Methods and pharmaceutical compositions for treating aging

Abstract

Methods for using gene expression changes and mutations in neural organoids to assess effectiveness of treatment methodologies and identify effective pharmaceutical compositions thereof for treating a disease, disorder, or disability as a consequence of biological aging are disclosed.

Description

[0001] METHODS AND PHARMACEUTICAL COMPOSITIONS FOR TREATING AGING CROSS-REFERENCE TO RELATED APPLICATION This application claims priority to U.S. Provisional Application No.63 / 665,238, filed June 27, 2024, which is incorporated herein by reference in its entiretly. FIELD OF THE INVENTION This disclosure provides methods for reducing or ameliorating age-related disease, disorder, or disability severity. The methods provided herein include methods for early diagnostics of diseases or disabilities related to biological aging and administration of therapeutically effective amounts of pharmaceutical compositions for reducing or ameliorating age-related disease, disorder, or disability severity. Said compositions are capable of correcting or reducing dysfunctional expression of genes related to those discovered in an accelerated aging in human Progeria (Werner Syndrome) in vitro neural organoid platform. Further provided are pharmaceutical compositions comprising one or a plurality of active pharmaceutical ingredients in combination to achieve reduction or amelioration of dementia. BACKGROUND OF THE INVENTION Aging and the sequalae thereof in animal organs and tissues is a universal phenomenon. In humans in particular aging is detected in all organ systems, particularly the brain. Aging is broadly defined as an irreversible and inevitable biological process, which is characterized by progressive deterioration of the social, physical and mental conditions of the individual organism with advancing chronological age, which generally starts after sexual maturity and ultimately results in morbidity (Melzer et al., 2020, The genetics of human ageing. Nat. Rev. Genet.21:88–101). The human brain, and diseases associated with it have been the object of investigation and study by scientists for decades. Throughout this time, neurobiologists have attempted to increase their understanding of the brain’s capabilities and functions. Neuroscience has typically relied on experimental manipulation of living brains or tissue samples, but a number of factors have limited scientific progress. For ethical and practical reasons, obtaining human brain tissue is difficult while most invasive techniques are impossible to use on humans whilst they are still alive. Experiments in animals are expensive and time-consuming and many animal experiments are conducted in rodents, which have a brain structure and development that vary greatly from humans. Results obtained in animals must be verified in long and expensive human clinical trials and much of the time such animal disease models are not fully representative of disease pathology in the human brain. Humans and other mammals are subject to a variety of forms of age-related disease, disorder, or disability and fragility characterized generally as a diminution of overall well- being or cessation of memory and functional cognition. Examples of specific age-related diseases include Werner syndrome, also called progeria, a hereditary condition associated with premature aging and an increased risk of cancer and other diseases. Mutations (alterations) in the LMNA gene, WRN gene. H6PD and DHX9 gene are known to cause Werner syndrome or Hutchinson–Gilford progeria. Alzheimer's Disease (AD), which is an common form of irreversible degenerative brain disorder that is associated with memory loss and interferes with other intellectual abilities that complicate daily life. Alzheimer's disease accounts for 60 to 80 percent of dementia cases. Disease onset occurs most often for individuals in their mid-60s and is estimated to affect approximately five million individuals at present. However, disease onset occurs many years prior to physical expression of symptoms. The cost to society currently exceeds $270 billion and no effective treatment currently exists. These and other consequences of biological aging create a need in the art to develop therapeutically effective treatments for such maladies. SUMMARY OF THE INVENTION This invention provides methods for reducing or ameliorating diseases and disabilities in an individual as a consequence of biological aging, including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (AD / ADRD) or Mixed Etiology Dementia (MED), said methods comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising a drug capable of reducing or correcting dysfunctional expression of genes related to biological aging in vitro in a neural organoid platform that accordingly reduces or ameliorates disease severity in such individuals. Specifically, the methods provided herein rely upon identification of genes related to biological aging and specifically AD / ADRD or MED that show dysfunctional or altered gene expression in neural organoid platforms in vitro for which the drugs disclosed herein are capable of reducing this dysfunctional expression. In particular embodiments these genes are set forth in Tables 1-6. A particular class of drugs provided herein are agonists of adenosine A2a receptor. (Genbank Accession No. NP_001265429.1) encoded by ADORA2A (Genbank Accession No. NM_001278497.2). In specific embodiments, such drugs include methyl (1R,4r)-4-(3-(6-amino-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2- yl)-9H-purin-2-yl)prop-2-yn-1-yl)cyclohexane-1-carboxylate (known in the art as apadenoson). In other specific embodiments, such drugs include 2-p-(2-Carboxyethyl)phenethylamino-5 -N-ethylcarboxamidoadenosine hydrochloride hydrate (known in the art as CGS-21680). In addition to such particular and specific embodiments this disclosure encompasses related drug molecules that are agonists of adenosine A2a receptors encoded by ADORA2A and allelic variants thereof, particularly such variants associated with biological aging including but not limited to Alzheimer’s Disease Related Dementia (AD / ADRD) or Mixed Etiology Dementia (MED). The invention also provides pharmaceutical compositions of drugs capable of reducing or ameliorating diseases and disabilities in an individual as a consequence of biological aging, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (AD / ADRD) or Mixed Etiology Dementia (MED). In specific embodiments the invention provides pharmaceutical compositions comprising therapeutically effective amounts of drugs capable of reducing or correcting dysfunctional expression of genes related to said diseases and disabilities. As disclosed herein, such genes are identified from a neural organoid platform wherein administration of the drugs in vitro reduces or corrects this dysfunctional gene expression toward normalcy, and accordingly ameliorates disease severity in an individual having diseases and disabilities in an individual as a consequence of biological aging when the pharmaceutical composition is administered to such patients. In particular embodiments these genes are set forth in Tables 3-10. In specific embodiments the pharmaceutical compositions comprise drugs that are agonists of adenosine A2a receptor. (Genbank Accession No. NP_001265429.1) encoded by ADORA2A ( Genbank Accession No. NM_001278497.2). In specific embodiments, such drugs include methyl (1R,4r)-4-(3-(6-amino-9-((2R,3R,4S,5S)-5- (ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-yn-1- yl)cyclohexane-1-carboxylate (known in the art as apadenoson). In other specificembodiments, such drugs include 2-p-(2-Carboxyethyl) phenethylamino-5 -N-ethylcarboxamidoadenosine hydrochloride hydrate (known in the art as CGS-21680). In addition to such particular and specific embodiments this disclosure encompasses related drug molecules that are agonists of adenosine A2a receptors encoded by ADORA2A and allelic variants thereof, particularly such variants associated with diseases and disabilities in an individual as a consequence of biological aging including Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED). Additional embodiments of the methods and pharmaceutical compositions disclosed herein comprise combinations of adenosine A2a receptor agonists as disclosed herein as well as combinations of these drugs with other medicaments useful for reducing or ameliorating disease severity in an individual having diseases and disabilities in an individual as a consequence of biological aging, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED). In specific embodiments such combinations include methyl (1R,4r)-4-(3-(6-amino-9- ((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2- yn-1-yl)cyclohexane-1-carboxylate (known in the art as apadenoson), 2-p-(2-Carboxyethyl)phenethylamino-5 -N-ethylcarboxamidoadenosine hydrochloride hydrate (known in the art asCGS-21680), in therapeutically useful combinations and dosages thereof, as well as combinations with alternative medicaments capable of reducing or ameliorating disease severity in an individual having diseases and disabilities in an individual as a consequence of biological aging including Alzheimer’s Disease Related Dementia (AD / ADRD) or Mixed Etiology Dementia (MED). The invention also provides pharmaceutical compositions of drugs capable of reducing or ameliorating disease severity in an individual having diseases and disabilities in the individual as a consequence of biological aging, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (AD / ADRD) or Mixed Etiology Dementia (MED), wherein a particular class of drugs provided herein are antagonists of adenosine A2b receptor (Genbank Accession No. NP_0006667.1) encoded by ADORA2B (Genbank Accession No. NM 000676.4). Specific embodiments of drugs comprising these adenosine A2b receptor antagonists include but are not limited to PBF-1129 and MRS-1706. The invention also provides methods for reducing or ameliorating disease severity in an individual having diseases and disabilities in an individual as a consequence of biological aging, by treating individuals with pharmaceutical compositions of drugs capable of reducing or ameliorating disease severity in such an individual, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (AD / ADRD) or Mixed Etiology Dementia (MED). The invention also provides methods for reducing or ameliorating disease severity in an individual having diseases and disabilities as a consequence of biological aging, by treating individuals with pharmaceutical compositions of drugs capable of reducing or ameliorating disease severity in such an individual, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (AD / ADRD) or Mixed Etiology Dementia (MED), having a particular effect of such drugs on phosphodiesterase inhibitors such as Roflumilast, a PDE4 inhibitor. These and other data findings, features, and advantages of the present invention will be more fully understood from the following detailed description taken together with the accompanying claims. It is noted that the scope of the claims is defined by the recitations therein and not by the specific discussion of features and advantages set forth in the present description. BRIEF DESCRIPTION OF THE FIGURES Fig 1A is a diagram setting forth the rationale for producing a neural organoid platform (NNOP) as used herein shown in a micrograph of a 4X dark field image of a NNOP. FIG.1B is a photomicrograph of an NNOP illustrated by comparison with a diagram of a 5-week-old fetus and corresponding anatomical structures. FIG.2 is a diagram illustrating the strategy for identifying gene expression and metabolic profiles in NNOP related to HMP and when comorbid with ADRD for use in drug development. FIG.3 shows that Normal-NNOP express all brain regions and all cell types including microglia. It also Whole Organoid Bright Field Imaging showing the anatomy of the whole organoid with corresponding brain structures. FIG.4 shows gene expression in brain regions of the neural organoid. FIG 5 shows that Normal-NNOP express all brain regions and all cell types including microglia. It also shows 3D Clarity Immuno-fluorescent staining and Confocal Imaging showing expression of the biomarker protein of the indicated region on the neural organoid. FIG.6 shows familial versus sporadic AD FIG.7 compares familial versus sporadic AD. FIG.8 shows ADRD-SPOR-NNOP FIG.9 shows W12 Werner Syndrome (Progeria) in WRN-NNOP. FIG.10 shows the Progeria and AD / ADRD Share Canonical and Novel Aging Biomarkers. FIG.11 shows quantitative western blots of proteins from NNOP Fig.12 shows quantitation of metabolites in NNOP as measured by 1H-NMR. Preliminary data using ADRD-APP-NNOP shows physiological sensitivity (peak area replicability): independent sample 1 and sample 2 of Normal-NNOP show reproducibility and feasibility of metabolomics. DETAILED DESCRIPTION Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed.1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). These references are intended to be exemplary and illustrative and not limiting as to the source of information known to the worker of ordinary skill in this art. As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise. It is noted here that as used in this specification and the appended claims, the singular forms ”a,” ”an,” and ”the” also include plural reference, unless the context clarity dictates otherwise. The term “about” or “approximately” means within 25%, such as within 20% (or 5% or less) of a given value or range. As used herein, the terms “or” and “and / or” are utilized to describe multiple components in combination or exclusive of one another. For example, “x, y, and / or z” can refer to “x” alone, “y” alone, “z” alone, “x, y, and z,” “(x and y) or z,” “x or (y and z),” or “x or y or z.” It is noted that terms like “preferably,” “commonly,” and “typically” are not utilized herein to limit the scope of the claimed invention or to imply that certain features are critical, essential, or even important to the structure or function of the claimed invention. Rather, these terms are merely intended to highlight alternative or additional features that can or cannot be utilized in a particular embodiment of the present invention. For the purposes of describing and defining the present invention, it is noted that the term “substantially” is utilized herein to represent the inherent degree of uncertainty that can be attributed to any quantitative comparison, value, measurement, or other representation. The term “substantially” is also utilized herein to represent the degree by which a quantitative representation can vary from a stated reference without resulting in a change in the basic function of the subject matter at issue. As used herein, the term ”neural organoid” and ”neural organoid platform” mean a non-naturally occurring three-dimensional organized cell mass that is cultured in vitro from a human induced pluripotent stem cell and develops similaly to the human nervous system in terms of neural marker expression and structure. Further a neural organoid has two or more regions. The first region expresses cortical or retinal marker or markers. The remaining regions each express markers of the brain stem, cerebellum, and / or spinal cord. Neural markers are any protein or polynucleotide expressed consistent with a cell lineage. By "neural marker" is meant any protein or polynucleotide, the expression of which is associated with a neural cell fate. Exemplary neural markers include markers associated with the hindbrain, midbrain, forebrain, or spinal cord. One skilled in the art will understand that neural markers are representative of the cerebrum, cerebellum and brainstem regions. Exemplary brain structures that express neural markers include the cortex, hyopthalamus, thalamus, retina, medulla, pons, and lateral ventricles. Further, one skilled in the art will recognize that within the brain regions and structures, granular neurons, dopaminergic neurons, GABAergic neurons, cholinergic neurons, glutamatergic neurons, serotonergic neurons, dendrites, axons, neurons, neuronal, cilia, purkinje fibers, pyramidal cells, spindle cells, express neuronal markers. One skilled in the art will recognize that this list is not all encompassing and that neural markers are found throughout the central nervous system including other brain regions, structures, and cell types. As set forth herein gene expression markers diseases and disabilities in an individual as a consequence of biological aging, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) are set forth in Tables 1 and 6 herein. NEURAL ORGANOIDS Neural organoids are generated in vitro from patient tissue samples. Neural organoids were previously disclosed in U.S. Patent No.11,345,890, incorporated herein in its entirety. A variety of tissues can be used including skin cells, hematopoietic cells, or peripheral blood mononuclear cells (PBMCs) or in vivo stem cells directly. One of skill in the art will further recognize that other tissue samples can be used to generate neural organoids. Use of neural organoids permits study of neural development in vitro. In one embodiment skin cells are collected in a petri dish and induced to an embryonic-like pluripotent stem cell (iPSC) that have high levels of developmental plasticity. iPSCs are grown into neural organoids in said culture under appropriate conditions as set forth herein and the resulting neural organoids closely resemble developmental patterns similar to human brain. In particular, neural organoids develop anatomical features of the retina, forebrain, midbrain, hindbrain, and spinal cord. Importantly, neural organoids express >98% of the about 15,000 transcripts found in the adult human brain. iPSCs can be derived from the skin or blood cells of humans identified with dementia postmortem. In one embodiment, the about 12-week old iPSC-derived human neural organoid has ventricles and other anatomical features characteristic of a 35-40 day old neonate. In an additional embodiment the about 12 week old neural organoid expresses beta 3-tubulin, a marker of axons as well as somato-dendritic Puncta staining for MAP2, consistent with dendrites. In yet another embodiment, at about 12 weeks the neural organoid displays laminar organization of cortical structures. Cells within the laminar structure stain positive for doublecortin (cortical neuron cytosol), Beta3 tubulin (axons) and nuclear staining. The neural organoid, by 12 weeks, also displays dopaminergic neurons and astrocytes. Accordingly as noted, neural organoids permit study of human neural development in vitro. Further, the neural organoid offers the advantages of replicability, reliability and robustness, as shown herein using replicate neural organoids from the same source of iPSCs. In one aspect at least one cell sample reprogrammed to the induced pluripotent stem cell is a fibroblast derived from skin or blood cells from humans. DEVELOPMENTAL TRANSCRIPTOMICS A “transcriptome” is a collection of all RNA, including messenger RNA (mRNA), long non-coding RNAs (lncRNA), microRNAs (miRNA) and, small nucleolar RNA snoRNA), other regulatory polynucleotides, and regulatory RNA (lncRNA, miRNA) molecules expressed from the genome of an organism through transcription therefrom. Thus, transcriptomics is the study of the mRNA transcripts produced by the genome at a given time in any particular cell or tissue of the organism. Transcriptomics employs high-throughput techniques to analyze genome expression changes associated with development or disease. In certain embodiments, transcriptomic studies can be used to compare normal, healthy tissues and diseased tissue gene expression. In further embodiments, mutated genes or variants associated with disease or the environment can be identified. Consistent with this, the aim of developmental transcriptomics is identifying genes associated with, or significant in, organismal development and disease and dysfunctions associated with development. During development, genes undergo up- and down-regulation as the organism develops. Thus, transcriptomics provides insight into cellular processes, and the biology of the organism. Generally, in one embodiment RNA is sampled from the neural organoid described herein within at about one week, about four weeks, or about twelve weeks of development; most particularly RNA from all three time periods are samples. However, RNA from the neural organoid can be harvested at minutes, hours, days, or weeks after reprogramming. For instance, RNA can be harvested at about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, and 60 minutes. In a further embodiment the RNA can be harvested 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In a further embodiment the RNA can be harvested at 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, or 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks 10 weeks, 11 weeks, 12 weeks or more in culture. After enriching for RNA sequences, an expressed sequence tag (EST) library is generated and quantitated using the AmpliSeqTMtechnique from ThermoFisher. Exemplars of alternate technologies include RNASeq and chip-based hybridization methods. Transcript abundance in such experiments is compared in control neural organoids from healthy individuals vs. neural organoids generated from individuals with disease and the fold change in gene expression calculated and reported. Furthermore, in one embodiment RNA from neural organoids for Alzheimer’s disease, are converted to DNA libraries and then the representative DNA libraries are sequenced using exon-specific primers for 20,814 genes using the AmpliSeqTMtechnique available commercially from ThermoFisher. Reads in cpm <1 are considered background noise. All cpm data are normalized data and the reads are a direct representation of the abundance of the RNA for each gene. In another informative embodiment, RNA from neural organoids for Progeria (Werner Syndrome) were converted to DNA libraries and then sequenced according to this protocol. Briefly, in one embodiment, the array consists of one or a plurality of genes identified in association with biological aging, specifically said aging related to Progeria (Werner Syndrome). In an alternative embodiment, the array consists of one or a plurality of genes used to predict risk of Alzheimer’s disease. In a further alternative embodiment, reads contain a plurality of genes that are used to treat Alzheimer’s disease in a human, using patient-specific pharmacotherapy known to be associated with Alzheimer’s disease. In one aspect, the gene libraries can be comprised of disease-specific gene as provided in Tables 3-10 or a combination of genes in Table 3-10 with alternative disease specific genes. Exemplarily, changes in expression or mutation of disease-specific genes are detected using such sequencing, and differential gene expression detected thereby, qualitatively by detecting a pattern of gene expression or quantitatively by detecting the amount or extent of expression of one or a plurality of disease-specific genes or mutations thereof. Results of said assays using the AmpliSeqTMtechnique can be used to identify genes that can predict disease risk or onset and can be targets of therapeutic intervention. In further embodiments, hybridization assays can be used, including but not limited to sandwich hybridization assays, competitive hybridization assays, hybridization-ligation assays, dual ligation hybridization assays, or nuclease assays. Neural Organoids and Pharmaceutical Testing Neural organoids are useful for pharmaceutical testing. Currently, drug screening studies including toxicity, safety and or pharmaceutical efficacy, are performed using a combination of in vitro work, rodent / primate studies and computer modeling. Collectively, these studies seek to model human responses, in particular physiological responses of the central nervous system. Human neural organoids are advantageous over current pharmaceutical testing methods for several reasons. First neural organoids are easily derived from healthy and diseased patients, mitigating the need to conduct expensive clinical trials. Second, rodent models of human disease are unable to mimic physiological nuances unique to human growth and development. Third, use of primates creates ethical concerns. Finally, current methods are indirect indices of drug safety. Alternatively, neural organoids offer an inexpensive, easily accessible model of human brain development. This model permits direct, and thus more thorough, understanding of the safety, efficacy, and toxicity of pharmaceutical compounds. Starting material for neural organoids is easily obtained from healthy and diseased patients. Further, because human organoids are easily grown they can be produced en mass. This permits efficient screening of pharmaceutical compounds. Neural organoids are advantageous for identifying biomarkers of a disease or a condition, the method comprising a) obtaining a biological sample from a human patient; and b) detecting whether at least one biomarker is present in the biological sample by contacting the biological sample with an array comprising binding molecules specific for the biomarkers and detecting binding between the at least one biomarker and the specific binding molecules. In further embodiments, the biomarker serves as a gene therapy target. Relevance for adenosine receptors in aging and dementia etiologies Certain studies in the prior art suggest the possibility of a role for adenosine receptors in the progression of the neuropathological changes that are observed in AD (Kinney et al., 2018, Alzheimer's & Dementia: Translational Research & Clinical Interventions, Alzheimer’s and Dementia: Translational Research and Clinical Intervention 4: 575-590). For example, an association between a polymorphism of the ADORA2A gene with hippocampal volume in mild cognitive impairment and AD has been reported (Horgusluoglu- Moloch et al., 2017, Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer’s disease, Neurobiol. Aging 60: 92–103). Adenosine receptors have different functions, and the A2A receptor has a broader anti-inflammatory effects throughout the body, additionally (Hasko and Pather, 2008, A2Areceptors in inflammation and injury: lessons learned from transgenic animals, J. Leucocyte Biol.83: 447-455). Both receptors also regulate the release of dopamine and glutamate in the brain (Sun and Hwang, 2016, Adenosine A2B Receptor: From Cell Biology to Human Diseases, Front. Chem.24: 37; Fuxe et al., 2007, Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function, Physiol Behav 92:210-7; Schiffmann et al., 2007, Adenosine A2A receptors and basal ganglia physiology, Prog Neurobiol 83: 277-92; and Cunha et al., 2008, How does adenosine control neuronal dysfunction and neurodegeneration?, J. Neurobiol.139:1019-1055). Set forth herein is evidence for a more general role for adenosine receptors in biological aging. The Adenosine A2AReceptor (ADORA2A) gene is expressed at a lower level compared to normal (p<0.05; Table 3) in gene expression analyses using NOP from individuals with AD / ADRD and shared biomarkers with Progeria (Werner’s syndrome). Furthermore, multiple genes in the STRING analysis (ADORA1; ACTN1, ACTN3, CALM3; GRM5, NECAB2, SYNGR1 and FURIN) show epigenetic co-regulation with the ADORA2A gene.. These data strongly suggest that A2Aagonists could augment ADORA2A anti- inflammatory pathway function. Multiple agonists have been characterized (CGS21680; DPMA; HE-NECA; ATL-146e; and CVT-3146). As set forth herein this invention utilizes two of them, CGS-21680 and Apadenoson (ATL-146e), as therapeutic compositions for treating ADRD / MED. Phosphodiesterase inhibitors have been used to augment the functions of Adenosine A2a Receptor. The effects of adenosine A2A agonists can be enhanced by type IV phosphodiesterase inhibitors, such as Rolipram. Hence, we tested another phosphodiesterase inhibitor in clinical use, Ruflumilast, by co-incubating it with A2A agonists. These experiments are performed at week 4 and 12 of development in culture. NNOPs are harvested after 1 week of exposure (at week 5, and at Week 13). Three independent experiments with replicates are performed and transcriptomic data analyzed by R-analysis. Another adenosine A2Areceptor agonist, apadenoson (ATL-146e), chemical name methyl (1R,4r)-4-(3-(6-amino-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-yn-1-yl)cyclohexane-1-carboxylate; CAS Number: 250386-15-3 Molecular Weight: 486.529; Soluble in DMSO. MedKoo Biosciences, Inc., is a selective adenosine A2Areceptor agonist and a potent inhibitor of inflammation. Apadenoson is tested using a range of concentrations (dose range: 100nM-1microM; EC50 of 110 nM); to enhance the effects of adenosine apadenoson certain experiments are performed in the presence of Roflumilast (10nM-1microM; IC50 of 0.8 nM ). The experiments will carried out and results statistically analyzed as described above. This invention provides methods for reducing or ameliorating disease severity in an individual having diseases and disabilities in an individual as a consequence of biological aging including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising a drug capable of reducing or correcting dysfunctional expression of genes associated with diseases and disabilities in an individual as a consequence of biological aging in vitro in a neural organoid platform and accordingly reduces or ameliorates disease severity in such individuals. Specifically, the methods provided herein rely upon identification of genes associated with diseases and disabilities in an individual as a consequence of biological aging that show dysfunctional or altered gene expression in neural organoid platforms in vitro for which the drugs disclosed herein are capable of reducing this dysfunctional expression. In particular embodiments these genes are set forth in Tables 3 and 10. As used herein, the terms “reducing or ameliorating” are intended to be understood to include improvements or reduction in impairments or progression thereof of symptoms of diseases and disabilities in an individual as a consequence of biological aging, particularly cognitive symptoms, of dementia, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED). As used herein, the term “therapeutically effective amount” of a drug for treating diseases and disabilities in an individual as a consequence of biological aging including but not limited to dementia, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) will be understood to include dosage amounts that provide improvements or reduction in impairments or progression thereof of symptoms, particularly cognitive symptoms, of dementia, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED). As used herein, the term “dysfunctional gene expression” will be understood to mean differences in gene expression in NOP as shown herein produced from skin cells, inter alia by methods for producing induced pluripotent stem cells that are then differentiated into NOP s set forth in U.S. Patent No.11,345, 890, incorporated herein in its entirety, between individuals having diseases and disabilities in an individual as a consequence of biological aging specifically including but not limited to Progeria (Werner’s Syndrome) and Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) or a genetic propensity for developing Alzheimer’s Disease (AD) or Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) and individuals without Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) or a genetic propensity for developing Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) or cancer. Useful NOPs as set forth herein can be generated as disclosed herein from adult skin cells of individuals having genetic traits including those of sporadic Alzheimer’s disease (identified as SPOR herein), amyloid plaque disorders (APP), mutations in ApoE (ApoE), or presenilin (PSEN2). The Progeria syndrome iPSC used to bioengineer PRG-NOP was derived from fibroblast from a white, female, 14-year-old patient donor with a LMNA gene mutation (Cat# AG27221; Coriell Biorepository, NJ). As used herein, the term “reducing or correcting dysfunctional gene expression” refers to changes in expression of certain genes (set forth herein in Tables 1 through 6) in NOP in response to addition of therapeutically effective amounts of a drug a disclosed herein, wherein dysfunctional gene expression has the meaning set forth above, and degree of effect on the NOP will be understood to reduce the extent of the dysfunction in expression of said genes. In particular embodiments, the genes having differential dysfunctional gene expression related to or associated with Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) are one or more of the genes set forth herein in Tables 3 through 10. A particular class of drugs provided herein are agonists of adenosine A2a receptor. (GENBANK ACCESSION NO. NP_001265429.1) encoded by ADORA2A (GENBANK ACCESSION NO. NM_001278497.2). In specific embodiments, such drugs include methyl (1R,4r)-4-(3-(6-amino-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-yn-1-yl)cyclohexane-1-carboxylate (known in the art as apadenoson). In other specific embodiments, such drugs include 2-p-(2-Carboxyethyl) phenethylamino-5 -N-ethylcarboxamidoadenosine hydrochloride hydrate(known in the art as CGS-21680). In addition to such particular and specific embodiments this disclosure encompasses related drug molecules that are agonists of adenosine A2a receptors encoded by ADORA2A and allelic variants thereof, particularly such variants associated with diseases and disabilities in an individual as a consequence of biological aging including but not limited to Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) or cancer. As used herein the adenosine A2a receptor agonists include related molecules, including variants in substituents, sidechains, and the like, that retain the capacity to reduce or ameliorate disease severity in patients having diseases and disabilities in an individual as a consequence of biological aging including but not limited to, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) or cancer. Such drugs also include structurally related drugs having improved specificity for any of the adenosine A2a receptors disclosed herein or known in the art to be associated with Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED). Such alternative embodiments of adenosine A2a receptors associated with Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) include but are not limited to allelic variants or genetic variants found to be associated with associated with Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) or cancer. The invention also provides pharmaceutical compositions of drugs capable of reducing or ameliorating disease severity in an individual having diseases and disabilities in an individual as a consequence of biological aging including but not limited to Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) or cancer. In specific embodiments the invention provides pharmaceutical compositions comprising therapeutically effective amounts of drugs capable of reducing or correcting dysfunctional expression of genes related to diseases and disabilities in an individual as a consequence of biological aging including but not limited to ADRD or MED. As disclosed herein, such genes are identified from a neural organoid platform wherein administration of the drugs in vitro reduces or alters this dysfunctional gene expression, and accordingly ameliorates disease severity in an individual having diseases and disabilities in an individual as a consequence of biological aging including but not limited to ADRD or Mixed MED when the pharmaceutical composition is administered to such patients. In particular embodiments these genes are set forth in Tables 1 through 6 herein. As used herein, the term “pharmaceutical composition” is intended to encompass and will be understood by those skilled in these arts to include agonists of adenosine A2a receptor, specifically adenosine A2a receptor having an amino acid sequence identified by GENBANK ACCESSION NO. NP_001265429.1 and encoded by ADORA2A (GENBANK ACCESSION NO. NM_001278497.2). Pharmaceutical compositions according to this invention include pharmacological salts, hydrates, or conjugates thereof. These compositions also include formulations, particularly formulations capable of traversing the blood-brain barrier and formulations that can be provided or oral administration for example in pill form. Alternative formulations, for example for injection, administration by inhalation, or rectal suppositories are also envisioned. Specific embodiments of drugs comprising the active pharmaceutical ingredient (API) of the pharmaceutical compositions provided herein include methyl (1R,4r)-4-(3-(6- amino-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2- yl)prop-2-yn-1-yl)cyclohexane-1-carboxylate (known in the art as apadenoson). In otherspecific embodiments, such drugs include 2-p-(2-Carboxyethyl) phenethylamino-5 -N-ethylcarboxamidoadenosine hydrochloride hydrate (known in the art as CGS-21680). In addition to such particular and specific embodiments this disclosure encompasses related drug molecules that are agonists of adenosine A2a receptors encoded by ADORA2A and allelic variants thereof, particularly such variants associated with Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED). Additional embodiments of the methods and pharmaceutical compositions disclosed herein comprise combinations of adenosine A2a receptor agonists as disclosed herein as well as combinations of these drugs with other medicaments useful for reducing or ameliorating disease severity in an individual having Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED). In specific embodiments such combinations include methyl (1R,4r)-4-(3-(6-amino-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-yn-1-yl)cyclohexane-1-carboxylate(known in the art as apadenoson), and / or 2-p-(2-Carboxyethyl) phenethylamino-5 -N-ethylcarboxamidoadenosine hydrochloride hydrate (known in the art as CGS-21680), in therapeutically useful combinations and dosages thereof, as well as combinations with alternative medicaments capable of reducing or ameliorating disease severity in an individual having diseases and disabilities as a consequence of biological aging including but not limited to Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED) or cancer. As used herein, “combinations” can include formulations comprising one or more of the drugs specifically identified herein for reducing or ameliorating disease severity in an individual having diseases and disabilities in an individual as a consequence of biological aging, specifically including but not limited to Alzheimer’s Disease, Alzheimer’s Disease Related Dementia (ADRD) or Mixed Etiology Dementia (MED). In certain combinations the drugs are administered concomitantly and in other administration can be achieved over a specified time course. In some embodiments the combinations are provided in a single formulation whereas in others the drugs are separately formulated. In further embodiments useful in the methods and provided in pharmaceutical compositions provided herein are adenosine A2b receptor antagonists, wherein the adenosine A2b receptor has an amino acid sequence is encoded by ADORA2B (GenBank Accession No. NM_000676.4). Specific embodiments of drugs comprising these adenosine A2b receptor antagonists include but are not limited to PBF-1129 and MRS-1706; see, Vazquez et al., 2008, "Local stimulation of the adenosine A2B receptors induces an increased release of IL-6 in mouse striatum: an in vivo microdialysis study," J. Neurochem.105: 904–9 and Ryzhov et l., 2008, "Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells," J. Immunol.180: 7212–20. As disclosed herein, genes have been identified from a neural organoid platform wherein administration of adenosine A2b receptor antagonists in vitro reduces or alters this dysfunctional gene expression, and accordingly ameliorates disease severity in an individual having diseases and disabilities as a consequence of biological aging including but not limited to ADRD or Mixed MED when the pharmaceutical composition is administered to such patients. In particular embodiments these genes are set forth in Tables 3 through 10 herein. These and other data findings, features, and advantages of the present disclosure will be more fully understood from the following detailed description taken together with the accompanying claims. It is noted that the scope of the claims is defined by the recitations therein and not by the specific discussion of features and advantages set forth in the present description. EXAMPLES The Examples that follow are illustrative of specific embodiments of the invention, and the use thereof. It is set forth for explanatory purposes only and is not taken as limiting the invention. In particular, the example demonstrates the effectiveness of neural organoids in predicting future disease risk. MATERIALS AND METHODS The neural organoids described above were developed using the following materials and methods. Summary of Methods: Neural Organoids derived from induced pluripotent stem cells derived from adult skin cells of patients were grown in vitro for 4 weeks as previous described in U.S. Patent No 11,435,890, incorporated by reference in its entirety herein. Transcriptomic data from these neural organoids were obtained. Differences in expression of 20,814 genes expressed in the human genome were determined between these neural organoids and those from neural organoids from a normal individual human. Detailed data analysis using Gene Card and Pubmed data bases were performed. Genes that were expressed at greater than 1.4-fold were found to be highly significant because a vast majority were correlated with genes previously associated with a multitude of neurodevelopmental and neurodegenerative diseases as well as those found to be dysregulated in postmortem patient brains. These genes comprise a suite of biomarkers for Alzheimer’s disease. Cells used in these methods include human iPSCs, feeder-dependent (System Bioscience. WT SC600A-W) and CF-1 mouse embryonic fibroblast feeder cells, gamma- irradiated (Applied StemCell, Inc #ASF- 1217) Growth media, or DMEM media, used in the examples contained the supplements as provided in Table 1 (Growth Media and Supplements used in Examples). Table1: Growth Media and Supplements used in Examples One skilled in the art will recognize that additional formulations of media and supplements can be used to culture, induce and maintain pluripotent stem cells and neural organoids. Experimental protocols required the use of multiple media compositions including MEF Media, IPSC Media, EB Media, Neural Induction Media, and Differentiation Medias 1, 2, and 3. Mouse embryonic fibroblast (MEF) was used in cell culture experiments. MEF Media comprised DMEM media supplemented with 10% Feta Bovine Serum, 100 units / ml penicillin, 100 microgram / ml streptomycin, and 0.25 microgram / ml Fungizone. Induction media for pluripotent stem cells (IPSC Media) comprised DMEM / F12 media supplemented with 20% Knockout Replacement Serum, 3% Fetal Bovine Serum with 2mM Glutamax, IX Minimal Essential Medium Nonessential Amino Acids, and 20 nanogram / ml basic Fibroblast Growth Factor Embryoid Body (EB) Media comprised Dulbecco's Modified Eagle's Medium (DMEM) (DMEM) / Ham's F-12 media, supplemented with 20% Knockout Replacement Serum, 3% Fetal Bovine Serum containing 2mM Glutamax, IX Minimal Essential Medium containing Nonessential Amino Acids, 55microM beta-mercaptoethanol, and 4ng / ml basic Fibroblast Growth Factor. Neural Induction Media contained DMEM / F12 media supplemented with a 1:50 dilution N2 Supplement, a 1:50 dilution GlutaMax, a 1:50 dilution MEM-NEAA, and 10 microgram / ml Heparin` Three differentiation medias were used to produce and grow neural organoids. Differentiation Media 1 contained DMEM / F12 media and Neurobasal media in a 1:1 dilution. Each media is commercially available from Invitrogen. The base media was supplemented with a 1:200 dilution N2 supplement, a 1:100 dilution B27 - vitamin A, 2.5microgram / ml insulin, 55microM beta-mercaptoethanol kept under nitrogen mask and frozen at -20°C, 100 units / ml penicillin, 100 microgram / ml streptomycin, and 0.25microgram / ml Fungizone. Differentiation Media 2 contained DMEM / F12 media and Neurobasal media in a 1:1 dilution supplemented with a 1:200 dilution N2 supplement, a 1:100 dilution B27 containing vitamin A, 2.5microgram / ml Insulin, 55umicroMolar beta-mercaptoethanol kept under nitrogen mask and frozen at -20°C, 100units / ml penicillin, 100microgram / ml streptomycin, and 0.25microgram / ml Fungizone. Differentiation Media 3 consisted of DMEM / F12 media: Neurobasal media in a 1:1 dilution supplemented with 1:200 dilution N2 supplement, a 1:100 dilution B27 containing vitamin A), 2.5microgram / ml insulin, 55microMolar beta-mercaptoethanol kept under nitrogen mask and frozen at -20°C, 100 units / ml penicillin, 100 microgram / ml streptomycin, 0.25microgram / ml Fungizone, TSH, and Melatonin. The equipment used in obtaining, culturing and inducing differentiation of pluripotent stem cells is provided in Table 2 (Equipment used in Experimental Procedures). One skilled in the art would recognize that the list is not at all exhaustive but merely exemplary. Table 2: Equipment used in Experimental Procedures. Example 1: Generation of human induced pluripotent stem cell-derived neural organoids. Human induced pluripotent stem cell-derived neural organoids were generated according to the following protocol, as set forth in U.S. Patent No 11,435,890, incorporated by reference in its entirety herein. Briefly, irradiated murine embryonic fibroblasts (MEF) were plated on a gelatin coated substrate in MEF media (Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% Fetal Bovine Serum, 100 units / ml penicillin, 100 microgram / ml streptomycin, and 0.25 microgram / ml Fungizone) at a density of 2 x 105cells per well. The seeded plate was incubated at 37°C overnight. After incubation, the MEFs were washed with pre-warmed sterile phosphate buffered saline (PBS). The MEF media was replaced with 1 mL per well of induced pluripotent stem cell (iPSC) media containing Rho-associated protein kinase (ROCK) inhibitor. A culture plate with iPSCs was incubated at 37°C. The iPSCs were fed every other day with fresh iPSC media containing ROCK inhibitor. The iPSC colonies were lifted, divided, and transferred to the culture wells containing the MEF cultures so that the iPSC and MEF cells were present therein at a 1:1 ratio. Embryoid bodies (EB) were then prepared. Briefly, a 100 mm culture dish was coated with 0.1% gelatin and the dish placed in a 37oC incubator for 20 minutes, after which the gelatin-coated dish was allowed to air dry in a biological safety cabinet. The wells containing iPSCs and MEFs were washed with pre-warmed PBS lacking Ca2+ / Mg2+. A pre-warmed cell detachment solution of proteolytic and collagenolytic enzymes (1 mL / well) was added to the iPSC / MEF cells. The culture dishes were incubated at 37°C for 20 minutes until cells detached. Following detachment, pre-warmed iPSC media was added to each well and gentle agitation used to break up visible colonies. Cells and media were collected and additional pre-warmed media added, bringing the total volume to 15 mL. Cells were placed on a gelatin-coated culture plate at 37°C and incubated for 60 minutes, thereby allowing MEFs to adhere to the coated surface. The iPSCs present in the cell suspension were then counted. The suspension was then centrifuged at 300xg for 5 minutes at room temperature, the supernatant discarded, and cells re-suspended in EB media supplemented with ROCK inhibitor (50uM final concentration) and 4ng / ml basic Fibroblast Growth Factor to a volume of 9,000 cells / 150 μL. EB media is a mixture of DMEM / Ham's F-12 media supplemented with 20% Knockout Replacement Serum, 3% Fetal Bovine Serum (2mM Glutamax), 1X Minimal Essential Medium Nonessential Amino Acids, and 55 M beta-mercaptoethanol. The suspended cells were plated (150 μL) in a LIPIDURE® low-attachment U-bottom 96-well plate and incubated at 37°C. The plated cells were fed every other day during formation of the embryoid bodies by gently replacing three fourths of the embryoid body media without disturbing the embryoid bodies forming at the bottom of the well. Special care was taken in handling the embryoid bodies so as not to perturb the interactions among the iPSC cells within the EB through shear stress during pipetting. For the first four days of culture, the EB media was supplemented with 50uM ROCK inhibitor and 4ng / ml beta-fibroblast growth factor (bFGF). During the remaining two to three days the embryoid bodies were cultured, no ROCK inhibitor or bFGF was added. On the sixth or seventh day of culture, the embryoid bodies were removed from the LIPIDURE® 96 well plate and transferred to two 24-well plates containing 500 μL / well Neural Induction media, DMEM / F12 media supplemented with a 1:50 dilution N2 Supplement, a 1:50 dilution GlutaMax, a 1:50 dilution MEM-Non-Essential Amino Acids (NEAA), and 10 g / ml Heparin. Two embryoid bodies were plated in each well and incubated at 37°C. The media was changed after two days of incubation. Embryoid bodies with a "halo" around their perimeter indicate neuroectodermal differentiation. Only embryoid bodies having a "halo" were selected for embedding in Matrigel, remaining embryoid bodies were discarded. Plastic paraffin film (PARAFILM) rectangles (having dimensions of 5cm x 7cm) were sterilized with 3% hydrogen peroxide to create a series of dimples in the rectangles. This dimpling was achieved, in one method, by centering the rectangles onto an empty sterile 200μL tip box press and pressing the rectangles gently to dimple it with the impression of the holes in the box. The boxes were sprayed with ethanol and left to dry in the biological safety cabinet. Frozen Matrigel matrix aliquots (500 μL) were thawed on ice until equilibrated at 4°C. A single embryoid body was transferred to each dimple of the film. A single 7cm x 5cm rectangle holds approximately twenty (20) embryoid bodies. Twenty microliter (20μL) aliquots of Matrigel were transferred onto the embryoid bodies after removing extra media from the embryoid body with a pipette. The Matrigel was incubated at 37°C for 30 min until the Matrigel polymerized. The 20μL droplet of viscous Matrigel was found to form an optimal three-dimensional environment that supported the proper growth of the neural organoid from embryoid bodies by sequestering the gradients of morphogens and growth factors secreted by cells within the embryoid bodies during early developmental process. However, the Matrigel environment permitted exchange of essential nutrients and gases. Gentle oscillation by hand twice a day for a few minutes within a tissue culture incubator (37°C / 5%C02) further allowed optimal exchange of gases and nutrients to the embedded embryoid bodies. Differentiation Media 1, a one-to-one mixture of DMEM / F12 and Neurobasal media supplemented with a 1:200 dilution N2 supplement, a 1:100 dilution B27 - vitamin A, 2.5 g / mL insulin, 55 M beta-mercaptoethanol kept under nitrogen mask and frozen at -20°C, 100 units / mL penicillin, 100 g / mL streptomycin, and 0.25 g / mL Fungizone, was added to a 100 mm tissue culture dish. The film containing the embryoid bodies in Matrigel was inverted onto the 100 mm dish with differentiation media 1 and incubated at 37°C for 16 hours. After incubation, the embryoid body / Matrigel droplets were transferred from the film to the culture dishes containing media. Static culture at 37°C was continued for 4 days until stable neural organoids formed. Organoids were gently transferred to culture flasks containing differentiation media 2, a one-to-one mixture of DMEM / F12 and Neurobasal media supplemented with a 1:200 dilution N2 supplement, a 1:100 dilution B27 + vitamin A, 2.5 g / mL insulin, 55microM beta- mercaptoethanol kept under nitrogen mask and frozen at -20°C, 100 units / mL penicillin, 100 g / mL streptomycin, and 0.25 g / mL Fungizone. The flasks were placed on an orbital shaker rotating at 40 rpm within the 37°C / 5% CO2 incubator. The media was changed in the flasks every 3-4 days to provide sufficient time for morphogen and growth factor gradients to act on targets within the recipient cells forming relevant structures of the brains. Great care was taken when changing media so as to avoid unnecessary perturbations to the morphogen / secreted growth factor gradients developed in the outer most periphery of the organoids as the structures grew into larger organoids. FIG.1 illustrates neural organoid development in vitro. Based on transcriptomic analysis, iPSC cells form a body of cells after 3D culture, which become neural progenitor cells (NPC) after neural differentiation media treatment. Neurons were observed in the cell culture after about one week. After about four (4) weeks or before, neurons of multiple lineage appeared. At about twelve (12) weeks or before, the organoid developed to a stage having different types of cells, including microglia, oligodendrocyte, astrocyte, neural precursor, neurons, and interneurons. Example 2: Human induced pluripotent stem cell-derived neural organoids express characteristics of human brain development. After approximately 12 weeks of in vitro culture, transcriptomic and immunohistochemical analysis indicated that organoids were generated according to the methods delineated in Example 1. Specifically, the organoids contained cells expressing markers characteristic of neurons, astrocytes, oligodendrocytes, microglia, and vasculature (FIG.1A and 1B) and all major brain structures of neuroectodermal derivation. Morphologically identified by bright field imaging, the organoids included readily identifiable neural structures including cerebral cortex, cephalic flexure, and optic stalk (compare, Grey's Anatomy Textbook). The gene expression pattern in the neural organoid was >98 % concordant with those of the adult human brain reference (Clontech, #636530). The organoids also expressed genes in a developmentally organized manner described previously (e.g. for the midbrain mesencephalic dopaminergic neurons; Blaese et al., Genetic control of midbrain dopaminergic neuron development. Rev Dev Biol.4(2): 113-34, 2015). The structures also stained positive for multiple neural specific markers (dendrites, axons, nuclei), cortical neurons (Doublecortin), midbrain dopamine neurons (Tyrosine Hydroxylase), and astrocytes (GFAP) as shown by immunohistology). All human neural organoids were derived from iPSCs of fibroblast origin (from System Biosciences, Inc). The development of a variety of brain structures was characterized in the organoids. Biomarkers specific for particular regions of human brain were detected as set forth in U.S. Patent No 11,435,890, incorporated by reference in its entirety herein. Changes in expression of representative genes in the ADORA2A STRING Network (Genecards) is shown in the following Table 9 for ADRD-SPOR-NNOP and WRX-NOP, illustrative of gene expression changes that can be assayed in the presence and absence of test compounds. Example 3: Testing adenosine A2a receptor agonists for efficacy in human NNOP model Table 3: ADORA2A Network DEG Bbomarkers in ADRD-SPOR-NNOP normalized by treatment with adenosine A2a receptor agonist CGS-21680 plus PDE4 inhibitor Roflumilast.

[0002] ADORA2A NETWORK BIOMARKERS Table 3: Differentially expressed genes (DEGs) in NNOP derived from ADRD patients (ADRD- NNOP), NNOP derived from a sporadic ADRD patient (ADRD-SPOR-NNOP) compared to NNOP derived from healthy patients, and in ADRD-SPOR-NNOP cultured and CGS-21680 was tested at a concentration of 1 micromolar in the presence of 0.1micromolar Roflumilast to assess the number of genes that are differentially expressed to ‘normalize’ their expression by epigenetic mechanism affecting gene regulatory networks in ADRD-SPOR-NNOP. The Italic Log 2 values indicate DEGs that showed dysregulation in ADRD-SPOR-NNOP. The same DEGs were corrected towards normalcy (BOLD Log 2 values) upon treatment with CGS-21680 plus Roflumilast. Adenosine agonists (A2A) are tested for effects on gene expression dysregulation in NOP platform cells as set forth herein. 2-p-(2-Carboxyethyl) phenethylamino-5 -N-ethylcarboxamidoadenosinehydrochloride hydrate (CGS-21680) is a specific adenosine A2Asubtype receptor agonist (CAS Number:124182-57-6; Molecular Weight:535.98 (anhydrous basis), available from Sigma Chemical Co.). It is usually presented as an organic hydrochloride salt with a molecular weight of 536.0 g / M, is soluble up to 3.4 mg / mL in DMSO and 20 mg / mL in 45%(w / v) aq 2-hydroxypropyl- -cyclodextrin.CGS-21680 was tested at a concentration of 1 micromolar to assess the number of disease modifying genes that are differentially expressed to ‘normalize’ their expression by epigenetic mechanism affecting gene regulatory networks in ADRD / MED. The results of these experiments are shown in Table 4. Table 4 shows gene expression changes in NNOP cultures developed from iPSCs from adult skin cells from a patient having sporadic Alzheimer’s disease (SPOR) , wherein addition of CGS-21680 plus Roflumilast combination of drugsnormalizing effects set forth in the Table. Table 4: Alzheimer’s disease DEG biomarkers in ADRD-SPOR-NNOP normalized by treatment with adenosine A2a receptor agonist CGS-21680 plus PDE4 inhibitor Roflumilast. Table 4: Differentially expressed genes (DEGs) in NNOP derived from ADRD patients (ADRD-NNOP), NNOP derived from a sporadic ADRD patient (ADRD-SPOR-NNOP) compared to NNOP derived from healthy patients, and in ADRD--SPOR-NNOP cultured and CGS-21680 was tested at a concentration of 1 micromolar in the presence of 0.1 micromolar Roflumilast to assess the number of genes that are differentially expressed to ‘normalize’ their expression by epigenetic mechanism affecting gene regulatory networks in ADRD-SPOR- NNOP. The Italic Log 2 values indicate DEGs that showed dysregulation in ADRD-SPOR- NNOP. The same DEGs were corrected towards normalcy (BOLD Log 2 values) upon treatment with CGS-21680 plus Roflumilast. Another adenosine A2Areceptor agonist, apadenoson (ATL-146e), chemical name methyl (1R,4r)-4-(3-(6-amino-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4- dihydroxytetrahydrofuran-2- yl)-9H-purin-2-yl)prop-2-yn-1-yl)cyclohexane-1-carboxylate; CAS Number: 250386-15-3 Molecular Weight: 486.529; Soluble in DMSO. MedKoo Biosciences, Inc., is a selective adenosine A2Areceptor agonist and a potent inhibitor of inflammation. Apadenoson is tested using a range of concentrations (dose range: 100nM-1microM; EC50 of 110 nM); to enhance the effects of adenosine apadenoson certain experiments are performed in the presence of PDE inhibitor. To enhance the effects of adenosine agonist experiments with CGS-21680 were performed in the presence of Roflumilast, a PDE4 inhibitor. Previous work indicated that Roflumilast can upregulate PDE4 expression (Susuki-Miyata et al., Cross-talk betweenPKA-C and p65 mediates synergistic induction of PDE4B by roflumilast and NTH. PNAS, E1800–E1809, 2015) to compensate for lower PDE4B expression in ADRD-HMP-SPOR- NNOP (base mean 491.67; Log2 Fold Change 1.49; p-value 1.29E-02). The experiments will be carried out and results statistically analyzed as described above. A positive Log 2 value indicates PDE4B expression is higher in the normal-NNOP compared to in ADRD- HMP-SPOR-NNOP. The results of transcriptomics experiments are shown in FIG.4 and were performed as described herein and in U.S. Patent No 11,435,890, incorporated by reference in its entirety. Briefly, neural organoids were cultured in media after neural differentiation was initiated with addition of retinoic acid as per the published protocol (International patent application publication No. WO2017123791A1). Cultures were replenished with fresh media every week. Organoids were harvested after D0, D3, Week 1 and Week 4 in culture. Figure 3 shows transcriptomic data from familial (APP) and sporadic (SPOR) patients in controlled clinical studies, wherein comparative data analysis from NOP platform between normal and dementia patient-derived samples permits identification of therapeutic targets and individualization of treatment decisions. FIG.5 shows AD-NNOP transcriptomic data illustrating significant overlap with transcriptomic data from accelerated aging Progeria Syndrome patient sample-derived PRGN-NNOP. Expression of differentially expressed genes in PRG-NNOP (Progeria; Werner Syndrome) and four AD-NOP neural organoids are compared to Normal-NOP in culture for 12 weeks. RNA extraction and gene expression analysis performed by AmpliseqTm(Thermofisher) as set forth herein. The four ADRD-NNOP models (ADRD-APP- NNOP; ADRD-PSEN2-NNOP-; ADRD-SPOR-NNOP; and ADRD-APOE-NNOP) were derived from AD patient donors and the iPSCs obtained from the Coreill Biorepository (NJ, USA). Clinical validation of NNOP for AD / ADRD is apparent from significant corroboration of AD-APP-NOP transcriptomic data with clinical postmortem AD brain transcriptomic data analyses (Annese et al. Sci Rep.2018;8(1):4282) of a match with a statistical p-value of 1e-103of a match by chance alone. FIG.6 shows normal-NNOP & PRG-NNOP having highly replicable, reliable, robust transcriptomic data. Independent NNOP sample transcriptomic at week 12 in culture. Plots represent data reproducibility for ~13,000 genes expressed with a variance of <0.95 in most independent replicates. These data are shown in Tables 1-6 herein. One of skill in the art will recognize that sequence data for the genes listed above can be obtained in publicly available gene databases such as GeneCards, GenBank, Malcard, Uniport and PathCard databases. The skilled worker will recognize these markers as set forth exemplarily herein to be human-specific marker proteins as identified, inter alia, in genetic information repositories such as GenBank; Accession Number. One having skill in the art will recognize that variants derive from the full length gene sequence. Table 5: Inflammation pathway DEG biomarkers in ADRD-SPOR-NNOP normalized by treatment with adenosine A2a receptor agonist CGS-21680 plus PDE4 inhibitor Roflumilast. Differentially expressed genes (DEGs) in NNOP derived from ADRD patients (ADRD- NNOP), NNOP derived from a sporadic ADRD patient (ADRD-SPOR-NNOP) compared to NNOP derived from healthy patients, and in ADRD-SPOR-NNOP cultured and CGS-21680 was tested at a concentration of 1 micromolar in the presence of 0.1micromolar Roflumilast to assess the number of genes that are differentially expressed to ‘normalize’ their expression by epigenetic mechanism affecting gene regulatory networks in ADRD-SPOR- NNOP. The Italic Log 2 values indicate DEGs that showed dysregulation in ADRD-SPOR- NNOP. The same DEGs were corrected towards normalcy (BOLD Log 2 values) upon treatment with CGS-21680 plus Roflumilast. Table 6: Gut microbiota secreted metabolites / toxin brain receptor DEG biomarkers in ADRD-SPOR-NNOP normalized by treatment with adenosine A2a receptor agonist CGS-21680 plus PDE4 inhibitor Roflumilast. Differentially expressed genes (DEGs) in NNOP derived from ADRD patients (ADRD- NNOP), NNOP derived from a sporadic ADRD patient (ADRD-SPOR-NNOP) compared to NNOP derived from healthy patients, and in ADRD-SPOR-NNOP cultured and CGS-21680 was tested at a concentration of 1 micromolar in the presence of 0.1micromolar Roflumilast to assess the number of genes that are differentially expressed to ‘normalize’ their expression by epigenetic mechanism affecting gene regulatory networks in ADRD-SPOR- NNOP. The Italic Log 2 values indicate DEGs that showed dysregulation in ADRD-SPOR- NNOP. The same DEGs were corrected towards normalcy (BOLD Log 2 values) upon treatment with CGS-21680 plus Roflumilast. Table 7A: Hormone responsive DEG biomarkers in ADRD-SPOR-NNOP Table 7B: Hormone responsive DEG biomarkers in ADRD-SPOR-NNOP normalized by treatment with adenosine A2a receptor agonist CGS-21680 plus PDE4 inhibitor Roflumilast. Differentially expressed genes (DEGs) in NNOP derived from ADRD patients (ADRD- NNOP), NNOP derived from a sporadic ADRD patient (ADRD-SPOR-NNOP) compared to NNOP derived from healthy patients, and in ADRD-SPOR-NNOP cultured and CGS-21680 was tested at a concentration of 1 micromolar in the presence of 0.1micromolar Roflumilast to assess the number of genes that are differentially expressed to ‘normalize’ their expression by epigenetic mechanism affecting gene regulatory networks in ADRD-SPOR- NNOP. The Italic Log 2 values indicate DEGs that showed dysregulation in ADRD-SPOR- NNOP. The same DEGs were corrected towards normalcy (BOLD Log 2 values) upon treatment with CGS-21680 plus Roflumilast. Table 8A: Vitamin and essential mineral nutrient receptor / enzymes DEG biomarkers dysregulated in ADRD-SPOR-NNOP. Table 8B: Nutrient and essential mineral nutrient receptor / enzymes DEG biomarkers in ADRD-SPOR-NNOP normalized by treatment with adenosine A2a receptor agonist CGS-21680 plus PDE4 inhibitor Roflumilast. Table 9: Shared Progeria (PRG-NNOP) and ADRD Accelerated Aging DEG biomarkers in ADRD-SPOR-NNOP normalized by treatment with adenosine A2a receptor agonist CGS-21680 plus PDE4 inhibitor Roflumilast.

[0003] Differentially expressed genes (DEGs) in NNOP derived from a Progeria patient (PRG) versus from a sporadic ADRD patient (ADRD-SPOR-NNOP) compared to NNOP derived from healthy person (NORM). The shared DEGs are indicated in BOLD Log 2 values. Table 10A: Comorbid disease DEG biomarkers in ADRD-SPOR-NNOP Differentially expressed genes (DEGs) in NNOP derived from ADRD patients (ADRD- NNOP), NNOP derived from a sporadic ADRD patient (ADRD-SPOR-NNOP) compared to NNOP derived from healthy patients, and in ADRD-SPOR-NNOP.

[0004] Table 10B: Comobid disease DEG biomarkers in ADRD-SPOR-NNOP normalized by treatment with adenosine A2a receptor agonist CGS-21680 plus PDE4 inhibitor Roflumilast. Differentially expressed genes (DEGs) in NNOP derived from ADRD patients (ADRD- NNOP), Table 10B: NNOP derived from a sporadic ADRD patient (ADRD-SPOR-NNOP) compared to NNOP derived from healthy patients, and in ADRD-SPOR-NNOP cultured and CGS-21680 was tested at a concentration of 1 micromolar in the presence of 0.1micromolar Roflumilast to assess the number of genes that are differentially expressed to ‘normalize’ their expression by epigenetic mechanism affecting gene regulatory networks in ADRD- SPOR-NNOP. The Italic Log 2 values indicate DEGs that showed dysregulation in ADRD- SPOR-NNOP. The same DEGs were corrected towards normalcy (BOLD Log 2 values) upon treatment with CGS-21680 plus Roflumilast. Other Embodiments: From the foregoing description, it will be apparent that variations and modifications can be made to the invention described herein to adopt it to various usages and conditions. Such embodiments are also within the scope of the following claims. The recitation of a listing of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or sub- combination) of listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference. Having described the invention in detail and by reference to specific aspects and / or embodiments thereof, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims. More specifically, although some aspects of the present invention may be identified herein as particularly advantageous, it is contemplated that the present invention is not limited to these particular aspects of the invention. Percentages disclosed herein can vary in amount by ±10, 20, or 30% from values disclosed and remain within the scope of the contemplated invention.

Claims

WHAT IS CLAIMED IS:

1. A method for reducing or ameliorating disease severity in an individual for a disease, disorder, or disability as a consequence of biological aging comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising a drug capable of reducing or correcting dysfunctional expression of genes related to said disease or disability as a consequence of biological aging in vitro in a neural organoid platform and reducing or ameliorating disease severity in an individual thereby.

2. The method of claim 1, wherein the disease, disorder, or disability is Alzheimer’s disease, Alzheimer’s Disease Related Dementia (ADRD), Mixed Etiology Dementia (MED), Lewy Body dementia, fronto-temporal dementia, or vascular contributors to dementia.

3. The method of claim 1, wherein the genes related to a disease, disorder, or disability as a consequence of biological aging for which the drug is capable of reducing or correcting dysfunctional expression are set forth in Tables 3-10.

4. The method of claims 1, 2, or 3, wherein the drug is an agonist of an adenosine A2a receptor. (Genbank Accession No. NP_001265429.1) 5. . The method of claim 4, wherein the adenosine A2a receptor is encoded by an ADORA2A gene (Genbank Accession No. NM_001278497.2).

6. The method of claim 5, wherein the drug is methyl (1R,4r)-4-(3-(6-amino-9- ((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin-2- yl)prop-2-yn-1-yl)cyclohexane-1-carboxylate (apadenoson).

7. The method of claim 5, wherein the drug is 2-p-(2-Carboxyethyl)phenethylamino-5 -N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680).

8. A pharmaceutical composition of a drug capable of reducing or ameliorating disease severity in an individual having a disease, disorder, or disability as a consequence of biological aging comprising a therapeutically effective amount of the pharmaceutical composition comprising a drug capable of reducing or correcting dysfunctional expression of genes in vitro in a neural organoid platform that reduces or ameliorates disease severity in an individual thereby.

9. The pharmaceutical composition of claim 8, wherein the disease, disorder, or disability is Alzheimer’s disease, Alzheimer’s Disease Related Dementia (ADRD), Mixed Etiology Dementia (MED), Lewy Body dementia, fronto-temporal dementia, or vascular contributors to dementia.

10. The pharmaceutical composition of claim 8 or 9, wherein the genes related to a disease, disorder, or disability as a consequence of biological aging for which the drug is capable of reducing or correcting dysfunctional expression are set forth in Tables 1-5.

11. The pharmaceutical composition of claim 10, wherein the drug is an agonist of an adenosine A2a receptor. (Genbank Accession No. NP_001265429.1) 12. The pharmaceutical composition of claim 10, wherein the adenosine A2a receptor is encoded by an ADORA2A gene (Genbank Accession No. NM_001278497.2).

13. The pharmaceutical composition of claim 10, wherein the drug is methyl (1R,4r)-4-(3-(6-amino-9-((2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4- dihydroxytetrahydrofuran-2-yl)-9H-purin-2-yl)prop-2-yn-1-yl)cyclohexane-1- carboxylate (apadenoson).

14. The pharmaceutical composition of claim 10, wherein the drug is 2-p-(2-Carboxyethyl) phenethylamino-5 -N-ethylcarboxamidoadenosine hydrochloridehydrate (CGS-21680).

15. A method for reducing or ameliorating disease severity in an individual having a disease, disorder, or disability as a consequence of biological aging including but not limited to dementia comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising a drug capable of correcting dysfunctional expression of genes related to said disease, disorder, or disability ability in vitro in a neural organoid platform in combination with an PDE4 inhibitor and reducing or ameliorating disease severity in an individual thereby.

16. The method of claim 15, wherein the disease, disorder, or disability sability is Alzheimer’s disease, Alzheimer’s Disease Related Dementia (ADRD), Mixed Etiology Dementia (MED), Lewy Body dementia, fronto-temporal dementia, or vascular contributors to dementia.

17. The method of claims 15 or 16, wherein the genes related to ADRD or MED for which the drug is capable of reducing or correcting dysfunctional expression are set forth in Table 3-10.

18. A pharmaceutical composition for use in the method of claim 16 or 17, comprising a drug capable of reducing or correcting dysfunctional expression of genes related to a disease, disorder, or disability as a consequence of biological aging in vitro in a neural organoid platform in combination with an PDE4 inhibitor that reduces or ameliorates disease severity in an individual thereby.

19. A pharmaceutical composition for use in the method of claim 18, comprising a drug capable of reducing or correcting dysfunctional expression of genes related to the disease, disorder, or disability in vitro in a neural organoid platform in combination with an PDE4 inhibitor that reduces or ameliorates disease severity in an individual thereby.

20. The method of claims 1, 2, or 3, wherein the drug is an antagonist of an adenosine A2b receptor. (GenBank Accession No. NP_00667.4) 21. The method of claim 20, wherein the adenosine A2a receptor is encoded by an ADORA2B gene (GenBank Accession No. NM00676.4).

22. The method of claim 23, wherein the genes related to the disease, disorder, or disability for which the drug is capable of reducing or correcting dysfunctional expression are set forth in Tables 3-10.

23. The method of claim 19, wherein the drug is PBF-1129 or MRS-1706.

24. The method of claim 19, wherein the ADORA2A receptor agonist is co- administered with an PDE4 inhibitor.

25. The method of claim 19, wherein the ADORA2A receptor agonist is co- administered with an PDE4 inhibitor that is Roflumilast.

26. The method of claim 19, wherein the ADORA2A receptor agonist is co- administered with an PDE4 inhibitor that is AWD-12-281, Elbion, Tofimilast, UK- 500,001, GSK256066, SCH900182, SCH900182, Almirall, Lotamilast, Ensifentrine / RPL554, or CHF 6001, 27. A pharmaceutical composition of a drug capable of reducing or ameliorating disease severity in an individual having a disease, disorder, or disability as a consequence of biological aging comprising a therapeutically effective amount of the pharmaceutical composition comprising a drug capable of reducing or correcting dysfunctional expression of genes related to the disease or disability in vitro in a neural organoid platform that thereby reduces or ameliorates disease severity in an individual having the disease, disorder, or disability wherein the drug is an antagonist of adenosine A2b receptor.

28. The pharmaceutical composition of claim 27, wherein the disease, disorder, or disability is Alzheimer’s disease, Alzheimer’s Disease Related Dementia (ADRD), Mixed Etiology Dementia (MED), Lewy Body dementia, fronto-temporal dementia, or vascular contributors to dementia.

29. The pharmaceutical composition of claim 27 or 28, wherein the genes related to the disease, disorder, or disability for which the drug alone or in combination iscapable of reducing or correcting dysfunctional expression are set forth in Tables 3- 10.

30. A method for performing gene therapy in a cell to correct expression of one or a plurality of adenosine receptor network components identified as ADORA1, ADORA2A, ADORA2B genes and their modulators resulting in modification of gene expression in the one or a plurality of components.

31. The method of claim 30, wherein the therapeutic agent is a RNA-based therapeutics.

32. The method of claim 30, wherein the RNA-based therapeutics is antisense oligonucleotide (ASO), Adeno-Associated Virus delivery of small interfering RNA (AAV-RNA), or micro RNA (miRNA).

33. The method of claim 30, wherein the differentially expressed genes for which the RNA-based therapeutics is capable of reducing or correcting are set forth in Tables 3-10.

34. The method of claim 30, wherein gene therapy effects are measured by detecting changes in expression of genes encoding human LMNA, WRN, DHX9, A2M, PSEN2, ApoE, APP variants or sporadic AD.

35. The method of claim 30, wherein gene therapy is performed using an anti- sense oligonucleotide (ASO) to correct expression of the human LMNA, WRN, DHX9, A2M, PSEN2, ApoE, APP variants or sporadic AD.

36. The method of claim 30, wherein the measured genes comprise one or a plurality of genes as identified in Tables 1-5.

37. The method of claim 30, wherein the neural organoid sample is procured from minutes to hours up to 15 weeks post inducement.

38. The method of claim 30, wherein the genes to be tested are one or a plurality of genes in Tables 3-10.

39. The method of claim 30, wherein the genetic are one or a plurality of genes in Table 6.

40. The method of claim 30, wherein the method is used for diagnostic, therapeutic target discovery and drug action discovery for aging including dementia, Alzheimer’s disease and Alzheimer’s disease related comorbidities as listed in Table 7 and cancer.

41. The method of claims 1, 8, 15, 27, or 30, wherein data obtained from neural organoid data is corroborated in postmortem tissues from idiopathic patients and identifies changes in gene expression for aging including age-related dementia and cancers.

42. The method of claim 41, wherein the method can be used with induced pluripotent stem cells from any skin cell, tissue, or organ from the human body for diagnostics, therapeutic target discovery, and drug development.

43. The method of claims 1, 8, 15, 27, or 30, wherein the method and / or neural organoid is used in patient specific toxicology to identify genes involved in a patient’s selective vulnerability to infectious agents or environmental toxins.

44. The method of claim 1, 8, 15, 27, or 30, wherein the method can be used to identify nutritional and toxicological care that can begin even before birth so that the child develops normally in utero.

45. The method of claims 1, 8, 15, 27, or 30, wherein the measured genes are representative of proteins or their metabolites dysregulated in disease, disorder, or disability.

46. The method of any one of claims 1, 8, 15, 27, or 30, wherein the method can be used to diagnosis of aging including age-related dementia and cancers at birth47. A method for treating aging including age-related dementia and cancers in a human, using a patient-specific pharmacotherapy, the method comprising: a) procuring one or a plurality of cell samples from a human, comprising one or a plurality of cell types including but not limited to fibroblasts, buccal cavity cells, or peripheral blood monocytes. b) detecting changes in aging including age-related dementia and cancers gene expression from the patient specific neural organoid sample that are differentially expressed in humans with accelerated aging including age- related dementia and cancers. f) performing assays on the patient specific neural organoid to identify therapeutic agents that alter the differentially expressed during aging including age-related dementia and cancers genes in the patient-specific neural organoid sample; and g) administering a therapeutic agent for aging including age-related dementia and cancers to treat the human.

48. The method of claim 30 or claim 47, wherein the fibroblast is used as a developmental tool for predicting the risk of aging including age-related dementia and cancers in a newborn.

49. The method of claim 30 or claim 47, wherein the fibroblasts are used as a drug discovery tool.

50. The method of claim 30 or claim 47, wherein the fibroblasts are used to follow the onset, progression, and / or treatment of aging including age-related dementia and cancers.

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