist (SAG) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate,83 / 240 12591029. H0824.70430WO00lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with linifanib (ABT-869) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In certain embodiments, the method comprises treating the cell, tissue, or organ with alpha-ketoglutaric acid (α-KG) and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

[0202] In certain embodiments, CHIR99021 is replaced with a GSK3 ^ inhibitor. In certain embodiments, the GSK3 ^ inhibitor is a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate), SB216763, SB415286, SB203580, TDZD-8, AR-A014418, CHIR99021, BIO, Kenpaullone, Indirubin-3′-monoxime, AZD1080, Tideglusib, LY2090314, LY2095496, LY2097409, LY2097634, FRAX597, Y-27632, DMAT, TWS119, or Berberine. In certain embodiments, the GSK3 ^ inhibitor is a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate), SB216763, SB415286, SB203580, TDZD-8, AR-A014418, CHIR99021, BIO, Kenpaullone, Indirubin-3′-monoxime, AZD1080, Tideglusib, LY2090314, LY2095496, LY2097409, LY2097634, FRAX597, Y-27632, DMAT, or TWS119.

[0203] In certain embodiments, the ascorbic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is ascorbic acid, lithium ascorbate, Ester-C (form of calcium ascorbate), ascorbyl palmitate, liposomal vitamin C, sodium ascorbate, magnesium ascorbyl phosphate (MAP), tetrahexyldecyl ascorbate, ascorbyl glucoside, calcium ascorbate, or sodium erythorbate.

[0204] In certain embodiments, ascorbic acid is replaced with a Tet activator. In certain embodiments, the Tet activator is lithium ascorbate, Ester-C, ascorbyl palmitate, liposomal vitamin C, sodium ascorbate, magnesium ascorbyl phosphate (MAP), tetrahexyldecyl ascorbate, ascorbyl glucoside, calcium ascorbate, or sodium erythorbate.

[0205] The following compounds may offer benefits compared to ascorbic acid: Ester-C (enhanced absorption and retention, providing similar antioxidant effects), ascorbyl palmitate (increased stability and solubility in lipid environments, with antioxidant properties), liposomal vitamin C (improved bioavailability and cellular uptake, maintaining antioxidant activity), sodium ascorbate (provides similar antioxidant effects with reduced acidity), magnesium ascorbyl phosphate (MAP) (water- soluble, with enhanced stability and similar antioxidant effects), tetrahexyldecyl ascorbate (increased stability and ability to penetrate lipid membranes, providing antioxidant benefits), ascorbyl glucoside (enhanced stability and sustained release of ascorbic acid, maintaining antioxidant properties), calcium ascorbate (buffered form, reducing gastrointestinal discomfort while providing antioxidant effects), and sodium erythorbate (similar antioxidant properties with enhanced stability).84 / 240 12591029. H0824.70430WO00

[0206] In certain embodiments, RepSox is replaced with a TGF-β inhibitor. In certain embodiments, the TGF-β inhibitor is SB431542, A-83-01, LY2109761, Galunisertib (LY2157299), Epigallocatechin gallate (EGCG), or Resveratrol. The TGF-β inhibitors may have the following mechanisms of action: SB431542 (inhibition of TGF-β signaling, facilitating mesenchymal-to-epithelial transition (MET)), A-83-01 (potent inhibition of ALK4, ALK5, and ALK7 receptors, effectively blocking TGF-β signaling), LY2109761 (blocking of both TGF-βRI and TGF-βRII, inhibiting TGF-β signaling pathways), Galunisertib (LY2157299) (selective inhibition of TGF-β receptor I, facilitating reprogramming), Epigallocatechin gallate (EGCG) (inhibition of TGF-β signaling pathways), and Resveratrol (inhibition of TGF-β signaling).

[0207] In certain embodiments, RepSox is replaced with a CDK8 inhibitor. In certain embodiments, the CDK8 inhibitor is BI-1347 or MSC2530818. The CDK8 inhibitors may have the following mechanisms of action: BI-1347 (selective inhibition of CDK8 and CDK19) and MSC2530818 (selective inhibition of CDK8 and CDK19).

[0208] In certain embodiments, forskolin is replaced with a cAMP agonist. In certain embodiments, the cAMP agonist is IBM-X (3-isobutyl-1-methylxanthine), 8-bromo-cAMP, or dibutyryl cAMP (db- cAMP). The cAMP agonists may have the following mechanisms of action: IBM-X (3-isobutyl-1- methylxanthine) (increases cAMP levels by inhibiting its breakdown, enhancing cellular reprogramming), 8-Bromo-cAMP (directly activates cAMP-dependent pathways, mimicking forskolin’s effects), and Dibutyryl cAMP (db-cAMP) (more stable and cell-permeable form of cAMP, effectively increasing intracellular cAMP levels).

[0209] In certain embodiments, forskolin is replaced with a cAMP activator. In certain embodiments, the cAMP activator is caffeine or theobromine. The cAMP activators may have the following mechanisms of action: caffeine (inhibits phosphodiesterase, increasing cAMP levels) and theobromine (mild phosphodiesterase inhibitor, increasing cAMP levels).

[0210] In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium ascorbate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium chloride. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium orotate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium carbonate. In certain embodiments, the method comprises treating the cell, tissue, or organ with ascorbic acid and lithium citrate.

[0211] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.85 / 240 12591029. H0824.70430WO00

[0212] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0213] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0214] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0215] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate). In some embodiments, the lithium salt is lithium chloride.

[0216] In another aspect, the present disclosure provides methods of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

[0217] In another aspect, the present disclosure provides methods of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

[0218] In another aspect, the present disclosure provides methods of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

[0219] In another aspect, the present disclosure provides methods of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

[0220] In another aspect, the present disclosure provides methods of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

[0221] In certain embodiments, two or more of the compounds in the group are associated through a noncovalent interaction.

[0222] In certain embodiments, the cell is a senescent cell. In certain embodiments, the senescent cell is within the tissue or organ. In certain embodiments, the cell, tissue, or organ is within a subject. In certain embodiments, the subject is a human. In certain embodiments, the subject is a pediatric86 / 240 12591029. H0824.70430WO00subject. In certain embodiments, the subject is an adult subject. In certain embodiments, the adult subject is a senior adult subject. In certain embodiments, the subject is healthy. In certain embodiments, the subject has a disease. In certain embodiments, the subject has, is suspected of having, or is at risk for an age-related disease. In certain embodiments, the age-related disease is a neurological disorder. In certain embodiments, the neurological disorder is a neurodegenerative disorder. In certain embodiments, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).

[0223] In certain embodiments, the method further comprises: increasing cellular respiration, reducing cellular inflammatory pathways, improving integrity of nucleocytoplasmic compartmentalization, or a combination thereof, ex vivo or in vitro. In certain embodiments, the method further comprises increasing cellular respiration, ex vivo or in vitro. In certain embodiments, the method further comprises reducing cellular inflammatory pathways, improving integrity of nucleocytoplasmic compartmentalization, ex vivo or in vitro. In certain embodiments, the method further comprises improving integrity of nucleocytoplasmic compartmentalization, ex vivo or in vitro.

[0224] In certain embodiments, the cell or tissue is from eye, ear, nose, mouth including gum and roots of teeth, bone, lung, breast, udder, pancreas, stomach, esophagus, muscle including cardiac muscle, liver, blood vessel, skin including hair, heart, brain, nerve tissue, kidney, testis, prostate, penis, cloaca, fin, ovary, or intestine. In certain embodiments, the tissue is damaged or the tissue may be considered healthy but suboptimal for performance or survival in current or future conditions.

[0225] In certain embodiments, the method alters expression of at least one gene associated with aging. In certain embodiments, the method reduces expression of at least one gene associated with aging. In certain embodiments, the method increases expression of at least one gene associated with aging.

[0226] In certain embodiments, at least one gene associated with aging is associated with: inflammation, mitochondrial metabolism, lysosomal function, apoptosis, p53, growth signaling, or a combination thereof, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with inflammation, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with mitochondrial metabolism, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with lysosomal function, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with apoptosis, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with p53, ex vivo or in vitro. In certain embodiments, at least one gene associated with aging is associated with growth signaling, ex vivo or in vitro.

[0227] In certain embodiments, at least one gene associated with aging is a central nervous system gene. In certain embodiments, at least one gene associated with aging is a brain gene.87 / 240 12591029. H0824.70430WO00

[0228] In certain embodiments, the method further comprises activating an enhancer of reprogramming in the cell, tissue, or organ. In certain embodiments, the enhancer of reprogramming is a class I histone deacetylase (HDAC1-3).

[0229] In certain embodiments, the method comprises restoring epigenetic information in the cell, tissue, or organ. In certain embodiments, the epigenetic information is lost due to aging, injury, disease, or a combination thereof in the cell, tissue, or organ.

[0230] In certain embodiments, the method comprises reestablishing an epigenetic status of the cell, tissue, or organ that is similar to the status formed soon after final differentiation.

[0231] In certain embodiments, the cell, tissue, or organ is not reprogrammed to a pluripotent state.

[0232] In certain embodiments, the method rejuvenates an epigenetic clock of a cell, tissue, organ, subject, or a combination thereof.

[0233] In some embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by a period of time. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by at least about 1 hour, at least about 6 hours, at least about 12 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 30 months, at least about 3 years, at least about 42 months, at least about 4 years, at least about 54 months, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, at least about 60 years, at least about 70 years, at least about 80 years, at least about 90 years, or at least about 100 years. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 1 year. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 2 years. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 3 years. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 4 years. In certain embodiments, the apparent chronological age of the cell, organ, or tissue is reduced by about 5 years.

[0234] In some embodiments, the cell, tissue, or organ is treated for a time period that is sufficient to rejuvenate the cell, tissue, or organ. In certain embodiments, the cell, tissue, or organ is treated for at least about 1 hour, at least about 6 hours, at least about 12 hours, at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 688 / 240 12591029. H0824.70430WO00months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months, at least about 2 years, at least about 30 months, at least about 3 years, at least about 42 months, at least about 4 years, at least about 54 months, at least about 5 years, at least about 6 years, at least about 7 years, at least about 8 years, at least about 9 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 35 years, at least about 40 years, at least about 45 years, at least about 50 years, at least about 60 years, at least about 70 years, at least about 80 years, at least about 90 years, or at least about 100 years. In certain embodiments, the cell, tissue, or organ is treated for about 1 day. In certain embodiments, the cell, tissue, or organ is treated for about 2 days. In certain embodiments, the cell, tissue, or organ is treated for about 3 days. In certain embodiments, the cell, tissue, or organ is treated for about 4 days. In certain embodiments, the cell, tissue, or organ is treated for about 5 days. In certain embodiments, the cell, tissue, or organ is treated for about 6 days. In certain embodiments, the cell, tissue, or organ is treated for about 1 week. In certain embodiments, the cell, tissue, or organ is treated for about 2 weeks. In certain embodiments, the cell, tissue, or organ is treated for about 3 weeks. In certain embodiments, the cell, tissue, or organ is treated for about 1 month. In certain embodiments, the cell, tissue, or organ is treated for about 2 months.

[0235] In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, 0.1 µM to about 10 µM, 0.5 µM to about 5 µM, about 0.75 µM to about 2.5 µM, about 1 µM, or about 1 µM to about 10 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 100 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 1 µM to about 50 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 2 µM to about 40 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 3 µM to about 30 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 4 µM to about 20 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 7.5 µM to about 12.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 10 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.1 µM to about 10 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.5 µM to about 5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 0.75 µM to about 2.5 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 1 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a89 / 240 12591029. H0824.70430WO00concentration of about 1 µM to about 10 µM. In certain embodiments, the laduviglusib (CHIR99021) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, about 10 µM, about 0.5 µM to about 5 µM, or about 1 µM.

[0236] In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM, about 0.1 µM to about 50 µM, about 0.1 µM to about 10 µM, about 0.1 µM to about 10 µM, about 1 µM to about 50 µM, about 2 µM to about 40 µM, about 3 µM to about 30 µM, about 4 µM to about 20 µM, about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 100 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 50 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 0.1 µM to about 10 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 1 µM to about 50 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 2 µM to about 40 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 3 µM to about 30 µM. In certain embodiments, the RepSox (E- 616452) is used at a concentration of about 4 µM to about 20 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 7.5 µM to about 12.5 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 10 µM. In certain embodiments, the RepSox (E-616452) is used at a concentration of about 5 µM to about 15 µM, about 7.5 µM to about 12.5 µM, or about 10 µM.

[0237] In certain embodiments, the ascorbic acid is used at a concentration of about 1 µg / mL to about 500 µg / mL, about 2.5 µg / mL to about 400 µg / mL, about 5 µg / mL to about 300 µg / mL, about 7.5 µg / mL to about 200 µg / mL, about 5 µg / mL to about 100 µg / mL, about 10 µg / mL to about 100 µg / mL, about 20 µg / mL to about 90 µg / mL, about 25 µg / mL to about 75 µg / mL, about 35 µg / mL to about 65 µg / mL, about 40 µg / mL to about 60 µg / mL, about 50 µg / mL, or about 10 µg / mL to about 60 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 1 µg / mL to about 500 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 2.5 µg / mL to about 400 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 5 µg / mL to about 300 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 7.5 µg / mL to about 200 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 5 µg / mL to about 100 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 10 µg / mL to about 100 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 20 µg / mL to about 90 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 25 µg / mL to about 75 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 35 µg / mL to about 65 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 40 µg / mL to about 60 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 5090 / 240 12591029. H0824.70430WO00µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 10 µg / mL to about 60 µg / mL. In certain embodiments, the ascorbic acid is used at a concentration of about 1 µg / mL to about 500 µg / mL, about 10 µg / mL to about 100 µg / mL, about 25 µg / mL to about 75 µg / mL, or about 50 µg / mL.

[0238] In certain embodiments, the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM. In certain embodiments, the valproic acid is used at a concentration of about 1 µM to about 1000 µM. In certain embodiments, the valproic acid is used at a concentration of about 10 µM to about 800 µM. In certain embodiments, the valproic acid is used at a concentration of about 50 µM to about 600 µM. In certain embodiments, the valproic acid is used at a concentration of about 100 µM to about 400 µM. In certain embodiments, the valproic acid is used at a concentration of about 150 µM to about 350 µM. In certain embodiments, the valproic acid is used at a concentration of about 250 µM. In certain embodiments, the valproic acid is used at a concentration of about 1 µM to about 1000 µM, about 100 µM to about 400 µM, about 150 µM to about 350 µM, or about 250 µM.

[0239] In certain embodiments, the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 1 µM to about 50 µM, about 1 µM to about 10 µM, about 2.5 µM to about 7.5 µM, or about 5 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 1 µM to about 50 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 1 µM to about 10 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 2.5 µM to about 7.5 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 5 µM. In certain embodiments, the tranylcypromine is used at a concentration of about 0.1 µM to about 100 µM, about 2.5 µM to about 7.5 µM, or about 5 µM.

[0240] In certain embodiments, the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 1 µM to about 400 µM, about 5 µM to about 250 µM, about 10 µM to about 100 µM, about 25 µM to about 75 µM, or about 50 µM. In certain embodiments, the forskolin is used at a concentration of about 0.1 µM to about 500 µM. In certain embodiments, the forskolin is used at a concentration of about 1 µM to about 400 µM. In certain embodiments, the forskolin is used at a concentration of about 5 µM to about 250 µM. In certain embodiments, the forskolin is used at a concentration of about 10 µM to about 100 µM. In certain embodiments, the forskolin is used at a concentration of about 25 µM to about 75 µM. In certain embodiments, the forskolin is used at a concentration of about 50 µM. In certain embodiments, the forskolin is used at a concentration of about 0.1 µM to about 500 µM, about 100 µM, 25 µM to about 75 µM, or about 50 µM.

[0241] In certain embodiments, the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 10 µM to about 800 µM, about 50 µM to about 600 µM, about 100 µM to about 400 µM, about 100 µM to about 300 µM, or about 200 µM. In certain91 / 240 12591029. H0824.70430WO00embodiments, the butyric acid is used at a concentration of about 1 µM to about 1000 µM. In certain embodiments, the butyric acid is used at a concentration of about 10 µM to about 800 µM. In certain embodiments, the butyric acid is used at a concentration of about 50 µM to about 600 µM. In certain embodiments, the butyric acid is used at a concentration of about 100 µM to about 400 µM. In certain embodiments, the butyric acid is used at a concentration of about 100 µM to about 300 µM. In certain embodiments, the butyric acid is used at a concentration of about 200 µM. In certain embodiments, the butyric acid is used at a concentration of about 1 µM to about 10000 µM, about 5 µM to about 5000 µM, about 100 µM to about 300 µM, or about 200 µM.

[0242] In certain embodiments, the basic fibroblast growth factor (bFGF) is used at a concentration of a...

Claims

CLAIMS What is claimed is:

1. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).210 / 240 12591029. H0824.70430WO002. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

3. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;211 / 240 12591029. H0824.70430WO00RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

4. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;212 / 240 12591029. H0824.70430WO00valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

5. A method of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;213 / 240 12591029. H0824.70430WO00forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

6. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;214 / 240 12591029. H0824.70430WO00arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

7. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;215 / 240 12591029. H0824.70430WO00smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

8. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.216 / 240 12591029. H0824.70430WO009. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

10. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;217 / 240 12591029. H0824.70430WO00ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

11. A method of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;218 / 240 12591029. H0824.70430WO00forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

12. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof two or more compounds selected from the group consisting of: laduviglusib, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;219 / 240 12591029. H0824.70430WO00Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

13. The method of any one of claims 1-12, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof three or more compounds selected from the group.

14. The method of any one of claims 1-13, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof four or more compounds selected from the group.

15. The method of any one of claims 1-14, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof five or more compounds selected from the group.

16. The method of any one of claims 1-15, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof six or more compounds selected from the group.

17. The method of any one of claims 1-16, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

18. The method of any one of claims 1-17, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;220 / 240 12591029. H0824.70430WO00tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

19. The method of any one of claims 1-18, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

20. The method of any one of claims 1-19, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.221 / 240 12591029. H0824.70430WO0021. The method of any one of claims 1-20, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

22. The method of any one of claims 1-21, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

23. The method of any one of claims 1-22, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;222 / 240 12591029. H0824.70430WO00RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

24. The method of any one of claims 1-23, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

25. The method of any one of claims 1-24, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate.

26. The method of any one of claims 1-25, wherein the ascorbic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is ascorbic acid, lithium ascorbate, Ester-C, ascorbyl palmitate, liposomal vitamin C, sodium ascorbate, magnesium ascorbyl phosphate (MAP), tetrahexyldecyl ascorbate, ascorbyl glucoside, calcium ascorbate, or sodium erythorbate.

27. The method of any one of claims 1-6 and 13-16, comprising treating the cell, tissue, or organ with or administering to the subject in need thereof ascorbic acid and a lithium salt, or a solvate, hydrate, polymorph, or co–crystal thereof.

28. The method of any one of claims 1-6, 13-16, and 27, wherein the lithium salt is selected from lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, and lithium citrate.223 / 240 12591029. H0824.70430WO0029. The method of any one of claims 1-6, 13-16, 27, and 28, wherein the lithium salt is lithium chloride.

30. A method of rejuvenating a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

31. A method of restoring cellular function in a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

32. A method of decreasing a biological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

33. A method of decreasing an apparent chronological age of a cell, tissue, or organ, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

34. A method of reprogramming a cell, tissue, or organ, thereby altering the expression of at least one gene associated with aging, the method comprising treating the cell, tissue, or organ with lithium ascorbate.

35. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof lithium ascorbate.

36. The method of any one of claims 1-5 and 7-34, wherein the cell is a senescent cell.

37. The method of claim 36, wherein the senescent cell is within the tissue or organ.

38. The method of any one of claims 1-5, 7-34, 36, and 37 , wherein the cell, tissue, or organ is within a subject.

39. The method of any one of claims 1-38, further comprising: increasing cellular respiration, reducing cellular inflammatory pathways, improving integrity of nucleocytoplasmic compartmentalization, or a combination thereof, ex vivo or in vitro.

40. The method of any one of claims 1-5, 7-11, 13-34, and 36-39, wherein the cell or tissue is from eye, ear, nose, mouth including gum and roots of teeth, bone, lung, breast, udder, pancreas, stomach, esophagus, muscle including cardiac muscle, liver, blood vessel, skin including hair, heart, brain, nerve tissue, kidney, testis, prostate, penis, cloaca, fin, ovary, or intestine, optionally wherein224 / 240 12591029. H0824.70430WO00the tissue is damaged or the tissue may be considered healthy but suboptimal for performance or survival in current or future conditions.

41. The method of any one of claims 5, 11, 13-29, 34, and 36-40, wherein the method reduces expression of the at least one gene associated with aging.

42. The method of any one of claims 5, 11, 13-29, 34, and 36-40, wherein the method increases expression of the at least one gene associated with aging.

43. The method of any one of claims 5, 11, 13-29, 34, and 36-42, wherein the at least one gene associated with aging is associated with: inflammation, mitochondrial metabolism, lysosomal function, apoptosis, p53, growth signaling, or a combination thereof, ex vivo or in vitro.

44. The method of any one of claims 1-5, 7-11, 13-34, and 36-43, further comprising activating an enhancer of reprogramming in the cell, tissue, or organ.

45. The method of claim 44, wherein the enhancer of reprogramming is a class I histone deacetylase (HDAC1-3).

46. The method of any one of claims 1-5, 7-11, 13-34, and 36-45, comprising restoring epigenetic information in the cell, tissue, or organ.

47. The method of claim 46, wherein the epigenetic information is lost due to aging, injury, disease, or a combination thereof in the cell, tissue, or organ.

48. The method of any one of claims 1-5, 7-11, 13-34, and 36-47, comprising reestablishing an epigenetic status of the cell, tissue, or organ that is similar to the status formed soon after final differentiation.

49. The method of any one of claims 1-5, 7-11, 13-34, and 36-48, wherein the cell, tissue, or organ is not reprogrammed to a pluripotent state.

50. The method of any one of claims 1-49, wherein the method rejuvenates an epigenetic clock of a cell, tissue, organ, subject, or a combination thereof.

51. The method of any one of claims 4, 10, 13-29, 33, 36-40, and 44-50, wherein the apparent chronological age of the cell, organ, or tissue is reduced by about three years.225 / 240 12591029. H0824.70430WO0052. The method of any one of claims 1-5, 7-11, 13-34, and 36-51, wherein the cell, tissue, or organ is treated for about four days.

53. The method of any one of claims 1-29 and 36-52, wherein the laduviglusib (CHIR99021), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM.

54. The method of any one of claims 1-29 and 36-53, wherein the RepSox (E-616452), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM.

55. The method of any one of claims 1-29 and 36-54, wherein the ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 10 µg / mL to about 100 µg / mL.

56. The method of any one of claims 1-29 and 36-55, wherein the valproic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 400 µM.

57. The method of any one of claims 1-29 and 36-56, wherein the tranylcypromine, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 2.5 µM to about 7.5 µM.

58. The method of any one of claims 1-29 and 36-57, wherein the forskolin, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 25 µM to about 75 µM.

59. The method of any one of claims 1-29 and 36-58, wherein the butyric acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 300 µM.226 / 240 12591029. H0824.70430WO0060. The method of any one of claims 1-29 and 36-59, wherein the basic fibroblast growth factor (bFGF), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 50 µg / mL to about 150 µg / mL.

61. The method of any one of claims 1-29 and 36-60, wherein the arotinoid acid (TTNPB), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM.

62. The method of any one of claims 1-29 and 36-61, wherein the Y-27632, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM.

63. The method of any one of claims 1-29 and 36-62, wherein the smoothened agonist (SAG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.25 µM to about 0.75 µM.

64. The method of any one of claims 1-29 and 36-63, wherein the linifanib (ABT-869), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.5 µM to about 1.5 µM.

65. The method of any one of claims 1-29 and 36-64, wherein the alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 250 µM to about 750 µM.

66. The method of any one of claims 1-6, 13-29, and 36-65, wherein the ascorbic acid is used at a concentration of about 25 µg / mL to about 75 µg / mL, and the lithium salt is used at a concentration of about 1 mM to about 25 mM.

67. The method of any one of claims 30-52, wherein the lithium ascorbate is used at a concentration of about 0.1 mM to about 5 mM.227 / 240 12591029. H0824.70430WO0068. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-67, wherein the subject is a human.

69. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-68, wherein the subject is a pediatric subject.

70. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-68, wherein the subject is an adult subject.

71. The method of claim 70, wherein the adult subject is a senior adult subject.

72. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-71, wherein the subject is healthy.

73. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-71, wherein the subject has, is suspected of having, or is at risk for an age-related disease.

74. The method of claim 73, wherein the age-related disease is a neurological disease.

75. The method of claim 74, wherein the neurological disease is a neurodegenerative disease.

76. The method of claim 75, wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).

77. The method of any one of claims 6, 12-29, 35, 38, 39, 50, and 53-76, wherein the administration comprises systemic administration to the subject.

78. A method of monitoring cellular aging, the method comprising: (a) providing a cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal; (b) contacting the cell with at least one test agent; (c) measuring a first signal from a first protein produced by the first reporter gene; (d) measuring a second signal from a second protein produced by the second reporter gene; (e) comparing the first signal and the second signal to assess the distribution of the first protein and the second protein in the cell.228 / 240 12591029. H0824.70430WO0079. The method of claim 78, wherein the first reporter gene encodes a first fluorescent protein.

80. The method of claim 79, wherein the first fluorescent protein is mCherry.

81. The method of any one of claims 78-80, wherein the second reporter gene encodes a second fluorescent protein.

82. The method of claim 81, wherein the second fluorescent protein is eGFP.

83. The method of any one of claims 78-82, wherein the cell is a fibroblast.

84. The method of any one of claims 78-83, wherein the cell is a human cell.

85. A cell comprising a nucleocytoplasmic compartmentalization (NCC) reporter system, wherein the NCC reporter system comprises: a first reporter gene linked to nuclear localization signal; and a second reporter gene linked to nuclear export signal.

86. The cell of claim 85, wherein the first reporter gene encodes a first fluorescent protein.

87. The cell of claim 86, wherein the first fluorescent protein is mCherry.

88. The cell of any one of claims 85-87, wherein the second reporter gene encodes a second fluorescent protein.

89. The cell of claim 88, wherein the second fluorescent protein is eGFP.

90. The cell of any one of claims 85-89, wherein the cell is a fibroblast.

91. The cell of any one of claims 85-90, wherein the cell is a human cell.

92. A pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;229 / 240 12591029. H0824.70430WO00RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).

93. A pharmaceutical composition comprising two or more compounds selected from the group consisting of: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;230 / 240 12591029. H0824.70430WO00valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

94. The pharmaceutical composition of claim 92 or claim 93, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

95. The pharmaceutical composition of any one of claims 92-94, comprising three or more compounds selected from the group.

96. The pharmaceutical composition of any one of claims 92-95, comprising four or more compounds selected from the group.

97. The pharmaceutical composition of any one of claims 92-96, comprising five or more compounds selected from the group.

98. The pharmaceutical composition of any one of claims 92-97, comprising six or more compounds selected from the group.231 / 240 12591029. H0824.70430WO0099. The pharmaceutical composition of any one of claims 92-98, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

100. The pharmaceutical composition of any one of claims 92-99, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

101. The pharmaceutical composition of any one of claims 92-100, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

102. The pharmaceutical composition of any one of claims 92-101, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;232 / 240 12591029. H0824.70430WO00RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

103. The pharmaceutical composition of any one of claims 92-102, comprising: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

104. The pharmaceutical composition of any one of claims 92-103, comprising: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof;233 / 240 12591029. H0824.70430WO00linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

105. The pharmaceutical composition of any one of claims 92-104, comprising: laduviglusib (CHIR-99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

106. The pharmaceutical composition of any one of claims 92-105, comprising: laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.

107. The pharmaceutical composition of any one of claims 92-106, wherein the pharmaceutically acceptable salt of butyric acid is sodium butyrate.

108. The pharmaceutical composition of any one of claims 92-107, comprising ascorbic acid and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate).234 / 240 12591029. H0824.70430WO00109. The pharmaceutical composition of any one of claims 92-108, wherein the lithium salt is selected from lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, and lithium citrate.

110. The pharmaceutical composition of any one of claims 92-109, wherein the lithium salt is lithium chloride.

111. The pharmaceutical composition of any one of claims 92-110, wherein the laduviglusib (CHIR99021), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM.

112. The pharmaceutical composition of any one of claims 92-111, wherein the RepSox (E- 616452), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 5 µM to about 15 µM.

113. The pharmaceutical composition of any one of claims 92-112, wherein the ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 10 µg / mL to about 100 µg / mL.

114. The pharmaceutical composition of any one of claims 92-113, wherein the valproic acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 400 µM.

115. The pharmaceutical composition of any one of claims 92-114, wherein the tranylcypromine, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 2.5 µM to about 7.5 µM.

116. The pharmaceutical composition of any one of claims 92-115, wherein the forskolin, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 25 µM to about 75 µM.235 / 240 12591029. H0824.70430WO00117. The pharmaceutical composition of any one of claims 92-116, wherein the butyric acid, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 100 µM to about 300 µM.

118. The pharmaceutical composition of any one of claims 92-117, wherein the basic fibroblast growth factor (bFGF), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 50 µg / mL to about 150 µg / mL.

119. The pharmaceutical composition of any one of claims 92-118, wherein the arotinoid acid (TTNPB), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM.

120. The pharmaceutical composition of any one of claims 92-119, wherein the Y-27632, or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 1 µM to about 3 µM.

121. The pharmaceutical composition of any one of claims 92-120, wherein the smoothened agonist (SAG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.25 µM to about 0.75 µM.

122. The pharmaceutical composition of any one of claims 92-121, wherein the linifanib (ABT- 869), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 0.5 µM to about 1.5 µM.

123. The pharmaceutical composition of any one of claims 92-122, wherein the alpha-ketoglutaric acid (α-KG), or pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, is used at a concentration of about 250 µM to about 750 µM.236 / 240 12591029. H0824.70430WO00124. The pharmaceutical composition of any one of claims 92-123, wherein the ascorbic acid is used at a concentration of about 25 µg / mL to about 75 µg / mL, and the lithium salt is used at a concentration of about 1 mM to about 25 mM.

125. A pharmaceutical composition comprising lithium ascorbate.

126. The pharmaceutical composition of claim 125, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

127. The pharmaceutical composition of claim 125 or claim 126, wherein the lithium ascorbate is used at a concentration of about 0.1 mM to about 5 mM.

128. The pharmaceutical composition of any one of claims 92-127 for use in rejuvenating a cell, tissue, or organ.

129. The pharmaceutical composition of any one of claims 92-127 for use in restoring cellular function in a cell, tissue, or organ.

130. The pharmaceutical composition of any one of claims 92-127 for use in decreasing a biological age of a cell, tissue, or organ.

131. The pharmaceutical composition of any one of claims 92-127 for use in decreasing an apparent chronological age of a cell, tissue, or organ.

132. The pharmaceutical composition of any one of claims 92-127 for use in reprogramming a cell, tissue, or organ, wherein reprogramming comprises altering the expression of at least one gene associated with aging.

133. A kit comprising: (a) a container housing the pharmaceutical composition of any one of claims 92-94; and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof.

134. A kit comprising: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of:237 / 240 12591029. H0824.70430WO00laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and lithium salts, or a solvate, hydrate, polymorph, or co–crystal thereof (e.g., lithium ascorbate, lithium chloride, lithium orotate, lithium carbonate, lithium citrate); and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof.

135. A kit comprising: (a) two or more containers, wherein each container houses one or more compounds selected from the group consisting of:238 / 240 12591029. H0824.70430WO00laduviglusib (CHIR99021), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; RepSox (E-616452), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; ascorbic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; valproic acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; tranylcypromine, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; forskolin, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; butyric acid, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; basic fibroblast growth factor (bFGF), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; arotinoid acid (TTNPB), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; Y-27632, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co– crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; smoothened agonist (SAG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; linifanib (ABT-869), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and alpha-ketoglutaric acid (α-KG), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co–crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof; and (b) instructions for rejuvenating a cell, tissue, or organ, optionally instructions for rejuvenating the cell, tissue, or organ of a subject in need thereof.239 / 240 12591029. H0824.70430WO00

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