Modulators for treatment and prevention of diseases, disorders and conditions

Abstract

The inventions relate to compounds and compositions comprising connexin hemichannel modulators, inflammasome modulators, and / or pannexin channel modulators and their use for the treatment of certain diseases, disorders, defects and conditions, including for the treatment of cells and subjects that contain shortened telomeres or that are in need of or may benefit from telomere extension, telomerase activity and / or telomerase reverse transcriptase activity, as well as for the treatment of cells and subjects for telomere-related diseases and / or telomere -related medical conditions, including cell senescence and cognitive decline. Also provided are methods of extending telomeres through the administration of the provided compounds and compositions to animal cells, either in vitro, ex vivo or in vivo, and kits including the compounds or compositions and instructions for use.

Description

[0001] MODULATORS FOR TREATMENT AND PREVENTION OF DISEASES, DISORDERS AND CONDITIONS FIELD The inventions relate to aging, cognitive decline, cell senescence, telomeres, telomerase, telomere reverse transcriptase, and telomere-related diseases, disorders and conditions. INCORPORATION BY REFERENCE All publications, patents, related applications, and other written or electronic materials mentioned, identified or referred to herein, including each and every United States patent, United States patent application publication, non-U.S. patent, non-U.S. and PCT published application, article and other document cited or noted herein, and all those listed as References Cited in any patent or patents that issue herefrom, are hereby incorporated by reference in their entirety. The information incorporated is as much a part of this application, and all patents issuing therefrom or claiming priority thereto, as if all of the text and other content was repeated in the application or patent, will be treated as part of the text and content of this application as filed and any patent issuing therefrom or claiming priority thereto, and any portion of any material incorporated by reference may be included herein by amendment if required. In the event of inconsistent usages between this document and any document incorporated by reference, the usage in the incorporated reference(s) should be considered supplementary to that of this document; for irreconcilable inconsistencies, including definitions appearing in patents or patent applications, the usage in this document controls. TECHNICAL INTRODUCTION The following includes information that may be useful in providing some technical guidance to the present inventions. It is not an admission that any of the information, publications or documents specifically or implicitly referenced herein are prior art, or important, to the inventions described and claimed herein. It is not a suggestion that the brief introductory descriptions are comprehensive. Many scientific articles have been written about these specialized areas and technical disciplines, as well as books and book chapters. To prevent the loss of genes as chromosome ends wear down, the tips of eukaryotic chromosomes have specialized DNA “caps” called telomeres, nucleoprotein complexes that include long chains of nucleotides. Telomeres are composed of specific guanine-rich DNA repeat sequences of 5'-TTAGGG-3' (conserved in vertebrates), and the shelterin complex, which consists of six proteins that maintain the structure and control telomere metabolism. Telomeres protect the ends of linear chromosomes from being recognized as DNA damage that triggers a DNA damage response. Because standard DNA polymerases cannot fully replicate linear DNA templates in the absence of telomerase, which is a DNA-template-independent DNA polymerase, and because of nucleolytic processing, DNA replication results in the generation of chromosomes with progressively shortened telomeres, which shorten each time the cell divides itself to the point where they become so short the cell is unable to divide itself further. As telomeres reach a critical length, they become unable to bind enough telomere-capping proteins and are sensed as exposed DNA ends, which activates DNA damage response pathways that, through the induction of the cell cycle inhibitors p21 and p16, arrest proliferation. These short telomeres, however, retain a sufficient number of telomere-binding proteins to inhibit DNA repair and avoid fusions, and consequently fuel a persistent DNA damage signal that enforces a permanent DNA damage-induced proliferative arrest. This initiates and maintains cellular senescence, a key contributor to organismal ageing and multiple age-related diseases. Activation of the DNA damage response at telomeres results in the formation of telomere-associated DNA damage response foci or telomere-induced DNA damage foci, which are markers of cellular senescence in cultured cells and tissues. Following telomere dysfunction, some cell types may also undergo cell death by apoptosis or autophagy. In addition to irreversible cell cycle arrest, cellular senescence is characterized by changes in chromatin, gene expression, organelles and cell morphology. Importantly, senescent cells secrete a complex set of pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This alters the composition of the extracellular matrix, impairs stem cell functions, promotes cell trans-differentiation and can spread the senescence phenotype to surrounding cells (a bystander effect), thereby causing systemic chronic inflammation. SASP is both promoted by DNA damage response and can promote DNA damage response and telomere- induced DNA damage foci formation in an autocrine and paracrine fashion. Telomeres have been referred to by some as an “ageing clock” that determines lifespan at the cellular level. Telomere length is not only linked to age, but also with other conditions including obesity, depression, and stress. Some cells reverse telomere shortening by expressing telomerase, a ribonucleic protein that counteracts the replication-related telomere attrition. Telomerase is an RNA-dependent DNA polymerase that extends the telomeres of chromosomes by addition of guanine-rich repeats, (TTAGGG)n in humans, by de novo DNA synthesis. It is responsible for maintenance of the length of telomeres. Telomerase, also sometimes referred to as terminal transferase, is an enzyme complex comprising two essential components: a telomerase reverse transcriptase (called TERT, or hTERT in humans) that creates single-stranded DNA using single-stranded RNA as a template, and an RNA template embedded within telomerase RNA (called TERC, i.e., telomerase RNA component, or hTERC in humans). Other components of the telomerase complex include the proteins TCAB1, Dyskerin, Gar1, Nhp2, Nop10, and RHAU. Brouilette et al., Arteriosclerosis, Thrombosis, and Vascular Biology 2003, 23:842-846; Hohensinner PJ, et al., Telomere dysfunction, autoimmunity and aging. Aging Dis.2011, 2:524-537. The hTERT gene is translated into a protein of 1132 amino acids. The TERT polypeptide folds with (and carries) TERC, a non-coding RNA that is 451 nucleotides long. TERT has a “mitten” structure that allows it to wrap around the chromosome to add single-stranded telomere repeats. By using TERC, TERT can serially add the 5'-TTAGGG six-nucleotide repeating sequence (in vertebrates), to the 3' strand of chromosomes (the sequence differs in other organisms). TERT is a limiting component of the telomerase complex, and thus treatments that increase TERT can increase telomerase activity. Telomerase activity can be measured using the telomeric repeat amplification protocol (TRAP) assay, which quantifies the ability of a cell lysate or other sample to extend a synthetic telomere-like DNA sequence. Telomerase reverses telomere shortening. The crucial role of TERT (e.g., hTERT) is to catalyze the synthesis of new telomeric repeats based on the RNA template, and other studies have shown that telomere length and telomerase activity or the critical subunit TERT play essential roles in stress-mediated aging. Jacczak B, et al., Potential of Naturally Derived Compounds in Telomerase and Telomere Modulation in Skin Senescence and Aging. Int. J. Mol. Sci.2021, 22:6381. hTERT has also been reported to play other, telomere-independent functions. One of them is associated with the modulation of mitochondrial metabolism and free radical elimination. This area is of high importance in considering the anti-aging and anti-senescence potential of telomerase. Cellular senescence is a cell state of irreversible proliferative arrest driven by different types of stress. Many senescent cells develop a senescent-associated secretory phenotype (SASP) comprising pro-inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids and other factors, able to promote chronic inflammation and tissue dysfunction. Senescent cells up-regulate senescent cell anti-apoptotic pathways (SCAPs) that prevent them from dying despite the accumulation of damage to DNA and other organelles. While cellular senescence has roles in tissue remodeling, including in wound repair, prolonged senescence can be maladaptive, leading to age-related diseases. Cellular senescence involves cell- cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21. In addition to driving ageing, senescence of immune and parenchymal cells contributes to the development of a variety of diseases and metabolic disorders. In the kidney, senescence can contribute to the progression of acute kidney injury and chronic kidney disease. Work has been done to evaluate the therapeutic benefit of compounds to target senescent cells, termed senotherapeutics, for the improvement of age-related diseases. See Zhang et al., Targeting cellular senescence with senotherapeutics: senolytics and senomorphics, The FEBS Journal 2023, 290:1362-1383. According to Zhang et al., senotherapeutics include senolytics, which selectively kill senescent cells or induce senolysis, and senomorphics, which attenuate the pathological SASPs to cause senostasis. In addition to obesity, depression and stress, current evidence also supports the idea that telomere length is associated with a number of chronic conditions including dyslipidemia (Dei Cas A, et al., Nutr Metab Cardiovasc Dis.2013, 23:272-278), hypertension (Yang Z, et al., Hypertension.2009, 53:639-645), atherosclerosis (Kark JD, et al., Atherosclerosis.2013, 229:363-368), stroke (Yetim E, et al., Sci Rep. 2021, 11:10967), coronary artery disease (Fyhrquist F, et al. Telomere length and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the LIFE study. J Hum Hypertens.2011, 25:711–718), myocardial infarction (Zee RY, Michaud SE, Germer S, Ridker PM. Association of shorter mean telomere length with risk of incident myocardial infarction: a prospective, nested case-control approach. Clin Chim Acta.2009, 403:139–141), and poor cardiovascular disease prognosis (Perez-Rivera JA, et al., Prognostic value of telomere length in acute coronary syndrome. Mech Ageing Dev.2012133:695-697). Other studies indicate that telomere attrition is positively correlated with diabetes and diabetic complications. Adaikalakoteswari A, et al., Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy. Atherosclerosis.2007, 195:83-89; Ma D, et al., Association between oxidative stress and telomere length in Type 1 and Type 2 diabetic patients. J Endocrinol Invest.2013, 36:1032-1037; Harte AL, et al., Telomere length attrition, a marker of biological senescence, is inversely correlated with triglycerides and cholesterol in South Asian males with type 2 diabetes mellitus. Exp Diabetes Res.2012, 2012:895185. Among type 2 diabetics, those experiencing complications such as diabetic nephropathy have shorter leukocyte telomere lengths than individuals without complications and those without diabetes. Arsenis NC, et al., Physical activity and telomere length: Impact of aging and potential mechanisms of action. Oncotarget 2017 Jul 4, 8(27):45008-45019. In addition to eliciting a DNA damage response that induces cellular senescence, impacting the regenerative capacity of tissues and giving rise to a range of age-associated diseases, shortened unprotected telomeres also lead to the so-called telomeropathies, in which tissue degeneration occurs prematurely as a consequence of inherited or acquired defects in telomere maintenance. Gap junctions are specialized intercellular connections found between most animal cell-types. They are expressed in virtually all tissues of the body, except for mature skeletal muscle and mobile cell types such as sperm and erythrocytes and provide regulated physical communication between cells by directly linking the interiors of adjoining cells, allowing various molecules, ions and electrical impulses to directly pass through. One gap junction channel is composed of two connexin hemichannels (also referred to as connexons), which connect across the intercellular space between adjacent cells. Each hemichannel of a gap junction resides in the adjacent cell membrane, and each hemichannel is formed by the covalent oligomerization of six individual connexin (Cx) proteins. See, e.g., Yeager (1998) Structure of cardiac gap junction intercellular channels, J Struct Biol 121: 231-245. Hemichannels can comprise one or more different connexin proteins but are usually in the form of homohexamers. The human connexin family of genes and proteins now numbers 21. They usually weigh between about 25 and 60 kDa and have an average length of 380 amino acids. All connexins share a common structure as a 4-pass transmembrane (TM) protein that includes several domains, namely, a short intracellular N-terminus (NT), an intracellular loop (IL) and a C-terminus (CT) that is also localized in the cytoplasm, plus two extracellular loops (EL1 and EL2) located outside the cell. The cytoplasmic carboxy terminus can vary considerably in length. See, e.g., Leith, E, et al., The connexin 43 C-terminus: A tail of many tales. Biochimica et Biophysica Acta 2018, 1860(1):48-64. Connexin proteins are commonly named according to their molecular weights, e.g. connexin 26 (Cx26) is a connexin protein of 26 kDa, connexin 43 (Cx43) is 43 kDa, etc. The principal structural difference between connexin proteins is the length of the C-terminal cytoplasmic tail, with connexin 26 having almost no tail (16 amino acids), while connexins 43 and 32 have long and intermediate ones (73 and 156 amino acids, respectively). While inherited or acquired alterations in the structure and function of connexin proteins have been linked with various diseases (e.g., Delmar, M, et al. Connexins and Disease, Cold Spring Harb Perspect Biol 2018, 10:a029348), research has also associated connexins with assorted conditions and disorders. See, e.g., Willebrords, J, et al., Connexins and their channels in inflammation Crit Rev Biochem Mol Biol. 2016, 51(6): 413–439; Feng, J, Becker, DL, et al., Connexin 43 upregulation in burns promotes burn conversion through spread of apoptotic death signals, Burns 2020, 46(6):1389-1397; McDouall, A, Green, CR, et al., Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury. Biomedicines 2022, 10:1445 (2022). Connexins have been proposed as therapeutics targets for a number of conditions, including spinal cord injury, perinatal brain injury, nervous system diseases (e.g. Alzheimer’s disease, Parkinson’s disease), cardiac disorders (e.g. myocardial infarction), ocular disorders (e.g. age-related macular degeneration, diabetic macular edema), acute and chronic wounds (e.g. venous leg ulcers, diabetic foot ulcers), ischemia- reperfusion injury, inflammation, burns and cancer. Reviewed in Laird and Lampe, Therapeutic strategies targeting connexins, Nat Rev Drug Discov. 201817(12): 905-921; Lampe and Laird, Recent advances in connexin gap junction biology, Faculty Reviews 2022, 27:11-14. See also, e.g., Van Campenhout R, et al., Mechanisms Underlying Connexin Hemichannel Activation in Disease. Int J Mol Sci. 22(7):3503 (Apr 2021) and US Pat. Nos. 10,401,188 and 11,401,516, issued for “Channel Modulators.” Pannexins are a family of transmembrane channel glycoproteins that include Panx1, Panx2 and Panx3. Pannexins share similar structural features with connexins, consisting of 4 transmembrane domains, 2 extracellular and 1 intracellular loop, along with intracellular N- and C-terminal tails. Pannexin 1 (Panx1) is a ubiquitously expressed protein forming large conductance channels that are central to various distinct inflammation and injury responses. nPanx1 is expressed in many mammalian tissues, while Panx2 and Panx3 expression is more limited. Panx1 channels have been implicated in ATP release, as well as calcium signaling, and keratinocyte and osteoblast differentiation. One major difference between connexin and pannexin channels is that pannexin channels do not form cell-to-cell channels. Pannexin modulators have previously been described. They include pannexin peptidomimetic compounds (e.g.,10Panx1), as well as probenecid and other compounds of Formula VI, including analogs and prodrugs thereof, as set forth in US Patent No. 10,465,188, issued on November 5, 2019, for “Channel Modulators.” Inflammasomes are large, cytosolic molecular complexes that typically consist of a sensor protein, the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and the proinflammatory caspase, caspase-1. They control activation of the proteolytic enzyme caspase-1. Caspase-1 in turn regulates the proteolytic maturation of Interleukin-1β and IL-18, as well as a rapid, noxious, inflammatory form of cell death termed pyroptosis. Assembly of inflammasome complexes is dependent on cytosolic sensing of pathogen- associated molecular patterns (PAMPs) that gain access to the cytosol during microbial infection. PAMPs are relatively non-specific, highly conserved, pathogenic molecular structures expressed in pathogens, and their products (including, e.g., lipopolysaccharide (LPS), which is found on the outer cell wall of gram-negative bacteria). Being derived from microorganisms, PAMPs drive inflammation in response to infections. In addition, endogenous danger signals (danger-associated molecular patterns, or DAMPs) released from damaged or dying cells also activate inflammasomes. DAMPs are derived from host cells including tumor cells, dead or dying cells, or products released from cells in response to signals such as hypoxia. DAMPs are a large number of related intracellular proteins or nucleic acids released by necrotic cells at the site of necrosis. Because they are derived from host materials, DAMPs induce what are known as sterile inflammatory responses. DAMPs are often created or exposed in environments of trauma, ischemia, or tissue damage and do not require pathogenic infection and drive pathological inflammation in sterile inflammatory diseases including atherosclerosis, Alzheimer’s disease, diabetes and cancer. See Rathinam and Fitzgerald, Inflammasome Complexes: Emerging Mechanisms and Effector Functions. Cell.2016, 165(4):792-800. Four key inflammasomes have been well characterized, i.e., NLRP1, NLRP3, NLRC4, and AIM2. They regulate innate immunity by serving as a signaling platform, and activation of these any one of these inflammasomes leads to the processing and secretion of inflammatory cytokines, including IL-1β and IL-18. The Nod-like receptor protein 3 (NLRP3) inflammasome, is by far the most extensively studied and well-characterized inflammasome. The NLRP3 inflammasome (also sometimes identified as the “nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3” inflammasome) is expressed in various cells of the cardiovascular system, including in cardiomyocytes, endothelial cells, and immune cells. It is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3, the adaptor protein apoptosis-associated speck-like protein (ASC), and inflammatory protease caspase-1 (pro-caspase-1). A variety of stimuli can activate the NLRP3 inflammasome. When activated, the NLRP3 protein recruits the adaptor ASC protein and activates pro-caspase-1, resulting in inflammatory cytokine maturation and secretion, which is associated with inflammation and the induction of gasdermin D-dependent pyroptosis. Like other inflammasomes, the assembled NLRP3 inflammasome facilitates the release of IL-1β and IL-18, which contribute to innate immune defense and homeostatic maintenance. However, aberrant activation of the NLRP3 inflammasome has been linked to the pathogenesis of various inflammatory diseases, including atherosclerosis, ischemic stroke, Alzheimer's disease, diabetes mellitus and inflammatory bowel disease. Recent studies have revealed that NLRP3 inflammasome activation contributes to not only pyroptosis but also other types of cell death, including apoptosis, necroptosis, and ferroptosis, and the NLRP3 inflammasome has emerged as a therapeutic target for inflammatory diseases. Reviewed in Zhang X, et al., Int J Mol Med.2023, 51(4):35, which discusses candidate inhibitors of the NLRP3 inflammasome including MCC950 (CP-456,773, CRID3), oridonin (an ent-kaurane diterpenoid), OLT1177 (an orally active β- sulfonyl cyanide molecule), INF39, tranilast (a tryptophan metabolite), CY-09, JC124, 3,4- methylenedioxy-β-nitrostyrene (MNS), parthenolide, BOT-4-one, and others. Countries throughout the world are now experiencing the impact of aging disorders as lifespans increase, and a greater fraction of the population suffers from aging-associated and other cognitive impairments, making it important to elucidate means by which to maintain cognitive integrity by protecting against, or even counteracting, the effects of aging. See, e.g., Bishop, N. A., et al., Neural mechanisms of ageing and cognitive decline. Nature 2010, 464(7288), 529-535. These disorders have already become a major burden on society with and increased incidence of dementia and cognitive decline in aging. Although the need for therapeutics for these and other chronic disorders that address aging and age-related disorders, including cell senescence and cognitive impairment, is acute, this therapeutic area largely untilled. See Meron E, et al. Meeting Report: Aging Research and Drug Discovery. Aging (Albany NY).2022, 14(2):530–43. Telomere length and cell function can be preserved by the reserve transcriptase telomerase, and there was much research following the identification of human telomerase. However, there are no drugs on the market and discovery of a simple and safe way to address cognitive decline, manipulate telomerase, preserve telomeres, and create cures for telomere and telomere-related diseases has also remained an unmet medical need. These and other needs are addressed by the inventions described and claimed herein. BRIEF INTRODUCTION TO THE INVENTIONS The inventions described and claimed herein have many attributes and embodiments including, but not limited to, those set forth or described or referenced in this brief introduction. It is not intended to be all-inclusive, and the inventions described and claimed herein are not limited to or by the features or embodiments identified in this introduction, which is included for purposes of illustration and outline only and not restriction. Further description and detail is contained in the Detailed Description and claims, all of which, including this introduction, form a part of the patent specification. Ageing in an organism is a progressive degenerative state accompanied by cellular senescence, tissue stem cell depletion, tissue inflammation, matrix alterations, and metabolic dysfunction. Ageing is also accompanied by structural and neurophysiological changes that drive cognitive decline and susceptibility to degenerative disorders in healthy individuals. These cellular and tissue changes reflect underlying molecular aberrations which lead to genomic instability and damage, including telomere dysfunction. Telomere length and telomerase expression are critical elements protecting cells from cellular senescence and the aging process. There is a long-felt need to address cellular senescence and related conditions and disorders described herein, including cognitive decline, despite the significant efforts that have been undertaken to solve these conditions and disorders that have failed or otherwise fallen short or would benefit from improved treatments. There is also a need to address telomere shortening, and telomere length which has inverse associations with chronic conditions (including cardiovascular disease, obesity, diabetes, etc.). There is a long-felt but unmet need to identify effective modulators of telomere length and telomerase activity. Short telomeres, furthermore, due to genetic or acquired insults, can cause a loss of cellular self- renewal that result in life-threatening diseases for which there are few if any effective medical therapies. In diseases involving short telomeres, e.g., aplastic anemia, hepatic cirrhosis, bone marrow failure, etc., there is an unmet clinical need for new therapies or improved treatments. The disclosure is based, in part, on the discoveries that connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) can reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length. The disclosure is also based, in part, on the discoveries that inflammasome modulators (e.g., NLRP3 inflammasome modulators), can reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length. The disclosure is further based, in part, on the discovery that connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) can reverse or alleviate telomerase reverse transcriptase (TERT) deficiency. The disclosure is further based, in part, on the discovery that inflammasome modulators (e.g., NLRP3 inflammasome modulators), can reverse or alleviate telomerase reverse transcriptase (TERT) deficiency. The disclosure is also based, in part, on the discovery that connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) can protect against and alleviate cognitive decline. The disclosure is also based, in part, on the discovery that inflammasome modulators (e.g., NLRP3 inflammasome modulators) can protect against and alleviate cognitive decline. The specification also includes disclosure of inventions based on the discoveries that connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) can reverse cognitive decline. The specification also includes disclosure of inventions based on the discoveries that inflammasome modulators (e.g., NLRP3 inflammasome modulators) can reverse cognitive decline. The disclosure is also based, in part, on the discovery that connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) can protect against and alleviate cellular senescence. The disclosure is also based, in part, on the discovery that inflammasome modulators (e.g., NLRP3 inflammasome modulators), can protect against and alleviate cellular senescence. The specification also includes disclosure of inventions based on discoveries that connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) can be used to reverse cellular senescence. The specification also includes disclosure of inventions based on discoveries that inflammasome modulators (e.g., NLRP3 inflammasome modulators), can be used to reverse cellular senescence. The disclosure is also based, in part, on the discoveries that connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) can protect against aging, including cellular aging. The disclosure is also based, in part, on the discoveries that inflammasome modulators (e.g., NLRP3 inflammasome modulators), can protect against aging, including cellular aging. The specification also includes disclosure of inventions based on discoveries that connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) can alleviate aging, including cellular aging. The specification also includes disclosure of inventions based on discoveries that inflammasome modulators (e.g., NLRP3 inflammasome modulators), can alleviate aging, including cellular aging. The disclosure is also based, in part, on the discoveries that connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) and inflammasome modulators (e.g., NLRP3 inflammasome modulators), can PECAM-1. In some embodiments of the inventions, uses, methods, doses, dose regimens, compositions and kits are provided to increase telomerase expression in a subject. In some embodiments of the inventions, uses, methods, doses, dose regimens, compositions and kits are provided for to protect against loss of telomerase reverse transcriptase (TERT) or to increase TERT or TERT activity in a subject. In some embodiments of the inventions, uses, methods, doses, dose regimens, compositions and kits are provided to protect against cellular senescence in a subject. In some embodiments of the inventions, uses, methods, doses, dose regimens, compositions and kits are provided to treat cognitive decline in a subject. In some embodiments of the inventions, uses, methods, doses, dose regimens, compositions and kits are provided to alleviate aging in a subject. In some embodiments of the inventions, uses, methods, doses, dose regimens, compositions and kits are provided to reduce protect against and decrease expression of platelet / endothelial cell adhesion molecule-1 PECAM-1 in a subject. It is an object of the invention to provide methods, doses, dose regimens, compositions, and kits for connexin hemichannel modulation (e.g., connexin hemichannel modulation) for the treatment of a subject as described herein. It is another object of the invention to provide methods, doses, dose regimens, compositions, and kits for inflammasome inhibition (e.g., NLRP3 inflammasome inhibition) for the treatment of a subject as described herein. In some embodiments, the subject is a human. In some embodiments, connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) used in methods, compositions and kits of the invention, including to reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length, may be referred to as direct connexin hemichannel modulators, including, for example, the compounds of Formula I, including tonabersat and carabersat, and connexin peptidomimetics such as Peptide5, Gap29 and Gap27. In other some embodiments, useful connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) may be referred to as indirect connexin hemichannel modulators, including, for example, the connexin peptidomimetics XG19, Gap19, CXT 1 to CXT 5, Antp / CXT 1 to Antp / CXT 5, as well as anti-connexin antisense compounds, including, for example, SEQ ID NO:1 and other connexin-modulating molecules, peptidomimetics and sequences described herein or known in the art. In some embodiments, the connexin hemichannel modulators are connexin 43 hemichannel modulators. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention relating to reversing or alleviating telomerase reverse transcriptase (TERT) deficiency. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention for protection against cognitive decline. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention for alleviating cognitive decline. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention for reversing cognitive decline. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention for protection against cellular senescence. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention for alleviating cellular senescence. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention to reverse cellular senescence. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention to protect against aging, including cellular aging. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention to alleviate aging, including cellular aging. In some embodiments, the connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) are used in and useful for methods, compositions and kits of the invention to protect against protect against and decrease expression of PECAM-1. In some embodiments, inflammasome modulators (e.g., NLRP3 inflammasome modulators) useful in methods, compositions and kits of the invention, including to reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length, may be referred to as direct or indirect inflammasome modulators. Useful inflammasome modulators that may be referred to as direct inflammasome modulators include, for example, oridonin, MCC950, tranilast and analogues thereof which directly binds to the NACHT domain of NLRP3 and change its conformation,; OLT1177 and parthenolide which suppress the ATPase activity of NLRP3; CY-09 which binds to the NACHT domain and inhibits ATPase of NLRP3; BAY11-7082 and VI-16 which block the binding between TXNIP and NLRP3; NIC7 (NLRP3-inhibitory compound), and its derivatives which inhibit NLRP3-mediated activation of caspase 1 along with the secretion of interleukin (IL)-1β, IL-18 and lactate dehydrogenase; metformin which has been shown to inhibit NLRP3 inflammasome activation; resveratrol, which is indicated in being able to suppress NLRP3 inflammasome activation through various mechanisms, including SIRT1 activation; quercetin, which has demonstrated NLRP3 inflammasome inhibitory effects in models of inflammation; fasudil, which can modulate NLRP3 and other inflammatory pathways; allopurinol which can modulate NLP3 inflammasome independently from its affect on uric acid; and emlenoflast that ca directly inhibit the NLRP3 inflammasome. Useful inflammasome modulators that may be referred to as indirect inflammasome modulators include, for example, glyburide, 1673-34-0, FC11A-2, β-hydroxybutyrate, etc., and modulators of ATP-induced inflammasome activation such as tonabersat and other small molecule connexin hemichannel modulators, connexin peptidomimetics including for example, Peptide5, XG19, etc. In some embodiments, the inflammasome modulators are NLRP3 inflammasome modulators. In some embodiments, the inflammasome modulators are direct NLRP3 inflammasome modulators. In some embodiments, the inflammasome modulators are indirect NLRP3 inflammasome modulators. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention relating to reversing or alleviating telomerase reverse transcriptase (TERT) deficiency. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention for protection against cognitive decline. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention for alleviating cognitive decline. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention for reversing cognitive decline. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention for protection against cellular senescence. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention for alleviating cellular senescence. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention to reverse cellular senescence. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention to protect against aging, including cellular aging. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention to alleviate aging, including cellular aging. In some embodiments, the inflammasome modulators (e.g., NLRP3 inflammasome modulators) are used in and useful for methods, compositions and kits of the invention to protect against protect against and decrease expression of PECAM-1. In some embodiments, at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length in a cell. In some embodiments the at least one inhibitor and / or blocker is used to reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length in a cell in vivo. In some embodiments the at least one inhibitor and / or blocker is used to reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length in a cell ex vivo. In some embodiments the at least one inhibitor and / or blocker is used to reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length in a cell in vitro. In some embodiments the at least one inhibitor and / or blocker is used to reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length in a cell in a subject. In any of these embodiments, the cell may comprise a population of cells. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is administered to a subject to reverse or alleviate telomerase deficiency, shortened telomers and / or reduced telomere length in the subject, for example a patient, including, for example, a human patient or subject. In some embodiments, at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to reverse or alleviate telomerase reverse transcriptase (TERT) deficiency in a cell. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to reverse or alleviate TERT deficiency in a cell in vivo, in a cell ex vivo, or in a cell in vitro. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to reverse or alleviate TERT deficiency in a cell in a subject, for example in cell in a patient, including a human patient or subject. In any of these embodiments, the cell may comprise a population of cells. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is administered to a subject to reverse or alleviate TERT deficiency in the subject, for example a patient, including, for example, a human patient or subject. In some embodiments, at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to increase TERT levels or activity in a cell. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to increase TERT levels or TERT activity in a cell in vivo, in a cell ex vivo, or in a cell in vitro. In some embodiments the at least one inhibitor and / or blocker is used to increase TERT levels or TERT activity in cell in a subject, for example in a cell in a patient, including a human patient or subject. In any of these embodiments, the cell may comprise a population of cells. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is administered to a subject to increase TERT levels or TERT activity in the subject, for example a patient, including, for example, a human patient or subject. In some embodiments, at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is administered to a subject to protect against and / or alleviate cognitive decline in the subject. In some embodiments, at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is administered to a subject to reverse cognitive decline in the subject. In some embodiments, at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to protect against and / or alleviate cell or cellular senescence. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to protect against and / or alleviate senescence of a cell in vivo, a cell ex vivo, or a cell in vitro. In some embodiments, the cell comprises a population of cells. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is administered to a subject to protect against and / or alleviate senescence of a cell or a population of cells in a subject. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is administered to a subject to protect against and / or alleviate cell or cellular senescence in the subject. In some embodiments, at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to reverse cellular senescence. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to reverse senescence of a cell in vivo, ex vivo, or in vitro. In some embodiments, the cell comprises a population of cells. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to reverse cellular senescence in a cell or population of cells in a subject. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to reverse cellular senescence in a subject. In some embodiments, at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to protect against aging, including cellular aging. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to protect against aging of a cell in vivo, of a cell ex vivo, or a cell in vitro. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to protect a cell in a subject against aging. In any of these embodiments, the cell may comprise a population of cells. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to protect against aging in a subject. In some embodiments, at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to protect against and decrease PECAM-1 expression in a cell. In some embodiments, the at least one connexin hemichannel blocker (e.g., connexin 43 hemichannel blocker), indirect inflammasome inhibitor and / or direct inflammasome inhibitor is used to protect against and decrease PECAM-1 expression in a cell in vivo, in a cell ex vivo, or in a cell in vitro. In some embodiments the at least one inhibitor and / or blocker is used to protect against and decrease PECAM-1 expression in a cell in a subject. In any of these embodiments, the cell may comprise a population of cells. In some embodiments the at least one inhibitor and / or blocker is administered to a subject to protect against and decrease PECAM-1 expression in the subject. In one aspect, the disclosure relates to methods of treating a disease, condition or disorder associated with telomerase deficiency or dysfunction in a subject. The methods include the steps of identifying the subject as having a disease, condition or disorder associated with telomerase deficiency or dysfunction; and administering to the subject an effective amount of a pharmaceutical composition comprising an agent that modulates connexin hemichannel activity (e.g., connexin 43 hemichannel activity including release of ATP), thereby treating the disease, condition or disorder associated with telomerase deficiency or dysfunction in the subject. In other embodiments of these methods, the pharmaceutical composition administered to the subject comprises an agent that decreases, suppresses or inhibits inflammasome activity or activation (e.g., an NLRP3 inflammasome inhibitor), alone, in addition to, or together with the agent that modulates connexin hemichannel activity. In some embodiments, the agent that decreases or suppresses inflammasome activity or activation is a direct inflammasome inhibitor (e.g., a direct NLRP3 inflammasome inhibitor). In some embodiments, the agent that decreases or suppresses inflammasome activity or activation is an indirect inflammasome inhibitor (e.g., an indirect NLRP3 inflammasome inhibitor). In some embodiments, these methods and compositions are used to increase telomerase expression in a subject by administering to the subject an effective amount of a pharmaceutical composition comprising an agent that modulates connexin hemichannel activity (e.g., connexin 43 hemichannel activity), thereby increasing telomerase expression in one or more cells in the subject. In other embodiments of these methods, the pharmaceutical composition administered to the subject comprises an agent that decreases, suppresses or inhibits inflammasome activity or activation (e.g., an NLRP3 inflammasome inhibitor), alone, in addition to, or together with the agent that modulates connexin hemichannel activity. In some embodiments, the methods and compositions are used to increase telomerase expression in a cell in a subject having a disease, condition or disorder associated with telomerase deficiency or dysfunction. In some embodiments, the methods and compositions are used to increase telomerase expression in a tissue having a disease, condition or disorder associated with telomerase deficiency or dysfunction. In some embodiments, the tissue is in a subject. In some embodiments, the tissue is outside the subject. In some embodiments, methods and compositions of the invention are used to treat a disease, condition or disorder that would benefit from telomerase activity, telomerase expression, increased telomerase activity and / or increased telomerase expression. In some embodiments, these methods and compositions are used to treat a disease, condition or disorder associated with telomerase reverse transcriptase deficiency or dysfunction in a subject by administering to the subject an effective amount of a pharmaceutical composition comprising an agent that modulates connexin hemichannel activity (e.g., connexin 43 hemichannel activity), thereby increasing telomerase expression in one or more cells in the subject. In other embodiments of these methods, the pharmaceutical composition administered to the subject comprises an agent that decreases, suppresses or inhibits inflammasome activity or activation (e.g., an NLRP3 inflammasome inhibitor), alone, in addition to, or together with the agent that modulates connexin hemichannel activity in order to increase telomerase expression in one or more cells in the subject. In other embodiments, the methods are used to treat a disease, condition or disorder that would benefit from increased telomerase reverse transcriptase (TERT). In other embodiments, the methods are used to treat a disease, condition or disorder that would benefit from increased TERT activity. In some embodiments, the methods and compositions are used to increase TERT expression in a cell in a subject having a disease, condition or disorder associated with telomerase deficiency or dysfunction. In some embodiments, the methods and compositions are used to increase TERT expression in a tissue having a disease, condition or disorder associated with telomerase deficiency or dysfunction. In some embodiments, the tissue is in a subject. In some embodiments, the tissue is outside the subject. In some embodiments, methods and compositions of the invention are used to increase telomerase reverse transcriptase (TERT) or increase TERT activity in a cell. In some embodiments, methods and compositions of the invention are used to increase telomerase reverse transcriptase (TERT) or increase TERT activity in a cell in a subject. In some embodiments, a cell may comprise a population of cells. In some embodiments, methods and compositions of the invention are used to increase telomerase reverse transcriptase (TERT) or increase TERT activity in a subject. In some embodiments, methods and compositions of the invention are used to increase telomere length in a cell. In some embodiments, methods and compositions of the invention are used to increase telomere length in one or more cells in a subject by administering an agent or agent as described. In some embodiments, methods and compositions of the invention are used to treat a disease, condition or disorder associated with shortened or shortening telomeres. In other embodiments, the methods are used to treat a disease, condition or disorder that would benefit from increased telomeres or increased telomere length. In some embodiments, methods and compositions of the invention are used to treat a disease, condition or disorder associated with cognitive decline. In other embodiments, the methods are used to treat a disease, condition or disorder associated with mild cognitive decline. In some embodiments, a disease, condition or disorder associated with cognitive decline and / or mild cognitive decline is treated by administering to a subject an effective amount of a pharmaceutical composition comprising an agent that modulates connexin hemichannel activity (e.g., connexin 43 hemichannel activity), thereby arresting, slowing, lessening or reversing cognitive decline in the subject. In other embodiments of these methods, the pharmaceutical composition administered to the subject comprises an agent that decreases, suppresses or inhibits inflammasome activity or activation (e.g., an NLRP3 inflammasome inhibitor), alone, in addition to, or together with the agent that modulates connexin hemichannel activity in order to arrest, slow, lessen or reverse cognitive decline in the subject. In some embodiments, the methods and compositions are used to treat a disease, condition or disorder associated with CD31 expression. In other embodiments, the methods are used to treat a disease, condition or disorder by reducing CD31 expression. In some embodiments, a disease, condition or disorder associated with CD31 expression is treated by administering to a subject an effective amount of a pharmaceutical composition comprising an agent that modulates connexin hemichannel activity (e.g., connexin 43 hemichannel activity), thereby arresting, slowing, or lessening CD31 expression in the subject, or in one or more cells or tissues of the subject. In other embodiments of these methods, the pharmaceutical composition administered to the subject comprises an agent that decreases, suppresses or inhibits inflammasome activity or activation (e.g., an NLRP3 inflammasome inhibitor), alone, in addition to, or together with the agent that modulates connexin hemichannel activity in order to arrest, slow, or lessen or reverse CD31 expression in the subject, or in one or more cells or tissues of the subject. In some embodiments of any of these methods a combination pharmaceutical composition that comprises two or more of an agent that decreases connexin hemichannel activity (e.g., connexin 43 hemichannel activity) and an agent that decreases or suppresses inflammasome activity or activation (e.g., an NLRP3 inflammasome inhibitor) is administered to a subject. In some embodiments, an agent that decreases pannexin channel activity (e.g., pannexin 1 channel activity) may be includes with a pharmaceutical composition comprising either agent that decreases connexin hemichannel activity (e.g., connexin 43 hemichannel activity) or an agent that decreases or suppresses inflammasome activity or activation (e.g., an NLRP3 inflammasome inhibitor) or both. In some embodiments, any of the methods may further include the step or steps of (a) determining or evaluating telomere length in the subject and / or (b) determining whether to administer an increased amount of the agent(s), administer a decreased amount of the agent(s), pause administration of the agent(s), or cease administration of the agent (or agents). In some embodiments, telomere length is determined or evaluated in one or more cells of the subject. In some embodiments, the method used to determine and / or evaluate telomere length is qPCR. In some embodiments, the disease, disorder or condition associated with telomere length, telomere shortening, telomerase dysfunction, TERT deficiency and / or cellular senescence, or that would otherwise benefit from increased telomere length, increased telomerase levels or activity, increased TERT levels or activity, and / or reduced cell senescence, is a neurological disease, disorder or condition (e.g., dementia, cognitive decline, etc.), a metabolic disease, disorder or condition (e.g., pre-diabetes, diabetes and dyslipidemia), or a cardiovascular disease, disorder or condition (e.g., atherosclerosis, coronary artery disease, stroke, acute coronary syndrome, etc.), obesity, depression or stress. In other embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens for the treatment of telomeropathies based on TERT mutations leading to decreased telomerase levels or activity and which are characterized by shorter or shortened telomeres. In some embodiments, the disorder associated with telomerase dysfunction is aplastic anemia, hematological disorder, hepatic disease or dyskeratosis congenital. In other embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens for the treatment of cognitive decline. In some embodiments, the cognitive decline is mild cognitive decline. In other embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens for the treatment of cell senescence. In some embodiments, the compounds, compositions, methods, kits, doses and dose regimens of the invention for the protect against cell senescence. The inventions described and claimed herein provide compounds, compositions, methods, kits, doses and dose regimens and long-needed means for treating subjects suffering with a disease, disorder or condition associated with telomere length or shortening. In some embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens and means for slowing cellular aging, slowing cognitive decline, slowing cellular senescence. In some embodiments, the inventions are used to increase telomerase expression. In some embodiments, the agent increases the level or activity of telomerase reverse transcriptase (TERT). In some embodiments, the agent protects against loss of TERT. In some embodiments, the agent protects against loss of TERT in the eye. In some embodiments, the agent protects against loss of TERT in the retina. In some embodiments, the agent protects against loss of TERT in retinal pigment epithelial cells. In some embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens and for restoring telomeres. In some embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens and for increasing telomere length and / or size. In some embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens and for modulating or improving telomere length in Type 1 and Type 2 diabetic patients. Telomere shortening is seen even in people with impaired glucose tolerance (IGT) and in some embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens and for modulating or improving telomere length in subjects with IGT or prediabetes. In some embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens and for modulating or improving telomere length in subjects with atherosclerosis. Among subjects with Type 2 diabetes, those with atherosclerotic plaques have greater shortening of telomere length compared to those without plaques and, in some embodiments, the inventions provide compounds, compositions, methods, kits, doses and dose regimens and for modulating or improving telomere length in subjects with Type 2 diabetes having atherosclerotic plaques. In some embodiments, the agent used for the purposes and in the methods described herein – including increasing telomere length, arresting or slowing telomere shortening, increasing telomerase activity and / or expression, increasing TERT activity and / or expression, addressing aging, addressing, cell senescence, addressing cognitive decline, slowing, decreasing or arresting PECAM-1 expression, etc., and treating any of the diseases, disorders or conditions described or referred to herein – is a connexin hemichannel modulator. In some embodiments, the connexin hemichannel modulator is a connexin 43 hemichannel modulator. In some embodiments, the connexin hemichannel modulator is a vascular connexin hemichannel modulator. In some embodiments, the connexin hemichannel modulator is a connexin 37 hemichannel modulator, a connexin 40 hemichannel modulator and / or a connexin 45 hemichannel modulator. Modulation of a hemichannel may occur by any means. In some embodiments, for example, modulation may occur by inducing or promoting closure of a hemichannel; by preventing, blocking, inhibiting or decreasing hemichannel opening; by suppressing hemichannel permeability; by suppressing ATP release from hemichannels; and / or by triggering, inducing or promoting cellular internalization of a hemichannel and / or gap junction. Hemichannel modulators include blockers and other compounds that interfere with the passage of molecules through a connexin hemichannel. A hemichannel modulator can block or reduce the release of molecules through a hemichannel to an extracellular space, and / or block or reduce the entry of molecules through a hemichannel into an intracellular space. In some embodiments, hemichannel modulators fully or partially block hemichannel opening. In some embodiments, hemichannel modulators fully or partially block, slow or suppress the leak or the passage of molecules through a hemichannel to or from an extracellular space. In some embodiments, hemichannel modulators are compounds that decrease the open probability of a hemichannel. In some embodiments of the invention, the connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator) is a benzoylamino benzopyran. In some embodiments, the benzoylamino benzopyran is a compound according to Formula I. In some embodiments compound according to Formula I is carabersat. In some embodiments compound according to Formula I is tonabersat. In some embodiments, the tonabersat compound is a tonabersat prodrug. In some embodiments the tonabersat prodrug is a compound according to Formula II. In some embodiments, the connexin modulator comprises a connexin peptidomimetic. In some embodiments, the connexin peptidomimetic is a connexin43 peptidomimetic. In some embodiments, the connexin 43 hemichannel modulator peptidomimetic molecule is, comprises, or consists essentially of, for example, Peptide5, Gap19, XG19, CXT 1 to CXT 5, Antp / CXT 1 to Antp / CXT 5, etc., or a compounds selected from SEQ ID NOS: 140-199, 200, 291-313 and 343- 355). In some embodiments, the connexin peptidomimetic is a connexin 37, connexin 40 and / or connexin 45 peptidomimetic. In some embodiments, the connexin peptidomimetic comprises, consists essentially of, or consists of SRPTEKT (SEQ ID NO:101). In some embodiments, the connexin peptidomimetic comprises, consists essentially of, or consists of Gap19, XG19, Gap26 or Gap27. In some embodiments, the connexin peptidomimetic is a connexin26 peptidomimetic (e.g. Gap26 i.e., VCYDKSFPISHVR (SEQ ID NO:102), a connexin32 peptidomimetic (e.g. INCTLQPGCNSV (SEQ ID NO: 103) or37,43Gap27, which is SRPTEKTIFII (SEQ ID NO: 104) or a connexin45 peptidomimetic, or a connexin50 peptidomimetic (e.g. TAT-Cx50L2, i.e., GGERAPLAADQGSVKKSSSSSKGTKK (SEQ ID NO: 105) or TAT-Cx50CT, i.e., SRARSDDLTV (SEQ ID NO: 106)). In some embodiments the connexin hemichannel modulator modulates connexin expression. In some embodiments, the connexin expression modulator modulates connexin 43 expression. In other embodiments, the connexin expression modulator modulates expression of a vascular connexin. In other embodiments, the connexin expression modulator modulates expression of connexin 37, connexin 40 and / or connexin 45. In some embodiments, the connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator) is a connexin (e.g., a connexin 43) antisense molecule. In some embodiments, the connexin modulator may be a connexin 43 antisense polynucleotide comprising, consisting essentially of, or consisting of a sequence according to SEQ ID NOS.1-16 and / or modified versions thereof. In some embodiments, antisense oligonucleotide comprises, consists essentially of, or consists of 5'-GTA ATT GCG GCA AGA AGA ATT GTT TCT GTC-3' (SEQ ID NO:1). In some embodiments, the antisense oligonucleotide may be chemically modified or may be an unmodified oligonucleotide, e.g. a modified or an unmodified DNA oligonucleotide. In some embodiments, the connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator) is an anti-connexin (e.g., an anti-connexin 43) antibody (e.g., an anti-connexin monoclonal antibody), an anti-connexin (e.g., an anti-connexin 43) antibody fragment (e.g., an anti-connexin Fab, F(ab’)2, etc.), an anti-connexin (e.g., an anti-connexin 43) engineered antibody (e.g., an anti-connexin single-chain variable (scFv) fragment or scFab, etc.), an anti-connexin (e.g., an anti-connexin 43) Ig domain (e.g., an anti-connexin 43 VHH), an anti-connexin nanobody (Nb), etc. In other embodiments, one or more of these connexin modulators is directed to a vascular connexin. In other embodiments, one or more of these connexin modulators is directed against connexin 37, connexin 40 and / or connexin 45. In some embodiments, the connexin hemichannel modulators used in methods of the invention modulates one or more of connexin 26 or a connexin 26 hemichannel, connexin 30 or a connexin 30 hemichannel, connexin 30.3 or a connexin 30.3 hemichannel, connexin 31 or a connexin 31 hemichannel, connexin 31.1 or a connexin 31,1 hemichannel, connexin 32 or a connexin 32 hemichannel, connexin 50 or a connexin 50 hemichannel and connexin 58 or a connexin 58 hemichannel. Other agents useful alone or together with connexin hemichannel modulators and / or inflammasome modulators in compositions, methods, kits, doses and dose regimens of the invention comprise pannexin channel modulators. In some embodiments, the pannexin channel modulator is a pannexin 1 channel modulator. In some embodiments, the pannexin 1 channel modulator is probenecid. In some embodiments, the pannexin 1 channel modulator an analog or prodrug of probenecid. In some embodiments, the pannexin 1 channel modulator is a compound according to Formula VI in US Patent No.10,465,188, or an analog or prodrug thereof. In some embodiments, the pannexin 1 channel modulator is a mimetic peptide blocker of pannexin 1 (e.g.,10Panx1, or an analogue of thereof). In some embodiments, the agent used for the purposes and in the methods described herein – including increasing telomere length, arresting or slowing telomere shortening, increasing telomerase activity and / or expression, increasing TERT activity and / or expression, addressing aging, addressing, cell senescence, addressing cognitive decline, slowing, decreasing or arresting PECAM-1 expression, etc., and treating any of the diseases, disorders or conditions described or referred to herein – is an inflammasome inhibitor. In some embodiments, the inflammasome inhibitor is an NLRP3 inflammasome inhibitor. In some embodiments the compounds used to increase telomerase expression are connexin hemichannel modulators. In some embodiments the connexin hemichannel modulators are connexin 43 hemichannel modulators. In some embodiments the compounds used to increase telomerase expression are inflammasome modulators. In some embodiments the inflammasome modulators are NLRP3 inflammasome modulators. In some embodiments the NLRP3 inflammasome modulators used to increase telomerase expression are caspase inhibitors. In some embodiments the caspase inhibitors are inhibitors of caspase-1. An example of a caspase-1 inhibitor is belnacasan (vx‐765). In some embodiments the NLRP3 inflammasome modulators used to increase telomerase expression are GSDMD (gasdermin d) inhibitors. They include necrosulfonamide, disulfiram and dimethyl fumarate (an ester of fumaric acid). In some embodiments the compounds used to increase TERT levels or activity are connexin hemichannel modulators. In some embodiments the connexin hemichannel modulators are connexin 43 hemichannel modulators. In some embodiments the compounds used to increase TERT levels or activity are inflammasome modulators. In some embodiments the inflammasome modulators are NLRP3 inflammasome modulators. In some embodiments of the inventions, uses, methods, doses, dose regimens, compositions and kits are provided for use in protecting against cognitive decline in a subject. In some embodiments the compounds used to treat cognitive decline are connexin hemichannel modulators, including, for example, connexin 43 hemichannel modulators. In some embodiments the compounds used to treat cognitive decline are inflammasome modulators, e.g., NLRP3 inflammasome modulators. In some embodiments, the cognitive decline is or mild cognitive decline. In some embodiments, a compound or composition for modulation or inhibition of a connexin hemichannel and / or an inflammasome is provided for treatment and is dosed as described herein. In some embodiments of the invention, a connexin 43 hemichannel is modulated or inhibited. In some embodiments, a connexin 43 hemichannel is modulated or inhibited in order to reduce the release of ATP from the hemichannel. In some embodiments, a compound or composition for modulation or inhibition of an inflammasome is provided for treatment and is dosed as described herein. In some embodiments, a compound or composition for modulation or inhibition of an NLRP3 inflammasomes is provided for treatment and is dosed as described herein. In some embodiments, a pannexin 1 channel is modulated or inhibited. In some embodiments, a pannexin 1 channel is modulated or inhibited in order to reduce ATP release from a pannexin channels. In some embodiments, the cell or cell population treated using a compound, composition or method of the invention comprises a human cell or a human cell population. In some embodiments, the tissue treated using a compound, composition or method of the invention is a human tissue. In some embodiments, an organ treated using a compound, composition or method of the invention is a human organ. In some embodiments, the subject treated using a compound, composition or method of the invention is a human. In some embodiments, the connexin hemichannel modulator or the inflammasome inhibitor is orally, systemically, topically, or parenterally. In some embodiments, administration is local. In some embodiments, the connexin hemichannel modulator or the inflammasome inhibitor is administered to the skin. In some embodiments, the connexin hemichannel modulator or the inflammasome inhibitor is administered transdermally. In some embodiments, the connexin hemichannel modulator or the inflammasome inhibitor is administered to the eye. In some embodiments, the connexin hemichannel modulator or the inflammasome inhibitor is administered topically to the eye. In some embodiments of the present invention for topical administration, e.g. to the skin, to the eye, or to an internal organ, the method comprises administering to the subject a therapeutically effective amount of composition comprising an agent (e.g., a connexin or connexin hemichannel modulator), wherein the composition comprises a compound selected from the group consisting of reverse thermosetting gels, poloxamer gels, nonionic polyoxyethylene-polyoxypropylene block co-polymers (e.g. Pluronic F-127) and cellulose-based carriers (e.g., hydroxyethylcellulose, carboxymethylcellulose hydroxymethylcellulose, hydroxypropylmethylcellulose, etc.) and other pharmaceutically acceptable carriers. In some embodiments, the agent is selected from the group consisting of small molecule, antisense, peptidomimetic, antibody and antibody fragment connexin hemichannel modulators (e.g., a connexin 43 hemichannel modulator). In some embodiments, the connexin 43 hemichannel modulator modulates connexin 43 hemichannel activity (e.g., ATP release). In some embodiments, the connexin 43 hemichannel modulator modulates connexin 43 protein expression. In some embodiments, the connexin 43 protein expression modulator is an antisense molecule. In some embodiments, the connexin 43 antisense molecule is SEQ ID NO:1. In some embodiments, the topical composition for use in the methods of the invention comprises poloxamer F-127 (poloxamer 407 or Pluronic F-127). In some embodiments, the composition for use in the methods of the invention comprises about 20-30 mg / mL of a poloxamer F-127. In some embodiments, the composition for use in the methods of the invention comprises about 22-25 mg / mL of a poloxamer F-127. In some embodiments, the composition for use in the methods of the invention comprises about 22.6 mg / mL of a poloxamer F-127. In some embodiments, a combination of two or more compounds selected from the group consisting of connexin hemichannel modulators (e.g. connexin hemichannel modulators), pannexin channel modulators (e.g. pannexin 1 channel modulators), inflammasome modulators (e.g. NLRP3 inflammasome modulators) are administered to a cell, to a cell population, to a tissue, to an organ, or to a subject. In some embodiments, the connexin hemichannel modulator is administered to a subject using any of the dosing schedules described herein in a therapeutically effective amount. In some embodiments, the amount of connexin modulator administered to a subject in any of the dosing schedules described herein is one or more of the dose amounts described herein (e.g. milligram per milliliter (mg / mL) connexin modulator dosing, micromolar (^M) connexin modulator concentration dosing, milligram (mg) connexin modulator dosing, etc.). In some embodiments, the invention provides the use of a connexin modulator in the manufacture of a medicament for treatment of any of the diseases, disorders or conditions described herein. In some embodiments, the medicament comprises, consists essentially of, or consists of, an agent as described herein, including one or more connexin expression or connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators) and / or including one or more inflammasome modulators (e.g., NLRP3 inflammasome modulators). In some embodiments, the agent is, comprises, or consists essentially of, a molecule according to Formula I (e.g., tonabersat or carabersat), a tonabersat prodrug (e.g., a molecule according to Formula II), a connexin peptide mimetic (e.g., XG19, Peptide5, Gap19, an aCT1 peptide (e.g., CXT 1, CXT , CXT 3, CXT 4, CXT 5, or any other C-terminal connexin peptidomimetic, with or without a C-terminally or N- terminally attached cell-penetrating peptide), etc.), and / or a connexin antisense molecule (e.g., SEQ ID NO:1), including in the amounts and / or concentrations described herein. In some embodiments, the invention relates to pharmaceutical compositions and articles of manufacture, including kits comprising a therapeutically effective amount of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator) and / or an inflammasome inhibitor (e.g., an NLRP3 inflammasome inhibitor), and dose regimens for treating one or more of the diseases, disorders or conditions described herein, including, for example, cognitive decline and cell senescence. In some embodiments, the kit includes or is associated with instructions (e.g. included instructions, online instructions, QR code instructions, etc.) for use. The instructions may provide instructions for dosing and treating diseases, disorders and conditions described or referred to herein. In some embodiments, the kit includes means for administration of the connexin hemichannel modulator(s) and / or the inflammasome inhibitor(s). In some embodiments, a connexin modulator(s) (e.g. a connexin expression modulator, a connexin gap junction modulators, a connexin hemichannel modulators, including, for example, modulators of Cx26, Cx30, Cx30.3, Cx31.1, Cx32, Cx36, Cx37, Cx40, Cx43, Cx45, Cx50 or Cx58 connexins, gap junctions and / or hemichannels) are combined with a pharmaceutically acceptable carrier or diluent to produce a pharmaceutical composition. In some embodiments, suitable carriers and diluents include buffered, aqueous solutions, isotonic saline solutions, for example phosphate- buffered saline, isotonic water, and the like. In some embodiments, the carrier is a pluronic or poloxamer gel. In some embodiments, the gel is pluronic F-127. In some embodiments, the pharmaceutical composition comprises a buffer. In some embodiments, the buffer comprises or consists essentially of sodium phosphate dibasic heptahydrate or sodium phosphate monobasic or both. In some embodiments, methods of the invention, the doses and the dose regimens, and the connexin modulators (e.g. connexin expression modulators, connexin gap junction modulators and connexin hemichannel modulators, including, for example, modulators of Cx26, Cx30, Cx30.3, Cx31.1, Cx32, Cx36, Cx37, Cx40, Cx43, Cx45, Cx50 or Cx58 connexins, gap junctions and / or hemichannels) and / or inflammasome inhibitor(s) (e.g., an NLRP3 inflammasome inhibitor(s)), described herein are used for the treatment of a subject for one or more of the diseases, disorders or conditions described or referred to herein alone or in combination with or in conjunction with another therapeutic agent. In another aspect the present disclosure provides a method of selecting or quantifying the activity of a candidate compound for the treatment of telomere-associated disease. In some embodiments, the method comprises providing a first isolated cell or preparation of cells; determining (a) telomere length or (b) telomerase reverse transcriptase (TERT) activity or levels in the cell or cell preparation; comparing the telomere length or TERT activity or level in the cell or cell preparation to a reference level; contacting it with a test compound (i.e., one or more candidate agents) to the cell or the cell preparation, or to another to preparation of like or similar cells, and remeasuring telomere length or TERT activity or levels in the cell or preparation of cells. In some embodiments, the test compound is a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator). In some embodiments, the test compound is an inflammasome inhibitor or candidate inhibitor (e.g. an NLRP3 inflammasome inhibitor or candidate NLRP3 inflammasome inhibitor). In other embodiments, the test compound may be a pannexin channel modulator (e.g., a pannexin 1 channel modulator). In some embodiments, the test compound is a small molecule. In some embodiments, the test compound is a small molecule that modulates, may modulate, or is suspected of modulating a connexin hemichannel (e.g., a connexin 43 hemichannel). In some embodiments, the test compound is a small molecule that modulates, may modulate, or is suspected of modulating an inflammasome or inflammasome activity (e.g., an NLRP3 inflammasome inhibitor or NLRP3 inflammasome activity). In some embodiments, the test compound may be a small molecule that modulates, may modulate, or is suspected of a pannexin channel (e.g., a pannexin 1 channel). In some embodiments, the test compound is a connexin hemichannel modulator that is tested for modulation of telomerase, telomerase reverse transcriptase, telomerase reverse transcriptase expression, or telomerase reverse transcriptase activity. In some embodiments, the test compound can modulate telomerase and / or TERT. In some embodiments, the modulation by the test compound is at the level of gene expression, e.g., the hTERT gene. In yet other instances, the modulation is at the level of activity, e.g., telomerase or TERT activity. Modulation by the test compound can be at the level of protein expression, e.g., telomerase and / or TERT. Modulation by the test compound can be at the level of telomere size or maturity. Modulation by the test compound can be at the level of altering telomere ends. In some embodiments, a test compound contacted with an isolated cell or preparation of cells, can also be used to identify, qualify or quantify a candidate compound to treat a patient. In some embodiments, the test compound modulates human telomerase and / or human TERT species. In some embodiments, a test compound is administered in a high dose. In some embodiments, a test compound is administered a cell isolated from a patient having a disease, disorder or condition. In some embodiments, the test compound is administered to a stem cell, e.g., an iPS cell. In some embodiments, the test compound is administered to a stem cell, e.g., an iPS, cell derived from a patient (e.g., a patient’s skin or other tissue). In some embodiments, the test compound modulates telomerase and / or TERT activity or levels in the stem cell, e.g., an iPS cell. In some embodiments, the test compound modulates telomerase activity and also modulates telomere size. In some embodiments, the test compound promotes accumulation of mature TERT protein. In some embodiments, the cell is an isolated human cell. In some embodiments, the cell is derived from a patient’s skin or other tissue. In some embodiments, the isolated human cell is derived from a patient’s bone marrow. In some embodiments, the cell is an isolated human cell and is derived from a patient’s blood. In some embodiments, the cell used to contact a test compound or other candidate compound or agent is an isolated human cell that is derived from a patient having a telomere disease. In some embodiments, the patient is suspected of having telomere disease. In some embodiments, the patient has symptoms of aplastic anemia. In some embodiments, the patient is diagnosed as having telomere deficiency. In some embodiments, the patient has symptoms of hepatic cirrhosis. In some embodiments, the patient has dyskeratosis congenita. In some embodiments, the cell is isolated from a patient having or suspected of having a hematological disorder. In some embodiments, the isolated cell is from a patient having or suspected of having dyskeratosis congenita. In some embodiments of this test / screening method, tonabersat, Peptide5 or XG19 is used as a positive control. In some embodiments, the method of testing / screening can be performed in an isolated cell, e.g., human cell, obtained from a patient having or suspected of having a hematological disorder. In some embodiments, the methods disclosed herein also involve identifying other connexin hemichannel modulator compounds or inflammasome inhibitor compounds that can be used to address telomere, telomerase and / or TERT deficiency. In some embodiments, the methods disclosed herein also involve identifying other connexin hemichannel modulator compounds or inflammasome inhibitor compounds that can be used to modulate telomere size. In some embodiments, the invention provides methods for treating a subject or a patient for cognitive decline comprising administering to the subject or patient an effective amount of an inflammasome modulator. Administration to the subject or patient of an effective amount of an inflammasome modulator lessens, slows, halts, or substantially halts cognitive in the subject. In some embodiments of the methods, the subject or patient has mild cognitive decline. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for treating a subject or patient for cognitive decline comprising administering to the subject or patient an effective amount of a connexin hemichannel modulator. Administration to the subject or patient of an effective amount of a connexin hemichannel modulator lessens, slows, halts, or substantially halts cognitive in the subject or patient. In some embodiments of the methods, the subject or patient has mild cognitive decline. In some embodiments, the invention provides methods for modulating senescence in a cell comprising administering to the cell an effective amount of an inflammasome modulator. Administration to the cell of an effective amount of an inflammasome modulator lessens, slows, halts, or substantially halts cell senescence. In some embodiments of the methods, the cell is an aging cell. In some embodiments, the administration to the cell is in vitro. In some embodiments, the administration to the cell is ex vivo. In some embodiments, the administration is in vitro. In some embodiments, the administration to the cell is in vivo. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for modulating senescence in a cell comprising administering to the cell an effective amount of a connexin hemichannel modulator. Administration to the cell of an effective amount of a connexin hemichannel modulator lessens, slows, halts, or substantially halts cell senescence. In some embodiments of the methods, the cell is an aging cell. In some embodiments, the administration to the cell is in vitro. In some embodiments, the administration to the cell is ex vivo. In some embodiments, the administration is to the cell in vitro. In some embodiments, the administration to the cell is in vivo. In some embodiments, the invention provides methods for treating a subject or patient for cell senescence comprising administering to the subject or patient an effective amount of an inflammasome modulator. Administration to the subject or patient of an effective amount of an inflammasome modulator lessens, slows, halts, or substantially halts cell senescence in the subject or patient. In some embodiments of the methods, the subject or patient has mild neurodegeneration. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for treating a subject or patient for cell senescence comprising administering to the subject or patient an effective amount of a connexin hemichannel modulator. Administration to the subject or patient of an effective amount of a connexin hemichannel modulator lessens, slows, halts, or substantially halts cell senescence in the subject or patient. In some embodiments of the methods, the subject or patient has mild neurodegeneration. In some embodiments, the invention provides methods for slowing cellular aging associated with telomere length and / or telomere shortening in a subject or a patient comprising administering to the subject or patient an effective amount of an inflammasome modulator. Administration to the subject or patient of an effective amount of an inflammasome modulator lessens, slows, halts, or substantially halts cellular aging in the subject or patient. In some embodiments of the methods, cellular aging is temporarily lessened, slowed, halted, or substantially halted. In some embodiments of the methods, the subject is a cell. In some embodiments, the administration to a cell is in vitro. In some embodiments, the administration to a cell is ex vivo. In some embodiments, the administration to the cell is in vivo. In some embodiments, the administration is to a cell on a subject or patient (e.g., skin cells) or to a cell in a subject or patient (e.g., heart, brain, liver, etc.). In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for slowing cellular aging associated with telomere length and / or telomere shortening in a subject or patient comprising administering to the subject or patient an effective amount of a connexin hemichannel modulator. Administration to the subject or patient of an effective amount of a connexin hemichannel modulator lessens, slows, halts, or substantially halts cellular aging in the subject or patient. In some embodiments of the methods, cellular aging is temporarily lessened, slowed, halted, or substantially halted. In some embodiments, the invention provides methods for increasing telomerase expression in a cell comprising administering to the cell an effective amount of an inflammasome modulator. Administration to the cell of an effective amount of an inflammasome modulator increases telomerase expression or activity in the cell. In some embodiments of the methods, telomerase expression or activity in the cell is temporarily increased. In some embodiments, the method is carried out in vitro. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for increasing telomerase expression in a cell comprising administering to the cell an effective amount of a connexin hemichannel modulator. Administration to the cell of an effective amount of a connexin hemichannel modulator increases telomerase expression or activity in the cell. In some embodiments of the methods, telomerase expression or activity in the cell is temporarily increased. In some embodiments, the method is carried out in vitro. In some embodiments, the invention provides methods for increasing telomerase expression in a subject or patient, or a cell in a subject or patient, comprising administering to the cell an effective amount of an inflammasome modulator. Administration to the subject or patient, or to a cell in a subject or patient or from a subject or patient, of an effective amount of an inflammasome modulator increases telomerase expression in the subject or patient, or in cell in a subject or patient or from a subject or patient. In some embodiments of the methods, telomerase expression is temporarily increased. In some embodiments, the method is carried out in vivo. In some embodiments, the method is carried out ex vivo. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for increasing telomerase expression in a subject or patient, or a cell in a subject or patient or from a subject or patient, comprising administering to the cell an effective amount of a connexin hemichannel modulator. Administration to the subject or patient of an effective amount of a connexin hemichannel modulator increases telomerase expression in the subject or patient, or in a cell in a subject or from a subject or patient. In some embodiments of the methods, telomerase expression is temporarily increased. In some embodiments, the method is carried out in vivo. In some embodiments, the method is carried out ex vivo. In some embodiments, the invention provides methods for increasing telomerase reverse transcriptase (TERT) expression and / or activity in a cell comprising administering to the cell an effective amount of an inflammasome modulator. Administration to the cell of an effective amount of an inflammasome modulator increases reverse transcriptase (TERT) expression or activity in the cell. In some embodiments of the methods, reverse transcriptase (TERT) expression or activity in the cell is temporarily increased. In some embodiments, the method is carried out in vitro. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for increasing telomerase reverse transcriptase (TERT) expression and / or activity in a cell comprising administering to the subject an effective amount of a connexin hemichannel modulator. Administration to the cell of an effective amount of a connexin hemichannel modulator increases telomerase reverse transcriptase (TERT) expression or activity in the cell. In some embodiments of the methods, telomerase reverse transcriptase (TERT) expression or activity in the cell is temporarily increased. In some embodiments, the method is carried out in vitro. In some embodiments, the method is carried out ex vivo. In some embodiments, the method is carried out in vivo. In some embodiments, the invention provides methods for increasing telomerase reverse transcriptase (TERT) expression and / or activity in a subject or patient, or in a cell in a subject or patient (or a cell from a subject or patient), comprising administering to the cell an effective amount of an inflammasome modulator. Administration to the subject or patient, or a cell in a subject or patient or a cell from a subject or patient, of an effective amount of an inflammasome modulator increases telomerase reverse transcriptase (TERT) activity and / or expression in the subject or patient, or a in cell in a subject or patient (or a cell from a subject or patient). In some embodiments of the methods, telomerase reverse transcriptase (TERT) activity and / or expression is temporarily increased. In some embodiments, the method is carried out in vivo. In some embodiments, the method is carried out ex vivo. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for increasing telomerase reverse transcriptase (TERT) expression and / or activity in a subject or patient, or in a cell in a subject or patient (or a cell from a subject or patient), comprising administering to the cell an effective amount of an connexin hemichannel modulator. Administration to the subject or patient, or a cell in a subject or patient or a cell from a subject or patient, of an effective amount of an connexin hemichannel modulator increases telomerase reverse transcriptase (TERT) activity and / or expression in the subject or patient, or a in cell in a subject or patient (or a cell from a subject or patient). In some embodiments of the methods, telomerase reverse transcriptase (TERT) activity and / or expression is temporarily increased. In some embodiments, the method is carried out in vivo. In some embodiments, the method is carried out ex vivo. In some embodiments, the invention provides methods for increasing telomere length in a cell comprising administering to the cell an effective amount of an inflammasome modulator. Administration to the cell of an effective amount of an inflammasome modulator increases telomere length in the cell. In some embodiments of the methods, telomere length in the cell is temporarily increased or improved. In some embodiments, the method is carried out in vitro. In some embodiments, the method is carried out ex vivo. In some embodiments, the method is carried out in vivo. In some embodiments, the cell is in or on a subject or a patient. In some embodiments, the methods are used for protecting telomere length in a cell, or in a cell in or on a subject or patient by administration of an inflammasome modulator. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for increasing telomere length in a cell comprising administering to the cell an effective amount of a connexin hemichannel modulator. Administration to the cell of an effective amount of a connexin hemichannel modulator increases telomere length in the cell. In some embodiments of the methods, telomere length in the cell is temporarily increased or improved. In some embodiments, the method is carried out in vitro. In some embodiments, the method is carried out ex vivo. In some embodiments, the method is carried out in vivo. In some embodiments, the cell is in or on a subject or a patient. In some embodiments, the methods are used for protecting telomere length in a cell, or in a cell in or on a subject or patient by administration of a connexin hemichannel modulator. In some embodiments, the invention provides methods for increasing telomere length in a subject or patient comprising administering to the subject an effective amount of a connexin hemichannel modulator. Administration to the subject or patient of an effective amount of a connexin hemichannel modulator increases telomere length in cells of the subject. In some embodiments of the methods, an increase in telomere length is targeted to certain cells or organ(s) in or on the subject or patient is temporarily increased. In some embodiments, the method is carried out ex vivo. In some embodiments, the method is carried out in vivo. In some embodiments, the methods are used for protecting telomere length by administration of a connexin hemichannel modulator to a subject or patient. In some embodiments, the invention provides methods for increasing telomere length in a subject or patient comprising administering to the subject an effective amount of a inflammasome modulator. Administration to the subject or patient of an effective amount of a inflammasome modulator increases telomere length in cells of the subject. In some embodiments of the methods, an increase in telomere length is targeted to certain cells or organ(s) in or on the subject or patient is temporarily increased. In some embodiments, the method is carried out ex vivo. In some embodiments, the method is carried out in vivo. In some embodiments, the methods are used for protecting telomere length by administration of a inflammasome modulator to a subject or patient. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for treating retinal thinning in a subject or patient comprising administering to the subject an effective amount of an inflammasome modulator. Administration to the subject or patient of an effective amount of an inflammasome modulator slows, halts, alleviates or reverses retinal thinning in the subject. In some embodiments, the methods are used for protecting against retinal thinning by administration of an inflammasome modulator to a subject or patient. In some embodiments, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments, the invention provides methods for treating retinal thinning in a subject or patient comprising administering to the subject an effective amount of a connexin hemichannel modulator. Administration to the subject or patient of an effective amount of a connexin hemichannel modulator slows, halts, alleviates or reverses retinal thinning in the subject. In some embodiments, the methods are used for protecting against retinal thinning by administration of a connexin hemichannel modulator to a subject or patient. In some embodiments of the methods of the invention, the inflammasome modulator is a direct inflammasome modulator. In some embodiments of the methods of the invention, the inflammasome modulator is an indirect inflammasome modulator. In some embodiments of the methods of the invention, the inflammasome modulator is an NLRP3 inflammasome modulator. In some embodiments of the methods of the invention, the inflammasome modulator is a connexin hemichannel modulator. In some embodiments of the methods of the invention, the NLRP3 inflammasome modulator is a connexin 43 hemichannel modulator. In some embodiments of the methods of the invention, the connexin hemichannel modulator is a compound according to Formula I. In some embodiments of the methods of the invention, the connexin hemichannel modulator is a compound according to Formula II. In some embodiments of the methods of the invention, the connexin hemichannel modulator is tonabersat or carabersat. In some embodiments of the methods of the invention, the connexin hemichannel modulator is tonabersat prodrug or a carabersat prodrug. In some embodiments of the methods of the invention, the connexin hemichannel modulator is connexin peptidomimetic. In some embodiments, the peptidomimetic connexin hemichannel modulator is a connexin 43 peptidomimetic. In some embodiments, the peptidomimetic connexin hemichannel modulator is XG19, Peptide5, Gap19, Gap20, Gap22, or any of the alpha CT peptides. In some embodiments, the peptidomimetic connexin hemichannel modulator is another peptidomimetic connexin hemichannel modulator described herein or known in the art. In some embodiments of the methods of the invention, the connexin hemichannel modulator is connexin antisense compound. In some embodiments, the connexin antisense compound is SEQ ID NO:1. In some embodiments, the connexin antisense compound is another connexin antisense compound described herein or known in the art. In some embodiments the connexin hemichannel modulator is a connexin binding compound (e.g., an antibody, antibody fragment, ScFv, etc.) In some embodiments of the methods of the invention, the inflammasome modulator is a pannexin channel modulator. In some embodiments, the pannexin channel modulator is an NLRP3 inflammasome modulator. In some embodiments, the pannexin channel modulator is a pannexin 1 channel modulator. In some embodiments, the pannexin channel modulator compound is a compound according to Formula III. In some embodiments, the pannexin channel modulator compound is probenecid. In some embodiments of the methods described herein, an effective amount of a pharmaceutical composition comprising an agent that decreases pannexin channel activity (e.g., pannexin 1 channel activity including release of ATP) is administered to a cell, subject or patient. In some embodiments of the methods of the invention, a therapeutically or prophylactically effective amount of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator), an inflammasome modulator (e.g., an NLRP3 inflammasome modulator), and / or a pannexin channel 1 modulator (e.g., a pannexin channel modulator) is / are administered to a subject or patient have a disease, disorder, defect, or condition associated with cognitive decline. In some embodiments, the cognitive decline is mild cognitive decline. In some embodiments, the cognitive decline is age-related and / or disease related cognitive decline. In some embodiments, the subject or patient is protected against cognitive decline. In some embodiments, the disease, disorder, defect or condition associated with cognitive decline is selected from the group consisting of Alzheimer’s disease, dementia with Lewy bodies disease, fronto-temporal dementia, early onset dementia, Parkinson’s disease-related cognitive dysfunction, posterior cortical atrophy, primary progressive aphasia and Huntington’s disease. In some embodiments of the methods of the invention, a therapeutically or prophylactically effective amount of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator), an inflammasome modulator (e.g., an NLRP3 inflammasome modulator), and / or a pannexin channel 1 modulator (e.g., a pannexin channel modulator) is / are administered to a subject or patient have a disease, disorder, defect, or condition associated with cell senescence. In some embodiments, the subject or patient is protected against cell senescence. In some embodiments of the methods of the invention, a therapeutically or prophylactically effective amount of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator), an inflammasome modulator (e.g., an NLRP3 inflammasome modulator), and / or a pannexin channel 1 modulator (e.g., a pannexin channel modulator) is / are administered to a subject or patient having a disease, disorder, defect, or condition associated with reduced or shortened telomere length. In some embodiments, the subject or patient is protected against telomere reduction or shortening. In some embodiments of the methods of the invention, a therapeutically or prophylactically effective amount of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator), an inflammasome modulator (e.g., an NLRP3 inflammasome modulator), and / or a pannexin channel 1 modulator (e.g., a pannexin channel modulator) is / are administered to a subject or patient having a disease, disorder, defect, or condition associated with reduced or reduced or deficient telomerase reverse transcriptase (TERT) expression and / or activity. In some embodiments, the telomerase reverse transcriptase is human telomerase reverse transcriptase (hTERT). In some embodiments of the methods of the invention, a therapeutically or prophylactically effective amount of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator), an inflammasome modulator (e.g., an NLRP3 inflammasome modulator), and / or a pannexin channel 1 modulator (e.g., a pannexin channel modulator) is / are administered to a subject or patient have a disease, disorder, defect, or condition associated with telomerase deficiency. In some embodiments, the telomerase is human telomerase (hT). In some embodiments, the disease, disorder, defect or condition associated with telomerase deficiency is selected from the group consisting of short telomere syndrome, dyskeratosis congenital (DC), bone marrow failure syndrome characterized by the reticulated skin hyperpigmentation, nail dystrophy, oral leukoplakia, Revesz syndrome, Hoyeraal-Hreidarsson syndrome, cerebroretinal microangiopathy with calcifications and cysts (CRMCC), inherited aplastic anemia / myelodysplastic syndrome, aplastic anemia, marrow failure, hematological disorder, hepatic disease, aplastic anemia, hepatic cirrhosis, osteoporosis, osteonecrosis, vascular malformations, diabetes, primary immunodeficiency, and inflammatory bowel disease. In some embodiments of the methods of the invention, a therapeutically or prophylactically effective amount of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator), an inflammasome modulator (e.g., an NLRP3 inflammasome modulator), and / or a pannexin channel 1 modulator (e.g., a pannexin channel modulator) is / are administered to a subject or patient at least once per day. In some embodiments of the methods of the invention, a therapeutically or prophylactically effective amount of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator), an inflammasome modulator (e.g., an NLRP3 inflammasome modulator), and / or a pannexin channel 1 modulator (e.g., a pannexin channel modulator) is / are administered orally, topically, or parenterally to a subject or patient. In some embodiments of the methods of the invention, a therapeutically or prophylactically effective amount of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator), an inflammasome modulator (e.g., an NLRP3 inflammasome modulator), and / or a pannexin channel 1 modulator (e.g., a pannexin channel modulator) is / are administered orally, topically, or parenterally to a subject or patient. In some embodiments of the methods of the invention, about 80 to about 400 milligrams per day of a connexin hemichannel modulator (e.g., a connexin 43 hemichannel modulator), is administered to a subject or patient. In some embodiments of the methods of the invention, about 80 to about 400 milligrams per day of an inflammasome modulator (e.g., an NLRP3 inflammasome modulator) is administered to a subject or patient. In some embodiments of the methods of the invention, the subject or patient is a human subject or a human patient. BRIEF DESCRIPTION OF THE FIGURES FIG.1 (A) Schematic representation of the design and timeline of a study to determine the ability of connexin hemichannel and inflammasome modulators to treat and prevent cognitive decline, using an exemplary modulator (tonabersat). (B) There were no differences difference between tonabersat and vehicle-treated groups in terms of weights (g) during the treatment period from ages 4 to 6 months. There were also no differences between the two treatment groups in terms of (C) distance travelled (cm), and (D) velocity (cm / s) at 4, 6, and 9 months of age. Statistical analysis was carried out with repeated-measures two-way ANOVA with Šídák's multiple comparison’s test. n = 12 mice per group. FIG. 2 Demonstrates the ability of modulators described herein to protect against and treat cognitive decline in aging animals. (A) Discrimination index decreased significantly by 6 and 9 months compared to 4 months in vehicle-treated but not tonabersat-treated mice. (B) Relative to baseline at 4 months, there was no difference between modulator (tonabersat) and vehicle treated mice at 6 months. By 9 months, modulator-treated mice had significantly higher change in discrimination index compared to the vehicle group. N = 12 mice per group. FIG.3 Modulator treatment increased connexin43 expression compared to the vehicle group. (A) Connexin43 expression was observed within all hippocampal regions in both treatment groups. (B) An increase in connexin43 expression in the tonabersat treatment group was observed compared to the vehicle group, and found to be statistically significant in the CA2 region. Statistical analysis was carried out with repeated-measures two-way ANOVA with Šídák's multiple comparison’s test. *8*p ≤ 0.001. n = 12 mice per group. FIG. 4 Treatment with an exemplary modulator (tonabersat) decreases the number of Iba1+ (green) cells in the hippocampus, and does not affect GFAP (red) expression. (A) GFAP expression was observed in the CA1, 2, 3 and dentate gyrus (DG) of the hippocampus in both vehicle and tonabersat-treated groups. (B) No statistically significant change was observed in the percentage area covered by GFAP labelling between the tonabersat group compared to vehicle. (C) Iba1+ cells were observed in all regions of the hippocampus for both groups. (D) Tonabersat treatment significantly decreased the number of Iba1+ cells in the CA1, CA2 and DG compared to the vehicle group. Statistical analysis was carried out with repeated-measures two-way ANOVA with Šídák's multiple comparison’s test. *p ≤ 0.05, **p ≤ 0.01. n = 12 mice per group. FIG.5 Treatment with an exemplary modulator (tonabersat) did not significantly affect NLRP3 (red) but reduced cleaved caspase 1 (green) expression in the hippocampus. (A) NLRP3 expression was observed in the CA1, 2, 3 and dentate gyrus (DG) of the hippocampus in both vehicle and tonabersat-treated groups. (B) However, there was no significant difference in the percentage area covered by NLRP3 labelling between both treatment groups. (C) Cleaved caspase 1 was expressed in all regions of the hippocampus with less labelling observed in the tonabersat treated group compared to vehicle. (D) Tonabersat treatment significantly reduced cleaved caspase 1 levels in the CA1, 2 and 3 regions of the hippocampus compared to the vehicle group. Statistical analysis was carried out with repeated-measures two-way ANOVA with Šídák's multiple comparison’s test. *p ≤ 0.05, **p ≤ 0.01. n = 12 mice per group. FIG. 6 Treatment with an exemplary modulator (tonabersat) decreased CD31 expression in the hippocampus. (A) CD31 expression was observed in all hippocampal regions in both treatment groups. (B) Modulator treatment was observed to reduce CD31 levels compared to the vehicle group with statistically significant reductions in the CA2 and CA3 regions. Statistical analysis was carried out with repeated-measures two-way ANOVA with Šídák's multiple comparison’s test. *p ≤ 0.05. n = 12 mice per group. FIG. 7 Treatment with an exemplary modulator (tonabersat) increased TERT expression within all the hippocampal regions. (A) While TERT was expressed in both the exemplary modulator (tonabersat) and vehicle groups, protein levels were higher in the tonabersat-treated mouse hippocampi compared to the vehicle-treated group. (B) Quantification of TERT levels showed that tonabersat treatment significantly increased TERT levels in all hippocampal regions compared to the vehicle group. Statistical analysis was carried out with repeated-measures two-way ANOVA with Šídák's multiple comparison’s test. **p ≤ 0.01, ***p ≤ 0.001. n = 12 mice per group. FIG. 8 Treatment with an exemplary modulator (tonabersat) decreases senescence of brain hippocampal neurons in aging mice. (A) Tonabersat decreases expression of senescence- associated beta-galactosidase in the hippocampus of 9-month-old male C57BL / 6J mice. Mice were treated daily via oral gavage with tonabersat or vehicle (tap water) from 4 to 6 months of age. Tissues were collected at 9 months of age. The encircled region 1 in Figures C and D indicates the cornu ammonis (CA) of the hippocampus. The dentate gyrus is the encircled region 2. Sample size = 12 mice per group. Statistical analysis was via 2-way ANOVA with Šídák's multiple comparison’s test. P value (cornu ammonis) = 0.015; P value (dentate gyrus) = 0.014. FIG. 9 Modulator treatment protects against loss of TERT in retinal pigment epithelial cells. Tonabersat treatment protected against high glucose (HG) and pro-inflammatory cytokine-induced (IL-1b and TNF-a) TERT downregulation in ARPE-19 cells. Relative to cells grown in only basal media there was a significant decrease of TERT expression in ARPE-19 cells exposed to HG and cytokines. When ARPE-19 cells were exposed to HG and cytokines along with tonabersat, the decrease in TERT expression was essentially eliminated with no significant difference in TERT levels compared to baseline. FIG.10 Modulator protection against TERT downregulation is reduced by ATP. When ARPE-19 cells were exposed to high glucose, cytokines (IL-1b and TNF-a) and ATP, the effect of treatment with the exemplary modulator tonabersat was reduced. (A) TERT expression was detected in all groups, with higher levels in the unmodified basal media group, and in the HG+Cyt+tonabersat group. The expression of TERT was lower in the HG+Cyt group, and the HG+Cyt group with tonabersat and ATP. (B) Quantification of TERT levels showed that tonabersat treatment was able to protect ARPE-19 cells against HG+Cyt, but that protection was diminished in the presence of ATP. The TERT expression of the HG+Cyt+Ton+ATP group was found to be not significantly different to the non-tonabersat treated HG+Cyt group. FIG.11 There is a negative correlation between IL-1β release and TERT expression. When ARPE- 19 cells were exposed to high glucose, cytokines (IL-1b and TNF-a) and ATP, the release of IL- 1β into the culture media was measured and correlated with the TERT expression in the cells. A negative correlation was found between the TERT expression in the cells and the level of IL-1β in the culture media. FIG.12 Modulator treatment protects against cellular senescence in an ATP dependent manner. The expression of beta galactosidase was measured as a marker of cellular senescence. The results in ARPE-19 cells showed increase in beta gal expression with HG+Cyt and this was reversed by 50uM tonabersat. The presence of ATP reversed tonabersat protection in a dose dependent manner from 50nM ATP to 100 nM ATP suggesting that cellular senescence was ATP dependent. FIG. 13 Tonabersat reverses HG+Cyt induced cellular senescence. The expression of beta galactosidase was measured as a marker of cellular senescence in ARPE-19 cells. Groups of cells in culture medium were exposed to HG+Cyt, and for group (B) the culture medium was changed to basal medium and for group (C) a tonabersat containing medium. The cells injured by HG+Cyt and then treated with the exemplary modulator tonabersat showed levels of cellular senescence equivalent to cells that had not been injured (A). (D) The analysis of the beta galactosidase expression confirms that there is a significant difference between the untreated and tonabersat treated groups, and no significant difference between the non-injured basal group the injured then tonabersat treated groups. FIG. 14 Tonabersat protects against repeated HG+Cyt induced cellular senescence. The expression of beta galactosidase was measured as a marker of cellular senescence in ARPE-19 cells. Groups of cells in culture medium were exposed to HG+Cyt, and then injured again with HG+Cyt, or with HG+Cyt+Ton. The analysis of the beta galactosidase expression confirms a significant difference in cellular senescence between the untreated and tonabersat treated groups, and a small difference between the non-injured basal group and the tonabersat treated group. The telomere length of the injured cells was found to be smaller relative to basal. The treatment of injured cells with tonabersat restored telomere length, with no significant difference between the basal and tonabersat treated groups. FIG.15 The level of ATP release correlates with the severity of cellular senescence. The level of ATP released in the cell culture media correlates positively with the level of Beta-Galactosidase expression in ARPE-19 cells. FIG.16 The relative telomere length in brain tissue from aged mice was significantly greater in the tonabersat treated group compared to the control, however there was no significant difference in telomere length in cells collected from blood. FIG.17 The relative telomere length in brain tissue of 4 month old mice treated with tonabersat for 2 weeks shows no significant difference in relative telomere length to untreated mice. These results suggest that in brain tissue, tonabersat has an effect on telomere length in aging mice, and is thus able to prevent cognitive decline. FIG.18 The relationship between the discrimination index and telomere length of normal aging mice is shown. FIG. 19 The measured discrimination index is significantly higher in mice with above average telomere length. FIG. 20 When the mice are grouped by discrimination index, there is no significant difference between mice with below average telomere index and above average telomere length. FIG.21 The expression of telomerase reverse transcriptase (TERT) in the hippocampus of mice was determined for wild-type and disease model mice. TERT, which is also a marker for the telomerase enzyme, was assessed for 5xFAD mice that are used as a model for Alzheimer’s disease. TERT was found within the axons in the CA1, 2, 3 and DG regions of the hippocampus in both the 5xFAD and wild-type mice FIG.22 The expression of telomerase reverse transcriptase (TERT) in the hippocampus of mice was determined for experimental autoimmune encephalitis (EAE) mice. TERT was found within the axons in the CA1, 2, 3 and DG regions of the hippocampus in both the EAE and wild-type mice. FIG.23 A study was performed to measure the effect of various brain disease models on relative telomere length in mice. A comparison of relative telomere length shows a significant difference between a group treated with intrahippocampal injection of amyloid β-Peptide, a group treated with ACSF (artificial cerebrospinal fluid), and a control group. FIG. 24 The relative telomere length was determined in brain tissue from 5xFAD mice. There was no significant difference found between wild-type mice and the 5xFAD mice. FIG. 25 Tonabersat treatment reverses TGF-βII release. Tonabersat, MCC950 and XG19 were used to inhibit the release of TGF-βII from ARPE-19 cells by blocking the inflammasome pathway. The combined treatments of tonabersat and MCC950; and MCC950 and XG19 did not produce any additive effects. FIG.26 The therapeutic effects of tonabersat, MCC950 and XG19 were observed in a hypoxic cell model. Treating ARPE-19 cells with CoCl2increased ATP release and beta-galactosidase activity but did not affect LDH (Lactate dehydrogenase) levels. Addition of the modulators tonabersat, XG19 and MCC950 all decreased ATP levels to baseline. Combining the connexin43 hemichannel blockers tonabersat and XG19 with MCC950 did not produce any additional reduction of ATP release. FIG. 27 Tonabersat treatment reverses TGF-βII release induced by by CoCl2. There was no difference found in the release of TGF-βII by cells treated with CoCl2compared to basal cells. Tonabersat decreased TGF-βII levels to 0, both when used alone and when combined with MCC950. While MCC950 and XG19 also decreased TGF-beta levels below baseline, they were not as effective as tonabersat. FIG.28 TGF-βII induces ATP, LDH, and beta-gal release and this is prevented and reversed by inflammasome blockers. TGF-βII treatment was used to induce release of ATP, LDH and beta- gal. When applied as a co-treatment, tonabersat and MCC950 significantly inhibited ATP, LDH, and beta-gal release, though there were no additive effects when both modulators are used together. FIG. 29 Tonabersat treatment prevents expression of senescence marker proteins p16 and p53. using western blotting, the expression of p16, p21, and p53 was investigated. These proteins are known as senescence associated markers. P21 was not expressed in the cells. Expression of p16 and p53 increased significantly with HG + Cyt insult, and the modulator tonabersat appears to decrease levels of both p16 and p53 particularly after 72 h. It was found that the addition of exogenous ATP partially recovers p16 but not p53 levels back towards injury levels. FIG. 30 Tonabersat inhibits p53-mediated sICAM-1 release. A study using ARPE-19 cells showed that sICAM-1 levels are increased by HG+Cyt and reduced with modulator (tonabersat) treatment. The addition of exogenous ATP did not reverse protection conferred by tonabersat. FIG.31 IC50s for effect of inflammasome modulators on ATP release. The IC50s for ATP release were determined for emlenoflast, metformin, allopurinol, quercetin, resveratrol, and fasudil. The IC50 values are based on the required modulator concentration to reduce ATP levels induced by application of high glucose and cytokines (HC) to basal level (BS). Some results for MCC950 (MC), tonabersat (TN) and the inactive enantiomer of tonabersat (TN E) were also measured for comparison. FIG.32 The effect on ATP release relative to HG+Cyt is shown with respect to Log concentration. FIG. 33 Calculated IC50 values for ATP release are shown for the modulators emlenoflast, metformin, allopurinol, quercetin, resveratrol, and fasudil. FIG.34 IC50s for effect of inflammasome modulators on cellular senescence as indicated by beta galactosidase levels. The IC50s for beta galactosidase were determined for emlenoflast, metformin, allopurinol, quercetin, resveratrol, and fasudil. The IC50 values are based on the required modulator concentration to reduce beta galactosidase induced by application of high glucose and cytokines (HC) to basal level (BS). Some results for MCC950 (MC), tonabersat (TN) and the inactive enantiomer of tonabersat (TN E) were also measured for comparison. FIG. 35 The effect on beta galactosidase relative to HG+Cyt is shown with respect to Log concentration. FIG.36 Calculated IC50 values for cellular senescence are shown for the modulators emlenoflast, metformin, allopurinol, quercetin, resveratrol, and fasudil. FIG. 37 Effect of inflammasome modulators on HG+Cyt induced TGF-βII release. Tonabersat (TN), MCC950 (MC), emlenoflast (EM), metformin (MT), allopurinol (AL), quercetin (QU), resveratrol (RS), and fasudil (FS) and the inactive enantiomer of tonabersat (TN E), were tested for their effect on HG+Cyt (HG) induced TGF-βII release DETAILED INVENTION DISCLOSURES “Telomeres” are known in the art and are regions of repetitive nucleotide sequences associated with specialized proteins at the ends of chromosomes that protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the very ends of the DNA strand for a double- strand break. A telomere is a region of repetitive DNA sequences at the end of a chromosome. Telomeres protect the ends of chromosomes from becoming frayed or tangled. Each time a cell divides, the telomeres become slightly shorter. Eventually, they become so short that the cell can no longer divide successfully, and the cell dies. The present specification relates in part to compounds, compositions and methods having effects of increasing telomerase expression. It also relates in part to compounds, compositions and methods having effects of increasing telomerase activity. The present specification relates in part to compounds, compositions and methods having effects of protecting against loss of TERT (telomerase reverse transcriptase). The present specification also relates in part to compounds, compositions and methods having effects of effective to increase TERT expression. The specification also relates in part to compounds, compositions and methods having effects of effective to increase TERT activity. The present specification relates in part to compounds, compositions and methods useful for extending a telomere. The specification also relates in part to compounds, compositions and methods useful for increasing telomere length. The present specification relates in part to compounds, compositions and methods useful for protecting against cell senescence. It also relates in part to compounds, compositions and methods useful for preventing or reducing cell senescence. It also relates in part to compounds, compositions and methods useful for slowing cell senescence. The present specification relates in part to compounds, compositions and methods useful for reducing cognitive decline. It also relates in part to compounds, compositions and methods useful for slowing cognitive decline. It also relates in part to compounds, compositions and methods useful for preventing cognitive decline. The present specification relates in part to compounds, to compositions containing such compounds, and methods of using the compounds and compositions for preventing, alleviating and treating cell senescence. The present specification relates in part to compounds, to compositions containing such compounds, and methods of using the compounds and compositions for alleviating and treating cognitive decline. The present specification relates in part to compounds, compositions and methods having effects of protecting against expression of platelet / endothelial cell adhesion molecule-1 (PECAM-1). PECAM-1 was originally described as the CD31 differentiation antigen expressed on the surface of human granulocytes, monocytes and platelets). It also relates to compounds, compositions and methods having effects of decreasing expression of PECAM-1. The present specification relates in part to compounds, to compositions containing such compounds, and methods of using the compounds and compositions for preventing, alleviating and treating diseases, caused in whole or in part by a decrease in telomerase expression and / or activity or a reduction in telomere length, and symptoms thereof. The present specification relates in part to compounds, to compositions containing such compounds, and methods of using the compounds and compositions for preventing, alleviating and treating diseases, and symptoms that may be caused in whole or in part by a decrease in TERT expression and / or activity. The present specification relates in part to compounds, to compositions containing such compounds, and methods of using the compounds and compositions for preventing, alleviating and treating diseases, and symptoms that may be caused in whole or in part by cell aging or damage. The present specification relates in part to compounds, to compositions containing such compounds, and methods of using the compounds and compositions for preventing, alleviating and treating diseases, and symptoms that may be caused in whole or in part by cell senescence. The present specification relates in part to compounds, to compositions containing such compounds, and methods of using the compounds and compositions for preventing, alleviating and treating diseases, and symptoms that may be caused in whole or in part by cognitive decline. The present disclosure also provides, among other things, methods of screening for or quantifying the activity of agents that can be used to increase telomerase expression and activity, to protect against loss of telomerase, to increase telomerase reverse transcriptase expression and activity, to protect against loss of telomerase reverse transcriptase, to protect against cellular senescence, to protect against cell aging, to protect against cognitive decline, and to decrease PECAM-1 (CD31) expression, and to protect against increased CD31 expression. In some embodiments, the invention provides methods of screening for or quantifying the activity of agents that modulate telomerase expression. In some embodiments, the invention provides methods of screening for or quantifying the activity of agents that modulate TERT expression. In some embodiments, the invention provides methods of screening for or quantifying the activity of agents that modulate TERT levels. In some embodiments, the invention provides methods of screening for or quantifying the activity of agents that modulate TERT activity. In some embodiments, the invention provides methods of screening for or quantifying the activity of agents that modulate cell senescence. In some embodiments, the invention provides methods of screening for or quantifying the activity of agents that modulate cognitive decline. In some embodiments, the invention provides methods of screening for or quantifying the activity of agents that modulate PECAM-1 expression. The present disclosure also provides methods of diagnosing patients and methods of treating patients having telomere disease. According to one aspect to the present invention, the compounds and compositions described herein increase telomerase expression or telomerase activity or both and are effective for extending a telomere. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in part by a decrease in telomerase expression or a decrease in telomerase activity or both, including those induced or caused, in whole or in any part, by any abnormal or irregular decrease in telomerase expression or activity, or by the length reduction or loss of a telomere, and alleviating symptoms caused thereby. According to another aspect to the present invention, the compounds and compositions described herein are to protect against loss of TERT (telomerase reverse transcriptase), effective to increase TERT expression or TERT activity or both. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in part by decreases in TERT expression, decreases in TERT activity, or both, including those induced or caused, in whole or in any part, by any abnormal or irregular decrease in TERT expression or activity, and alleviating symptoms caused thereby. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in part by decreases in TERT expression, decreases in TERT activity, or both, in the brain. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in part by decreases in TERT expression, decreases in TERT activity, or both, in the hippocampus. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in part by decreases in TERT expression, decreases in TERT activity, or both, in the eye. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in part by decreases in TERT expression, decreases in TERT activity, or both, in retina. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in part by decreases in TERT expression, decreases in TERT activity, or both, in retinal pigment epithelial cells. In another aspect to the present invention, the compounds and compositions described herein are effective to protect against, reduce or delay cell senescence. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in any part by cell senescence. In some embodiments, the compounds and compositions described herein are used for treating or alleviating symptoms caused conditions, diseases and disorders induced or caused in whole or in any part by cell senescence. In some embodiments, the cells protected against senescence or in which cell senescence is reduced or delayed are cells of the eye. In some embodiments, the cells of the eye are cells of the anterior eye. In some embodiments, the cells of the eye are cells of the cornea (including epithelial cells, keratocytes, and endothelial cells, and including stromal keratocytes). In some embodiments, the cells of the eye are cells of the posterior eye. In some embodiments, the cells of the eye are retinal cells. In some embodiments, the retinal cells are cells of the macula, cells of the peripheral retina, cells of the inner limiting membrane (ILM) of the retina (including Müller cells and astrocytes), cells of the nerve fiber layer (NFL) of the retina (including ganglion cells and glial cells), cells of the ganglion cell layer (GCL) of the retina (including ganglion cells, glial cells and amacrine cells), cells of the inner plexiform layer (IPL) of the retina (including bipolar, amacrine, and ganglion cells), cells of the inner nuclear layer (INL) of the retina (including the bipolar, horizontal, amacrine, and Muller cells), cells of the outer plexiform layer (OPL) of the retina (including photoreceptor cells, bipolar cells, and horizontal cells), cells of the outer nuclear layer (ONL) of the retina (including photoreceptor cells), cells of the outer limiting membrane (OLM) of the retina (including Muller cells, photoreceptor cells, junctional complexes between adjacent Muller cells, and junctional complexes between Muller and photoreceptor cells), cells of the photoreceptor layer (PL) of the retina (including cones and rods that form a palisading layer of photoreceptors), and cells of the retinal pigment epithelium (RPE) forming a continuous RPE monolayer. In some embodiments, the cells of the eye are retinal ganglion cells, cone photoreceptors, amacrine cells, horizontal interneurons, rod photoreceptors, bipolar interneurons, and / or Müller glia. In some embodiments, the cells of the eye are cells of the fovea (the central portion of the macula) or cells of the peripheral retina. In some embodiments, the cells of the eye are cells of the choroidal capillaries. In some embodiments, the cells of the eye are cells of the optic nerve or optic tract. In some embodiments, the cells protected against senescence or in which cell senescence is reduced or delayed are cells of the brain. In some embodiments, the cells protected against senescence or in which cell senescence is reduced or delayed are cells of the heart. In other embodiments, the cells protected against senescence or in which cell senescence is reduced or delayed are cells of another organ of the body (e.g., liver, kidney, lung, pancreas, etc.) or cells of the endocrine system (e.g., pituitary gland, thymus, thyroid, etc.), and so on, including other cells of the circulatory system, other cells of the digestive system, other cells of the respiratory system, other cells of the urinary system, other cells of the sensory organs and systems (including the ears), other cells of the central nervous system, other cells of the peripheral nervous system, cells of the lymphatic system (including bone marrow, lymph nodes, thymus and spleen, etc.), cells of the reproductive systems, and / or cells of the musculoskeletal system. Symptoms caused by cell loss and senescence that can be alleviated or treated by compounds, compositions and methods according to some embodiments of the present invention include skin loss, skin wrinkles, skin psoriasis, skin darkening and anemia. In some embodiments, the cells protected against senescence or in which cell senescence is reduced or delayed are cells of the integumentary system. In another aspect to the present invention, the compounds and compositions described herein are effective to protect against cognitive decline. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in any part by cognitive decline, and alleviating symptoms caused thereby. In some embodiments, the cognitive decline is mild cognitive decline. In another aspect to the present invention, the compounds and compositions described herein are effective to decrease CD31 expression. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in any part by cell senescence, and alleviating symptoms caused thereby. In another aspect to the present invention, the compounds and compositions described herein are effective to protect against aging or cell aging. In some embodiments, the compounds and compositions described herein are used for treating conditions, diseases and disorders induced or caused in whole or in any part by aging or cell aging, and alleviating symptoms caused thereby. In some embodiments, the aging is in cells of the skin. In some embodiments, inventions described and claimed herein relate to modulators of connexins, connexin gap junctions, and connexin hemichannels, and their use in methods for the treatment of cognitive decline (including, e.g., mild cognitive decline), in treatment to protect against or slow cognitive decline, in the treatment of cell senescence, in treatment to protect against cell senescence, in treatment to prevent or reduce cell senescence, in treatment to slow cell senescence, in treatment to increase telomerase activity, in treatment to protect against loss of telomerase reverse transcriptase (TERT), in treatment to increase TERT levels, in treatment to increase TERT expression, in treatment to increase TERT activity, in treatment to extend a telomere, in treatment to increase telomere length and / or in treatment to protecting against expression of platelet / endothelial cell adhesion molecule-1 (PECAM-1), and doses and dose regimens therefor. In some embodiments, the connexins, connexin gap junctions, and connexin hemichannels are vascular connexins, vascular connexin gap junctions, and vascular connexin hemichannels. Vascular connexins include connexin 37, connexin 40, connexin 43 and connexin 45. In some embodiments, the connexins, connexin gap junctions, and connexin hemichannels are connexin 43, connexin 43 gap junctions, and connexin 43 hemichannels. In some embodiments, inventions described and claimed herein relate to modulators of inflammasomes (e.g., an NLRP3 inflammasome), including inhibitors thereof, and their use in methods for the treatment of cognitive decline (including, e.g., mild cognitive decline), in treatment to protect against or slow cognitive decline, in the treatment of cell senescence, in treatment to protect against cell senescence, in treatment to prevent or reduce cell senescence, in treatment to slow cell senescence, in treatment to increase telomerase activity, in treatment to protect against loss of telomerase reverse transcriptase (TERT), in treatment to increase TERT levels, in treatment to increase TERT expression, in treatment to increase TERT activity, in treatment to extend a telomere, in treatment to increase telomere length and / or in treatment to protecting against expression of platelet / endothelial cell adhesion molecule-1 (PECAM-1). In one aspect this invention relates to pharmaceutical compositions, articles of manufacture, kits and methods for treating a subject having (or at risk for having) cognitive decline (including, e.g., mild cognitive decline), cell senescence, reduced telomerase activity, loss of telomerase reverse transcriptase (TERT) expression or activity, short, shortened or shortening telomeres, and / or unwanted expression or activity of platelet / endothelial cell adhesion molecule-1 (PECAM-1), by administering a therapeutically effective amount of at least one connexin modulator (e.g., at least one connexin 43 modulator) to a subject or patient. In some embodiments, the agent is administered using a dose and / or dosing regimen described herein. In some embodiments, the agent is administered using another dose and / or dosing regimen. In one aspect this invention relates to pharmaceutical compositions, articles of manufacture, kits and methods for treating a subject having (or at risk for having) cognitive decline (including, e.g., mild cognitive decline), cell senescence, reduced telomerase activity, loss of telomerase reverse transcriptase (TERT) expression or activity, short, shortened or shortening telomeres, and / or unwanted expression or activity of platelet / endothelial cell adhesion molecule-1 (PECAM-1), by administering a therapeutically effective amount of at least one inflammasome modulator (e.g. at least one NLRP3 inflammasome inhibitor) to a subject or patient. In some embodiments, the agent is administered using a dose and / or dosing regimen described herein. In some embodiments, the agent is administered using another dose and / or dosing regimen. In some embodiments, at least one connexin modulator (e.g., at least one connexin 43 modulator) and at least one inflammasome modulator (e.g., at least one NLRP3 inflammasome inhibitor) to a subject or patient are administered together. In some embodiments the connexin modulator and the inflammasome modulator are provided in a single composition and are administered together by administration of the composition. In some embodiments the connexin modulator and the inflammasome modulator are provided in separate compositions and are administered at about the same time or on the same day. In one embodiment, a composition or compositions comprising a connexin modulator (e.g., a connexin 43 modulator) or an inflammasome modulator (e.g., an NLRP3 inflammasome inhibitor) or both is / are applied orally, topically, systemically (including intravenous, intra-arterial, intra- peritoneal, transdermal, intranasal, or by suppository), parenterally (including intramuscular, subcutaneous, or intravenous or intra-arterial injection), and the like, to a subject. In some embodiments, the connexin modulator is a modulator of Cx26, Cx30, Cx31.1, Cx36, Cx37, Cx40, Cx43, Cx45, Cx50, Cx57 or any other connexin in the eye or blood vessels. In some embodiments, the connexin modulator is a modulator of Cx26, Cx30, Cx30.3, Cx31, Cx31.1, Cx32, Cx43, Cx45, Cx50, and Cx58, or any other connexin in the epithelium. In some embodiments, the connexin modulator is a Cx43 connexin modulator, for example, a Cx43 expression modulator (e.g., an anti-Cx43 antisense), a Cx43 gap junction modulator or a Cx43 hemichannel modulator (e.g. an anti-connexin 43 peptidomimetic or a small molecule). In some embodiments, the modulator is a modified or unmodified antisense polynucleotide or peptidomimetic, e.g. a modified or unmodified Cx43 antisense polynucleotide or Cx43 peptidomimetic, or other corneal epithelial, endothelial or vascular connexin. In some embodiments, the modulator can include or exclude any of the foregoing connexins. In some embodiments, the connexin modulator administered daily, weekly, or monthly to a subject. In some embodiments, a therapeutically effective amount of tonabersat is administered. In some embodiments, the inflammasome modulator (e.g., NLRP3 inflammasome inhibitor) is administered daily, weekly, or monthly to a subject. In some embodiments, a therapeutically effective amount of tonabersat is administered. In some embodiments, the amount of a connexin modulator administered to a subject is one or more of the particular dose amounts described herein, including, for example, milligram per milliliter (mg / mL) connexin modulator dosing, micromolar (^M) connexin modulator dosing, milligram (mg) connexin modulator dosing, and so on, etc.). In some embodiments, the connexin hemichannel modulator comprises an orally available small molecule connexin hemichannel modulator (e.g., tonabersat, carabersat, or another small molecule connexin hemichannel modulator according to Formula I). See the Examples herein describing the use of an exemplary connexin hemichannel modulator (tonabersat). In some embodiments, the connexin hemichannel modulator is a prodrug of tonabersat (e.g., a tonabersat prodrug according to Formula II). In some embodiments, a connexin hemichannel modulator according to Formula I, or a prodrug according to Formula II, or a pharmaceutically acceptable salt thereof, is administered to a subject at dose ranges of approximately 0.01 to 15 mg / kg / day, more usually 0.1 to 6 mg / kg / day, for example 0.5 to 6 mg / kg / day. In some embodiments, the connexin modulator comprises a connexin peptidomimetic (e.g., a connexin 43 peptidomimetic). In some embodiments, the connexin peptidomimetic binds to an intracellular portion of a connexin (e.g. XG19). In some embodiments, the connexin peptidomimetic binds to an extracellular portion of a connexin (e.g. Peptide 5). Various connexin peptidomimetics, including connexin43 peptidomimetics, and methods of making them are known in the art. In some embodiments, the connexin modulator comprises an antisense molecule (e.g., a connexin43 antisense oligonucleotide). In some embodiments, the connexin 43 antisense polynucleotide comprising, consisting essentially of, or consisting of a sequence according to SEQ ID NOS.1-3, SEQ ID NOS:4-16 and / or modified versions thereof. In some embodiments, the antisense oligonucleotide comprises, consists essentially of, or consists of 5'-GTA ATT GCG GCA AGA AGA ATT GTT TCT GTC-3' (SEQ ID NO:1). In some embodiments, the antisense oligonucleotide may be chemically modified or may be an unmodified oligonucleotide, e.g. a modified or an unmodified DNA oligonucleotide. In some embodiments, oligonucleotides are modified by changing onr or more of the phosphodiester linkages, the ribose backbone and / or the nucleobase. Other modifications are described herein. Other modifications are known in the art and described in various publications, including, for example, in Shen, X. and Corey, DR, Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs, Nucleic Acids Res.2018 Feb 28; 46(4): 1584–1600. Methods of their manufacture are also known in the art. See, e.g., Abramova T, Frontiers and Approaches to Chemical Synthesis of Oligodeoxyribonucleotides, Molecules 2013 Jan; 18(1): 1063–1075; Hao M, et al., Current and Emerging Methods for the Synthesis of Single-Stranded DNA Genes (Basel) 2020 Jan 21;11(2):116. See also Anwar, S., et al. Enhancing the Effectiveness of Oligonucleotide Therapeutics Using Cell-Penetrating Peptide Conjugation, Chemical Modification, and Carrier- Based Delivery Strategies. Pharmaceutics 2023, 15, 1130. In some embodiments, a subject or patient is treated with a composition comprising or consisting essentially of SEQ ID NO:1. In some embodiments, the non-healing surface defect or disorder in a subject is treated with a composition comprising or consisting essentially of about of SEQ ID NO:1 in the regimens described herein. In some embodiments, administration is to a cell, to a tissue or to an organ. In some embodiments, administration is to the brain. In some embodiments, administration is to the eye. In some embodiments, administration is to the skin. In some embodiments, the connexin modulator administered to a subject or patient (including in one or more amounts described herein) is a small molecule connexin hemichannel modulator (e.g., tonabersat, carabersat, or another small molecule connexin hemichannel modulator according to Formula I). In some embodiments, the connexin hemichannel modulator is a prodrug of tonabersat (e.g., a tonabersat prodrug according to Formula II). In some embodiments, the connexin modulator administered to a subject or patient (including in one or more amounts described herein) is a connexin antisense molecule. In some embodiments, the connexin modulator administered to a subject or patient (including in one or more amounts described herein) is a connexin peptidomimetic (e.g. XG19, Peptide 5, etc.). In some embodiments, the therapeutically effective amount of the modulator, e.g. connexin modulator, for example a connexin 43 modulator, connexin 43 gap junction modulator and / or connexin 43 hemichannel modulator, which is effective in methods of the invention, comprises a composition that is about, or at least about, 10 micromolar (10 ^M), 15 micromolar (15 ^M), or 20 micromolar (20 ^M), , of a connexin modulator (e.g. SEQ ID NO:1), or any amount within or between any two of these recited dosages. Other effective doses that are effective in methods of the invention for the treatment of ocular surface defects or disorders (e.g. ocular PEDs and PCEDs) include about, or at least about, a composition comprising 30 micromolar (30 ^M) or 40 micromolar (40 ^M) of a connexin modulator, for example, a connexin 43 modulator, a connexin 43 gap junction modulator and / or a connexin 43 hemichannel modulator (e.g. SEQ ID NO:1). In some embodiments, the therapeutically effective amount of the connexin modulator administered as described is a connexin antisense molecule other than (or in addition to) SEQ ID NO:1. In some embodiments, the therapeutically effective amount of the connexin modulator administered as described is a connexin peptidomimetic (e.g. XG19). In some embodiments, the therapeutically effective amount of the connexin modulator as described is a connexin hemichannel blocker (e.g. tonabersat). In some embodiments of these doses and dosing regimens and methods, the connexin modulator dose administered comprises another connexin antisense or modulator, e.g., another Cx43 antisense or Cx43 modulator other than or in addition to SEQ ID NO:1, or a modulator of another ocular or corneal epithelial connexin other than or in addition to Cx43. In some embodiments, the modulator is a small molecule connexin antagonist. In some embodiments, the modulator is a small molecule connexin antagonist comprises a compound according to Formula I, which includes tonabersat. Tonabersat, a benzoylamino benzopyran, is a modulator of gap junction channel and hemichannel activity, including connexin 43. Tonabersat can block or inhibit hemichannels comprising connexin 43. In some embodiments, the modulator is a connexin peptidomimetic. Connexin modulators including Peptide5 inhibit Cx43 hemichannel activity and / or ATP release during and following injury. Other connexin modulator peptidomimetics include Gap19 and XG19, and analogues thereof. The instant inventions provide, inter alia, (1) methods for treating cognitive decline and cellular senescence in a subject or a patient by administration of a therapeutically effective amount of one or more of a connexin hemichannel modulator (e.g., a connexin 43 expression modulator, a connexin 43 gap junction modulator, a connexin 43 hemichannel modulator, etc.) and an inflammasome modulator (e.g. an NLRP3 inflammasome modulator) in a dose regimen described herein to treat a disease, disorder, defect or condition; (2) methods for treating cellular aging, telomere attrition, TERT deficiency, premature aging, and skin aging in a subject or a patient (e.g. a PED or a PCED) by administration of a connexin modulator and / or an inflammasome modulator at doses described herein (e.g. in any of the dosing regimens described herein; and (3) the use of such modulators, including, for example, anti-connexin and / or anti-inflammasome antisense modulators, peptidomimetic modulators and small molecule modulators, in the manufacture of a medicament (e.g. a pharmaceutical composition), and kits containing said medicaments that include or are associated with instructions for use in a method of the invention. In some embodiments, instant inventions provide, inter alia, (1) methods for treating mild cognitive decline, age-related cognitive decline, Alzheimer’s disease, dementia with Lewy bodies disease, fronto-temporal dementia, early onset dementia, Parkinson’s disease-related cognitive dysfunction, posterior cortical atrophy, primary progressive aphasia and Huntington’s disease in a subject or a patient by administration of a therapeutically effective amount of at least one connexin modulator (e.g., a connexin expression modulator, a connexin gap junction modulator and / or a connexin hemichannel modulator) and / or at least one inflammasome modulator in a dose regimen described herein to treat the disease, disorder or condition; (2) methods for treating short telomere syndrome, dyskeratosis congenital (DC), bone marrow failure syndrome characterized by the reticulated skin hyperpigmentation, nail dystrophy, oral leukoplakia, Revesz syndrome, Hoyeraal- Hreidarsson syndrome, cerebroretinal microangiopathy with calcifications and cysts (CRMCC), inherited aplastic anemia / myelodysplastic syndrome, aplastic anemia, marrow failure, hematological disorder, hepatic disease, aplastic anemia, hepatic cirrhosis, osteoporosis, osteonecrosis, vascular malformations, diabetes, primary immunodeficiency, and inflammatory bowel disease in a subject or a patient by administration of the connexin modulator and / or inflammasome modulator doses described herein (e.g. in any of the dosing regimens described herein); and (3) the use of such connexin modulators and / or inflammasome modulators, including, for example, small molecule modulators, peptidomimetic modulators and antisense modulators in the manufacture of a medicament (e.g. a pharmaceutical composition), and kits containing said medicaments that include or are associated with instructions for use in a method of treatment the invention. In some embodiments, one or more of the connexin modulators and / or inflammasome modulators described or referenced herein are formulated with one more other therapeutically or prophylactically active agents for use in the methods and regimens described herein. Definitions As used herein, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a “connexin hemichannel blocker” or an “inflammasome inhibitor” optionally includes a combination of two or more such molecules, and the like. As used herein, the terms “about” and “approximately,” when used to modify a numeric value (e.g., “about 80 mg”) or one or more amounts specified in a range of numeric values (e.g., “about 80 mg to about 400 mg”), indicate the numeric value and functionally equivalent values, as well as reasonable deviations from the value known to or understood by those in the art, including persons of ordinary skill in the art or those skilled in the art. For example, values within ±10% or ±5% are within the intended meaning of a recited value. As such, “about 80 mg” is understood to encompass from “76 mg to 84 mg” or from “72 mg to 88 mg” as if written out each time. Thus, as used herein, the terms “about” and “approximately” intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise. In other words, when ranges are expressed herein as from “about” one particular value, and / or to “about” another particular value, the range also includes from the one particular value and / or to the other particular value, including the variations noted above or understood in the art. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if “10 to 15” (or “10-15”) is disclosed, then 11, 12, 13, and 14 are also specifically disclosed (even it not spelled out in writing), in addition to 10 and 15, as well as “about 11,” “about 12,” “about 13,” and “about 14.” As used herein, the terms “administering” and “administration” refer to any method of providing a compound or composition to a subject. In some embodiments, the compound or composition is a pharmaceutical preparation. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intradural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be one-time, intermittent, or continuous. In some embodiments, a compound or composition of the invention is administered therapeutically, e.g., to treat an existing, diagnosed or suspected disease, disorder or condition. In some embodiments, a compound or composition of the invention is administered prophylactically, e.g., administered to prevent or inhibit progression of a disease, disorder or condition, or prevent the spread of a disease, disorder or condition. All cells experience changes with aging. Cellular senescence is a key feature of cell aging. An “aging cell” is a cell that becomes larger and less able to divide and multiply. Among other changes, there can also be an increase in pigments and lipids inside the cell. Cellular aging was first described by Hayflick and Moorhead in 1961. They showed that human cells in culture do not divide indefinitely but reach a limit (called the Hayflick limit) of replication and stop all further division. Cells approach this limit by slowing their divisions and entering cellular senescence, a dormant period. Both insufficient telomere replication and telomere shortening are common signals leading to these events. Telomere length in cells may be measure by the method described in Callicott R and Womack J., Real-time PCR assay for measurement of mouse telomere. Comp Med 2006 Feb;56(1):17-22; or by other methods known in the art. See, e.g., O’Callaghan N et al. A quantitative real-time PCR method for absolute telomere length. Biotechniques. 2008 May;44(6):807-9; Lai TP, et al. Comparison of telomere length measurement methods. Philos Trans R Soc Lond B Biol Sci.20185:373(1741):20160451; Montpetit AJ, et al. Telomere length: a review of methods for measurement. Nurs Res.201463(4):289-99. Other aspects of aging cells are described in issues of the journal Aging Cell. As used herein, an “antisense compound,” also referred herein to as “antisense polynucleotides” or “antisense oligonucleotides” (also known as ASOs or AONs), means a compound comprising or consisting of an oligonucleotide, at least a portion of which is complementary to a target nucleic acid to which it is capable of hybridizing, thereby resulting in at least one antisense activity. As used herein, “antisense activity” means any detectable and / or measurable change attributable to hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity comprises modulation of the amount or activity of a target nucleic acid transcript (e.g., mRNA). In certain embodiments, antisense activity comprises modulation of splicing of a precursor mRNA. Antisense compounds, and their design, manufacture and use are well known in the art. In some embodiments, they comprise single stranded pieces of DNA that match the complementary sequence of a specific mRNA (e.g., a connexin mRNA). In some embodiments, the antisense activity of an antisense compounds prevents or alters the production of a protein (e.g., pannexin 1). In some embodiments, the antisense compound is a connexin 43-directed antisense oligonucleotide. In some embodiments, the antisense compound is an NLRP3-directed antisense oligonucleotide. NLRP3-specific ASOs are known in the art. In some embodiments, the NLRP3- directed antisense oligonucleotide is directed to NLRP3 regions predicted to be in an open, as opposed to folded, conformation based, for example, on their minimum free energy prediction. See, e.g. Braatz, C, et al. (2023). NLRP3-directed antisense oligonucleotides reduce microglial immunoactivities in vitro. Journal of Neurochemistry, 202300:1-15. In some embodiments, the antisense compound is a pannexin 1-directed antisense oligonucleotide. In some embodiments, antisense polynucleotides or oligonucleotides comprise unmodified nucleotides. In some embodiments, antisense polynucleotides or oligonucleotides comprise one or more modified nucleotides. Many different chemical modifications are currently available. See, e.g., Crooke ST, et al. Antisense technology: an overview and prospectus. Nat Rev Drug Discov.202120(6):427- 453; Crooke ST, et al. Antisense technology: A review. J Biol Chem.2021296:100416; Kuijper EC, et al. Opportunities and challenges for antisense oligonucleotide therapies. J Inherit Metab Dis.202144(1):72-87. Many articles, book chapters and books have been written that are devoted to all aspects of the design, manufacture and use of antisense technologies, as well as issued patents (see, e.g., US Patent No. 9,382,540, issued July 5, 2016, for “Compositions and methods for modulating angiopoietin-like 3 expression), the detail of which are all well-known to those having even ordinary skill in the art and need not be detailed here. “Cellular senescence” is a phenomenon characterized by the cessation of cell division. It is a form of long-term cell-cycle arrest, caused by excessive intracellular or extracellular stress or damage. The concept of cell senescence is well known, and can be triggered, for example, by oxidative stress, telomere damage / shortening, DNA damage, mitochondrial dysfunction, chromatin disruption, inflammation, epigenetic dysregulation, and oncogene activation. See, e.g., Dodig S, et al. Hallmarks of senescence and aging. Biochem Med (Zagreb).201929(3):03050. In addition to irreversible cell cycle arrest, cellular senescence is characterized by changes in chromatin, gene expression, organelles and cell morphology. Importantly, senescent cells secrete a complex set of pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). Senescent cells are unique in that they eventually stop multiplying but don’t die off when they should. Instead, they continue to release chemicals that can trigger inflammation. Additionally, a relatively small number of senescent cells can persist and spread inflammation that can damage neighboring cells. It is also understood that the number of senescent cells in a person’s body increases with age. As the aging immune system becomes less efficient, senescent cells accumulate and taint healthy cells. This can affect the ability to withstand stress or illness; recuperate from injuries; and learn new things, as senescent cells in the brain can degrade cognitive functions. Cellular senescence has been connected to various age-related conditions, including diabetes, osteoporosis, cardiovascular disease, stroke, Alzheimer’s disease and related dementias, osteoarthritis, and cancer. It has also been linked to declines in eyesight, mobility, and thinking ability. Hallmarks of senescent cells include increased senescence-associated β-galactosidase activity (SA-β-gal); p16INK4A, p53, and p21 levels; higher levels of DNA damage, including γ-H2AX; the formation of Senescence-Associated Heterochromatin Foci (SAHF); and the acquisition of a Senescence-Associated Secretory Phenotype (SASP), a phenomenon characterized by the secretion of a number of pro-inflammatory cytokines and signaling molecules. Various techniques and protocols exist for monitoring the senescent phenotype including using senescence-associated markers, for example, SA-β-gal, γ-H2AX and SAHF staining, and for quantifying protein and mRNA levels of cell cycle regulators and SASP factors. See, e.g., Hooten N and Evans MK. Techniques to Induce and Quantify Cellular Senescence. J Vis Exp.2017 May 1;(123):55533. Soluble ICAM-1 (sICAM-1) is a further component of SASP. Elevated sICAM-1 levels are a potential circulating biomarker of cellular senescence. Studies have shown that sICAM-1 levels can increase with aging and in conditions with accelerated senescence. When cells undergo senescence due to DNA damage or other stressors, p53 activation can trigger increased production and release of sICAM-1. Potentially, sICAM-1 can contribute to the inflammatory signaling network, promoting senescence in neighboring cells. As used herein, the term “connexin hemichannel modulator” (which may also be referred to herein as a connexin hemichannel, connexin, or hemichannel “inhibitor,” “blocker” or “antagonist”) is a compound that prevents, inhibits, and / or reduces the formation, function or activity of a connexin hemichannel. Connexin hemichannel modulators include chemical-based connexin hemichannel modulators (e.g. tonabersat, carabersat or other compounds within Formula I, or pro-drugs thereof, e.g. compounds of Formula II, which are prodrugs of tonabersat), peptide-based connexin hemichannel modulators (e.g. XG19, Peptide 5, aCT1 peptides, etc.), DNA- and RNA-based connexin hemichannel modulators (e.g. SEQ ID NO:1, etc.), antibody- and antibody fragment- based connexin hemichannel modulators (e.g. monoclonal antibodies, ScFvs, etc.). See, e.g., Willebrords J, et al. Inhibitors of connexin and pannexin channels as potential therapeutics. Pharmacol Ther.2017180:144-160. In some embodiments, the connexin hemichannel modulators are connexin 43 hemichannel modulators. Modulation of a function and / or activity of a connexin hemichannel includes, for example, the prevention, inhibition and / or reduction, in whole or in part, in the expression of a connexin protein, its trafficking and / or assembly as a hemichannel (e.g., a connexin 43 hemichannel). In some embodiments, modulation of a function and / or activity of a connexin hemichannel comprises modulating, blocking, reducing or inhibiting of the flow of molecules through a hemichannel (e.g., a connexin 43 hemichannel). It includes, for example, the flow of molecules from the extracellular space or environment through a hemichannel (e.g., a connexin 43 hemichannel) into a cell, and / or the flow of molecules (e.g. adenosine triphosphate (ATP)) through a connexin hemichannel from the intracellular space or environment of a cell into the extracellular space or environment. Thus, by way of example, modulation may occur by one or more of: reducing, preventing, blocking, inhibiting or decreasing hemichannel formation; inducing or promoting closure of a hemichannel; reducing, preventing, blocking, inhibiting or decreasing hemichannel opening; reducing, preventing, blocking, inhibiting or decreasing hemichannel permeability; inducing coupling between hemichannels; triggering, inducing or promoting cellular internalization of a connexin hemichannel and / or gap junction. Words such as “blocking”, “inhibiting”, “preventing”, “decreasing” and “antagonizing”, and the like, may not be taken to imply complete reducing, blocking, inhibition, prevention, or antagonism. Similarly, “inducing” or “promoting” is not be understood to require complete induction or promotion of formation of a gap junction through hemichannel docking, inducing or promoting the complete closure of a hemichannel; completely preventing, blocking, inhibiting or decreasing hemichannel opening; completely preventing, blocking, inhibiting or decreasing hemichannel permeability; completely inducing coupling between hemichannels; or triggering, inducing or promoting the complete loss of coupling or the complete internalization of a connexin hemichannel and / or gap junction (or group of hemichannels and / or gap junctions) and should be taken to include the partial induction or promotion of any of them. Modulation of one or more functions or activities of a connexin hemichannel may occur by any means. Additionally, preventing, blocking, inhibiting and / or reducing a function or activity of a connexin hemichannel (e.g., a connexin 43 hemichannel) may be direct or indirect. Preventing, blocking, inhibiting and / or reducing connexin hemichannel function or activity includes, for example, directly blocking a connexin hemichannel, inducing a conformational change, and modifying a connexin phosphorylation state or its open-close probability. Open probability is a measure of the percentage of time a channel remains open versus being closed (reviewed in Goldberg G S, et al., Selective permeability of gap junction channels Biochimica et Biophysica Acta 20041662:96-101). Modulation of a connexin hemichannel also includes suppressing the permeability of a connexin hemichannel (for example, lessening the flow of molecules through a connexin hemichannel, e.g., a connexin 43 hemichannel). In some embodiments, the molecule is adenosine triphosphate (ATP). Thus, in some embodiments, a “hemichannel blocker” is a compound that interferes with the passage of molecules through a connexin hemichannel. A hemichannel blocker can block or decrease hemichannel opening, block, decrease or suppress hemichannel opening, block or reduce the release of molecules through a hemichannel to an extracellular space, and / or block or reduce the entry of molecules through a hemichannel into an intracellular space. Hemichannel blockers include compounds that fully or partially block hemichannel leak or the passage of molecules through a hemichannel (e.g. to or from an extracellular space). Hemichannel blockers also include compounds that decrease the open probability of a hemichannel. Examples of hemichannel blockers include peptides, peptidomimetics, small molecules, antibodies and antibody fragments. Hemichannel blockers include hemichannel modulators and may interfere directly or indirectly with the passage of molecules through a connexin hemichannel, or with the permeability of a connexin hemichannel (e.g., a connexin 43 hemichannel). The modulator may be of any chemical nature. As noted, by way of example, the connexin hemichannel modulator may be a nucleic acid (including antisense molecules, RNAi molecules, morpholinos, and other nucleic acids as described herein or known in the art), a peptide or peptidomimetic, or a small molecule or other chemical. Connexin modulators include connexin expression modulators, connexin gap junction modulators and connexin hemichannel modulators, including connexin gap junction modulators that can modulate a connexin hemichannel. In some embodiments, connexin expression modulators, connexin gap junction modulators and / or connexin hemichannel modulators are compounds can modulate – i.e., inhibit, block, prevent, reduce or antagonize, in whole or in part, the function, activity, expression, trafficking and / or assembly of – a connexin 43 hemichannel. However, as stated, the words “inhibit” or “block” or “antagonize” or “modulate” or “prevent” shall not be taken to imply that the function, activity, expression, trafficking and / or assembly of a connexin, a connexin hemichannel (e.g. a connexin 43 hemichannel) or gap junction (e.g. a connexin 43 gap junction) is completely inhibited or blocked or wholly antagonized or modulated or prevented, but should be understood to include any reduction or inhibition in the function, activity, expression, trafficking and / or assembly of a connexin (including its transcription, translation and / or expression), a connexin hemichannel (including its permeability or its opening, or release of ATP, to the extracellular environment) or gap junction (including its opening to an adjacent cell, or creation from hemichannels in adjacent cells). Hemichannels and gap junction channels may be present in cells of any type. The modulation of connexins, hemichannels and gap junctions may be in cells of any type. Accordingly, reference to a “connexin,” “hemichannel” or “gap junction” should be taken to include reference to a connexin, a hemichannel or gap junction present in any cell type, unless the context requires otherwise. In some embodiments, the connexin, hemichannel or gap junction is present in an epithelial cell. In some embodiments, the connexin, hemichannel or gap junction is present in an endothelial cell. In some embodiments, the connexin, hemichannel or gap junction is a vascular connexin, hemichannel or gap junction. In some embodiments, the connexin, hemichannel or gap junction is a connexin, hemichannel or gap junction found in vascular endothelial cells and / or vascular smooth muscle cells. In some embodiments, the connexin, hemichannel or gap junction is present in a brain cell, a retinal cell and / or in other cells noted herein or that are targeted in carrying out a method of the invention. In some embodiments, the connexin modulator may be a modulator of a connexin hemichannel present in blood vessels, for example, a connexin 43 hemichannel modulator and / or connexin 37 hemichannel modulator, a connexin 40 hemichannel modulator, a connexin 45 hemichannel modulator or another blood vessel connexin hemichannel. In some embodiments, the connexin modulator may be a modulator of a connexin hemichannel present in ocular cells, e.g., in cells of the retina. In some embodiments, the connexin modulator may be a modulator of a connexin hemichannel present in brain cells, e.g., in cells of the amygdala, hippocampus, hypothalamus and thalamus. In some embodiments, the connexin modulator may be a modulator of a connexin hemichannel present in glial and / or microglial cells. In some embodiments, the connexin modulator is a modulator of a Cx26, Cx30, Cx30.3, Cx31, Cx31.1, Cx32, Cx43, Cx45, Cx50, and / or Cx58 hemichannel, or any other connexin hemichannel in the corneal epithelium. In other embodiments, the connexin modulator is a modulator of any other connexin hemichannel in the eye or in blood vessels, including Cx36 and Cx57 hemichannels in addition to Cx37, Cx40, Cx43 and Cx45 hemichannels. In some embodiments, the connexin hemichannel modulator is a connexin 43 hemichannel modulator. In some embodiments, the connexin hemichannel modulator is a modulator of another connexin hemichannel. In some embodiments, the connexin hemichannel modulator is a modulator of one or more of a connexin 26 hemichannel, a connexin 30 hemichannel, a connexin 30.3 hemichannel, a connexin 31 hemichannel, a connexin 31.1 hemichannel, a connexin 32 hemichannel, a connexin 45 hemichannel, a connexin 50 hemichannel, and a connexin 58 hemichannel. In some embodiments, the connexin modulator may be a modulator of a connexin present in blood vessels or endothelial cells, for example, a connexin 37 hemichannel modulator, or a connexin 49 hemichannel modulator, for example. Thus, as used herein, the term “connexin hemichannel modulator” refers generally to connexin hemichannel modulators, but also specifically to connexin 43 hemichannel modulators and modulators of other connexin hemichannels referenced herein, or any other desired target connexin hemichannel. In some embodiments, the connexin hemichannel modulator is a connexin 43 hemichannel modulator, e.g., a modulator of a connexin 43 expression, a connexin 43 hemichannel modulator that inhibits or blocks hemichannel opening including small molecule and peptidomimetic modulators of connexin 43 hemichannel. In some embodiments, the connexin hemichannel modulating agent can include or exclude any of the connexins or connexin hemichannels referenced herein. The phrase “consisting essentially of” refers to specified materials and those additional materials that do not materially affect the basic and novel characteristics of a composition or medicament (or steps, in the case of a method). The basic and novel characteristics of the inventions are described throughout the specification, and include the ability of connexin hemichannel modulators, inflammasome modulators, connexin hemichannel modulator compositions, inflammasome modulator compositions, and methods of the invention to block or modulate connexins, connexin gap junctions and / or connexin hemichannels (e.g., connexin 43 connexins, gap junctions and / or hemichannels) and / or inflammasomes (e.g., the NLRP3 inflammasome) or pannexin modulators (e.g., Panx1 modulators) and to attenuate, block or inhibit, for example, the production, function or activity of a connexin, a connexin gap junction and / or a connexin hemichannel, or inflammasome activity (including, for example, hemichannel-mediated inflammasome activity, such as a connexin hemichannel-mediated inflammasome activity or pannexin hemichannel-mediated inflammasome activity). Material changes in the basic and novel characteristics of the inventions, including the compositions, medicaments and methods described herein, include changes or additions resulting in an unwanted or clinically undesirable, detrimental, disadvantageous or adverse activity to treating or preventing a disease, disorder or condition described or referred to herein, for example, or an unwanted or undesirable diminution of the activity of a connexin hemichannel modulator (e.g. a connexin 43 hemichannel modulator), an inflammasome modulator (e.g. an NLRP3 inflammasome modulator) and / or a pannexin modulator (e.g. a pannexin 1 channel modulator). In some embodiments, a composition or medicament of the invention will comprise, consist essentially of, or consist of at least one connexin 43 hemichannel modulator, for example, a connexin 43 antisense molecule, a connexin 43 peptidomimetic or small molecule connexin 43 hemichannel blocker or prodrug thereof. In some embodiments, a composition or medicament of the invention will comprise, consist essentially of, or consist of at least one NLRP3 inflammasome modulator, for example, a direct NLRP3 inflammasome modulator and / or an indirect NLRP3 inflammasome modulator. In some embodiments, a composition or medicament of the invention will comprise, consist essentially of, or consist of at least one pannexin 1 channel modulator, for example, a pannexin 1 antisense molecule, a pannexin 1 peptidomimetic or small molecule pannexin 1 hemichannel blocker or prodrug thereof. As used herein, “effective amount” or “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time as described in the dose regimens herein, to achieve a desired result in treatment of a disease, disorder, defect or condition for which one or more compounds or compositions of the invention are administered to a subject or to a patient. For example, and not by way of limitation, a “therapeutically effective amount” can refer to an amount of a connexin hemichannel modulator compound or composition (e.g. a compound or composition comprising or consisting essentially of a connexin 43 hemichannel modulator), to an amount of an inflammasome modulator compound or composition (e.g. a compound or composition comprising or consisting essentially of an NLRP3 inflammasome inhibitor), or to an amount of a pannexin channel modulator (e.g. a compound or composition comprising or consisting essentially of a pannexin 1 channel modulator), including but not limited to those disclosed herein, that is able to treat a disease, defect, disorder or condition when administered in accordance with the invention. In some embodiments, “effective amount” or “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time as described in the dose regimens herein or used by those in accordance with methods of the invention, to achieve a desired result or results in the treatment of cognitive decline (including, e.g., mild cognitive decline), in treatment to protect against or slow cognitive decline, in the treatment of cell senescence, in treatment to protect against cell senescence, in treatment to prevent or reduce cell senescence, in treatment to slow cell senescence, in treatment to increase telomerase activity, in treatment to protect against loss of telomerase reverse transcriptase (TERT), in treatment to increase TERT levels, in treatment to increase TERT expression, in treatment to increase TERT activity, in treatment to extend a telomere, in treatment to increase telomere length and / or in treatment to protecting against expression of platelet / endothelial cell adhesion molecule-1 (PECAM-1). Therapeutically effective amounts include an amount that is sufficient to achieve at least one desired therapeutic result, or to have at least one effect on at least one undesired symptom associated with a disease, disorder, defect or condition, including but not limited to those referenced herein. The specific therapeutically effective dose level for any particular patient may be varied or depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors used in the medical arts in determining dose levels. For example, those in the art may start doses of a compound or composition at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. In some embodiments, the result of treatment with an “effective amount” provides a durable result following treatment. In some embodiments, treatment with an effective amount is discontinued following a desired result. In some embodiments, treatment with an effective amount is continued following a desired result. In some embodiments, treatment with an effective amount is paused and then continued following a desired result. The doses disclosed herein are therapeutically effective amounts; however, the methods are not limited to those doses or dose amounts and include the use of other therapeutically effective amounts. In some embodiments aspects, a compound, composition or preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease, disorder or condition. As used herein, “prophylactically effective amount” refers to an amount effective to achieve or assure a desired prophylactic result, including, for example, preventing cognitive decline, cell senescence, telomere shortening, etc. As used herein, a “gap junction,” a “connexin gap junction” and a “connexin gap junction channel” refer to two hemichannels connected across an intercellular space between adjacent cells that allow certain molecules to flow between the cells. They refer to the intercellular channels or clusters of intercellular channels (gap junction plaques) that allow direct diffusion of ions and small molecules between adjacent cells. Gap junctions have been studies for decades and are well known in the art. All connexins share the same topological structure, including four transmembrane domains, two extracellular loops (EL1 and EL2), a cytoplasmic loop (CL) and amino (NT) and carboxyl termini (CT) in the cytoplasm. The carboxyl termini exhibit the greatest heterogeneity in amino acid sequences, whereas the transmembrane and extracellular domains are most conserved among the connexin isoforms. In general, connexins are expressed in the endoplasmic reticulum, transported to the Golgi apparatus to form hexamers (connexons), trafficked to the plasma membrane as connexin hemichannels, which then flow laterally to fuse with gap junction plaque and assemble with connexin hemichannels from apposing cells, forming into gap junctions. Thus, connexin hemichannels exist on plasma membranes before forming gap junctions. The presence of connexin hemichannels, however, does not always lead to the formation of gap junctions. For example, hemichannels formed by connexin 43, the most widely expressed connexin, can remain non- junctional on cell membranes if adequate adhesion molecules are not expressed. Non-junctional connexin structures are also reported in vivo. In one study using atomic force microscopy, hemichannels were found to account for about 12–17% of the total number of plaques in gap junction preparations from rat hearts, suggesting that connexin hemichannels may possess substantial permeation capacity in some critical organs. Connexin hemichannels are normally closed to maintain cellular homeostasis, but can be activated in pathophysiological processes to serve as toxic membrane pores, and have been referred to by some as “pathological pores.” As used herein, the term “hemichannel” (or “connexin hemichannel”) is a structure comprised of connexin proteins, typically homo- or hetero-meric hexamers of connexin proteins that form the pore for a gap junction between the cytoplasm of two adjacent cells. The hemichannel is supplied by a cell on one side of the junction, and by a cell on the other side, with two hemichannels from opposing cells normally coming together to form the complete intercellular gap junction channel. However, as noted, in some cells, and in cells under some circumstances, the hemichannel itself is active as a conduit between the cytoplasm and the extracellular space allowing the transference of ions and small molecules (e.g. ATP). Like their gap junction counterparts, connexin hemichannels have been long-studied and are also well known in the art. Increased connexin 43 hemichannel opening is associated with inflammasome pathway activation and inflammation. As used herein, the term “inflammasome modulator” (which may also be referred to as an inflammasome “inhibitor,” “blocker” or “antagonist”) is a compound that directly or indirectly prevents, inhibits, and / or reduces the formation, function or activity of an inflammasome (e.g., an NLRP3 inflammasome), including, for example, prevention, inhibition and / or reduction in the function and / or activity and / or the formation of an inflammasome (e.g., an NLRP3 inflammasome), including its assembly. In some embodiments, activation of an inflammatory cascade by the NLRP3 inflammasome is modulated (e.g. blocked or downregulated) by a direct NLRP3 inflammasome modulator. In some embodiments, activation of an inflammatory cascade by the NLRP3 inflammasome is modulated (e.g. blocked or downregulated) by an indirect modulator of the NLRP3 inflammasome. In some embodiments, a direct or indirect inflammasome modulator may include or exclude any known direct or indirect inflammasome modulator. In some embodiments, activation and / or activity of the NLRP3 inflammasome is modulated (e.g. blocked, inhibited or downregulated) by a connexin hemichannel modulator. In some embodiments, an inflammasome modulator may include a connexin hemichannel modulator. In some embodiments, an inflammasome modulator may exclude a connexin hemichannel modulator. Inflammasome modulation is useful in treating or preventing one or more of the diseases, defects, disorders or conditions described herein, including in the treatment or prevention of cognitive decline (including, e.g., treatment or prevention of mild cognitive decline), in treatment to protect against or slow cognitive decline, in the treatment of cell senescence, in treatment to protect against cell senescence, in treatment to prevent or reduce cell senescence, in treatment to slow cell senescence, in treatment to increase telomerase activity, in treatment to protect against loss of telomerase reverse transcriptase (TERT), in treatment to increase TERT levels, in treatment to increase TERT expression, in treatment to increase TERT activity, in treatment to extend a telomere, in treatment to increase telomere length and / or in treatment to protect against expression of platelet / endothelial cell adhesion molecule-1 (PECAM-1). In some embodiments, a disease, defect, disorder or condition is treated with an inflammasome modulator (e.g. a modulator of the NLRP3 inflammasome) that may not be a connexin modulator (e.g. a connexin 43 hemichannel modulator). Inflammasome modulators include those described, for example, in Leung and Lowery, The patent landscape of inflammasome modulators. Nature Reviews Drug Discovery 19, 158 (2020). See also Chauhan, D., et al., Therapeutic modulation of inflammasome pathways. Immunol Rev.297(1): 123–138 (Sept 2020). Inflammasome modulators include selective G-protein coupled receptor 40 (GPR40) agonists (e.g. fasiglifam, which inhibits inflammasome activation by blocking formation of apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain (CARD), an inflammasome component), and ethyl pyruvate, which significantly suppresses activation of the NLRP3 inflammasome. Other inflammasome modulators unrelated to connexins and connexin hemichannels are known in the art. The term “in vivo” (Latin for “within the living”) refers to use in a whole, living organism as opposed to an ex vivo or in vitro controlled environment. Animal testing, clinical trials, and use in humans or other living subjects are forms of in vivo research. In vivo testing is often employed over in vitro to observe the overall effects of an experiment on a living subject. Ex vivo work or experimentation is done in live isolated cells, tissues or organs, rather than in a whole organism, for example, cultured cells derived from biopsies. Once cells are disrupted and individual parts are tested or analyzed, this is referred to as in vitro. Methods carried out in vivo include the use of animal models for research. In vivo methods also include the use of methods in humans and other subjects, including for therapy. The term “ex vivo” (Latin: “out of the living”) refers to use outside an organism, and is used to indicate methods, work, experimentation or measurements done in or on tissue in an artificial environment outside an organism. Ex vivo work is often done with the minimum alteration of natural conditions. Ex vivo conditions often allow methods, work, experimentation and / or measurements to be carious out under more controlled conditions than may be possible in in vivo experiments (in the intact organism), albeit at the expense of altering the "natural" environment. A main difference between in vitro and ex vivo assays is that the former is simply a cell system established in a cell culture or in a laboratory. In contrast, the latter is a tissue directly taken from a living organism, or a tissue that has been created artificially. The term “in vitro” (“within the glass,” or “in glass,” e.g., in a test tube or petri dish). In vitro experiments were historically conducted in glass test tubes and Petri dishes, however, modern laboratory practices include the use of single-use plasticware, and other non-glass instruments, in part to avoid cross- contamination, the need for washing, sterilization, etc. In vitro experiments are often performed on cells or cultures of cells, which sometimes include immortalized human or other animal cell lines, or other cell lines, and sometimes include bacteria. When the test subjects are cells, they are derived from living organisms or cell lines and maintained in culture in special conditions. Sometimes those conditions seek to mimic physiological circumstances including temperature and sterility. There is a wide variety of cell types which in many cases can be amplified in plastic flasks and distributed in plates with hundreds of small wells for high throughput screening, for example. Some cell types cannot adhere to plastic and are cultured in suspension, forming aggregates. Three- dimensional cell systems may also be used where the higher cell-cell interaction adds another layer of complexity to cellular communication. Furthermore, advanced in vitro systems such as the organ-on-a-chip technology, offer a next level of complexity introducing, for example, microfluidic channels that reproduce human blood and / or airflow. These are only some examples of in vitro methodologies. As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as a recorded presentation. As used herein, “instruction(s)” means documents or information describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as a recorded presentation. Instructions can comprise one or multiple documents, and include future updates. The term “mild cognitive decline” (also referred to as “mild cognitive impairment” or MCI) refers to an early stage of memory loss or other cognitive ability loss (such as language or visual / spatial perception) in individuals who maintain the ability to independently perform most activities of daily living. Mild cognitive decline includes amnestic MCI (mild cognitive impairment that primarily affects memory, e.g. forgetting important information that would previously have recalled easily, such as appointments, conversations or recent events) and nonamnestic MCI (mild cognitive impairment that affects thinking skills other than memory, including the ability to make sound decisions, judge the time or sequence of steps needed to complete a complex task, or visual perception). As used herein, the term “modulator” refers to connexin hemichannel modulators, a pannexin channel modulators, direct inflammasome modulators and indirect inflammasome modulators. A modulator may refer to at least one, any two or more, any three or more, or all compounds and compositions selected from the group consisting of connexin hemichannel modulators, a pannexin channel modulators, direct inflammasome modulators and indirect inflammasome modulators. As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. As used herein, the term “pannexin channel modulator” (which may also be referred to as a pannexin channel or pannexin “inhibitor,” “blocker” or “antagonist”) is a compound that prevents, inhibits, and / or reduces the formation, function or activity of a pannexin channel, including, for example, the prevention, inhibition and / or reduction, in whole or in part, in the expression of a pannexin protein, its trafficking and / or assembly as a channel. Pannexin channel modulators include chemical-based pannexin channel modulators (e.g. probenecid, or a compound according to Formula VI in US Patent No. 10,465,188, etc.), peptide-based pannexin hemichannel modulators (e.g.10Panx1), DNA- and RNA-based pannexin channel modulators, antibody- and antibody fragment-based pannexin channel modulators (e.g. monoclonal antibodies, ScFvs, etc.). See, e.g., Koval, M, et al. Pharmacology of pannexin channels. Current Opinion in Pharmacology 202369:102359; Willebrords J, et al. Inhibitors of connexin and pannexin channels as potential therapeutics. Pharmacol Ther. 2017180:144-160. In some embodiments, the pannexin channel modulators are pannexin 1 (Panx1) channel modulators. Pannexin modulation (e.g., pannexin 1 modulation) will be useful in treating or preventing one or more of the diseases, defects, disorders or conditions described herein by inhibiting ATP release from a pannexin channel (e.g., a pannexin 1 channel). References in the specification and claims to parts by weight of a particular agent or component in a composition denotes the weight relationship between the agent or component and any other agents or components in the composition or article for which a part by weight is expressed. Thus, in a compound or composition containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound. A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. Thus, the amount of X in a compound or composition containing X (5 wt.%) contains 5% X. Peptidomimetics are molecules able to mimic natural peptides and proteins. Generally, peptidomimetics are structural or functional mimics (e.g., identical or similar) to a paradigm polypeptide (i.e., a polypeptide that has a biological or pharmacological function or activity). The terms “peptidomimetic” and “mimetic” (also known or referred to as peptide mimetics) include synthetic or recombinantly manufactured compounds, including polyamides and poly(amino acid) polymers, that have the same or substantially the same characteristics of protein or peptide regions that they mimic. Typically a peptidomimetic will have the same or substantially the same structural and / or functional characteristics of protein or peptide regions they mimic. A peptidomimetic modulator (also sometimes referred to as a “modulator peptide,” a “modulator peptidomimetic,” a “mimetic” or a “peptidomimetic inhibitor”) comprises a peptide or peptide- like molecule that is able to serve as a model for a peptide substrate upon which it is structurally based and to modulate (i.e., inhibit, lessen, decrease or reduce) one or more activities of the peptide substrate on which is structurally based. In some embodiments, the peptidomimetics and mimetics comprise one or more or all naturally occurring amino acids. In some embodiments, the peptidomimetics and mimetics comprise one or more or all L-amino acids. In some embodiments, the peptidomimetics and mimetics comprise one or more or all D-amino acids. D-peptide peptidomimetics include D-peptides designed to mimic natural L-peptides. The peptide bonds formed by D-amino acids are more resistant to proteases than those formed by L-amino acids. In some embodiments, the peptidomimetics and mimetics comprise one or more L-amino acids and one or more D-amino acids. In some embodiments, a peptidomimetic can be a mimetic composed entirely of natural amino acids, composed entirely synthetic chemical compounds, composed entirely of non-natural amino acids, composed entirely of analogues of naturally-occurring and / or non-naturally-occurring amino acids, or a chimeric molecule composed of partly of natural amino acids and partly of non-natural occurring amino acids or analogs of amino acids. In some embodiments, a peptidomimetic comprises any amount of natural amino acid conservative substitutions as long as such substitutions also do not substantially alter mimetic activity. In some embodiments, peptidomimetics are unmodified. In some embodiments, peptidomimetics are modified. In some embodiments, a peptidomimetic is a modified or chemically modified peptide. In some embodiments, peptidomimetics is a modified peptide that has one or more peptide linkages optionally replaced by a linkage selected from the group consisting of, for example, -CH2NH-, -CH2S-, -CH2-CH2-, - CH=CH- (cis and trans), - COCH2-, -CH(OH)CH2-, and -CH2SO-. In some embodiments, a peptidomimetics is chemically modified to include unnatural amino acid substitutions, backbone amide bond modifications, rigid scaffolds, added hydrophobic residues, and / or in other ways known in the art. In some embodiments, a peptidomimetic is a modified peptide-like molecule. In some embodiments, a modified peptide-like peptidomimetic contains one or more or all non-naturally occurring amino acids or is a peptoid. Although their backbones are similar, side chains of peptides are attached to the α-carbon in peptides, while peptoids have side chains attached to the amide nitrogen. This modification confers resistance to proteolytic degradation. Peptoids include poly-N-substituted glycines. See, e.g., Wolf LM, et al. Peptoids: Emerging Therapeutics for Neurodegeneration J Neurol Neuromedicine 2017 2(7):1-5. Other peptidomimetics known in the art include, for example, peptide-like molecules which contain a constrained amino acid, a non-peptide component that mimics peptide secondary structure, or an amide bond isostere. A peptidomimetic that contains a constrained amino acid or a constainws non-naturally occurring amino acid can include, for example, an α-methylated amino acid, an α,α-dialkyl-glycine or α- aminocycloalkane carboxylic acid; an Nα-Cα cylized amino acid, an Nα-methylated amino acid, a β- or γ-amino cycloalkane carboxylic acid, an α,β-unsaturated amino acid, a β, β-dimethyl or β- methyl amino acid, a β-substituted-2,3-methano amino acid, an NCδ or Cα-Cδ cyclized amino acid, or a substituted proline or another amino acid mimetic. A peptidomimetic that mimics peptide secondary structure can contain, for example, a nonpeptidic β-turn mimic; γ-turn mimic; mimic of β-sheet structure; or mimic of helical structure, each of which is well known in the art. A peptidomimetic that contains an amide bond isostere, for example, may contain an amide bond isostere such as a retro-inverso modification, a reduced amide bond, a methylenethioether or methylenesulfoxide bond, a methylene ether bond, an ethylene bond, a thioamide bond, a trans- olefin or fluoroolefin bond, a 1,5-disubstituted tetrazole ring, a ketomethylene or fluoroketomethylene bond, or another amide isostere. One skilled in the art understands that these and other peptidomimetics are encompassed within the meaning of the term “peptidomimetic” as used herein. Peptidomimetics that are structurally similar to portions of a connexin (e.g., connexin 43), an inflammasome (e.g., an NLRP3 inflammasome) or a pannexin (e.g., pannexin 1) can be used to produce a therapeutic or prophylactic effect. Peptidomimetics useful as connexin hemichannel modulating agents include peptide and peptide- like molecules capable of down-regulating, reducing or decreasing, in whole or in part, one or more biological actions or activities of a connexin hemichannel, such as, for example, preventing the docking of hemichannels to form gap-junction-mediated cell-cell communications, or preventing the opening of hemichannels to expose the cell cytoplasm to the extracellular millieu, and so on. By way of example, in some embodiments, a peptidomimetic mimics an extracellular loop of connexins involved in hemichannel-hemichannel docking and cell-cell channel formation, and / or an extracellular loop of a connexin hemichannel, as well as an extracellular loop or the intracellular loop or intracellular C-terminus of a connexin. In some embodiments, a peptidomimetic mimics an extracellular loop, intracellular loop or intracellular C-terminus of connexin 43. In some embodiments, a peptidomimetic mimics an portion of another connexin, including those listed herein. Compositions of the invention may comprise one or more connexin peptidomimetics that can serve as connexin hemichannel modulators (also referred to “mimetic connexin hemichannel modulators” or “peptidomimetic connexin hemichannel modulators”). Connexin peptidomimetics are known in the art and many connexin peptidomimetics useful as peptidomimetic connexin hemichannel modulators are described or referenced herein. All known connexin isoforms are structurally similar, being composed of four transmembrane domains, two extracellular loops (EL1, EL2) bound in conformation by extracellular disulfide bonds, a single intracellular loop (IL), an amino-terminus (NT), and a carboxyl-terminus (CT). Connexin peptidomimetics useful as connexin hemichannel modulators include, for example, EL1 extracellular loop-binding peptidomimetics such as Gap 26 and P5, EL1 extracellular loop-binding peptidomimetics such as Peptide5, Gap 27, and P180-195, IL intracellular loop-binding peptidomimetics such as Gap19, Gap20 and Cx43L2 peptide, and intracellular CT-binding peptidomimetic connexin hemichannels modulators such as XG19, JM2, cSRC, TAT-Cx43, TAT-CT10, and the alpha CT peptidomimetics such as alpha CT-1, alpha CT-2, alpha CT-3, etc. See, e.g., King DR, et al. Mechanisms of Connexin Regulating Peptides. Int J Mol Sci.202122(19):10186; Simon, Á, et al. Peptide Binding Sites of Connexin Proteins. Chemistry 2020, 2:662-673. FDA-approved peptidomimetics drugs include Romidepsin (Istodax), Atazanavir (Reyataz), Saquinavir (Invirase), Oktreotid (Sandostatin), Lanreotide (Somatuline), Plecanatide (Trulance), Ximelagatran (Exanta), Etelcalcetide (Parsabiv), and Bortezomib (Velcade). The first extracellular loops of connexin 37, connexin 40 as well as connexin 43 are mimicked bypeptides under the Gap26 code. Gap27 and Peptide5, on the other hand, mimic regions of the second extracellular loop. Gap27 targets connexin 32, connexin 40 and connexin 43, while Peptide5 is used for connexin 43 inhibition. Other peptidomimetics include JM2 (VFFK- GVKDRVKGRSD; SEQ ID NO:134), ΔSH3, CT9 (RPRDDLEI; SEQ ID NO:135) and CT9-TAT, CT10 (SRPRDDLEI; SEQ ID NO:136), αCT (RQPKIWFPNRRKPWKK-RPRPDDLEI (SEQ ID NO:137) in which the inhibitor peptide includes the connexin 43 C-terminal amino acids 374–382 (RPRPDDLEI; SEQ ID NO:141) that encompass the ZO-1-binding sequence, which is in turn attached at its N-terminus to a 16-amino acid antennapedia internalization vector) mimic the C- terminal tail of connexin 43 and Gap24 (GHGDPLHLEEVKC; SEQ ID NO:138) reproduces a sequence of the cytoplasmic loop of connexin 32 while TAT-Gap24 (YGRKKRRQRRRGHGDPLHLEEVKC; SEQ ID NO:139) also mimics a portion of the intracellular loop of connexin 43. Both L2 and Gap19 also mimic the cytoplasmic loop of connexin 43. Peptides and peptidomimetics useful in the compositions and methods of the invention also include those set forth in Tables II and III. In some embodiments, a peptidomimetic connexin hemichannel modulator has been modified to increase stability, to improve bioavailability and / or to increase cell membrane permeability, for example, by linking the amino or carboxy terminus to a cellular internalization transporter. Cellular internalization transporters include those described herein or otherwise known in the art or later developed. In some embodiments, a peptidomimetic corresponds to at least one portion of a connexin (e.g., connexin 43) that can be used to modulate a connexin hemichannel activity (including, for example, release of ATP). In some embodiments, a peptidomimetic corresponds to at least one portion of an inflammasome (e.g., an NLRP3 inflammasome). In some embodiments, by way of example, an NLRP3 inflammasome peptidomimetic comprises a sequence corresponding to segment of an NLRP3 inflammasome component (e.g., an amino (N)-terminal pyrin domain (PYD), a carboxy (C)- terminal LRR, or a central NBD-containing ATPase domain (NACHT)), or to an apoptosis- associated speck-like protein containing a CARD (ASC). Inhibitors constituents of the NLRP3 Inflammasome include VX-740 (Pralnacasan) and its analog VX-765, which are peptidomimetic inhibitors of caspase-1. Small-molecule inflammasome modulators useful in methods of the invention the orally bioavailable proteasome inhibitor NIC-0102 (IUPAC / Chemical Name: ((R)-1-((S)-2-(2,6- difluorobenzamido)-3-phenylpropanamido)-3-methylbutyl)boronic acid). NIC-102 specifically prevents NLRP3 inflammasome activation but has no effect on NLRC4 or AIM2 inflammasomes. NIC-0102 induces the polyubiquitination of NLRP3, interferes with the NLRP3-ASC interaction, and blockes ASC oligomerization, thereby inhibiting NLRP3 inflammasome activation. In addition, NIC-0102 also inhibits the production of pro-IL-1β. In some embodiments, a peptidomimetic corresponds to at least one portion of a pannexin (e.g., pannexin 1) to modulate pannexin channel activity (including, for example, release of ATP). In some embodiments, the pannexin 1 peptidomimetic comprises or consists essentially of H-Trp- Arg-GIn-Ala-Ala-Phe-Val-Asp-Ser-Tyr-OH (also known as10Panx). Peptidomimetics encompass those described herein, as well as those as may be known in the art, whether now known or later developed. The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which does not contain additional components that are unacceptably toxic to a subject to which the formulation would be administered. A “pharmaceutical composition” refers to a mixture of substances suitable for administering to a subject that includes one or more active ingredients or pharmaceutical agents (e.g., one or more connexin hemichannel modulators (e.g., one or more connexin 43 hemichannel modulators), one or more inflammasome modulators (e.g., one or more NLRP3 inflammasome modulators) or a combination of one or more connexin hemichannel modulator and one or more inflammasome modulators). For example, a pharmaceutical composition may comprise one or more compounds of the invention and a sterile aqueous solution or a pharmaceutically acceptable carrier. A “pharmaceutically acceptable carrier,” as used herein, refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which can be safely administered to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed, and that they refer to reducing, inhibiting or preventing in whole or in part for the therapeutic and / or prophylactic purposes described herein. Prodrugs are well known to those in the art with knowledge of chemistry. As used herein, a “prodrug” is understood to refer to a compound that, after administration, is metabolized or otherwise converted to an active or more active form with respect to at least one biological property, relative to itself. To produce a prodrug, a pharmaceutically active compound (e.g., tonabersat), or a suitable precursor thereof, is modified chemically such that the modified form is less active or inactive, but the chemical modification is effectively reversible under certain biological conditions such that a pharmaceutically active form of the compound is generated by metabolic or other biological processes. A prodrug can have, relative to the drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor, for example. Prodrugs can also be prepared using compounds that are not drugs but which upon activation under certain biological conditions generate a pharmaceutically active compound. As used herein, for example, a “tonabersat prodrug” or “prodrug of tonabersat” refers to a compound that undergoes a chemical conversion, through a metabolic process or otherwise (e.g., within the body of the mammal or other subject receiving the compound) into an active form of tonabersat that has a desired effect. In other words, a tonabersat prodrug includes a compound that upon activation releases tonabersat or an active analog thereof. A “small molecule” includes compounds with a molecular weight below about 600 daltons and is generally an organic compound. Small molecule connexin modulators include the compounds of Formula I. A small molecule can be an active agent of a prodrug. Small molecules prodrugs include the compounds of Formula II, which are prodrugs of the small molecule connexin hemichannel modulator, tonabersat. As used herein, the term “subject” or the like, including “individual,” and “patient”, all of which may be used interchangeably herein, refers to any mammal, including humans, domestic and farm animals, and zoo, wild animal park, sports, or pet animals, such as dogs, horses, cats, sheep, pigs, cows, etc. In some instances, however, a patient may refer to a subject afflicted with specific a condition, disease, defect, syndrome or disorder. The terms “subject” and “patient” include human and veterinary subjects. The preferred mammal herein is a human, including adults, children, and the elderly. Preferred sports animals are horses and dogs. Preferred pet animals are dogs and cats. The subject may be, for example, an aquatic park animal, such as a dolphin, whale, seal or walrus. In certain embodiments, the subject, individual or patient is a human. The term “subject” does not denote a particular age or sex. In some embodiments, subjects may include animals used in scientific experiments (e.g. mice, rats, rabbits, sheep, goats, or other laboratory subjects). In other embodiments, the term “subjects” may exclude one or more or all animals used in scientific experiments, and a method may specify that is does not include one or more or all animals used in scientific experiments. In some embodiments, subjects may include non-animals and other things used in scientific experiments (e.g., fruit flies, cells, cell cultures, tissues, organs, 3D tissue culture (such as organs-on-a-chip). In other embodiments, the term “subjects” may exclude one or more or all non-animals or other things used in scientific experiments and a method may specify that is does not include one or more or all non-animals or other things used in scientific experiments. In some embodiments of the disclosed methods, a subject has been diagnosed with a need for treatment of one or more conditions or diseases associated with telomere length. In some embodiments of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more conditions or diseases associated with telomerase levels or activity. In some embodiments of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more conditions or diseases associated with TERT levels or activity. In some embodiments of the disclosed methods, the subject has been diagnosed with a need for treatment of cognitive decline, or one or more conditions or diseases associated with cognitive decline. In some embodiments of the disclosed methods, the subject has been diagnosed with a need for treatment of cell senescence, or one or more conditions or diseases associated with cell senescence. In some embodiments of the disclosed methods, the subject has been diagnosed with a need for treatment of one or more conditions or diseases associated with increased PECAM-1 levels, expression or activity. Telomeres, telomerase, and the molecular components of telomerase, including telomerase reverse transcriptase, are well known in the art. See, e.g., Shay, JW and Wright, WE. Telomeres and telomerase: three decades of progress. Nat Rev Genet 201920:299-309. A “telomere” is a region of repetitive nucleotide sequences located at the ends of a chromosome. For vertebrates, the sequence of nucleotides in telomeres is TTAGGG. In humans, this sequence of TTAGGG may be repeated approximately 2,500 times. “Telomerase” is an RNA-dependent DNA polymerase that adds TTAGGG that repeats at the ends of chromosomes. This ribonucleoprotein enzyme is composed of multi-subunits, but its core holoenzyme contains only an RNA template (TERC) and catalytic telomerase reverse transcriptase (TERT). The human TERT protein (1132 amino acids, 127 kDa) contains four conserved structural domains: the telomerase essential N-terminal (TEN) domain, the TERT RNA binding domain (TRBD), the reverse transcriptase (RT) domain and the C-terminal extension (CTE) domain. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified. The TERT protein is responsible for the synthesis of telomeric DNA repeats from the RNA template located within TR. The TERT protein component is present across all known taxa (with the exception of a subgroup of select insects). Cells with impaired telomerase or TERT function have limited capacity for self-renewal, i.e., an abnormal state or condition characterized by an inability of cells (e.g., stem cells) to divide sufficiently. This deficiency in cells can lead to various diseases and disorders, including telomere- related diseases and telomere syndromes, for example. As used herein, “telomeric region” refers to the DNA segment at the ends of a chromosome with repeat telomeric sequences. In the case of vertebrates, it can be the (TTAGGG)n repeat sequence at the ends of chromosomes. As used herein, “sub-telomeric region” means the segment of DNA immediately adjacent to telomere at the centromeric end of telomeres. Subtelomeric region often contains degenerate telomeric repeats. In the case of humans, repeats of TGAGGG and TCAGGG can be present in subtelomeric region. As used herein, a “telomere-related” disease, disorder, defect and / or condition (and grammatical variations thereof), refers to a disease, disorder, defect and / or condition related, in whole or part to, to telomerase, telomerase reverse transcriptase, telomere shortening and / or telomere length, that may be treated by compounds, compositions and methods that help to recover, improve, increase telomeres, telomere length, telomerase activity or telomerase reverse transcriptase activity, including compounds, compositions and methods described or referred to herein, such as, for example, compounds, compositions and methods comprising connexin hemichannel modulators (e.g., connexin 43 hemichannel modulators), inflammasome modulators (e.g., NLRP3 inflammasome modulators), and pannexin channel modulators (e.g., pannexin 1 channel modulators). Telomere-related diseases, disorders and conditions include telomerase-related, telomerase reverse transcriptase-related, and telomere length-related diseases, disorders and conditions. The term “telomere syndrome,” “telomere disease” or “disorder associated with telomerase dysfunction” refers to a disease, disorder, defect, syndrome or condition associated with abnormal telomeres. They include, but not are limited to, short telomere syndrome, dyskeratosis congenital (DC), a bone marrow failure syndrome characterized by the reticulated skin hyperpigmentation, nail dystrophy, and oral leukoplakia; Revesz syndrome, a phenotypic variant of DC; Hoyeraal- Hreidarsson syndrome, an X-linked syndromic intellectual disability considered to be a variant of DC; cerebroretinal microangiopathy with calcifications and cysts (CRMCC), also known as Coats plus syndrome, is an autosomal recessive pleomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline; some forms of inherited aplastic anemia / myelodysplastic syndrome; aplastic anemia; marrow failure; hematological disorder hepatic disease (e.g., chronic liver disease, and hepatic cirrhosis). Telomere diseases also include those affecting the blood and immune systems, lungs, liver, skin, mucosal surfaces, bones, cardiovascular system, endocrine system, and / or gastrointestinal system, as cells with the impaired self-renewal capacity can affect the normal function of organs or systems. Some of these disorders include aplastic anemia, hepatic cirrhosis, osteoporosis and osteonecrosis, vascular malformations, diabetes, primary immunodeficiency, and inflammatory bowel disease. This group of diseases are associated with a cellular state marked with decreased self-renewal capacity that can be attributed to an alteration in telomere length. Thus, the term “telomere deficiency” as used herein refers to a cellular state in the body, including stem cells, induced pluripotent cells and fibroblasts, and is often marked by a perturbation in expression or activity of an enzyme that is involved in regulating telomere size, such as TERT. As used herein, the term “telomerase dysfunction” refers to abnormal levels, activity or function of telomerase in a cell or patient. For example, telomerase dysfunction can include telomerase deficiency, including where telomerase levels are lower than normal due, for example, to excess or unwanted telomerase degradation, telomerase under-activity, etc. As used herein, the term “telomerase reverse transcriptase dysfunction” or “TERT dysfunction” refers to abnormal levels, activity or function of telomerase reverse transcriptase in a cell or patient. For example, telomerase reverse transcriptase dysfunction can include telomerase reverse transcriptase deficiency, including reduced TERT levels, reduced TERT activity or reduced TERT function, such as where telomerase levels are lower than normal due to excess or unwanted telomerase reverse transcriptase degradation, and telomerase reverse transcriptase under-activity. A short telomere or abnormal telomere can refer to a telomere that has a length that is significantly shorter than what is expected for the age of the subject. If a subject has telomere lengths that are <1stpercentile in granulocytes and lymphocytes, there is a high probability of a short-telomere syndrome, as discussed in Abhishek A., et al. Short Telomere Syndromes in Clinical Practice – Bridging Bench and Bedside. Mayo Clin Proc. 2018 July; 93(7): 904-916. A telomere length within the 1-10thpercentile range can be considered as at risk of having a short-telomere syndrome. As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to an attempt to alter the course of the individual, tissue or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Thus, the term “treatment” includes the management or care of a subject, or of a patient, with the intent to cure, ameliorate, stabilize, or prevent a disease, disorder, defect or condition. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, disorder, defect or condition, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, disorder, defect or condition. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, disorder, defect or condition; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, disorder, defect or condition; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, disorder, defect or condition. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing a disease, disorder or condition from occurring in a subject that can be predisposed to the disease, disorder or condition but has not yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition, i.e., arresting or slowing its development; or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder or condition. In some embodiments, the subject is a mammal such as a primate, and, in further embodiments, the subject is a human. In some embodiments, the subject is a non- human mammal. Treatment does not necessarily imply that a subject or patient is treated until total recovery following treatment, or that treatment of a subject or patient results in total recovery. Accordingly, “treatment” may also include maintaining or promoting a complete or partial state of remission in a subject or patient, or an alleviation or relief from symptoms of the disease, disorder, defect of conditions being treated, whether in whole or in part, temporary or permanent. The term “preventing” means preventing in whole or in part or ameliorating or controlling. In some embodiments, compounds, compositions, methods, and kits of the invention are used in the treatment of a subject or a patient for cognitive decline (including, e.g., mild cognitive decline), cell senescence, lack, loss or diminution of telomerase or telomerase activity, loss or diminution of telomerase reverse transcriptase (TERT), TERT expression or TERT activity, telomere length (e.g., telomere shortening), and / or activity or expression of platelet / endothelial cell adhesion molecule-1 (PECAM-1). In some embodiments, a cell or group of cells is treated. In some embodiments, compounds, compositions, methods, and kits of the invention are used in the prevention of cognitive decline (including, e.g., mild cognitive decline), cell senescence, lack, loss or diminution of telomerase or telomerase activity, loss or diminution of telomerase reverse transcriptase (TERT), TERT expression or TERT activity, telomere shortening, and / or unwanted activity or expression of platelet / endothelial cell adhesion molecule-1 (PECAM-1) in a subject or a patient. In some embodiments, these are prevented in a cell or group of cells. In some embodiments, compounds, compositions, methods, and kits of the invention are used alleviation of one or more signs or symptoms of, or diminishment of one or more direct or indirect pathological consequences of cognitive decline (including, e.g., mild cognitive decline), cell senescence, lack, loss or diminution of telomerase or telomerase activity, loss or diminution of telomerase reverse transcriptase (TERT), TERT expression or TERT activity, telomere shortening, and / or unwanted activity or expression of platelet / endothelial cell adhesion molecule-1 (PECAM- 1) in a subject or a patient. In some embodiments, the signs or symptoms of, or one or more direct or indirect pathological consequences, are alleviated or diminished in a cell or group of cells. Telomere diseases or disorders associated with telomerase dysfunction are typically associated with changes in the size of telomere. Proteins involved in the telomere regulatory pathway, including TERT and telomerase itself. Also provided herein are methods of evaluating, screening, comparing, selecting and quantifying one or more activities of agents that modulate these proteins. Any modulator that is capable of eliciting a desired inhibition of the passage (e.g., transport) of molecules through a connexin gap junction and / or connexin hemichannel (e.g., ATP), may be used in embodiments of the invention and dosed according to the one or more of the schedules described herein. Any connexin agents that modulates the passage of molecules through a gap junction or connexin hemichannel are also provided in particular embodiments (e.g., those that modulate, block or lessen the passage of molecules from the cytoplasm of a cell into an extracellular space or adjoining cell cytoplasm, including ATP). Such anti-connexin modulators may modulate the passage of molecules through a gap junction or connexin hemichannel with or without gap junction uncoupling (blocking the transport of molecules through gap junctions). Such compounds include, for example, binding proteins (e.g. scFvs, antibodies, etc.), polypeptides (e.g. peptidomimetics), polynucleotides (e.g., antisense compounds) and organic compounds (e.g. tonabersat and compounds of Formula I and / or prodrugs thereof, including the tonabersat prodrugs of Formula II) that can, for example, block the function or activity of a gap junction or a hemichannel in whole or in part (e.g. by modulating release of ATP from connexin hemichannels). Chemical Connexin Hemichannel Modulators In some embodiments, the modulator used in methods of the invention is a gap junction closing or blocking compound or hemichannel closing or blocking compound (e.g. tonabersat). In some embodiments, the modulator can be a small molecule, which may also be referred to herein as an anti-connexin or a connexin or connexin gap junction or connexin hemichannel modulator. In some embodiments, methods of the invention feature the use of compounds of Formula I, for example tonabersat and / or carabersat, to directly and immediately block Cx43 hemichannels and to cause a concentration and time-dependent reduction in GJ coupling and / or hemichannel inhibition (e.g., blocking hemichannel opening and / or modulating or blocking ATP release from connexin hemichannels). Carabersat is N-[(3R,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4- dihydrochromen-4-yl]-4-fluorobenzamide) and is also referred to as trans-(+)-6-acetyl-4-(S)-(4- fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzo[b]pyran-3R-ol,hemihydrate. Tonabersat is also known by the IUPAC name N-[(3S,4S)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4- dihydrochromen-4-yl]-3-chloro-4-fluorobenzamide or (3S-cis)-N-(6-acetyl-3,4-dihydro-3- hydroxy-2,2-(dimethyl-d6)-2H-1-benzopyran-4-yl)-3-chloro-4-fluorobenzamide). In some embodiments, the anti-connexin or connexin or connexin gap junction or connexin hemichannel modulator is a compound according to Formula I: wherein Y is C—R1; R1is acetyl; R2is hydrogen, C3-8cycloalkyl, C1-6alkyl optionally interrupted by oxygen or substituted by hydroxy, C1-6alkoxy or substituted aminocarbonyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6 alkylcarbonyloxy, C1-6 alkoxy, nitro, cyano, halo, trifluoromethyl, or CF3-S-; or a group CF3-A-, where A is —CF2—,—CO—, —CH2—, CH(OH), SO2, SO, CH2—O, or CONH; or a group CF2H- A′- where A′ is oxygen, sulphur, SO, SO2, CF2or CFH; trifluoromethoxy, C1-6alkylsulphinyl, perfluoro C2-6 alkylsulphonyl, C1-6 alkylsulphonyl, C1-6 alkoxysulphinyl, C1-6 alkoxysulphonyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, phosphono, arylcarbonyloxy, heteroarylcarbonyloxy, arylsulphinyl, heteroarylsulphinyl, arylsulphonyl, or heteroarylsulphonyl in which any aromatic moiety is optionally substituted, C1-6 alkylcarbonylamino, C1-6alkoxycarbonylamino, C1-6alkyl-thiocarbonyl, C1-6alkoxy-thiocarbonyl, C1-6alkyl- thiocarbonyloxy, 1-mercapto C2-7alkyl, formyl, or aminosulphinyl, aminosulphonyl or aminocarbonyl, in which any amino moiety is optionally substituted by one or two C1-6alkyl groups, or C1-6alkylsulphinylamino, C1-6alkylsulphonylamino, C1-6alkoxysulphinylamino or C1-6alkoxysulphonylamino, or ethylenyl terminally substituted by C1-6alkylcarbonyl, nitro or cyano, or —C(C1-6alkyl)NOH or —C(C1-6alkyl)NNH2; or amino optionally substituted by one or two C1-6alkyl or by C2-7alkanoyl; one of R3and R4is hydrogen or C1-4alkyl and the other is C1-4alkyl, CF3, or CH2Xa, where Xais fluoro, chloro, bromo, iodo, C1-4alkoxy, hydroxy, C1-4alkylcarbonyloxy, —S—C1-4alkyl, nitro, amino optionally substituted by one or two C1-4alkyl groups, cyano or C1-4alkoxycarbonyl; or R3and R4together are C2-5polymethylene optionally substituted by C1-4alkyl; R5is C1-6alkylcarbonyloxy, benzoyloxy, ONO2, benzyloxy, phenyloxy or C1-6alkoxy and R6and R9are hydrogen or R5is hydroxy and R6is hydrogen or C1-2alkyl and R9is hydrogen; R7is heteroaryl or phenyl, both of which are optionally substituted one or more times independently with a group or atom selected from chloro, fluoro, bromo, iodo, nitro, amino optionally substituted once or twice by C1-4alkyl, cyano, azido, C1-4alkoxy, trifluoromethoxy and trifluoromethyl; R8is hydrogen, C1-6alkyl, OR11or NHCOR10wherein R11is hydrogen, C1-6alkyl, formyl, C1-6alkanoyl, aroyl or aryl-C1-6alkyl and R10is hydrogen, C1-6alkyl, C1-6alkoxy, mono or di C1-6alkyl amino, amino, amino-C1-6alkyl, hydroxy-C1-6alkyl, halo-C1-6alkyl, C1-6acyloxy-C1-6alkyl, C1-6alkoxycarbonyl-C1-6alkyl, aryl or heteroaryl; the R8—N—CO—R7group being cis to the R5group; and X is oxygen or NR12where R12is hydrogen or C1-6alkyl. For any of the Markush groups set forth above, in some embodiments, each group can include or exclude any of the species listed for that group. In some embodiments, the small molecule connexin modulator can be Tonabersat, carabersat, or SB-204269. SB-204269 is also known as (trans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3, 4- dihydro-2,2-dimethyl-2H-benzo[b]pyran-3R-ol). Carabersat is also known as N-[(3R,4S)-6- Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-4-fluorobenzamide. Tonabersat is also known as N-(6-Acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl)-3-chloro-4- fluorobenzamide. For any of the Markush groups set forth above, that group can include or exclude any of the species listed for that group. In some embodiments, the modulator may be a prodrug of any the compounds for use in this invention. In one aspect the connexin modulator prodrug of this invention may be a compound of Formula II: wherein Q is O or an oxime, R2 is H, A is a direct bond, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*- wherein the atom marked * is directly connected to R1, R3 and R4 are selected independently from H, fluoro, C1-4 alkyl, and C1-4 fluoroalkyl, or R3 and R4 together with the atom to which they are attached form a cyclopropyl group, R1 is selected from groups [1], [2], [2A],[3], [4], [5] and [6] wherein the atom marked ** is directly connected to A:

[0002] wherein R5 and R6 are each independently selected from H, C1-4 alkyl, C1-4 fluoroalkyl, and benzyl; R7 is independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl; R8 is selected from: (i) H, C1-4 alkyl, or C1-4 fluoroalkyl, (ii) the side chain of a natural or unnatural alpha-amino acid, or a peptide as described herein, and (iii) biotin or chemically linked to biotin; R9 is selected from H, –N(R11)(R12), –N+(R11)(R12)(R13)X-, and –N(R11)C(O)R14; wherein R11, R12, and R13 are independently selected from H, C1-4 alkyl, and C1-4 fluoroalkyl, R14 is H, C1-4 alkyl, or C1-4 fluoroalkyl, R15 is selected from C1-4 alkyl and C1-4 fluoroalkyl, and X- is a pharmaceutically acceptable anion. In some embodiments, R2 is B-R21 wherein, B is a direct bond, -C(O)O*-, -C(R23)(R24)O*, C(O)OC(R23)(R24)*, or -C(R23)(R24)OC(O)O* wherein the atom marked * is directly connected to R21, R23 and R24 are selected independently from H, fluoro, C1-4 alkyl, and C1-4 fluoroalkyl, R21 is selected from groups

[0021] ,

[0022] , [22A],

[0023] ,

[0024] ,

[0025] and

[0026] wherein the atom marked ** is directly connected to B:

[0003] wherein R5, R6, R7, R8, R9, and R15are as defined herein. For any of the Formula II Markush groups set forth above, that group can include or exclude any of the species listed for that group. In some embodiments, the peptide as described herein can be a connexin modulator, calmodulin modulator, or pannexin modulator. In some embodiments, Q is an oxime of formula =NOR43, wherein R43is (i) selected from H, C1-4fluoroalkyl or optionally substituted C1-4alkyl, and (ii) -A300-R300wherein A300is a direct bond, -C(O)O*-, -C(R3)(R4)O*-, -C(O)O-C(R3)(R4)O*-, or -C(R3)(R4)OC(O)O*- wherein the atom marked * is directly connected to R300, R3and R4are selected independently from H, fluoro, C1-4alkyl, and C1-4fluoroalkyl, or R3and R4together with the atom to which they are attached form a cyclopropyl group, R300is selected from groups [1], [2], [2A], [3], [4], [5] and [6] wherein the atom marked ** is directly connected to A300: wherein R5and R6are each independently selected from H, C1-4alkyl, C1-4fluoroalkyl, and benzyl; R7is independently selected from H, C1-4alkyl, and C1-4fluoroalkyl; R8is selected from: (iii) H, C1-4alkyl, or C1-4fluoroalkyl, (iv) the side chain of a natural alpha-amino acid, and (v) biotin or chemically linked to biotin; R9is selected from H, -N(R11)(R12), –N+(R1l)(R12)(R13)X-, and -N(R11)C(O)R14; wherein R11, R12, and R13are independently selected from H, C1-4alkyl, and C1-4fluoroalkyl, R14is H, C1-4alkyl, or C1-4fluoroalkyl, R15is selected from C1-4alkyl and C1-4fluoroalkyl, and X- is a pharmaceutically acceptable anion. In one embodiment of Formula II R43, is C1-4alkyl optionally substituted with a phosphate group (P(O)OR61R62). In an example of such an embodiment OR43is -OCH2P(O)OR61OR62, wherein R61and R62are independently H or C1-4alkyl. In another embodiment of Formula II R43is an amino acid derivative having the structure C(O)CH(R100)NH2wherein the group R100is the side chain of a natural or unnatural amino acid or a peptide as described herein. In some embodiments, the natural amino acid is selected from one of the 22 canonical amino acids. In some embodiments, the unnatural amino acid is selected from any amino acid which is not one of the 22 canonical amino acids. In some embodiments, the unnatural amino acid is selected from: (cis)-3-Aminobicyclo[2.2.1]heptane-2-carboxylic acid hydrochloride, exo-cis-3- Aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid hydrochloride, cis-2-Amino-2- methylcyclohexanecarboxylic acid hydrochloride, (R)-2-(Boc-amino)octanedioic acid, Boc-4- (Fmoc-amino)-L-phenylalanine, Boc-(2-indanyl)-Gly-OH, (R)-4-Boc-3-morpholineacetic acid, (S)-4-Boc-3-morpholineacetic acid, Boc-pentafluoro-D-phenylalanine, Boc-pentafluoro-L- phenylalanine, Boc-Phe(2-Br)-OH, Boc-Phe(4-Br)-OH, Boc-D-Phe(4-Br)-OH, Boc-D-Phe(3-Cl)- OH, Boc-Phe(4-NH2)-OH, Boc-Phe(3,5-F2)-OH, 2-(4-Boc-piperazino)-2-(2-fluorophenyl)acetic acid, 2-(4-Boc-piperazino)-2-(4-fluorophenyl)acetic acid, 2-(4-Boc-piperazino)-2-phenylacetic acid, 2-(4-Boc-piperazino)-2-(3-pyridyl)acetic acid, penicillamine, thialysine. quisqualic acid, canavanine. azetidine-2-carboxylic acid, Carboxyglutamic acid, Hydroxyproline, Hypusine, and Pyroglutamic acid. In one embodiment of Formula II OR43is -OC(O)CH(CH(CH3)2)NH2. For any of the Formula II Markush groups set forth above, in some embodiments, each group can include or exclude any of the species listed for that group. In some embodiments “promoiety” refers to a species acting as a protecting group which masks a functional group within an active agent, thereby converting the active agent into a pro-drug. The active agent may be any of the modulators or ocular therapeutics disclosed herein. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo, thereby converting the pro-drug into its active form. In some embodiments the promoiety may also be an active agent. In some embodiments the promoiety may be bound to a connexin modulator, a connexin gap junction modulator, or a connexin hemichannel modulator. In some embodiments the promoiety may be bound to any of the polynucleotides, peptides or peptidomimetics, small molecule antagonists and / or other treatments disclosed herein. In some embodiments the promoeity may be bound to a compound of Formula I. In some embodiments the pro-drug may be a compound of Formula II. In some embodiments the promoiety may be any peptidomimetic or peptide antagonist of this disclosure. In some embodiments, the promoeity is a single amino acid which is optionally protected on its functional groups. In some embodiments, the promoeity is a targeting species. In some embodiments, the promoeity is a substrate for an influx or efflux transporters on the cell membrane, for example those described in Gaudana, R. et al. Ocular Drug Delivery. The AAPS Journal, 12:3, 348-360 (2010). The promoeity can be, for example, chemically-linked biotin. The promoeity can be, for example, chemically-linked D-serine. In some embodiments, compounds of Formula I or Formula II, e.g., tonabersat, carabersat or analogues thereof, are nonionic, are in the form of a free base, a free acid, or a pharmaceutically acceptable salt. By way of example, a pharmaceutically acceptable salt includes a hydrochloride salt and salts derived from acid including, but not limited to, hydrobromic acid, hydrochloric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, salicylic acid, citric acid, oxalic acid, lactic acid, malic acid, succinic acid, methanesulphonic acid and p-toluene sulphonic acid, a salt of itself. In one embodiment, the salt is a hydrochloride salt. In one embodiment, the salt is a succinate salt. In other embodiments, one or more polymorph, one or more isomer, and / or one or more solvate of a compound of Formula I or Formula II, e.g., tonabersat, carabersat or analogues thereof, may be used. Peptidomimetic Connexin Hemichannel Modulators In some embodiments, connexin modulators, including connexin, connexin gap junction and connexin hemichannel modulators, useful in methods of the invention include not only organic molecule-based connexin hemichannel modulators, but also but also connexin peptides or peptidomimetics, such as connexin 43 peptides or peptidomimetics, sometimes referred to anti- connexin peptides or peptidomimetics, e.g., anti-connexin hemichannel blocking peptides or peptidomimetics, which may be used in methods of the invention and dosed according to the one or more of the schedules described herein. They include, for example, peptides or peptidomimetic connexin modulators comprising or consisting essentially of sequences corresponding to portions of connexin extracellular domains, connexin transmembrane regions, and connexin carboxy- terminus regions. In some embodiments, connexin, connexin gap junction and connexin hemichannel modulators useful in methods of the invention include connexin 43 peptides or peptidomimetics with sequences according to a portion of the amino acid sequence of SEQ ID NO:100 (connexin 43 protein). In some embodiments, the connexin modulators useful in methods of the invention for treating a disease, disorder, defect in a subject are anti-connexin 43 peptides or peptidomimetics. In some embodiments, anti-connexin 43 peptides or peptidomimetic that may be used in methods of the invention and dosed according to the one or more of the regemins described herein is a peptide comprising or consisting essentially of a portion of an extracellular domain of a connexin (e.g. connexin 43) and / or a peptide comprising or consisting essentially of a portion of a carboxy- terminal portion of a connexin (e.g. connexin 43), including those described and / or referenced herein. The protein sequence of connexin 43 is shown below. Connexin 43 (SEQ ID NO:100) Met Gly Asp Trp Ser Ala Leu Gly Lys Leu Leu Asp Lys Val Gln Ala 1 5 10 15 Tyr Ser Thr Ala Gly Gly Lys Val Trp Leu Ser Val Leu Phe Ile Phe 20 25 30 Arg Ile Leu Leu Leu Gly Thr Ala Val Glu Ser Ala Trp Gly Asp Glu 35 40 45 Gln Ser Ala Phe Arg Cys Asn Thr Gln Gln Pro Gly Cys Glu Asn Val 50 55 60 Cys Tyr Asp Lys Ser Phe Pro Ile Ser His Val Arg Phe Trp Val Leu 65 70 75 80 Gln Ile Ile Phe Val Ser Val Pro Thr Leu Leu Tyr Leu Ala His Val 85 90 95 Phe Tyr Val Met Arg Lys Glu Glu Lys Leu Asn Lys Lys Glu Glu Glu 100 105 110 Leu Lys Val Ala Gln Thr Asp Gly Val Asn Val Asp Met His Leu Lys 115 120 125 Gln Ile Glu Ile Lys Lys Phe Lys Tyr Gly Ile Glu Glu His Gly Lys 130 135 140 Val Lys Met Arg Gly Gly Leu Leu Arg Thr Tyr Ile Ile Ser Ile Leu 145 150 155 160 Phe Lys Ser Ile Phe Glu Val Ala Phe Leu Leu Ile Gln Trp Tyr Ile 165 170 175 Tyr Gly Phe Ser Leu Ser Ala Val Tyr Thr Cys Lys Arg Asp Pro Cys 180 185 190 Pro His Gln Val Asp Cys Phe Leu Ser Arg Pro Thr Glu Lys Thr Ile 195 200 205 Phe Ile Ile Phe Met Leu Val Val Ser Leu Val Ser Leu Ala Leu Asn 210 215 220 Ile Ile Glu Leu Phe Tyr Val Phe Phe Lys Gly Val Lys Asp Arg Val 225 230 235 240 Lys Gly Lys Ser Asp Pro Tyr His Ala Thr Ser Gly Ala Leu Ser Pro 245 250 255 Ala Lys Asp Cys Gly Ser Gln Lys Tyr Ala Tyr Phe Asn Gly Cys Ser 260 265 270 Ser Pro Thr Ala Pro Leu Ser Pro Met Ser Pro Pro Gly Tyr Lys Leu 275 280 285 Val Thr Gly Asp Arg Asn Asn Ser Ser Cys Arg Asn Tyr Asn Lys Gln 290 295 300 Ala Ser Glu Gln Asn Trp Ala Asn Tyr Ser Ala Glu Gln Asn Arg Met 305 310 315 320 Gly Gln Ala Gly Ser Thr Ile Ser Asn Ser His Ala Gln Pro Phe Asp 325 330 335 Phe Pro Asp Asp Asn Gln Asn Ser Lys Lys Leu Ala Ala Gly His Glu 340 345 350 Leu Gln Pro Leu Ala Ile Val Asp Gln Arg Pro Ser Ser Arg Ala Ser 355 360 365 Ser Arg Ala Ser Ser Arg Pro Arg Pro Asp Asp Leu Glu Ile 370 375 380 In some embodiments, connexin 43 (Cx43) and other connexin peptide modulators useful in carrying out methods of the invention include peptides such as Peptide5, i.e., VDCFLSRPTEKT (SEQ ID NO:107), as Gap19, i.e., KQIEKKFK (SEQ ID NO:108), Gap26, i.e., VCYDKSFPISHVR (SEQ ID NO:102), Gap27, a peptide called alpha connexin carboxyl terminus 1 (αCT1), and more, each targeting different binding sites with varying specificity and size. The connexin mimetic peptide Gap27, targeted to the SRPTEKTIFFI sequence (amino acids 204–214) on the second extracellular loop of Cx43 (SEQ ID NO:109), is a versatile inhibitor of connexin- mediated communication. In some embodiments the connexin 43 modulator may comprise or consist essentially of, for example, a peptide or peptidomimetic comprising or consisting essentially of SRPTEKTIF (SEQ ID NO:110). In addition to Peptide5, Gap19, Gap 26, and Gap 27, another peptidomimetic particularly useful in the compositions, doses and dosing methods and schedules, kits and articles of manufacture disclosed herein is the fusion peptide designated XG19, i.e., lclrpvGGKQIEIKKFK, wherein lower case denotes the D-isomer [SEQ ID NO:111]). The XG19 peptidomimetic and its connexin modulation actions are described in US Patent No.11,466,069, incorporated in its entirety herein by reference, as noted above. In some embodiments, the invention provides compositions for use in the methods of the invention for treating a subject or a patient disease, or administration to a subject (e.g., in a laboratory) comprising a construct comprising (a) a targeting carrier peptide derived from the X-protein of the Hepatitis B virus and (b) a peptide capable of interacting with an intracellular domain of a connexin. In some embodiments, the targeting carrier peptide derived from the X-protein of the Hepatitis B virus comprises an amino acid sequence selected from the group consisting of all targeting carrier peptide described in US Patent No. 11,466,069. In some embodiments, the peptide capable of interacting with an intracellular domain interacts with the intracellular domain of one or more of connexin Cx26, Cx30, Cx30.3, Cx31.1, Cx32, Cx36, Cx37, Cx40, Cx43, Cx45, Cx50 and Cx58, including those described herein. In some embodiments, the peptide capable of interacting with an intracellular domain interacts with the intracellular domain of connexin 43. In some embodiments, the peptide capable of interacting with the intracellular domain of connexin 43 includes any of the connexin 43 intracellular interacting peptides described in US Patent No. 11,466,069, as well as those peptides described herein that interact with the intracellular domain of connexin 43. In some embodiments, the connexin 43 modulators which may be used in methods of the invention can comprise peptides having a sequence comprising or consisting essentially of, for example, one or more of the following sequences: “Peptide 1” ADCFLSRPTEKT (SEQ ID NO: 112), “Peptide 2” VACFLSRPTEKT (SEQ ID NO: 113), “Peptide 11” VDCFLSRPTAKT (SEQ ID NO: 114), “Peptide 12” VDCFLSRPTEAT (SEQ ID NO: 115), “Peptide 5” VDCFLSRPTEKT (SEQ ID NO: 107), “Mod1” CFLSRPTEKT (SEQ ID NO: 116) and “Mod2” LSRPTEKT (SEQ ID NO: 117). In some embodiments, the carboxy-terminus of an anti-connexin peptide or peptidomimetic modulator can be modified. In some embodiments, the carboxy-terminus modification can comprise n-alkyl chains which can optionally be further linked to hydrogen or other moieties. In some embodiments, the connexin 43 peptides can include or exclude any of the peptides listed above or disclosed herein. In some embodiments, the peptide or peptidomimetic comprises or consists essentially of from 7 to 40 amino acids of a connexin including, e.g., SEQ ID NO: 101 (SRPTEKT), SEQ ID NO: 107 (VDCFLSRPTEKT) and does not comprise a connexin C-terminal peptide. Anti-connexin agents include peptides having an amino acid sequence that comprises about 5 to 20 contiguous amino acids of a connexin protein such as connexin 43 (SEQ ID NO:100), peptides having an amino acid sequence that comprises about 8 to 15 contiguous amino acids of connexin 43, or peptides having an amino acid sequence that comprises about 11 to 13 contiguous amino acids of connexin 43. Other anti-connexin agents include a peptide having an amino acid sequence that comprises at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 20, at least about 25, or at least about 30 contiguous amino acids of connexin 43. Other anti-connexin 43 modulators comprise the extracellular domains of connexin 43, for example, peptide or peptidomimetic comprising or consisting essentially of SRPTEKT (SEQ ID NO: 101) or VDCFLSRPTEKT (SEQ ID NO: 107). In other anti-connexin compounds, mimetic peptides are based on the extracellular domains of connexin 43 corresponding to the amino acids at positions 37-76 and 178-208 of connexin 43 protein sequence. Thus, certain anti-connexin peptides useful in methods of the invention have an amino acid sequence comprising or consisting essentially of about 7 to about 40 of the amino acids corresponding to the regions at positions 37-76 and 178-208 of the connexin 43 protein sequence. The peptides need not have an amino acid sequence identical to those portions of the connexin 43 protein sequence, and conservative amino acid changes may be made such that the peptides retain binding activity or functional activity in the assays described herein and otherwise known in the art. In other embodiments, mimetic peptides are based on peptide target regions within the connexin protein other than the extracellular domains (e.g. portions of the connexin 43 protein sequence not corresponding to positions 37-76 and 178-208). In addition to therapeutically effective modified or unmodified peptide or peptidomimetics comprising or consisting essentially of a portion of an extracellular or transmembrane domain or C-terminal domain of a connexin 43, for example, other embodiments include modified or unmodified peptides or peptidomimetics comprising or consisting essentially of a portion of, for example, an extracellular or transmembrane domain of one or more other target connexins may be used in methods of the invention described herein. Other embodiments include modified or unmodified peptides or peptidomimetics comprising or consisting essentially of, for example, a portion of an extracellular or transmembrane domain of one or more other connexins found in blood vessels (e.g. endothelium, etc.), cells of a target organ (e.g., kidney, liver, eye, brain, skin, etc.). In some embodiments, the anti-connexin peptidomimetic useful in a method of the invention is a connexin 45 peptidomimetic modulator comprising portions of the connexin 45 protein that antagonize or inhibit or block connexin-connexin interactions. In some embodiments the connexin 45 modulator may comprise, for example, a peptide or peptidomimetic comprising or consisting essentially of a portion of the E2 or C terminal domain of connexin 45, for example, comprising SRPTEKT (SEQ ID NO: 101). The peptide or peptidomimetic may also comprise, for example DCFISRPTEKT (SEQ ID NO: 118). Exemplary peptide sequences for connexin 45 peptides and peptidomimetic modulators useful in methods of the invention are also provided in Table 63 of US Patent No.10,465,188. In some embodiments, a connexin modulator comprises a peptide comprising an amino acid sequence corresponding to a portion of a transmembrane region of connexin 45 or a C-terminal region of connexin 45. In particular non-limiting embodiments, for example, the anti-connexin compound is a peptide having an amino acid sequence that comprises about 3 to about 30 contiguous amino acids of the known connexin 45 sequence, a peptide having an amino acid sequence that comprises about 5 to about 20 contiguous amino acids of the known connexin 45 sequence, a peptide having an amino acid sequence that comprises about 8 to about 15 contiguous amino acids of the known connexin 45 sequence, or a peptide having an amino acid sequence that comprises about 11, 12, or 13 contiguous amino acids of the known connexin 45 sequence. Other non-limiting embodiments include an anti-connexin compound that is a peptide having an amino acid sequence that comprises at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30 contiguous amino acids of a known connexin 45 sequence. In certain anti-connexin compounds provided herein, mimetic peptides are based on the extracellular domains of connexin 45 corresponding to the amino acids at positions 46-75 and 199-228 of a known connexin 45 sequence. Thus, certain peptide described herein have an amino acid sequence corresponding to the regions at positions 46-75 and 199-228 of a known connexin 45 sequence. The peptides need not have an amino acid sequence identical to those portions of known connexin 45 sequence, and conservative amino acid changes may be made such that the peptides retain binding activity or functional activity in the assays described herein and otherwise known in the art. In other embodiments, mimetic peptides are based on peptide target regions within the connexin protein other than the extracellular domains (e.g. portions of a known connexin 45 sequence not corresponding to positions 46-75 and 199-228). See WO2006 / 134494, disclosing various connexin sequences. Some peptidomimetic connexin modulators useful in methods of the invention include VDCFLSRPTEKT (SEQ ID NO: 107) and SRPTEKTIFII (SEQ ID NO: 101), which bind, for example, to the Cx43 extracellular domain. In some embodiments, the connexin 26 peptidomimetic connexin modulator useful in a method of the invention and dosed according to the one or more of the schedules described herein is Gap26. In other embodiments, the anti-connexin peptidomimetic for use in a method of the invention is a connexin32 peptidomimetic (e.g. INCTLQPGCNSV (SEQ ID NO: 103) or32Gap27, i.e., SRPTEKTIFII (SEQ ID NO:104) or a connexin50 peptidomimetic (e.g. TAT-Cx50L2, i.e., GGERAPLAADQGSVKKSSSSSKGTKK (SEQ ID NO:105) or TAT-Cx50CT, i.e., SRARSDDLTV (SEQ ID NO:106)). In some embodiments, peptides and peptidomimetics include peptides and peptidomimetics useful for the inhibition of gap junction channels and hemichannels corresponding to specific sequences within extracellular loops E1 and E2 involving the conserved QPG and SHVR motifs of E1 (Gap26 peptide) and the SRPTEK motif in E2 (Gap27 peptide) as well as the cytoplasmic loop (Gap19 peptide). Useful peptidomimetic connexin modulators are described in US Patent No. 9,248,141 (“Methods of treatment by administering anti-connexin peptides and mimetics”). Other useful peptide connexin modulators are described in US Patent No.11,466,069 (“Methods of treatment and novel constructs”), including XG19 and other constructs comprising a targeting carrier peptide derived from the X-protein of the Hepatitis B virus and a peptide capable of interacting with an intracellular domain of a connexin (e.g. connexin 43). Other connexin peptide modulators useful in methods of the invention are provided in Table 64 of US Patent No.10,465,188. Useful peptide modulators of connexin 43 (Cx43) and other connexins that may be dosed in embodiments of the invention are also referenced in King, DR, et al., Mechanisms of Connexin Regulating Peptides Int. J. Mol. Sci.22:10186 (Sept 2021) and Figure 1 (“Schematic of the Cx43 protein in the plasma membrane with colored lines indicating the positions of described peptides targeting EL, IL and CT regions”) and Table 1 (“Connexin Peptides”). In some embodiments the peptides may also be used as promoieties. See, e.g. Vig, BS, et al., Amino acids as promoieties in drug design and Development. Advanced Drug Delivery Reviews 65(10): p 1370-1385 (2013); Dhokchawle, B, et al., Promoieties Used In Prodrug Design: A Review. Indian Journal of Pharmaceutical Education 48(2):35-40 (2013). Connexin hemichannel-blocking or modulating peptides or peptidomimetics may be unmodified, or modified as desired (e.g. to increase stability, to further stabilize peptide conformation, increase bioactivity, increase cell permeability, etc.). See e.g. Boto, A, et al. Site-selective modification of peptide backbones. Org. Chem. Front. 8:6720-6759 (2021) (review article). Thus, for example, peptidomimetics used in methods of the invention may contain one or more modified amino acids, amino acid analogs, or may be otherwise modified to improve bioavailability or to increase penetration across the cell membrane. Other peptide sequences known to inhibit the inter-connexin binding that can regulate connexin activity are the cytoplasmic loop of connexin 43 (amino acids 119–144) L2 peptide and subparts of the L2 peptide of connexin 43. In some embodiments, these peptides may include or exclude, for example, the nine amino acid sequence of Gap19, KQIEIKKFK (SEQ ID NO: 108); the native Gap19 sequence, DGVNVEMHLKQIEIKKFKYGIEEHGK (SEQ ID NO: 119); the His144→Glu L2 derivative of Gap19, as reported by Shibayama (Shibayama, J. et al., Biophys. J. 91, 405404063, 2006), DGVNVEMHLKQIEIKKFKYGIEEQGK (SEQ ID NO: 120); the TAT- Gap19 sequence, YGRKKRRQRRRKQIEIKKFK (SEQ ID NO: 121); the SH3 binding domain, CSSPTAPLSPMSPPGYK (SEQ ID NO: 122), or subpart thereof PTAPLSPMSPP (SEQ ID NO: 123); the C-terminal sequence of the CT9 or CT10 peptide, with or without a TAT leader sequence to increase cell penetration, for example, RPRDDEI (CT9; SEQ ID NO: 124), SRPRDDLEI (CT10; SEQ ID NO: 125), YGRKKRRQRRRSRPRDDEI (TAT-CT9; SEQ ID NO: 126), or YGRKKRRQRRRRPRDDEI (TAT-CT10; SEQ ID NO: 127). Other peptidomimetic sequences that can be included or excluded in the compositions, methods, kits or articles of manufacture disclosed herein are those reported by Dhein (Dhein, S., Naunyn-Schmiedeberg’s Arch. Pharm., 350: 174-184, 1994); the AAP10 peptide, H2N-Gly-Ala-Gly-4Hyp-Pro-Tyr-CONH2(SEQ ID NO: 128), and the ZP123 peptide (rotigapeptide), Ac-D-Tyr-Pro-D-4Hyp-Gly-D-Ala-Gly-NH2(SEQ ID NO: 129), (Dhein, S., et al. Cell Commun. Adhes. 10, 371-378, 2003). Rotigapeptide is comprised of the D-form of the peptides for enhanced efficacy over the native L-form of the peptide. In some embodiments, the therapeutically effective modified or unmodified peptide or peptidomimetic comprises a portion of the E1 extracellular domain of a connexin, such as the connexin 43 E1 (ESAWGDEQSAFRCNTQQPGCENVCYDKSFPISHVR; SEQ ID NO:130) or the connexin 45 E1 (GESIYYDEQSKFVCNTEQPGCENVCYDAFAPLSHVR; SEQ ID NO:131). In some embodiments, the therapeutically effective modified or unmodified peptide or peptidomimetic comprises a portion of the E2 extracellular domain of a connexin, such as the connexin 43 E2 (LLIQWYIYGFSLSAVYTCKRDPCPHQVDCFLSRPTEKT; SEQ ID NO:132) or the connexin 45 E2 (LIGQYFLYGFQVHPFYVCSRLPCHPKIDCFISRPTEKT; SEQ ID NO:133). In certain embodiments, the connexin 43 modulator peptides of the present invention can be linked at the amino or carboxy terminus to a cellular internalization transporter. The cellular internalization transporter linked to connexin 43 modulator peptides of the present invention may be any internalization sequence known or newly discovered in the art, or conservative variants thereof. Non-limiting examples of cellular internalization transporters and sequences include antennapedia sequences, TAT, HIV-Tat, Penetratin, Antp-3A (Antp mutant), Buforin II, Transportan, MAP (model amphipathic peptide), K-FGF, Ku70, Prion, pVEC, Pep-1, SynB1, Pep- 7, HN-1, BGSC (Bis-Guanidinium-Spermidine-Cholesterol, and BGTC (BisGuanidinium-Tren- Cholesterol). Cellular internalization transporters are useful for peptidomimetics such as Gap19 and the aCT peptides. The sequences of exemplary cellular internalization peptides are known in the art. See, e.g., Table 65 in US Patent No.10,465,188; US Patent No.11,466,069. In other embodiments, the peptide or peptidomimetic may be modified to increase transfection uptake by conjugating the peptide to a hydrophobic compound, in some embodiments, through a linker moiety. The hydrophobic compound may be, for example, one or more n-alkyl groups, which may be, for example, C6-C14 alkyl groups. In some embodiments, the peptides may be conjugated at the N terminus to one or two dodecyl (C12) groups as described in Chen, YS et al., Cytotoxicity and Vitreous Stability of Chemically Modified Connexin43 Mimetic Peptides for the Treatment of Optic Neuropathy. J.Pharm. Sci., 102: 2322-2331 (2013). In one embodiment, the peptide sequence CFLSRPTEKT (SEQ ID NO:116) or VDCFLSRPTEKT (SEQ ID NO:107) can be conjugated to two dodecyl groups to create a modified peptide which can modulate connexin43, “C12-C12-Cxn43 MP.” See SEQ ID NO: 326 in US Patent No. 10,465,188.In some embodiments, the therapeutically effective modified or unmodified peptide or peptidomimetic comprises a portion of the C-terminal domain of a connexin, such as connexin 43 or connexin 45, preferably connexin 43. Some embodiments of anti-connexin 43 modulators useful in methods of the invention comprise the C-terminus region of connexin 43, or modified versions thereof. See, e.g., O’Quinn, MP, et al., A Peptide Mimetic of the Connexin43 Carboxyl-Terminus Reduces Gap Junction Remodeling and Induced Arrhythmia Following Ventricular Injury. Circ Res. 108(6): 704-715 (Mar 2011). C-terminus connexin peptidomimetic modulators, including αCT1 (alpha connexin carboxy terminus 1) peptides (also referred to as aCT1 or ACT1 peptides in publications), are described, for example, in Montgomery et al., Connexin 43-Based Therapeutics for Dermal Wound Healing Int. J. Mol. Sci. 2018, 19, 1778, and US Patent No. 8,815,556 (“Compositions and methods for tissue engineering, tissue regeneration and wound healing”). See also WO2006 / 069181. Preferred connexin carboxy-terminal polypeptides are connexin 43 carboxy-terminal polypeptides. Such compounds are described in US Patent Publication No. 20070042964 (“Compositions and methods for modulating connexin hemichannels”). If a connexin peptide or peptidomimetic modulator comprises a portion of an intracellular domain of a connexin (e.g. an aCT peptide, such as CT9, CT10, ^CT1, etc.), the peptide may be conjugated to a cell internalization transporter including those noted or referenced herein. In some embodiments, a connexin peptidomimetic modulator useful in methods of then invention may block zona occludens (ZO-1) binding to connexin 43 and modulate connexin gap junctions and hemichannels to advantage. See Figure 2 in Caufriez, A, et al. Peptide-based targeting of connexins and pannexins for therapeutic purposes. Expert Opinion on Drug Discovery 15(10):1213-1222 (2020). In some embodiments, the connexin modulator may be a gap junction closing compound and / or hemichannel closing compound. In some embodiments, the gap junction closing compounds and hemichannel closing compounds are connexin 43 gap junction closing compounds and connexin 43 hemichannel closing compounds (e.g. a Cx43 C-terminus peptidomimetic). Various useful peptidomimetic peptides mimic sequences of connexin extracellular regions. The first extracellular loops of Cx37, Cx40 as well Cx43 are mimicked by peptides under the Gap26 code. Gap27 and Peptide5 mimic regions of the second extracellular loop. Gap27 targets Cx32, Cx40 and Cx43, while Peptide5 is used for Cx43 inhibition. JM2, ΔSH3, CT9, CT10, αCT mimic the C-terminal tail of Cx43 and Gap24 reproduces a sequence of the cytoplasmic loop of Cx32. Both L2 and Gap19 also mimic the cytoplasmic loop but of Cx43. The extracellular loops of connexin hemichannels are also good targets for peptidomimetic connexin modulators useful in the invention due to their accessibility in contrast to their full channel counterparts. Nevertheless, peptides containing the conserved motives QPG and SHVR of the first extracellular loop and the SRPTEK motif of the second extracellular loop interfere with the formation of gap junctions. This led to the development of peptide mimetics43Gap26,37,40Gap26,32Gap27,40Gap27,43Gap27 and43Peptide5 (note that the superscript in thenomenclature of these peptide analogues refers to Cx subtypes they can target). The conserved SHVR motif of the first extracellular loop is incorporated in the sequence of useful Gap26 peptide mimetics. The two slightly different sequences are both categorized under the Gap26 code, one targeting Cx37 and Cx40, and the other targeting only Cx43. Cells treated with either of these Gap26 peptides showed Cx hemichannel inhibition within minutes. There are three Gap27 peptides, each targeting different Cx types, namely Cx32, Cx40 and Cx43 that are useful in compositions and methods of the invention. These peptides mimic the conserved SRPTEK motif of the second extracellular loop, but have the same time-dependent effect on gap junction activity as Gap26. Like Gap27, Peptide5 contains the SRPTEK motif. However, the mimicked sequence of Peptide5 is shifted in the direction of the N-terminal tail in comparison to that of Gap27. Peptide5 can inhibit Cx43 hemichannels at a concentration of 5–10 μM, but incubation at higher concentration (100 μM or higher) can also leads to inhibition of gap junctions in some circumstances. Other peptides useful in compositions and methods of the invention mimic sequences of connexin intracellular regions. The interaction between the cytoplasmic loop and C-terminal tail mediates the gating mechanism of connexin hemichannels and gap junctions. Gap junctions are in an open state when there is no interaction between the C-terminal tail and cytoplasmic loop, while such interaction is critical for connexin hemichannel opening. The CT10 peptidomimetic reproduces the last 10 amino acids of the C-terminal tail of Cx43. Inhibition of connexin 43- (Cx43)-mediated ATP release by a peptide mimetic, called TAT-L2, pinpointed its mimicked L2 region (amino acid 119 to 144) as an essential sequence of the cytoplasmic loop in the interaction with the Cx43 C- terminal tail. To date, 2 peptides mimicking the L2 region are available, namely43Gap19 and32Gap24.43Gap19 inhibits Cx43 hemichannel currents by binding to the C-terminal tail, thereby inhibiting the cytoplasmic loop / C-terminal tail interaction.43Gap19 has the advantage of being a selective inhibitor, as it does not affect gap junction or Panx1 channel activity.32Gap24 is a peptide that mimics a 13 amino acid long stretch of the L2 region of Cx32 and can also be used in methods of the invention. Cx32 is one of the ten human corneal epithelial connexin that can be usefully targeted as described herein. In vitro studies showed that Cx32 hemichannel-mediated ATP release is inhibited by32Gap24 at concentrations of 17 μM without affecting gap junctions. Peptides targeting intracellular regions of connexin proteins need to access the intracellular environment. Cell-penetrating peptides for this purpose are described herein (e.g. the TAT- peptide, an oligoarginine tag and the Xentry peptide), and can be anchored to connexin-derived peptide sequences in order to enhance the uptake into the cell via endocytosis.43Gap19 can enter the cell on its own due to the KKFK cell-translocation motif of the L2 region. Nonetheless, comparison of the IC50(half maximal inhibitory concentration) of43Gap19 itself (47 μM) and TAT-43Gap19 (7 μM) for the inhibition of ATP release in glioma cells showed that the entry of43Gap19 into the cell can be improved by linking to a TAT-tag. All 5 available peptides mimicking the C-terminal tail are derived from Cx43. The αCT1 peptidomimetic mimics the last 9 amino acids of Cx43 and is linked to an antennapedia sequence that facilitates cellular internalization of the peptide mimetic. The interaction between Cx43 and the PDZ-domain of ZO-1, a region that is suggested to be involved in the regulation of Cx trafficking and gap junction assembly, is disrupted by αCT1. This interference reportedly leads to increased gap junction plaque formation and decreased Cx hemichannel activity. If a peptide or peptidomimetic modulator comprises a portion of an intracellular domain of a connexin, the peptide may, in some embodiments, be conjugated to a cell internalization transporter and may, in some instances, block zona occludens (ZO-1) binding to connexin 43. In some embodiments of this invention, the connexin modulator is a peptide or peptidomimetic shown in Table II below (E2 and T2 refer to the location of a peptide in, for example, the second extracellular domain or the second transmembrane domain). Table II In some embodiments the connexin 43 modulator may comprise, for example, a peptide or peptidomimetic comprising, for example SEQ ID NO: 101 (SRPTEKT). The peptide or peptidomimetic may also comprise, for example SEQ ID NO: 168 (VDCFLSRPTEKT). The peptide may contain one or more modified amino acids, amino acid analogs, or may be otherwise modified to improve bioavailability or to increase penetration across the cell membrane. For example, SEQ ID NO: 107 may be modified to obtain SEQ ID NOS:177-191 and 311-313. In some embodiments, the peptide or peptidomimetic comprising, for example SEQ ID NO: 101 (SRPTEKT) or SEQ ID NO: 107 (VDCFLSRPTEKT) comprises from 7 to 40 amino acids or amino acid analogues and does not comprise a C-terminal peptide. In some embodiments the peptides may also be used as promoieties. In some embodiments, the Connexin 45 modulators can be peptide or peptidomimetics comprising portions of the Connexin 45 protein that antagonize or inhibit or block connexin-connexin interactions. Exemplary peptide sequences for Connexin 45 peptides and peptidomimetic modulators are provided in Table III. Table III. Sequences of Connexin 45 modulator peptides or peptidomimetics In some embodiments the connexin 45 modulator may comprise, for example, a peptide or peptidomimetic comprising, a portion of the E2 or C terminal domain of connexin 45, for example, comprising SEQ ID NO: 280 (SRPTEKT). The peptide or peptidomimetic may also comprise, for example SEQ ID NO: 279 (DCFISRPTEKT). In some embodiments the peptides may only be 3 amino acids in length, including SRL, PCH, LCP, CHP, IYY, SKF, QPC, VCY, APL, HVR, or longer. When specific proteins are referred to herein, derivatives, variants, and fragments are contemplated and included. Protein derivatives and variants are well understood to those of skill in the art and can involve insertional, substitutional or deletional amino acid sequence variants known in the art. The gap junction modulators and anti-connexin hemichannel blocking peptides or peptidomimetics are made chemically, synthetically, or otherwise manufactured. Antisense Connexin Hemichannel Modulators A gap junction and / or connexin polynucleotide or oligonucleotide may be selected, for example, from modified or unmodified connexin polynucleotides or oligonucleotides (e.g. modified or unmodified connexin 43 antisense polynucleotides or oligonucleotides). In some embodiments, the modified connexin antisense polynucleotides, or oligonucleotides or polynucleotides comprise mixtures of modified and unmodified nucleotides. In some embodiments, the connexin 43 antisense compound used in the methods herein is an antisense oligonucleotide comprising naturally occurring nucleobases and an unmodified internucleoside linkage. In some embodiments, the connexin 43 antisense compound is targeted to at least about 8 nucleobases of a nucleic acid molecule encoding a connexin having a nucleobase sequence selected from SEQ ID NO:17. The polynucleotides and oligonucleotides, for example, connexin 43 antisense compounds, may have from about 8 to about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, or about 80 nucleotides of SEQ ID NO:17, or a sequence complementary thereto, and / or the antisense polynucleotide or oligonucleotide may contain any range of lengths between any two of the recited lengths. The polynucleotides of this invention include synthesized polynucleotides having a length of less than 80 nucleotides, e.g., from 12-18 to about 50-80 nucleotides, preferably about 30 nucleotides or less, e.g., from 12 to about 30 nucleotides, and more preferably from about 15 to about 30 nucleotides. In one example, the polynucleotide has 30 nucleotides. The methods of this invention features, in some embodiments, the use of connexin 43 antisense compounds up to 40 nucleotides in length, for example, 15 to 40 nucleotides in length, comprising or consisting essentially of a nucleotide sequence selected from SEQ ID NO:1-17. The methods of this invention features, in some embodiments, the use of connexin 43 antisense compounds up to 40 nucleotides in length, for example, 15 to 40 nucleotides in length, comprising a nucleotide sequence selected from SEQ ID NO:4-17. Human Cx 43, ^1 (SEQ ID NO: 17) LOCUS NM_000165 3088 bp mRNA linear PRI 26-OCT-2004 DEFINITION Homo sapiens gap junction protein, alpha 1, 43kDa (connexin 43) (GJA1), mRNA. 1 acaaaaaagc ttttacgagg tatcagcact tttctttcat tagggggaag gcgtgaggaa 61 agtaccaaac agcagcggag ttttaaactt taaatagaca ggtctgagtg cctgaacttg 121 ccttttcatt ttacttcatc ctccaaggag ttcaatcact tggcgtgact tcactacttt 181 taagcaaaag agtggtgccc aggcaacatg ggtgactgga gcgccttagg caaactcctt 241 gacaaggttc aagcctactc aactgctgga gggaaggtgt ggctgtcagt acttttcatt 301 ttccgaatcc tgctgctggg gacagcggtt gagtcagcct ggggagatga gcagtctgcc 361 tttcgttgta acactcagca acctggttgt gaaaatgtct gctatgacaa gtctttccca 421 atctctcatg tgcgcttctg ggtcctgcag atcatatttg tgtctgtacc cacactcttg 481 tacctggctc atgtgttcta tgtgatgcga aaggaagaga aactgaacaa gaaagaggaa 541 gaactcaagg ttgcccaaac tgatggtgtc aatgtggaca tgcacttgaa gcagattgag 601 ataaagaagt tcaagtacgg tattgaagag catggtaagg tgaaaatgcg aggggggttg 661 ctgcgaacct acatcatcag tatcctcttc aagtctatct ttgaggtggc cttcttgctg 721 atccagtggt acatctatgg attcagcttg agtgctgttt acacttgcaa aagagatccc 781 tgcccacatc aggtggactg tttcctctct cgccccacgg agaaaaccat cttcatcatc 841 ttcatgctgg tggtgtcctt ggtgtccctg gccttgaata tcattgaact cttctatgtt 901 ttcttcaagg gcgttaagga tcgggttaag ggaaagagcg acccttacca tgcgaccagt 961 ggtgcgctga gccctgccaa agactgtggg tctcaaaaat atgcttattt caatggctgc 1021 tcctcaccaa ccgctcccct ctcgcctatg tctcctcctg ggtacaagct ggttactggc 1081 gacagaaaca attcttcttg ccgcaattac aacaagcaag caagtgagca aaactgggct 1141 aattacagtg cagaacaaaa tcgaatgggg caggcgggaa gcaccatctc taactcccat 1201 gcacagcctt ttgatttccc cgatgataac cagaattcta aaaaactagc tgctggacat 1261 gaattacagc cactagccat tgtggaccag cgaccttcaa gcagagccag cagtcgtgcc 1321 agcagcagac ctcggcctga tgacctggag atctagatac aggcttgaaa gcatcaagat 1381 tccactcaat tgtggagaag aaaaaaggtg ctgtagaaag tgcaccaggt gttaattttg 1441 atccggtgga ggtggtactc aacagcctta ttcatgaggc ttagaaaaca caaagacatt 1501 agaataccta ggttcactgg gggtgtatgg ggtagatggg tggagaggga ggggataaga 1561 gaggtgcatg ttggtattta aagtagtgga ttcaaagaac ttagattata aataagagtt 1621 ccattaggtg atacatagat aagggctttt tctccccgca aacaccccta agaatggttc 1681 tgtgtatgtg aatgagcggg tggtaattgt ggctaaatat ttttgtttta ccaagaaact 1741 gaaataattc tggccaggaa taaatacttc ctgaacatct taggtctttt caacaagaaa 1801 aagacagagg attgtcctta agtccctgct aaaacattcc attgttaaaa tttgcacttt 1861 gaaggtaagc tttctaggcc tgaccctcca ggtgtcaatg gacttgtgct actatatttt 1921 tttattcttg gtatcagttt aaaattcaga caaggcccac agaataagat tttccatgca 1981 tttgcaaata cgtatattct ttttccatcc acttgcacaa tatcattacc atcacttttt 2041 catcattcct cagctactac tcacattcat ttaatggttt ctgtaaacat ttttaagaca 2101 gttgggatgt cacttaacat tttttttttt tgagctaaag tcagggaatc aagccatgct 2161 taatatttaa caatcactta tatgtgtgtc gaagagtttg ttttgtttgt catgtattgg 2221 tacaagcaga tacagtataa actcacaaac acagatttga aaataatgca catatggtgt 2281 tcaaatttga acctttctca tggatttttg tggtgtgggc caatatggtg tttacattat 2341 ataattcctg ctgtggcaag taaagcacac tttttttttc tcctaaaatg tttttccctg 2401 tgtatcctat tatggatact ggttttgtta attatgattc tttattttct ctcctttttt 2461 taggatatag cagtaatgct attactgaaa tgaatttcct ttttctgaaa tgtaatcatt 2521 gatgcttgaa tgatagaatt ttagtactgt aaacaggctt tagtcattaa tgtgagagac 2581 ttagaaaaaa tgcttagagt ggactattaa atgtgcctaa atgaattttg cagtaactgg 2641 tattcttggg ttttcctact taatacacag taattcagaa cttgtattct attatgagtt 2701 tagcagtctt ttggagtgac cagcaacttt gatgtttgca ctaagatttt atttggaatg 2761 caagagaggt tgaaagagga ttcagtagta cacatacaac taatttattt gaactatatg 2821 ttgaagacat ctaccagttt ctccaaatgc cttttttaaa actcatcaca gaagattggt 2881 gaaaatgctg agtatgacac ttttcttctt gcatgcatgt cagctacata aacagttttg 2941 tacaatgaaa attactaatt tgtttgacat tccatgttaa actacggtca tgttcagctt 3001 cattgcatgt aatgtagacc tagtccatca gatcatgtgt tctggagagt gttctttatt 3061 taaagtt ttaatttagt ataaacat Modified oligonucleotides may comprise, for example, one or more of the following selected components: a modified internucleoside linkage, for example, a phosphorothioate linkage, and / or a modified sugar moiety, for example, a conformationally-strained sugar, for example, a Linked Nucleic Acid (LNA) or Bridged Nucleic Acid (BNA). The chemical modification of the antisense polynucleotides disclosed or referenced herein may enhance their resistance to nucleases and may enhance their ability to enter cells. For example, phosphorothioate oligonucleotides may be used. Other deoxynucleotide analogs include methylphosphonates, phosphoramidates, phosphorodithioates, N3’P5’-phosphoramidates and oligoribonucleotide phosphorothioates and their 2’-O-alkyl analogs and 2’-O- methylribonucleotide methylphosphonates. Alternatively mixed backbone oligonucleotides (MBOs) may be used. MBOs contain segments of phosphothioate oligodeoxynucleotides and appropriately placed segments of modified oligodeoxy-or oligoribonucleotides. MBOs have segments of phosphorothioate linkages and other segments of other modified oligonucleotides, such as methylphosphonate, which is non-ionic, and very resistant to nucleases or 2’-O- alkyloligoribonucleotides. Methods of preparing modified backbone and mixed backbone oligonucleotides are known in the art. In some embodiments, an antisense polynucleotide disclosed or referenced herein may include an oligonucleotide sugar moiety that is a modified sugar moiety. In some embodiments, the modified sugar moiety can be a sugar moiety which is a conformationally-strained sugar. In some embodiments, the conformationally-strained sugar can be a locked nucleotide (locked nucleic acid, or LNA). In some embodiments, the locked nucleotide can be selected from one of the following types: 2′-O—CH2-4′ (oxy-LNA), 2′- CH2—CH2-4′ (methylene-LNA), 2′—NH—CH2-4′ (amino- LNA), 2′—N(CH3)— CH2-4′ (methylamino-LNA), 2′-S—CH2-4′ (thio-LNA), and 2′-Se—CH2-4′ (seleno-LNA). In some embodiments, the conformationally-strained sugar can be a bridged nucleic acid (BNA). Some conformationally-strained sugar can be a locked nucleic acid are shown in Formula III and Formula IV in US Patent No.10,465,188. In some embodiments, antisense compounds comprise antisense polynucleotides comprising from 8 to about 80 nucleotides of an connexin extracellular loop, intracellular region, C-terminus or other region for modulating expression of one or more connexins selected from the group consisting of connexin 26, connexin 30, connexin 30.3, connexin 31, connexin 31.1, connexin 32, connexin 43, connexin 45, connexin 50 and connexin 58. The polynucleotides include synthesized polynucleotides having a length of less than 80 nucleotides, e.g., from 12-18 to about 50-80 nucleotides, preferably about 30 nucleotides or less, e.g., from 12 to about 30 nucleotides, and more preferably from about 15 to about 30 nucleotides. In one example, the polynucleotide has 30 nucleotides. In some embodiments, antisense compounds comprise modified or unmodified epithelial, endothelieal, and / or vascular endothelial connexin antisense polynucleotides. In some embodiments of this invention, the connexin 43 or other antisense oligonucleotide or polynucleotide has at least about 80%, 85%, 90%, 95%, 97%, 98% or 99% homology to a polynucleotide having a sequence selected from SEQ ID NOs: 1 to 17. Connexin modulators that are oligonucleotides or polynucleotides may have at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% homology to an 8 to 80 nucleotide portion of their respective sequences. Table I. List of some connexin 43 antisense oligonucleotide embodiments Table I lists the polynucleotide sequences of several embodiments of connexin 43 polynucleotide modulators useful in the methods of the invention. When sequences such as SEQ ID NO:1-16 are noted, they and other Cx43 and other connexin antisense compounds represent both modified and unmodified oligonucleotides or polynucleotides. In some embodiments, the linkages between the nucleotides, and the structure of the sugar moiety of the nucleotides may be modified. In some embodiments, the internucleoside linkage between any two nucleotides can be a standard phosphodiester linkage. In some embodiments, the internucleoside linkage between any two nucleotides can be a phosphorothioate linkage. For example, SEQ ID NO:1 can be one of the following selected structures: GsTsAsAsTTGCGGCAAGAAGAATTGTTTCsTsGsTsC, wherein “s” denotes a phosphorothioate linkage between the two nucleotides. As another non-limiting example, SEQ ID NO:1 can be (G)(T)(A)(A)TTGCGGCAAGAAGAATTGTTTC(T)(G)(T)(C), wherein the parenthetical nucleotides have modified sugar moieties, as described below. In some embodiments the Cx43 antisense compounds may be modified by substituting one or more uridine nucleotides residues for one or more thymine nucleotides in SEQ ID NOs:1-17 or in the sequence of another connexin (e.g., Cx26, C32, Cx45, etc.). Certain connexin modulators, including for example connexin 43 modulators, provide downregulation of connexin expression (for example, by downregulation of mRNA transcription or translation) or otherwise decrease or inhibit the activity of the connexin protein, connexin hemichannels or gap junctions. In the case of downregulation, this will have the effect of reducing direct cell-cell communication by gap junctions, or exposure of cell cytoplasm to the extracellular space by hemichannels, at the site at which connexin expression is downregulated. In some embodiments, an anti-connexin antisense compound prevents, decreases or alters the activity or function of a hemichannel or a gap junction. As described herein, modulation of the gap junction activity or function by anti-connexin antisense compounds can lead to the closing of gap junctions, closing of hemichannels, and / or passage of molecules or ions through gap junctions and / or hemichannels. Connexin modulators may also comprise one or polynucleotides selected, for example, from the group consisting of morpholino oligonucleotides, RNAi molecules, siRNA molecules, PNA molecules, DNAzymes, and 5’-end–mutated U1 small nuclear RNAs, and analogs of the preceding. These and other compounds may be used alone or in combination with one more connexin modulators. Synthesis of antisense polynucleotides and other anti-connexin polynucleotides such as RNAi, siRNA, and ribozyme polynucleotides as well as polynucleotides having modified and mixed backbones can be performed. See e.g. Stein C.A. and Krieg A.M. (eds), Applied Antisense Oligonucleotide Technology, 1998 (Wiley-Liss). The antisense polynucleotide may inhibit transcription and / or translation of a connexin protein (e.g. connexin 43). The antisense polynucleotide is generally antisense to connexin protein mRNA, for example, connexin 43. Such a polynucleotide may be capable of hybridizing to connexin protein mRNA and may thus inhibit the expression of connexin by interfering with one or more embodiments of connexin protein mRNA metabolism including transcription, mRNA processing, mRNA transport from the nucleus, translation or mRNA degradation. The antisense polynucleotide typically hybridizes to the connexin mRNA to form a duplex which can cause direct inhibition of translation and / or destabilization of the mRNA. Such a duplex may be susceptible to degradation by nucleases. Preferably the polynucleotide is a specific inhibitor of transcription and / or translation from the connexin 43 gene or mRNA, and does not inhibit transcription and / or translation from other genes or mRNAs. The connexin modulator product may bind to the connexin 43 gene or mRNA either (i) 5’ to the coding sequence, and / or (ii) to the coding sequence, and / or (iii) 3’ to the coding sequence. The antisense polynucleotide may hybridize to part of the connexin protein mRNA, such as connexin 43 mRNA. Typically, the antisense polynucleotide hybridizes to the ribosome binding region or the coding region of the connexin protein mRNA. The polynucleotide may be complementary to a region of the connexin mRNA. For example, the polynucleotide may be the exact complement of a part of connexin mRNA. However, absolute complementarity is not required and polynucleotides which have sufficient complementarity to form a duplex having a melting temperature of greater than about 20ºC, 30ºC or 40ºC under physiological conditions are particularly suitable for use in the present invention. Thus, the polynucleotide is typically a homologue of a sequence complementary to the mRNA. The polynucleotide may be a polynucleotide which hybridizes to the connexin protein mRNA under conditions of medium to high stringency such as 0.03M sodium chloride and 0.03M sodium citrate at from about 50ºC to about 60ºC. Antisense polynucleotides may be part of compositions which may comprise polynucleotides to more than one connexin protein. Preferably, one connexin protein to which polynucleotides are directed is connexin 43. Others include connexins found in the ocular and / or corneal epithelium. Some embodiments of the invention are described with reference to oligodeoxynucleotides. However, other suitable polynucleotides (such as RNA polynucleotides) may be used. Other Connexin Modulators In addition to connexin antisense (e.g. SEQ ID NO:1), connexin peptidomimetics (e.g., Peptide5, XG19, etc.) and connexin hemichannel antagonists (e.g. tonabersat), connexin binding proteins, including antibodies, antigen-binding antibody fragments, and the like, are also suitable connexin modulators for use in methods of the invention and dosed with a therapeutically effective amount according to the one or more of the dosing schedules described herein. Binding proteins include, for example, monoclonal antibodies, polyclonal antibodies, antibody fragments (including, for example, Fab, F(ab’)2 and Fv fragments; single chain antibodies; single chain Fvs; and single chain binding molecules such as those comprising, for example, a binding domain, hinge, CH2 and CH3 domains, recombinant antibodies, and antibody fragments which are capable of binding an antigenic determinant (i.e., that portion of a molecule, generally referred to as an epitope) that makes contact with a particular antibody or other binding molecule. These binding proteins, including antibodies, anti-binding antibody fragments, and so on, may be chimeric or humanized or otherwise made to be less immunogenic in the subject to whom they are to be administered, and may be synthesized, produced recombinantly, or produced in expression libraries. Any binding molecule known in the art or later discovered is envisioned, such as those referenced herein and / or described in greater detail in the art. For example, binding proteins include not only antibodies, and the like, but also ligands, receptors, peptidomimetics, or other binding fragments or molecules (for example, produced by phage display) that bind to a target (e.g., a connexin protein or connexin hemichannel epitope). Methods of synthesizing antibodies and binding fragments as well as peptides and polypeptides, including peptidomimetics and peptide analogs can also be performed using suitable methods. See e.g. Lihu Yang et al., Proc. Natl. Acad. Sci. U.S.A., 1; 95(18): 10836- 10841 (Sept 11998). Connexin modulators also include antibodies and binding fragments (e.g. scFvs, human VHor VLdomains, humanized camelid VHHdomains, IgNARsingle domains, etc.) thereof that bind connexin protein, and connexin peptides and polypeptides, including peptidomimetics and peptide analogs of connexin that modulate hemichannel or gap junction activity or function, and other gap junction blocking agents and gap junction protein phosphorylating agents. Connexin protein peptides and polypeptides may, for example, bind to connexin protein to inhibit its function, or may inhibit connexin function by mimicking regions of connexin protein to inhibit or disrupt its binding to other gap junction proteins. Strategies known in the art may be used to improve the naturally short half-life of antibody fragments, including PEGylation, the use of repeating peptide sequences, polysialylation, albumin or IgG binding or fusions, and other approaches. Binding molecules will generally have a desired specificity, including but not limited to binding specificity, and desired affinity. Affinity, for example, may be a Kaof greater than or equal to about 104M-1, greater than or equal to about 106M-1, greater than or equal to about 107M-1, greater than or equal to about 108M-1. Affinities of even greater than about 108M-1are suitable, such as affinities equal to or greater than about 109M-1, about 1010M-1, about 1011M-1, and about 1012M-1. Affinities of binding proteins useful to treat subjects according to the present invention can be readily determined using conventional techniques. Other compounds that may be used for modulating, blocking or closing gap junctions (e.g. phosphorylating connexin 43 tyrosine and / or serine residue) are known and have been reported in U.S. Pat. No.7,153,822 and U.S. Pat. No.7,250,397, for example. Pannexin Modulators Any modulator that is capable of eliciting a desired inhibition of the passage (e.g., transport) of molecules through a pannexin channel (e.g., ATP), including a pannexin 1 channel, for example, may be used in embodiments of the invention and dosed according to the one or more of the schedules described herein. Such compounds include, for example, binding proteins (e.g. scFvs, antibodies, etc.), polypeptides (e.g. peptidomimetics), polynucleotides (e.g., antisense compounds) and organic compounds (e.g. probenecid and compounds of Formula III) and / or prodrugs thereof that can, for example, block the function or activity of a pannexin channel in whole or in part (e.g. by modulating release of ATP from a pannexin channel). See, e.g., Caufriez, A, et al. Determination of Structural Features That Underpin the Pannexin1 Channel Inhibitory Activity of the Peptide (10)Panx1. Bioorg. Chem.2023, 138:106612. See also Van Campenhout, R, et al. Nanobody-based pannexin1 channel inhibitors reduce inflammation in acute liver injury. J Nanobiotechnol 21, 371 (2023); Lissoni, A, et al. Cx43 Hemichannel and Panx1 Channel Modulation by Gap19 and10Panx1 Peptides. Int. J. Mol. Sci.2023, 24, 11612; Lamouroux, A, et al. Structure-Based Design and Synthesis of Stapled10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases J. Med. Chem.202366:13086-13102. Compounds for pannexin modulation can be any compound of Formula III: wherein Z1and Z2are independently selected from: (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4), (C1-C4)cycloalkyl, (C1-C4)alkyl-S—, (C1-C4)alkylamino, (C1-C4)cycloalkylamino, di(C1-C4)alkylamino, and amino(C1-C4)alkyl; Y is selected from: hydrogen, halo, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1- C4)alkoxy, halo(C1-C4)alkoxy, cyano(C1-C4)alkyl, amino, (C1-C4)alkylamino, di(C1- C4)alkylamino, amino(C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di[(C1-C4)alkyl]amino(C1- C4)alkyl, trifluoromethylthio, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, —C(O)R1, C(O)OR1, —OC(O)R1, —C(O)—N(R1)2, —CH2—C(O)R1, —CH2—C(O)OR1, —CH2— OC(O)R1, —CH2—C(O)—N(R1)2, S(O)2R1, S(O)2N(R1)2, (C3-C5)cycloalkyl, (C3- C8)cycloalkyl(C1-C4)alkyl, SO3H, and SO4H; R1is selected from: hydrogen, NH2, NR2R3, OH, —CH2OH, and —CH2CH2OH; R2 and R3 are independently selected from: hydrogen, (C1-C4)alkyl, (C1-C4)alkoxy, and (C1- C4)cycloalkyl; and, halo is chlorine, bromine, iodine, or fluorine. One Formula III compound for pannexin modulation is probenecid, shown below: Probenecid may be known by the IUPAC name p-[Dipropylsulfamoyl]benzoic acid and has the structure shown above. In certain embodiments, probenecid and / or an analogue thereof are nonionic, are in the form of a free base, a free acid, or a pharmaceutically acceptable salt. By way of example, a pharmaceutically acceptable salt includes a hydrochloride salt and salts derived from acid including, but not limited to, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, salicylic acid, citric acid, oxalic acid, lactic acid, malic acid, methanesulphonic acid and p-toluene sulphonic acid, a salt of itself. In one embodiment, the salt is a hydrochloride salt. In other embodiments, one or more polymorph, one or more isomer, and / or one or more solvate of probenecid and / or an analogue thereof may be used. In some embodiments, the pannexin modulators can include or exclude pannexin peptidomimetics. Pannexin peptide sequences can comprise about 8 to about 40 (e.g., 40-80) consecutive amino acids of an extracellular domain, an intracellular domain, a carboxy terminus part, or an amino terminus part, of the polypeptides Panx1, Panx2 or Panx3. Pannexin modulators may comprise, in some embodiments, a portion of an extracellular loop of Panx 1, 2 or 3. In some embodiments, a pannexin peptidomimetic can comprise about 8 to about 40 consecutive amino acids of an extracellular domain, an intracellular domain, a carboxy terminus part, or an amino terminus part, of pannexin 1. In some embodiments, for example, the pannexin modulator may comprise, for example, the Panx1 mimetic blocking peptide is10Panx1 (WRQAAFVDSY (SEQ ID NO: 21)). In some embodiments, the Panx1 mimetic peptide is a stapled10Panx1 analogue (see, e.g., Lamouroux, A, et al. (2023), supra. In some embodiments, the mimetic peptide Gap19 may be used to modulate pannexin 1 channels. In some embodiments,10Panx1 may be used to modulate connexin 43 hemichannels. See Lissoni, A, et al. (2023) supra. In some embodiments, pannexin mimetic modulators can comprise, for example, about 40 to about 80 (including from 8-40) consecutive amino acids. They may comprise part of an extracellular domain, an intracellular domain, a carboxy terminus, or an amino terminus of the Panx1 peptide, the Panx2 peptide and / or the Panx3 peptide, or variants thereof. The sequence of the Panx1 polypeptide is known and can be found, for example, at U.S. Patent No.10,465,188 (also published as WO2016029191) as SEQ ID NO: 122 therein (also identified as NCBI RefSeq: NP_056183.2) at Col.42, lines 35-50 therein, The sequence of the Panx2 polypeptide is known and can be found, for example, at U.S. Patent No. 10,465,188 as SEQ ID NO: 123 therein (Panx2 peptide, also identified as RefSeq NP_443071.2) at Col.42 line 51 to Col.43, line 9 therein. The sequence of the Panx3 polypeptide is known and can be found, for example, at U.S. Patent No.10,465,188 as SEQ ID NO: 124 therein (Panx3 peptide, also identified as RefSeq NP_443191.1) at Col.43, line 10 to Col.44, line 12 therein. IN some embodiments, the pannexin peptidomimetic is a pannexin 1 peptidomimetic. In some embodiments the pannexin modulators that are oligonucleotides or polynucleotides may have at least about 80%, 85%, 90%, 95%, 97%, 98%, or 99% homology to an 8 to 80 nucleotide portion of Panx1 nRNA (Panx1 polynucleotide RefSeq ID NM_015368.3), Panx2 mRNA (Panx2 polynucleotide RefSeq ID NM_052839.3 for variant 1; RefSeq ID NM_001160300.1 for Panx2 polynucleotide variant 2; RefSeq ID NR_027691.1 for Panx2 polynucleotide variant 3), or Panx3 mRNA (Panx3 polynucleotide RefSeq ID NM_052959.2). The sequence of the Panx1 mRNA is known and can be found, for example, at U.S. Patent No. 10,465,188 (also published as WO2016029191) as SEQ ID NO: 117 therein at Col.44, line 15 to Col.45, line 34. The sequence of the Panx2, variant 1 mRNA is known and can be found, for example, at U.S. Patent No. 10,465,188 as SEQ ID NO: 118 therein at Col.45, line 36 to Col.47, line 58. The sequence of the Panx2, variant 2 mRNA is known and can be found, for example, at U.S. Patent No.10,465,188 as SEQ ID NO: 119 therein at Col.47, line 60 to Col.49. The sequence of the Panx2, variant 3 mRNA is known and can be found, for example, at U.S. Patent No. 10,465,188 as SEQ ID NO: 120 therein at Col.51, line 1 to Col.53, line 22. The sequence of the Panx3 mRNA is known and can be found, for example, at U.S. Patent No.10,465,188 as SEQ ID NO: 121 therein at Col.53, line 24 to Col. 53, end of page. Some useful pannexin 1 antisense sequences include 5′- TATGCAGCCACAGTGGGAGG-3′ (685–704) and 5′-TCAGATACCTCCCACAAACT-3′ (929–948), 5′-TAGCACCTGCCAGTCCAGAAT-3′, and 5′-GGTCCAGGTCCATCTCTCAGG- 3′, and may be made, for example, using unmodified nucleotides or produced as phosphorothioate ODNs. Inflammasome Modulators The NLRP3 inflammasome is currently the best characterized. It comprises NLRP3, ASC (PYCARD) and procaspase-1 (and CARD8 (Cardinal) may also be a component). It is activated by a number of pathogens and bacterial toxins as well as diverse PAMPs, danger-associated molecular patterns (DAMPS). Multiple studies have shown that activation of the NLRP3 inflammasome by particulate activators (e.g. Hornung V, et al. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 2008 9(8):847-56) requires phagocytosis, but this is not required for the response to ATP, which is mediated by the P2X7 receptor (Kahlenberg JM, Dubyak GR. Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am J Physiol Cell Physiol. 2004286(5):C1100-8) and appears to involve the pannexin membrane channel (Pelegrin P, Surprenant A. Pannexin-1 mediates large pore formation and interleukin-1beta release by the ATP-gated P2X7 receptor. EMBO J.200625(21):5071-82). Any modulator that is capable of eliciting a desired inhibition of an inflammasome (e.g., the NLRP3 inflammasome), either directly or indirectly, may be used in compositions and methods of the invention. Such compounds include, for example, binding proteins (e.g. scFvs, antibodies, etc.), polypeptide modulators (e.g. peptidomimetics), polynucleotide modulators (e.g., antisense compounds) and organic compounds useful to modulate an inflammasome, whether now known or later developed, including those described herein. In some embodiments, inflammasome modula...

Claims

CLAIMS WE CLAIM:

1. A method of treating a subject for cell senescence or a disease, disorder or condition associated with cell senescence, the method comprising administering to the subject an effective amount of an inflammasome modulator.

2. The method of claim 1, wherein the disease, disorder or condition associated with cell senescence is a disease, disorder or condition associated with cognitive decline.

3. The method of claim 2, wherein the disease, disorder or condition associated with cognitive decline is selected from the group consisting of mild cognitive decline, age-related cognitive decline, Alzheimer’s disease, dementia with Lewy bodies disease, fronto- temporal dementia, early onset dementia, Parkinson’s disease-related cognitive dysfunction, posterior cortical atrophy, primary progressive aphasia and Huntington’s disease.

4. The method of claim 1, wherein the disease, disorder or condition associated with cell senescence is cellular aging and / or premature aging.

5. The method of claim 1, wherein the disease, disorder or condition associated with cell senescence is a disease associated with short telomere length or reduced or deficient TERT activity.

6. The method of claim XX, wherein the disease associated with short telomere length or reduced or deficient TERT activity is selected from the group consisting of short telomere syndrome, dyskeratosis congenital (DC), bone marrow failure syndrome characterized by the reticulated skin hyperpigmentation, nail dystrophy, oral leukoplakia, Revesz syndrome, Hoyeraal-Hreidarsson syndrome, cerebroretinal microangiopathy with calcifications and cysts (CRMCC), inherited aplastic anemia / myelodysplastic syndrome, aplastic anemia, marrow failure, hematological disorder, hepatic disease, aplastic anemia, hepatic cirrhosis, osteoporosis, osteonecrosis, vascular malformations, diabetes, primary immunodeficiency, and inflammatory bowel disease.

7. The method of claim 1, wherein the method of treating the subject increases telomerase expression in a cell in the subject.

8. The method of claim 1, wherein the method of treating the subject protects telomere length in a cell in the subject.

9. The method of any of claims 1 to 8, wherein the inflammasome modulator is a compound of Formula I.

10. The method of any one of claims 1 to 8, wherein the inflammasome modulator is a compound of selected from the group consisting of tonabersat, emlenoflast, metformin, allopurinol, quercetin, resveratrol, fasudil, MCC950, and XG19.

11. The method of any one of claims 1 to 8, wherein the inflammasome modulator is a connexin hemichannel modulator.

12. A method of increasing telomerase reverse transcriptase (TERT) activity in a subject, comprising administering to the subject an effective amount of an inflammasome modulator.

13. The method of claim 12, wherein the inflammasome modulator is a compound of Formula I.

14. The method of claim 12, wherein the inflammasome modulator is a compound of selected from the group consisting of tonabersat, emlenoflast, metformin, allopurinol, quercetin, resveratrol, fasudil, MCC950, and XG19.

15. The method of claim 12, wherein the inflammasome modulator is a connexin hemichannel modulator.

16. An inflammasome modulator for use in the treatment of cellular aging, premature aging, or a disease associated with short telomere length or reduced or deficient TERT activity.

17. The inflammasome modulator of claim 16, wherein the inflammasome modulator is a compound of Formula I.

18. The inflammasome modulator of claim 16, wherein the inflammasome modulator is a compound of selected from the group consisting of tonabersat, emlenoflast, metformin, allopurinol, quercetin, resveratrol, fasudil, MCC950, and XG19.

19. The inflammasome modulator of claim 16, wherein the inflammasome modulator is a connexin hemichannel modulator.

20. Use of an inflammasome modulator in the manufacture of a medicament for the treatment of cell senescence or a disease, disorder or condition associated with cell senescence.

21. The use of claim 20, wherein the inflammasome modulator is a compound of Formula I.

22. The use of claim 20, wherein the inflammasome modulator is a compound of selected from the group consisting of tonabersat, emlenoflast, metformin, allopurinol, quercetin, resveratrol, fasudil, MCC950, and XG19.

23. The use of claim 20, wherein the inflammasome modulator is a connexin hemichannel modulator.

Images