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              "content": "The main genetic factors that influence aging include:\n\n1. **Genomic Instability**: Aging is associated with the accumulation of DNA damage and the dysregulation of repair mechanisms, leading to genomic instability [9].\n\n2. **Telomere Attrition**: The shortening of telomeres, which are protective caps at the ends of chromosomes, is a significant factor in aging [9], [10].\n\n3. **Epigenetic Alterations**: Changes in epigenetic marks, which regulate gene expression without altering the DNA sequence, play a crucial role in aging [2], [4], [9], [10].\n\n4. **Deregulated Nutrient Sensing**: The pathways that sense and respond to nutrients become deregulated with age, affecting longevity [10].\n\n5. **Mitochondrial Dysfunction**: Mitochondria, the energy-producing organelles in cells, become less efficient with age, contributing to the aging process [10].\n\n6. **Cellular Senescence**: The process by which cells lose the ability to divide and function properly is a hallmark of aging [9], [10].\n\n7. **Loss of Proteostasis**: The ability of cells to maintain protein homeostasis declines with age, leading to the accumulation of damaged proteins [9], [10].\n\n8. **Stem Cell Exhaustion**: The decline in the regenerative capacity of stem cells contributes to aging [10].\n\nThese factors collectively shape the complex genetic landscape of aging, influencing the expression of aging phenotypes and lifespan [7].",
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              "text": "It is undisputed that genetic factors influence aging. In a remarkable",
              "title": "2009 - The Human Ageing Genomic Resources online.pdf",
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              "text": "males: what are the molecular and evolutionary causes? Aging Cell. 2007;6:225233. doi:10.1111/j.1474-9726.2007.00279.x\n 63. Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: link-\ning environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015;16:593610. doi:10.1038/nrm4048\n 64. Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms of longevity \nand aging. Cell. 2016;166:822839. doi:10.1016/j.cell.2016.07.050",
              "title": "2018 - Sex Differences in Aging Genomic Instability.pdf",
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              "text": "Clinical Genetics and Genomics of Aging",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "standing the cause and mechanisms of aging is imperative in\nassisting to suppress age-related diseases and promote healthylongevity. It is well-known that aging is influenced by a combin-\nation of genetic and environmental factors. Previous twin stud-\nies have shown that the genetic contribution to general human\nlongevity is about 2030% [ 4,5], whereas environmental factors\nin human aging and longevity still account for the largest effect.\nEpigenetic factors influence the regulation of gene expres-",
              "title": "2016 - Progress on the role of DNA methylation in aging.pdf",
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              "text": "Recent developments on the genetics of aging can be seen as several streams\nof effort. In general, humans show a relatively modest ( <50%) heritability of",
              "title": "2001 - The genetics of aging.pdf",
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              "text": "effect  genetic  variants  on  human  longevity.  Aging  2,  612620.\nYu,  C.E.,  Seltman,  H.,  Peskind,  E.R.,  Galloway,  N.,  Zhou,  P.X.,  Rosenthal,  E.,  Wijsman,\nE.M.,  Tsuang,  D.W.,  Devlin,  B.,  Schellenberg,  G.D.,  2007.  Comprehensive  analysis\nof  APOE  and  selected  proximate  markers  for  late-onset  Alzheimers  disease:\npatterns  of  linkage  disequilibrium  and  disease/marker  association.  Genomics",
              "title": "2011 - A genome-wide association study confirms APOE as the major gene influencing.pdf",
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              "text": "factors shape a complex scenario for which clear answers\nof the regulation of longevity have been dicult to distill.\nWith the discovery of genetic factors underlying aging in\nexperimental laboratory models, forays into the genetic\nregulation of these properties have rapidly expanded,\nuncovering conserved mechanisms across diverse metazoa\nthat inuence expression of aging phenotypes and lifespan.\nYet, the story gets muddled in that these factors are often",
              "title": "2021 - Footprints in the Sand Deep Taxonomic Comparisons in Vertebrate Genomics to Unveil the Genetic Programs of Human Longevity.pdf",
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              "text": "In addition to aging- and CR-related genes, another\nsource of candidate genes and pathways for drug designare human longevity-associated genes (Barzilai andShuldiner, 2001; Browner et al., 2004; Kenyon, 2010).Dozens of genes have now been associated with humanlongevity (de Magalha es et al., 2009a), although only ahandful of genes have been shown to have consistenteffects across populations.\nMany longevity-associated genes are related to spe-",
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              "text": "tion for decades, the underlying molecular genetic\ncauses of and responses to aging remain an area of\nactive study. Research from model systems hascharacterized a range of physiological and molecular\nphenotypes associated with aging. These include genomic\ninstability caused by accumulation of DNA damage,\ndysregulation of repair mechanisms, and telomere attri-\ntion; epigenetic alterations; dysregulation of transcription;\nloss of proteostasis; cellular senescence; and deregulated",
              "title": "2017 - Genome-wide transcriptomics of aging.pdf",
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              "text": "143\nThe molecular bases of ageing are multi factorial, but there are nine distinctive \nfeatures related to this process, which include genomic instability, telomere shorten-\ning, de-regulated nutrient sensing, mitochondrial dysfunction, cellular senescence, \nstem cell exhaustion, altered cellular senescence, loss of proteostasis and a change \nin the patterns of epigenetic modifications [4, 5].\n Epigenetics andAgeing\nEpigenetics is considered as a dynamic interface between the genome and the envi-",
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              "content": "Genes affect the aging process in humans through complex interactions and pathways. Research has shown that single genes can regulate aging in model organisms, indicating that aging can be genetically manipulated [2]. Hundreds of genes have been identified that modulate longevity in these organisms, and some of these genes and their associated pathways, such as the insulin/IGF1/GH pathway, have been shown to affect longevity across different species, suggesting that some mechanisms of aging are evolutionarily conserved [3]. \n\nIn humans, it has been more challenging to identify specific longevity candidate genes, but studies have shown that certain genes associated with aging in model organisms are evolutionarily conserved and may be relevant to human aging [5]. Additionally, approximately 4% of genes analyzed in a study of postmortem human brain tissue showed significant age-related expression changes, indicating that these genes play central roles in processes like synaptic plasticity, vesicular transport, and mitochondrial function [8]. \n\nOverall, while aging is a complex process involving multiple genes and their interactions with the environment, genetic studies in model organisms provide insights that may be applicable to understanding human aging [9].",
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              "text": "potentially associated with human ageing. For eachgene, a description compiled from the studies that linkthe gene to ageing is provided. It should be noted thatour focus is on genes that might affect the ageingprocess, rather than individual age-related pathologies;\ngenes affecting multiple, even if not all, age-related",
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              "text": "showing that single genes can regulate aging in modelorganisms demonstrate that aging can be geneticallymanipulated (Finch and Ruvkun, 2001; Kenyon, 2010).Hundreds of genes that modulate longevity have nowbeen identified in model organisms (de Magalha es et al.,2009a). In some cases (e.g., in worms), mutations insingle genes can extend lifespan by almost 10-fold (Ayy-adevara et al., 2008). Nonetheless, aging is a complexprocess that derives not from single genes but from theinteractions of multiple genes",
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              "text": "genes (http://genomics.senescence.info/genes/), more than700 genes have been identified that regulate lifespan inmodel organisms (de Magalha es et al., 2009a). Many ofthese genes and their associated pathwayssuch as theinsulin/IGF1/GH pathwayhave been shown to affect lon-gevity across different model organisms (Kenyon, 2010).Therefore, at least some mechanisms of aging are evolu-tionarily conserved and may have potential therapeuticapplications (Baur et al., 2006). For example, evidencesuggests the use of",
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              "text": "key genes and pathways important in aging; geneticstudies of heritable diseases that cause the appearanceof premature aging in affected people; physiological ex-Introductionperiments that relate the pace of aging to caloric intake;Is aging the final act in the script of developmental biol-and advances in human genetics, as well as cell andogy? The characteristic changes that are part and parcelmolecular biology leading to an understanding of theof aging appear similar to developmentally regulatedbasis of",
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              "text": "shown that genes associated with aging and/or longevity inmodel organisms are evolutionary conserved in terms of havingmore homologues than predicted by chance (Budovsky  \net \n  \nal \n.,2007, 2008) and exhibiting slower molecular evolution rates (de\nMagalhes & Church, 2007). Therefore, it is now clear that atleast some genes identified in model organisms may be relevantto human aging.\nTo allow researchers to focus specifically on human aging,",
              "title": "2009 - The Human Ageing Genomic Resources online.pdf",
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              "text": "expression of certain genes have an effect upon longevity.\nAlthough similar aging processes are likely to operateacross multiple species [30], it has been much more diffi-cult to identify longevity candidate genes in human studies[30]. A key question in human aging is to what extent asignature of aging may be detectable across tissues. Until\nnow there has been a lack of large transcriptional profiles\nfrom the same human individuals in multiple tissues. TheMuTHER study provides ins ight into the human aging",
              "title": "2013 - Gene expression changes with age in skin.pdf",
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              "text": "complex.108,109Studies on models such as the yeast Sac-\ncharomyces cerevisiae110the nematode Caenorhabditis\nelegans,111the fly Drosophila melanogaster,112-114the\nmouse Mus musculus,115and humans116show that single\ngene mutations can contribute to the initiation of aging andinduce premature aging syndromes. There are, however, nospecial genes that can cause aging-associated damages. Themanifestation of aging is mostly due to the failure of main-tenance and repair mechanisms.\n117,118",
              "title": "2011 - Clinical aspects and molecular diagnostics of skin aging.pdf",
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              "text": "on model organisms [3] or have been confined to specificaging-associated disorders such as progeria syndromes\n[4]. A study of postmortem human brain tissue from 30\nindividuals aged 26 to 106 years [5] showed that approxi-\nmately 4% of approximately 11,000 genes analyzed show\na significant age-related expression change (1.5-fold or\nmore) in individuals aged >40 years. These genes were\nreported to play central roles in synaptic plasticity, vesi-\ncular transport, and mitoch ondrial function. Another",
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              "text": "of multiple genes with each other and withthe environment. Evidence from animal systems showsa major impact of the environment on aging, yet envi-ronmental manipulations of aging act through genesand proteins, usually by triggering signaling pathwaysand modulating gene expression. In fact, some geneshave been shown in model organisms to have varyingeffects on lifespan depending on diet (Heikkinen et al.,2009). Genes that can regulate aging in model organ-isms cannot be directly applied to humans through",
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              "text": "[2] L. Partridge, D. Gems, Mechanisms of ageing: public or private? Nat. Rev.\nGenet. 3 (2002) 165 175.\n[3] A.M. Leroi, et al., What evidence is there for the existence of individual\ngenes with antagonistic pleiotropic effects? Mech. Ageing Dev. 126 (2005)421429.\n[4] S.N. Austad, Is aging programmed? Aging Cells 3 (2004) 249 251.\n[5] V.D. Longo, J. Mitteldorf, V.P. Skulachev, Opinion: programmed and\naltruistic ageing, Nat. Rev. Genet. 6 (2005) 866 872.",
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              "content": "To slow down genetic aging, several lifestyle choices can be beneficial:\n\n1. **Dietary Restriction (DR)**: Reducing food intake without causing malnutrition has been shown to extend lifespan in various organisms. This approach improves healthspan by influencing nutrient-sensing signaling networks and metabolism [1].\n\n2. **Healthy Diet and Physical Exercise**: Engaging in regular physical activity and maintaining a healthy diet can slow down aging and prevent or modify many chronic diseases prevalent in older adults. This contributes to successful aging, allowing individuals to achieve physical, social, and mental well-being [4].\n\n3. **Caloric Restriction**: This is considered a reasonable anti-aging intervention, as it has been shown to slow aging in multiple species, including yeast, nematodes, fruit flies, and rodents [6].\n\n4. **Exercise**: While exercise may not retard aging in all tissues, it can contribute to molecular-level aging retardation, which is beneficial for overall health and longevity [10].\n\nThese lifestyle choices, when combined, can help mitigate the effects of genetic aging and promote a longer, healthier life.",
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              "text": "as diabetes, cancer and neurodegenerative disorders\n[1, 2]. Environmental and genetic interventions can\nameliorate the effects of aging, with nutrition,\nnutrient-sensing signaling networks and metabolism\nplaying evolutionarily conserved roles [1, 3 5]. Diet-\nary restriction (DR), in which food intake is reducedwhile avoiding malnutrition, extends lifespan in di-\nverse model and non-model organisms [3, 6]. DR\ninduces a remarkably broad-spectrum improvement in",
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              "text": "limiting exposure to exogenous genotoxins and by suppressing metabolism  thereby producing fewer reactive species. However, DNA damage, like caloric restriction, can also elicit a protective survival response that promotes longevity and healthy aging. Recently, the use of sirolimus in mice was found to extend their life span and de -\nlay the development of conditions associated with aging, including cancer.\n1 Sirolimus is one of pre -",
              "title": "2009 - DNA Damage, Aging, and Cancer.pdf",
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              "text": "Longev. Heal. 2, 10 (2013).\n7. Kreienkamp Ret al.Doubled lifespan and patient-like pathologies in progeria mice fed high-fat diet. \nAging Cell18, e12852 (2019). [PubMed: 30548460] \n8. Heilbronn LK & Ravussin E Calorie restriction and aging: review of the literature and implications \nfor studies in humans. Am. J. Clin. Nutr. 78, 361369 (2003). [PubMed: 12936916] \n9. Liang Yet al.Calorie restriction is the most reasonable anti-ageing intervention: a meta-analysis of",
              "title": "2021 - Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.pdf",
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              "text": "can be slowed down to some extent by eating a healthy diet and taking physical exercise, and many of the chronic diseases prevalent in older adults are either preventable or modi  able with healthy lifestyle habits. Thus, older adults \ncan experience successful aging that allows them to achieve physical, social and mental well - being over the life course and to participate in society. \n Much research has been conducted in recent years to",
              "title": "2012 - Systems Biology Approaches to Nutrition.pdf",
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              "text": "During the past century, remarkable progress has been \nmade in unveiling the mechanisms of aging. Genetic and molecular pathways that regulate healthspan and lifespan have been identified in various model organisms, provid-ing a rich knowledge base (Longo etal. 2015; Lopez-Otin etal. 2013, 2016; Singh etal. 2019). However, the focus on",
              "title": "2020 - Mitonuclear genomics and aging.pdf",
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              "text": "13,14\nPrior studies have identified dozens of genetic and environ -\nmental modifiers of chronological or replicative longevity, some of which are now known to function similarly to modulate life span in multicellular eukaryotes.\n15-17 One example of such a con -\nserved longevity intervention is dietary restriction, which has been shown to slow aging in many different species including yeast, nematodes, fruit flies and rodents,\n18,19 and most recently",
              "title": "2011 - A genomic analysis of chronological longevity.pdf",
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              "text": "Genetic studies have shown that aging can be slowed in\nmutants that are defective in a wide range of cellularprocesses (such as mitochondrial function, chromatin regu-\nlation, insulin signaling, tran scriptional regulation, and\ngenome stability). This indicates that aging is a complex\nprocess driven by diverse molecular pathways and biochem-\nical events. As such, a powerful approach to study aging is touse systems biology, which allows a multitude of factors",
              "title": "2004 - A Transcriptional Profile of Aging.pdf",
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              "text": "Dietary interventions, including starvation and protein\ndeprivation, can also alter patterns of DNA methyla-\ntion, potentially in a long-lasting manner [42, 43],\nincluding transgenerationally [26, 44].\nDietary, genetic and pharmacological interventions\nthat improve health during aging and extend lifespan\ninduce long-lasting changes in gene expression that\nmediate their effects. Here we have asked if and how\nage-related DNA methylation, transcription and lipid",
              "title": "2017 - Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism.pdf",
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              "text": "in yeast , Drosophila, and C. elegans  is able to slow aging and increase lifespan  [252-255]. Follow -up stud ies \nout of Richard Millers laboratory reproduced these findings in mice fed a diet with rapamycin incorporated  \n[256, 257]. These studies suggested that inhibiting mTOR via rapamycin could delay age-associated diseases \nand extend lifespan in mammals. A subsequent study replicated these  findings by genetically manipulating a",
              "title": "2015 - Cellular and Molecular Biology of Aging Endothelial Cells.pdf",
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              "text": "appears to retard aging at the molecular level as indi-cated by the gene expression analysis? Most likely,aging retardation at the molecular level by exercise isnot observed in all tissues, including some that maylimit lifespan. For example, if exercise does not reduceaging rates in replicative tissues, then it will not retardage-related tumor onset, which tends to limit maxi-mum lifespan. Another possibility relates to the obser-vation that wheel running decreased to an average 680m/day at 33 mo of age",
              "title": "2003 - Lifelong voluntary exercise in the mouse prevents.pdf",
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              "content": "Scientists study the genetics of aging in animals using a variety of approaches and model organisms. Here are some key methods and models mentioned in the context:\n\n1. **Animal Model Systems**: Rodents, such as rats and mice, are indispensable for molecular biological studies on aging due to their practical advantages and similarities in aging processes to humans [1]. \n\n2. **Tissue-Specific Studies**: Recent genomic studies have been performed on specialized mammalian tissues, both post-mitotic (e.g., heart, nervous system) and mitotic (e.g., liver), to understand the tissue-specific effects of aging. These studies also explore how caloric restriction affects age-related transcriptional changes, which are tissue- or species-specific [2].\n\n3. **Laboratory Models**: Common laboratory models for studying aging include Caenorhabditis elegans (nematode worm) and Mus musculus (mice), which have shorter lifespans than humans, allowing for more rapid observation of aging processes [5].\n\n4. **Transgenic Mouse Strains and Interventional Studies**: These studies have identified evolutionarily conserved pathways involved in lifespan regulation and common denominators of aging across different organisms [6].\n\nThese methods and models help scientists uncover the genetic and molecular mechanisms underlying aging, providing insights that can be applied to understanding human aging and developing potential interventions.",
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              "text": "for molecular biological studies on aging. Although material \nfrom humans should be employed where possible, for prac- \ntical reasons animal model systems like rats and mice are \nindispensible. There is evidence that, provided their health sta- \ntus and husbandry is optimal, rodents age much in the same \nway as humans do (Burek 1978). For studying certain funda- \nmental processes, such as the occurrence of various types of \nDNA rearrangement, lower organisms and cell lines can also",
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              "text": "Until now most of the genomic studies of invertebrate\nmodels have been performed on whole animals. Several\nstudies, however, recently performed on specialized\nmammalian tissues, either post-mitotic (heart or nervous\nsystem) or mitotic (liver), show that the effects of aging\nare tissue-specific [19-25]. In addition, effects of caloric\nrestriction on age related transcriptional changes are also\ntissue- or species-specific [19].\nTo better understand the aging process in invertebrate",
              "title": "2006 - Specific age related signatures in Drosophila body parts.pdf",
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              "text": "opportunities for assessing the efcacy of interventions onaging.\nWhen considering the advantages and disadvantages of\ndogs as a model for geroscience research, it is useful tonote that the vast majority of mammalian studies on thebasic biology of aging are performed in a relatively small\nnumber of inbred mouse strains. Typical average lifespan\nfor most of these mouse strains is approximately 23 years,",
              "title": "2016 - The dog aging project translational geroscience in companion.pdf",
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              "text": "[14] Gerstbrein, B., Stamatas, G., Kollias, N., Driscoll, M. In vivo  spec-\ntrofluorimetry reveals endogenous biomarkers that report health-\nspan and dietary restriction in Caenorhabditis elegans . Aging Cell  \n2005 , 4: 127-137. \n[15] Kennedy, B.K. The genetics of ageing: insight from genome-wide \napproaches in invertebrate model organisms. J. Intern. Med.  2008 , \n263: 142-152. \n[16] Kenyon, C., Chang, J., Gensch, E., Rudner, A., Tabtiang, R. A C.",
              "title": "2009 - MicroRNAs in C. elegans Aging Molecular Insurance for Robustness.pdf",
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              "text": "the DNA level leads to changes in gross phenotype, we must \nnow look downstream at changes in gene expression associ -\nated with genetic variation, aging, and ARD.\nComparison With Laboratory Models of Aging\nLaboratory models typically used to study aging, such as \nCaenorhabditis  elegans  (nematode worm) and Mus musculus  \n(mice), have drastically shorter life spans than our own \n(~3 wk [ 51] and ~3 y [ 52], respectively, vs a 122 y maxi -\nmum for humans thus far; [ 53]). In some respects, these",
              "title": "2012 - Genomics and Successful Aging Grounds for Renewed.pdf",
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              "text": "ing studies on invertebrate models of aging, long-lived mam-mals, transgenic mouse strains, and interventional studies, have led to the identification of evolutionarily conserved path-\nways involved in life span regulation, as well as common de-\nnominators of aging in different organisms.\n4 In this review, the \npathophysiological roles of these aging mechanisms, including \noxidative stress, mitochondrial dysfunction, impaired resis-",
              "title": "2018 -  Mechanisms of Vascular Aging.pdf",
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              "text": "chain triglyceride oil on life span of genetically heterogeneous mice. J. Gerontol. A. Biol. Sci. \nMed. Sci. 68, 616 (2013). [PubMed: 22451473] \n24. Yuan R, Peters LL & Paigen B Mice as a mammalian model for research on the genetics of aging. \nILAR J. Natl. Res. Counc. Inst. Lab. Anim. Resour. 52, 415 (2011).\n25. Saul MC, Philip VM, Reinholdt LG & Chesler EJ High-diversity mouse populations for complex \ntraits. Trends Genet. 35, 501514 (2019). [PubMed: 31133439]",
              "title": "2021 - Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.pdf",
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              "text": "lowing the discovery of genes and pathways involved inanimal lifespan extension, human research has focusedon the corresponding candidate human genes withgenetic, genomic and epigenetic studies into ageingand longevity. The designs of these studies differwith respect to the selection of naturally occurringphenotypes and the study populations, which includepopulation-based, patient-based, family-based andexposure-based cohorts.\nStudies into human age-related disease phenotypes",
              "title": "2011 - Genomics of human longevity.pdf",
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              "text": "Animal studies as stalking horses for human biogerontology.  For\nthe most part, studies on the biology of aging are as difficult and imprac-tical in humans as are studies of health insurance in rodents.  It is fairlyCopyright  National Academy of Sciences. All rights reserved.Cells and Surveys:  Should Biological Measures Be Included in Social Science Research?\nhttp://www.nap.edu/catalog/9995.html",
              "title": "2001 - Demography in the age of genomics.pdf",
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              "text": "review of the evidence for genotype-dependent eects on lifespan. Ageing Res.\nRev. 11, 254270. doi: 10.1016/j.arr.2011.12.006\nTurturro, A., Witt, W. W., Lewis, S., Hass, B. S., Lipman, R. D., and Hart, R. W.\n(1999). Growth curves and survival characteristics of the animals used in the\nbiomarkers of aging program. J. Gerontol. Ser. Biol. Sci. Med. Sci 54, B492B501.\ndoi: 10.1093/gerona/54.11.b492\nVertti-Quintero, N., Berger, S., Solvas, X. C. I, Statzer, C., Annis, J., Ruppen,",
              "title": "2021 - Lifespan-Associated Gene Expression Signatures of Recombinant BXD Mice Implicates Coro7 and Set in Longevity.pdf",
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              "content": "Yes, specific genes have been linked to longer lifespans. Research has identified more than 700 genes that regulate lifespan in model organisms, with many of these genes and their associated pathways, such as the insulin/IGF1/GH pathway, shown to affect longevity across different model organisms [2]. Additionally, variants near genes such as CHRNA3/5 and APOE have been found to have age- and sex-related effects on human lifespan [7]. Genome-wide association studies have also identified loci associated with exceptional human longevity [10].",
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              "text": "genes analyzed for their possible association with human lon-gevity (http://genomics.senescence.info/genes/longevity.html).All longevity association studies in humans we could find by thetime of the latest update were added to this list. These includestudies reporting negative results, which we see as essentialsince many genes display population-specific associations withlongevity.\nFig. 1 From the main page of the Human Ageing",
              "title": "2009 - The Human Ageing Genomic Resources online.pdf",
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              "text": "genes (http://genomics.senescence.info/genes/), more than700 genes have been identified that regulate lifespan inmodel organisms (de Magalha es et al., 2009a). Many ofthese genes and their associated pathwayssuch as theinsulin/IGF1/GH pathwayhave been shown to affect lon-gevity across different model organisms (Kenyon, 2010).Therefore, at least some mechanisms of aging are evolu-tionarily conserved and may have potential therapeuticapplications (Baur et al., 2006). For example, evidencesuggests the use of",
              "title": "2012 - Genome-Environment Interactions That Modulate.pdf",
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              "text": "Exceptional Longevity\nOne approach to identifying genes associated with low mortality is to\nexamine the genes of those who survive to the oldest ages.  Several studieshave examined gene frequencies among centenarians or nonagenariansand compared them with frequencies at younger ages.  Since changes ingene frequencies are more rapid when mortality rates are high, cross-sectional comparisons must be adjusted for differences in mortality amongcohorts.",
              "title": "2001 - Demography in the age of genomics.pdf",
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              "text": "informed by age-related disease identifies loci for exceptional human longevity. Li H, editor. \nPLoS Genet. 2015. https://doi.org/10.1371/journal.pgen.\n 15. Polderman TJC, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, \netal. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat \nGenet. 2015;47:7029.\n 16. Cellerino A, Ori A.What have we learned on aging from omics studies? Semin Cell Dev Biol. \n2017;70:17789.",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "GENOME-WIDE ASSOCIATION STUDY OF LONGEVITY 479\nINCREASES in longevity of the general population world -\nwide are an unprecedented phenomenon with significant \nhealth and social impact. Although environmental factors \nhave led to an increase in life span, there is ample evidence \nthat genetic factors are involved in extreme longevity both \nin humans (17) and in other organisms (8). The protective \ngenetic factors that lead to longevity are likely to involve",
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              "text": "expression of certain genes have an effect upon longevity.\nAlthough similar aging processes are likely to operateacross multiple species [30], it has been much more diffi-cult to identify longevity candidate genes in human studies[30]. A key question in human aging is to what extent asignature of aging may be detectable across tissues. Until\nnow there has been a lack of large transcriptional profiles\nfrom the same human individuals in multiple tissues. TheMuTHER study provides ins ight into the human aging",
              "title": "2013 - Gene expression changes with age in skin.pdf",
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              "text": "4. Joshi, P. K. et al. Variants near CHRNA3/5 and APOE have age- and sex-\nrelated effects on human lifespan. Nat. Commun. 7, 11174 (2016).\n5. Pilling, L. C. et al. Human longevity is in uenced by many genetic variants:\nevidence from 75,000 UK Biobank participants. Aging 8, 547560 (2016).\n6. Deelen, J. et al. Genome-wide association meta-analysis of human longevity\nidenti es a novel locus conferring survival beyond 90 years of age. Hum. Mol.\nGenet. 23, 4420 4432 (2014).",
              "title": "2017 - Genome-wide meta-analysis associates HLA.pdf",
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              "text": "79-91. \n[97] Smith, E.D.; Kennedy, B.K.; Kaeberlein, M. Genome-wide \nidentification of conserved longevity genes in yeast and worms . \nMech. Ageing Dev. , 2007 , 128(1), 106-11. \n[98] Chen, D.; Pan, K.Z.; Palter, J.E.; Kapahi, P. Longevity determined \nby developmental arrest genes in Caenorhabditis elegans.  Aging \nCell, 2007 , 6(4), 525-33. \n[99] Curran, S.P.; Ruvkun, G. Lifespan regulation by evolutionarily \nconserved genes essential for viability . PLoS Genet. , 2007 , 3(4), \ne56.",
              "title": "2012 - Genome-Wide RNAi Longevity Screens in Caenorhabditis elegans.pdf",
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              "text": "9. vB Hjelmborg J, Iachine I, Skytthe A, Vaupel JW, McGue M, et al. (2006)\nGenetic influence on human lifespan and longevity. Hum Genet 119: 312321.doi:10.1007/s00439-006-0144-y.\n10. Sebastiani P, Perls TT (2012) The genetics of extreme longevity: lessons from the\nnew England centenarian study. Front Genet 3: 277. doi:10.3389/fgene.2012.00277.11. Perls TT, Wilmoth J, Levenson R, Drinkwater M, Cohen M, et al. (2002) Life-",
              "title": "2014 - Whole-Genome Sequencing of the World?s Oldest People.pdf",
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              "text": "39. Fortney K, Dobriban E, Garagnani P, etal. Genome-wide scan informed by \nage-related disease identifies loci for exceptional human longevity. PLoS Genet. 2015;11:e1005728. doi:10.1371/journal.pgen.1005728\n 40. Beekman M, Nederstigt C, Suchiman HE, et al. Genome-wide asso-\nciation study (GWAS)-identified disease risk alleles do not compromise \nhuman longevity. Proc Natl Acad Sci U S A. 2010;107:1804618049. \ndoi:10.1073/pnas.1003540107",
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              "content": "Telomeres affect the aging process in several ways:\n\n1. **Telomere Shortening**: Telomeres are specialized structures that protect the ends of linear chromosomes. They shorten during aging due to the unidirectional activity of DNA polymerase, which leaves a section of DNA unreplicated on the lagging strand [1]. This shortening is a natural part of the aging process and is exacerbated by genotoxic stress, such as oxidative damage [1].\n\n2. **Cellular Senescence and Apoptosis**: The shortening of telomeres can induce processes such as apoptosis (programmed cell death) and cellular senescence (a state where cells stop dividing), which affect the health and lifespan of an individual [2]. When telomeres become critically short, they trigger a DNA damage response, leading to cellular senescence or apoptosis [4].\n\n3. **Genome Stability**: Telomeres ensure the stability of the genome and protect chromosomes from incorrect actions by the DNA repair machinery [3]. When telomeres are too short, they can no longer form protective structures, leading to genome instability and potentially contributing to aging [8].\n\n4. **Cancer Prevention**: Short telomeres limit the number of cell cycles, which is important for preventing the onset of cancer. However, this also contributes to the aging process as cells enter a state of permanent cell cycle arrest (senescence) [7].\n\n5. **Telomerase Activity**: The enzyme telomerase can maintain telomere length, but its activity varies over the lifespan and between cell types, tissues, and species [1]. In most human somatic cells, telomerase activity is limited, which contributes to telomere shortening and aging [4].\n\nOverall, telomere shortening acts as a biological clock that limits cellular replication, contributing to aging and age-related diseases [6].",
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              "text": "Telomeres are specialized structures that protect the ends of linear chromosomes. They shorten during aging due to the unidirectional activity of DNA polymerase, which leaves a section of DNA unrepli-cated on the lagging strand. Telomeres also are subject to shortening by genotoxic stress, such as oxidative damage (33). Among many eukaryotes, the enzyme telomerase maintains telomere length; but telomerase activity varies over the lifespan and between cell types, tissues, and species (34). In most human",
              "title": "2018 - Sex Differences in Aging Genomic Instability.pdf",
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              "text": "that shorten their length with progressing age. This shortening of telomeres is the \nresult of the absence of the activity of an enzyme called telomerase, and in turn it \ninduces several processes, such as apoptosis, senescence, or oncogenic transforma-\ntion of somatic cells, affecting the health and lifespan of an individual [42]. Human \ntelomere shortening has been mostly studied in leukocytes and linked not only to \nageing and life expectancy [43] but also to age-related diseases, including cardio-",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "nization may directly affect telomere attrition, resulting in accelerated replicative \nsenescence and progeroid phenotypes [180].\nTelomeres are regions constituted by tandem repeats of non-coding DNA \nsequences 5-(TTAGGG)n-3 and a protein complex called shelterin, bound to them. \nThis structure ensures the stability of the genome and protects the chromosomes \nfrom a wrong action of the DNA repair machinery [184] by allowing the formation \nof a chromatin loop called T-Loop [185].",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on thebasis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must cap eachchromosome end to avoid activation of DNA repair pathways. Repair of critically short or uncapped telomeres by telomeraseor recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many uncappedtelomeres accumulate.",
              "title": "2008 - Telomeres and Aging.pdf",
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              "text": "ing (84). This process is believed to be the trigger for the aging \nprocess, according to the telomere theory (11, 85, 86). It is further \nsupported by Bodnar etal. who proved that telomere elongation caused by ectopic expression of telomerase avoids the senescence phenotype (87). His work relied on one of the earliest studies \nlinking telomere shortening to aging which was performed",
              "title": "2018 - Genomic Instabilities, Cellular Senescence, and Aging In Vitro, In Vivo and Aging-Like Human Syndromes.pdf",
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              "text": "telomeres, the repetitive sequence at the end of linear chromosomes, has garnered much attention for\nits relation to aging. Telomere repeats serve as an internal clock for cycling cells because each round of\nreplication results in the loss of telomeric DNA in the absence of active telomerase (reviewed in [66]).\nEventually, this loss over cellular generations culminates in telomere crisis and a permanent state of",
              "title": "2018 - Repetitive Fragile Sites Centromere Satellite DNA.pdf",
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              "text": "and consequently lose telomeric sequences, thereby limiting the number of cell cycles, which is\nimportant for preventing the onset of cancer. Cells perceive critically short telomeres as persistentDNA damage. This activates the DNA damage responses, including cell cycle checkpoints, which\nultimately leads to a permanent cell cycle arrest (cellular senescence). Senescence protects from\ncancer but contributes to the aging process (37).",
              "title": "2016 - Genome Integrity in Aging.pdf",
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              "text": "When the telomeres shorten, this loop is no longer able to form \nand in turn, the epigenetic regulation is changed to activation of the TPE-OLD genes. This happens before the telomeres reach \nthe critical length that causes activation of DDR, thus leading to \nanother earlier possible effect of telomere shortening on aging (138, 139). Interestingly, a following study by Kim etal. showed \nthat one of the TPE-OLD sensitive genes is hTERT, the core reverse transcriptase component of telomerase (140). This is",
              "title": "2018 - Genomic Instabilities, Cellular Senescence, and Aging In Vitro, In Vivo and Aging-Like Human Syndromes.pdf",
              "version": "v0",
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              "text": "to maintain proliferation potential (94). Cells with mutated telomerase exhibited irregular morphology and short telomeres, but these changes did not cause deadly damage and determinate senescence (95). One hypothesis connects aging to telomere \nerosion through the transcription of subtelomeric genes. Genes \nlocated in subtelomeric regions are affected by transcriptional silencing which was found to change in an age-related manner. \nKim et al. (96) found that silencing of genes in subtelomeric",
              "title": "2018 - Genomic Instabilities, Cellular Senescence, and Aging In Vitro, In Vivo and Aging-Like Human Syndromes.pdf",
              "version": "v0",
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              "text": "evidence implicates telomere shortening in cellularsenescence. Telomeres consist of repetitive nucleotides e q u e n c e s( T T A G G G )a tt h ee n d so fm a m m a l i a nc h r o -mosomes, that preserve chromosome stability andintegrity by preventing deterioration or fusion withneighboring chromosomes (76) (Central Illustration ).JACC VOL. 69, NO. 15, 2017 Paneni et al .\nAPRIL 18, 2017:1952 67 The Aging Cardiovascular System1957",
              "title": "2017 - The Aging Cardiovascular System.pdf",
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              "content": "DNA repair plays a significant role in aging by maintaining the integrity and stability of the nuclear genome. Impairment of DNA repair mechanisms can result in accelerated aging and/or cancer [2]. As organisms age, endogenous sources of genotoxins increase, DNA repair capacity declines, and levels of DNA damage and mutations increase [2]. This accumulation of DNA damage is associated with aging phenotypes, as DNA damage can activate cellular responses that contribute to aging [6]. The DNA damage theory of aging suggests that genomic instability, caused by accumulated DNA damage, plays a causal role in aging [5]. Additionally, the burden of DNA lesions is greater in older mammals compared to younger ones, indicating that DNA repair is crucial for mitigating the effects of aging [5].",
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              "text": "Effect of age on DNA repair\nResearch over the past decades suggest that many steps\nin DNA metabolism are altered with age in a variety\nof tissues and animal models (56,57). The relation of DNArepair to aging has been studied by measuring the ability\nof cells from organisms of various life spans to repair\nDNA damage and by experiments that have comparedthe ability of cells from young and old organisms to repair\nDNA damage. Interest was peaked by the original",
              "title": "2007 - Caloric restriction and genomic stability.pdf",
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              "text": "BI87CH14_Niedernhofer ARI 18 May 2018 15:1\nSUMMARY POINTS\n1. Evolutionarily conserved DNA repair pathways maintain the integrity and stability of\nthe nuclear genome. Impairment of DNA repair mechanisms results in accelerated agingand/or cancer.\n2. Evidence in humans and model organisms supports the conclusions that with age\n(a) endogenous sources of genotoxins increase, ( b) DNA repair capacity declines, and\n(c) levels of DNA damage and mutations increase.",
              "title": "2018 - Nuclear Genomic Instability.pdf",
              "version": "v0",
              "chunk_order": 180,
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              "text": "Several lines of evidence suggest that DNA repair capacity might decrease with age. However,it should be noted that measuring DNA repair in tissues is challenging and that the validity ofsurrogate markers of repair capacity is not well established. For example, a reduction in expression\nof DNA repair genes/proteins is not proven to impact DNA repair. Frequently, the reduction in",
              "title": "2018 - Nuclear Genomic Instability.pdf",
              "version": "v0",
              "chunk_order": 75,
              "document_id": "54d28a91-8db6-56b1-baaa-b67274c93a36",
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              "text": "improved DNA repair. Finally, there should be a plausible mechanism by which DNA damage\ncan drive aging. Here, we review the evidence currently supporting each of these predictions.\nEVIDENCE THAT DNA DAMAGE INCREASES WITH AGE\nSources of Damage Increase with Age\nThe free radical theory of aging posits that aging is caused primarily by oxidative damage in-\ncurred by ROS that chemically modify critical cellular biomolecules (13). This theory has evolved",
              "title": "2018 - Nuclear Genomic Instability.pdf",
              "version": "v0",
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              "text": "All rights reservedKeywords\nDNA damage, aging, mutations, senescence, DNA damage response, DNA\nrepair\nAbstract\nThe nuclear genome decays as organisms age. Numerous studies demon-\nstrate that the burden of several classes of DNA lesions is greater in older\nmammals than in young mammals. More challenging is proving this is acause rather than a consequence of aging. The DNA damage theory of\naging, which argues that genomic instability plays a causal role in aging,",
              "title": "2018 - Nuclear Genomic Instability.pdf",
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              "text": "repaired; otherwise the genome would soon become saturated with\ndamage and life would cease. There is some evidence that DNA damage\naccumulates with age in some tissues ( Maslov et al., 2013 ), but the exact\nnature of the damage remains unclear. Indeed, even these low levels of\nspontaneous DNA damage may represent a steady state due to continu-\nous repair and induction of new damage. However, DNA damage can\ncause certain aging phenotypes by activating cellular responses, such",
              "title": "2017 - Mutation and catastrophe in the aging genome.pdf",
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              "text": "36:1049-1062.\n66. Hasty P, Vijg J: Accelerating aging by mouse reverse genetics:\na rational approach to understanding longevity.   Aging Cell\n2004, 3:55-65.\n67. Bohr VA: Deficient DNA repair in the human progeroid dis-\norder, Werner syndrome.   Mutat Res  2005, 577:252-259.\n68. Nouspikel T, Hanawalt PC: DNA repair in term inally differenti-\nated cells.   DNA Repair  2002, 1:59-75.\n69. Nouspikel T, Hanawalt PC: When parsimony backfires: neglect-\ning DNA repair may doom neurons in Alzheimer's disease.",
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              "text": "DNA repair. In the latterdifficult to arrive at a strict, experimentally useful defini-context, most premature aging syndromes are causedtion of aging. Factors implicated in organismal declineby mutations in genes encoding proteins involved inin genetic models might not play a role in the normalDNA repair ( Karanjawala and Lieber, 2004 ). Accumula-aging processes. A related difficulty is that prematuretion of mutations in critical genes may be one generalaging models fail to recapitulate all aspects of",
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              "text": "escape the repair process and accumulate in the genome, impacting several processes and\naging [67,145147].\nThere is little evidence of association between DNA repair improvement and life-\ntime expansion [ 148,149], thus, indicating that such mechanism seems to have evolved\nto maintain DNA stabilityand therefore healthonly until reproductive age, without\nany regard for the fate of the individual in old age, both in terms of quality and length of",
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              "text": "with age, and DNA repairtween different tissues. These differences likely reflectdefects can cause phenotypes resembling prematurefunctional characteristics of those tissues, such as mi-aging. We discuss how cellular DNA damage re-totic rate, transcriptional activity, metabolism, and thesponses may contribute to manifestations of aging.action of specific DNA repair systems.We review Sir2, a factor linking genomic stability, me-Reactive Oxygen Species: An Important Sourcetabolism, and aging. We conclude",
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              "content": "Yes, genetic research can potentially lead to treatments that slow down aging. Several pieces of evidence from the context support this possibility:\n\n1. The discovery of genetic markers for slow aging in humans suggests that understanding these genes could pave the way for therapeutic interventions for age-related maladies, including cancers, neurodegeneration, and metabolic syndrome [4].\n\n2. Research indicates that manipulating aging-related genes through various means, such as diet, lifestyle, and pharmaceuticals, could dramatically improve human health and lead to the development of drugs against age-related diseases [7].\n\n3. Advances in molecular biology, such as CRISPR/Cas9, are expected to clarify aging processes and identify new potential therapeutic targets, which could be crucial for developing treatments that slow aging [6].\n\n4. The use of senolytic drugs, which target senescent cells, has shown promise in halting biological aging in mice, and trials are underway to test their effectiveness in humans [3].\n\n5. There is a suggestion that interventions targeting DNA methylation and other genetic modifications could prevent age-related diseases and promote longevity, highlighting the potential of genetic research in developing therapeutic strategies against aging [10].\n\nOverall, while the research is still ongoing and some findings are speculative, there is significant potential for genetic research to contribute to treatments that slow down the aging process.",
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              "text": "raises the possibility of therapies to slow aging.  Therefore the discoveryof a gerontogene with even very rare mutations that increased longevitywould cause speculation about future trends in mortality.    However, thediscovery of such a gene would be relevant only to long-term (and, there-fore, very speculative) projections.\nProspective Epidemiologic Surveys that Include Genetic Information\nSome epidemiologic cohort studies of populations have collected",
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              "text": "need to develop approaches and therapies targeting theaging process and age-related diseases (Butler et al.,2008). Delaying the process of aging, even slightly,would have profound social, medical and economic ben-efits (Olshansky et al., 2006; Butler et al., 2008). Forexample, slowing aging by a mere 7 years would cutmortality of age-related diseases by half at every age.Therefore, the potential benefits from research on thebasic biology and genetics of aging are unparalleled interms of improving quality",
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              "text": "Interestingly, when senescent cells are abolished either through genetic manipulation or via senolytic\ndrugs, biological aging is signicantly halted in mice [ 53,54]. Therefore, trials are now under way to\ntest the ability of senolytics to postpone age-associated pathologies in humans [ 55]. Notably, multi-\nple drugs are being pursued that either directly or indirectly impact DNA repair or the consequenceof DNA damage.\nFuture Prospects: Developing Interventions through DNA Repair",
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              "text": "and potentially important genetic markers for slow aging\nhave been found in humans (Suh et al. 2008). Elucidating\nthe function of such genes is believed to enable decipher-\ning the core of the aging process, answer to what extentthe process is conserved, and pave the way for therapeutic\ninterventions of age-related maladies, including cancers,\nneurodegeneration, and metabolic syndrome (Guarente\n2011).\nThe identity of the virtual gerontogenes so far discov-",
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              "text": "discover specific genes that directly influence how quickly people age, beyond diseases. If such\ngenes exist, their effects were too small to be detected in this study. The next step will be to\nexpand the study to include more participants, which will hopefully pinpoint further genomic regions\nand help disentangle the biology of ageing and disease.\nDOI: https://doi.org/10.7554/eLife.39856.002",
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              "text": "using bulk mRNA or even analyzing single cells (scRNA-seq). In addition, advances in\nmolecular biology and cell culture approaches (for instance Clustered Regularly Interspaced\nShort Palindromic Repeats (CRISPR)/Cas9) will be benecial in clarifying aging-processes\nacross species.\nAn improved understanding of epigenetic mechanisms affecting longevity will be\ndeciding crucial step towards the identication of new potential therapeutic targets. In",
              "title": "2021 - Epigenetics of Aging and Aging-Associated Diseases.pdf",
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              "text": "century. Manipulation of aging-related genes by diet,lifestyle, and pharmaceuticals could dramatically im-prove human health and could be used to develop drugsagainst age-related diseases such as cancer, heart dis-ease, type 2 diabetes, obesity, and neurodegenerativediseases. The hundreds of aging-related genes and genesrelated to CR already identified offer enormous oppor-tunities for target discovery (Fig. 2). Although aging-related genes cannot be modified in humans, under-standing how these can be",
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              "text": "5. Goldman DP, etal. Substantial health and economic returns from delayed aging may warrant \na new focus for medical research. Health Aff (Millwood). 2013;32(10):1698705.\n 6. Esplin ED, Oei L, Snyder MP.Personalized sequencing and the future of medicine: discov-\nery, diagnosis and defeat of disease. Pharmacogenomics. 2014;15(14):177190.\n 7. Marian AJ.Clinical applications of molecular genetic discoveries. Transl Res. 2016;168:614.",
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              "text": "a medical intervention), without changing the fundamental rateof organismal aging. Nevertheless, it does seem that manyso-called longevity genes, as well as dietary restriction,\nappear to extend not only life span, but also health span\n(Kauffman et al., 2010; Luo et al., 2010 ). In that regard, it does\nappear that it is possible to experimentally slow the rate of aging.\nStill, in each case, aging does continue on as if there is some",
              "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf",
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              "text": "genetic modification. Currently, emerging evidence suggeststhat certain interventions (e.g. CR, dietary supplementation andchemical drugs) can prevent age-related diseases and promote\nlongevity, at least in part, through reversing the aberrant age-\nassociated changes in DNA methylation, suggesting the greatpotential of DNA methylation in therapeutic strategies againstage-related diseases ( Figure 1B ).However, to further understand the roles of DNA methyla-",
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              "content": "Mitochondrial DNA (mtDNA) influences aging through several mechanisms:\n\n1. **Oxidative Damage**: Mitochondria are crucial for energy production and are highly susceptible to oxidative damage. The accumulation of oxidative lesions in mtDNA is a significant source of age-related damage [1].\n\n2. **Mutations and Lifespan**: Mutations in mtDNA can reduce lifespan. These mutations can aggravate aging and impair brain development, indicating a direct link between mtDNA mutations and the aging process [2].\n\n3. **Mitochondrial Dysfunction**: Aging is associated with mtDNA mutations, which contribute to mitochondrial dysfunction. This dysfunction is linked to age-related diseases and metabolic disorders, further influencing lifespan [4].\n\n4. **Genetic Instability**: The mutation rate for mtDNA is significantly higher than for nuclear DNA. These mutations can compromise mitochondrial functions, such as electron transport and oxidative phosphorylation, leading to declines in ATP levels and increased production of reactive oxygen species, which further damage both nuclear and mitochondrial DNA [9].\n\nOverall, mtDNA influences aging by accumulating mutations and oxidative damage, leading to mitochondrial dysfunction and contributing to age-related physiological decline.",
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              "text": "In addition to nuclear DNA, mitochondrial DNA (mtDNA) also is affected by aging. Alterations in mitochondrial function and mito-chondrial-nuclear signaling occur during aging and have been linked to sex biases in aging and age-related diseases (28). Due to their role in energy production, mitochondria are at high risk of oxida-tive damage. Not surprisingly, accumulation of oxidative lesions is an important source of age-related mtDNA damage (29). In aged Wistar rats brains, DNA oxidation, as measured by",
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              "text": "mitochondrial DNA mutations can reduce lifespan. Sci Rep. 2014;4:6569.\n20. Ross JM, Stewart JB, Hagstrm E, Bren S, Mourier A, Coppotelli G,\nFreyer C, Lagouge M, Hoffer BJ, Olson L. Germline mitochondrial DNA\nmutations aggravate ageing and can impair brain development. Nature.\n2013;501(7467):412 5.\n21. Sondheimer N, Glatz CE, Tirone JE, Deardorff MA, Krieger AM, Hakonarson H.\nNeutral mitochondrial heteroplasmy and the influence of aging. Hum Mol\nGenet. 2011;20(8):1653 9.",
              "title": "2017 - Independent impacts of aging.pdf",
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              "text": "102. Zhang R, Wang Y , Ye K, Picard M, Gu Z.Independent impacts of aging on mitochondrial \nDNA quantity and quality in humans. BMC Genomics. 2017;18:890. https://doi.org/10.1186/\ns12864-017-4287-0.\n 103. Norddahl GL, et al. Accumulating mitochondrial DNA mutations drive premature hema-\ntopoietic aging phenotypes distinct from physiological stem cell aging. Cell Stem Cell. \n2011;8:499510. https://doi.org/10.1016/j.stem.2011.03.009.",
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              "text": "other studies, the risk for metabolic disorders is highly associated with age-related \ndiseases that affect lifespan, and interestingly these conditions exhibit mitochon-\ndrial dysfunction [73].\nAging is a complex process as a time-dependent progressive loss of physiologi-\ncal integrity, leading to impaired function and increased vulnerability to death [74], \nand as we described above, aging is highly associated with mtDNA mutations; in",
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              "text": "mt, and overall mitonuclear genomic compatibility. \nGiven the uncertainty of mtDNA mutation accumulation in driving the natural aging process, it is plausible that mito -\nchondrial communication may be a significant evolutionarily conserved force that influences lifespan and/or healthspan.\nAcknowledgements Funding was provided by the American Federa-\ntion for Aging Research (AFAR), the National Institute on Aging (T32",
              "title": "2020 - Mitonuclear genomics and aging.pdf",
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              "text": "abolic regulation through mitochondrial signaling. Am J Physiol Endocrinol Metab. \n2014;306:E58191.\n 74. Zhang R, Wang Y , Ye K, Picard M, Gu Z.Independent impacts of aging on mitochondrial DNA \nquantity and quality in humans. BMC Genomics. 2017;18:890.\n 75. Hebert SL, Lanza IR, Nair KS.Mitochondrial DNA alterations and reduced mitochondrial \nfunction in aging. Mech Ageing Dev. 2010;131:45162.\n 76. Liu D, Li H, Lu J, Bai Y .Tissue-specific implications of mitochondrial alterations in aging.",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "Sun., N, Youle, R. J. and Finkel, T. (2016). The mitochondrial basis of aging.\nMol. Cell 61, 654-666. doi:10.1016/j.molcel.2016.01.028\nSymer, D. E., Connelly, C., Szak, S. T., Caputo, E. M., Cost, G. J., Parmigiani, G.\nand Boeke, J. D. (2002). Human L1 retrotransposition is associated with genetic\ninstability in vivo. Cell110, 327-338. doi:10.1016/S0092-8674(02)00839-5\nSzabo, L., Morey, R., Palpant, N. J., Wang, P. L., Afari, N., Jiang, C., Parast,",
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              "text": "than ones that affect mitochondrial DNA12,57,58,71.So,this is an important reason for favouring\nnuclear DNA as the ultimate damage target in natural ageing. Nevertheless, it is conceivable that\nwhen mutations occur in the mitochondrial genome, mutant-protein production could increase\nthe inefficiency of the mitochondrial respiratory chain, thereby resulting in more reactive oxygenspecies, which would then damage nuclear and mitochondrial DNA further.",
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              "text": "generation animals as they grow older.Mitochondrial DNAGenetic instability outside of the nuclear genome mightalso contribute to aging (reviewed in Lee et al., 1997;Wallace et al., 1998). The mutation rate for mitochondrialDNA (mtDNA) is 10- to 20-fold greater than for nuclearDNA, and it is believed that mtDNA mutations may com-promise mitochondrial functions in different ways (Fig-ure 4). First, defects in electron transport and oxidativephosphorylation could lead to declines in ATP levelsand the NAD:NADH",
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              "text": "of the human aging process(Corral-Debrinski et al., 1992; Soong et al., 1992;Wei etal., 1996b), and it has been demonstrated that certain pointmutations of mitochondrial DNA accumulate in the aginghuman brain (Zhang et al., 1993; Liu et al., 1997). However,thefunctionalimplicationsofthesendingsarecontroversial(Hayashietal.,1994).Tocomplicatethematterfurther,Takaiand co-workers discuss the possibility that the commonage-associated changes in human and mouse",
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              "content": "Yes, there are known genetic mutations that cause premature aging. Specifically, mutations in the LMNA gene are associated with Hutchinson-Gilford Progeria Syndrome, a disease characterized by premature aging [4]. Additionally, mutations in the RECQL4 gene are linked to Rothmund-Thomson syndrome, which also involves premature aging [4]. These genetic disorders highlight the connection between genome integrity and premature aging [7].",
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              "text": "logical phenomena is often facilitated by the \nstudy of genetic mutants, and, in the case of \nhumans, genetic disorders. Accordingly, a search \nwas made, over the years, for genetic disorders \ncharacterized by premature aging. If DNA dam- \nage and repair has anything to do with aging it \nshould be evidenced in such individuals. Martin \n(1978) listed 162 genetic syndromes in humans with some or many signs of premature aging. \nAbout 21 feahares are considered as markers for",
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              "text": "[315] Szilard, L. On the nature of the aging process. Proc. Natl. Acad. Sci. USA\n45:3545; 1959.\n[316] Vijg, J.; Dolle, M. E. Large genome rearrangements as a primary cause of\naging. Mech. Ageing Dev. 123:907915; 2002.\n[317] Vijg, J. Somatic mutations and aging: a re-evaluation. Mutat. Res.\n447:117135; 2000.\n[318] Martin, G. M. Genetic syndromes in Man with potential relevance to the\npathobiology of aging. Birth Defects Orig. Artic. Ser. 14:539; 1978.",
              "title": "2007 - Trends in oxidative aging theories.pdf",
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              "text": "19\n 6. Milholland B, Suh Y , Vijg J.Mutation and catastrophe in the aging genome. Exp Gerontol. \n2017;94:3440.\n 7. Maslov AY , Ganapathi S, Westerhof M, Quispe-Tintaya W, White RR, Van Houten B, etal. \nDNA damage in normally and prematurely aged mice. Aging Cell. 2013;12:46777.\n 8. Blokzijl F, de Ligt J, Jager M, Sasselli V , Roerink S, Sasaki N, etal. Tissue-specific mutation \naccumulation in human adult stem cells during life. Nature. 2016;538:2604.",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "143 Gonzalo S, Kreienkamp R & Askjaer P (2017) Hutchinson -Gilford Progeria \nSyndrome: A premature aging disease caused by LMNA gene mutations. \nAgeing Res. Rev.  33, 1829. \n144 Lu L, Jin W & Wang LL (2017) Aging in Ro thmund -Thomson syndrome and \nrelated RECQL4 genetic disorders. Ageing Res. Rev.  33, 3035. \n145 de Renty C & Ellis NA (2017) Blooms syndrome: Why not premature aging? \nAgeing Res. Rev.  33, 3651. \n146 Shiloh Y & Lederman HM (2017) Ataxia -telangiectasia (A -T): An emerging",
              "title": "2019 - Towards Understanding Genomic Instability, Mitochondrial.pdf",
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              "text": "genetic disease model of premature aging, In: Harrison,D.E., eds, Genetic Effects on Aging II (Telford Press, Caldwell,NJ), pp. 521542.\n[2] Djawdan, M., Sugiyama, T., Schlaeger, L., Bradley, T.J. and\nRose, M.R. (1996) Metabolic aspects of the trade-off between\nfecundity and longevity in Drosophila melanogaster ,Physiol.\nZool. 69, 11751195.\n[3] Fleming, J.E., Spicer, G.S., Garrison, R.C. and Rose, M.R.",
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              "text": "genes of a whole chromosome ineffective, couldbe a main causal factor in aging (Szilard, 1959).According to Maynard Smith, such types of mu-tations do not seem likely to be common enoughto be the main cause of aging. However, at thetime quantitative information on the possible age-related accumulation of different types of muta-tions in various tissues of mammals wascompletely lacking. The question, therefore,whether somatic mutations are a cause of aging,has not been resolved, more than four decadesafter",
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              "text": "features of premature aging (16, 17). Subsequent experiments conrmed that mitochondrial DNA\nmutations and deletions were the driving force behind the observed accelerated aging phenotypes(18).\nTHE LINK BETWEEN NUCLEAR GENOME INTEGRITY\nAND PREMATURE AGING\nThe notion that the majority of currently identied progeria syndromes originate from defects\nin genome maintenance highlights the importance of the condition of DNA in the process of",
              "title": "2016 - Genome Integrity in Aging.pdf",
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              "text": "Tryggvason K,ZhouZ.Genomicinstability inlaminopathy based\npremature aging,NatMed. 2005;11:780 785.\n13.MisteliT,ScaffidiP.Genomeinstability inprogeria:when\nrepairgetsold,NatMed. 2005;11:718 719.\n14.PereiraS,Bourgeois P,NavarroC,EstevesVieiraV,CauP,De\nSandreGiovannoli A,LvyN.HGPSandrelatedpremature aging\ndisorders: Fromgenomicidentification tothefirsttherapeutic \napproaches, MechAgeingDev.2008;129:449 459.\n15.SmithED,Kudlow BA,FrockRL,KennedyBK.Atypenuclear",
              "title": "2009 - Genomic instability and DNA damage responses in progeria arising.pdf",
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              "text": "Nature Genetics | Volume 55 | February 2023 | 268279 278\nArticle https://doi.org/10.1038/s41588-022-01279-621. Tiwari, V. & Wilson, D. M. 3rd. DNA damage and associated DNA \nrepair defects in disease and premature aging. Am. J. Hum. Genet.  \n105, 237257 (2019).\n22. Tamae, D., Lim, P., Wuenschell, G. E. & Termini, J. Mutagenesis and repair induced by the DNA advanced glycation end product N2-1-(carboxyethyl)-2-deoxyguanosine in human cells. Biochemistry  \n50, 23212329 (2011).",
              "title": "2023 - Genome-wide RNA polymerase stalling.pdf",
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              "text": "[36] J.  de  Boer,  J.O.  Andressoo,  J.  de  Wit,  J.  Huijmans,  R.B.  Beems,  H.  van  Steeg,  et  al.,\nPremature  aging  in  mice  decient  in  DNA  repair  and  transcription,  Science\n296  (2002)  12761279.\n[37]  S.M.  Schuh-Huerta,  N.A.  Johnson,  M.P.  Rosen,  B.  Sternfeld,  M.I.  Cedars,  R.A.\nReijo Pera,  Genetic  markers  of  ovarian  follicle  number  and  menopause  in\nwomen  of  multiple  ethnicities,  Hum.  Genet.  131  (2012)  17091724.",
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              "content": "Recent discoveries in the genetics of aging include the identification of a number of genes capable of altering the aging process significantly in animal models and even in some humans [2]. Additionally, recent efforts have focused on isolating aging mutants through mutagenesis experiments to determine the mechanistic basis for unusual life spans, leading to the discovery of genes that can either enhance or reduce life span [4]. These findings contribute to a growing understanding of the genetic factors influencing aging and longevity.",
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              "text": "series of recent breakthroughs, a number of genes capable ofaltering the aging process as a whole  or at least to a largedegree  have been identified in animal models and even a fewin humans (Finch & Ruvkun, 2001; de Magalhes, 2005; Kenyon,2005). Furthermore, multiple alleles have been examined fortheir association with human exceptional longevity (Vijg & Suh,2005). This is a fascinating and important area of research, yetthere are now so many genes being associated with aging andlongevity that keeping",
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              "text": "Recent developments on the genetics of aging can be seen as several streams\nof effort. In general, humans show a relatively modest ( <50%) heritability of",
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              "text": "genetics of aging I. What is aging? Frontiers in Genetics. doi:10.3389/fgene.2012.00134.\nr\nose, Michael \nr\n., Anthony D. Long, Laurence D. Mueller, Cristina L. \nr\nizza, Kennedy C. Matsagas, \nLeeF. Greer, and Bryant \nvilleponteau. 2009. \ne\nvolutionary nutrigenomics. In The future of aging, eds. \nG. M. Fahy, M. D. West, L. S. Coles, and S. B. \nh\narris. Berlin: Springer.\nr\nushton, J. \np\nhillippe. 1995. Race, evolution, and behavior: A life history approach. New Brunswick, NJ: \nTransaction \np\nublishers.",
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              "text": "informed by age-related disease identifies loci for exceptional human longevity. Li H, editor. \nPLoS Genet. 2015. https://doi.org/10.1371/journal.pgen.\n 15. Polderman TJC, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, \netal. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat \nGenet. 2015;47:7029.\n 16. Cellerino A, Ori A.What have we learned on aging from omics studies? Semin Cell Dev Biol. \n2017;70:17789.",
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              "text": "eries that have inspired thousands of researchers across the world \nto study aging, and we acknowledge the wider significance of the \ncreation of a field that has the potential to transform human health.\nGenetics\nAging is influenced by genetic factors. It may be surprising to know \nthat as recently as the 1970s and 1980s, the concept of modulating \nDownloaded from https://academic.oup.com/biomedgerontology/article/76/7/e85/6145792 by guest on 15 October 2023",
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              "content": "Epigenetic changes affect aging through several mechanisms:\n\n1. **Alterations in Chromatin Structure**: During aging, there are various epigenetic alterations such as the accumulation of histone variants, changes in chromatin accessibility, loss of histones and heterochromatin, and imbalances in activating/repressing histone modifications. These changes can affect transcription and translation processes, impacting cellular function [1].\n\n2. **Epigenetic Drift**: As individuals age, epigenetic changes accumulate, leading to a phenomenon known as epigenetic drift. This drift results in the cumulative loss of gene regulation over time, impairing cellular and tissue function. It is suggested that this disruption may also play a role in the development of age-related diseases, such as cancer [3].\n\n3. **DNA Damage and Chromatin Remodeling**: It is suggested that epigenetic alterations during aging are largely triggered by DNA damage. This damage leads to chromatin remodeling and redistribution of chromatin modifiers, which are recruited away from their normal sites to engage in DNA repair [4].\n\n4. **Increased Expression of Pro-aging Genes**: Epigenetic dysregulation can lead to increased expression of pro-aging genes, such as the cell-cycle inhibitor p16, which drives cell senescence. This contributes to increased transcriptional noise and decreased coordination of gene expression, further contributing to organismal aging [10].\n\n5. **Potential for Reversibility**: Despite these changes, there is potential reversibility in epigenetic modifications, offering opportunities to alter the trajectory of age-related diseases. This highlights the plasticity of aging and the potential for interventions that could slow down the aging process [7].\n\nOverall, epigenetic changes play a crucial role in the aging process by affecting gene expression, cellular function, and the development of age-related diseases.",
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              "text": "Figure 1. Epigenetics of aging and aging-relate d diseases. During aging, various ep igenetic alterations occur including \naccumulation of histone variants, change s in chromatin accessibility mediated by chromatin remodeling complexes, loss \nof histones and heterochroma tin, imbalance of activating /repressing histone modifications and aberrant expres-\nsion/activity of miRNAs. These deregulations can affect transcrip tion and, subsequently, transl ation, as well as the stabi-",
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              "text": "ment of 5 years corresponded to a 21% increased risk of\nmortality overall [7]. Thus, predictions of epigenetic\nagemay be an indication of an individual s biological\nstate of aging.\nBeyond these examples of advanced epigenetic aging, a\ncomplementary but unanswered question is whether\nepigenetic clocks can also be slowed. Epigenetic aging\nstudies in humans have not thus far been well suited to\naddress questions of slowed aging, given the lack of\nwell-documented interventions that enhance health or",
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              "text": "al., 2005 ).  The epigenetic changes that accumulated with age had a dramatic effect on gene expression, thus the authors propos e that a so-called epigenetic drift accompanies the aging process.   Epigenetic modifications can result in the cumulative loss of gene regulation over time, ultimately impairing cellular and tissue function.  Further, recent data sugge st that epigenetic disruption of tissue specific stem and progenitor cells may play a role in cancer development (Feinberg et al., 2006 ).  The",
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              "text": "epigenetic changes during aging are currentlyunknown (Fig. 3). It has been suggested thatthe epigenetic alterations are largely triggered\nby DNA damage (reviewed in Oberdoerffer\nand Sinclair 2007). In this scenario, randomlyoccurring DNA damage leads to chromatin\nremodeling and to redistribution of chromatin\nmodiers within the genome with modiersbeing recruited away from their normal sites\nso that they can engage in the repair of the",
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              "text": "Recently, studying the direct relationship between epigeneticmechanisms and the aging process itself is gaining increasing\nattention. The potential reversibility of these epigenetic\nchanges that occur as a hallmark of aging offers excitingopportunities to alter the trajectory of age-related diseases.\n8\nThis is especially important given the remarkable plasticityof aging.\n9,10In the literature, age-associated epigenetic alter-\nations have been identified by epigenome-wide association",
              "title": "2016 - Epigenetic drift in the aging genome a ten-year.pdf",
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              "text": "in gene transcription and, as a consequence, translation as well as the stabilization or\ndegradation of molecular factors. While mechanisms underlying aging-related pathologies\nremain to be elucidated in detail, various studies demonstrate an epigenetic component.\nIn fact, the aforementioned epigenetic modications were shown to play essential roles\nin diseases including inammation, cancer, osteoporosis, neurodegenerative diseases,\nand diabetes.",
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              "text": "PLoS Biology | www.plosbiology.org August 2007 | Volume 5 | Issue 8 | e201 1759\nEpigenetic Dysregulation with Age",
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              "text": "and increased expression of proaging genes such as the cell-cycle inhibitor p16, which drives cell senescence. Additional consequences of epigenetic dys-regulation include increased transcriptional noise and decreased coordination of gene expression that contributes to organismal aging.\nCell148, January 20, 2012 2012 Elsevier Inc. 53",
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              "content": "The gene FOXO3 plays a significant role in human longevity. Multiple studies have shown a strong association between variations in the FOXO3 gene and increased lifespan. For instance, the FOXO3A genotype has been strongly linked with human longevity, as demonstrated in studies by Willcox et al. (2008) and confirmed in various populations, including German and Southern Italian centenarians [1], [2], [3]. The FOXO3 locus is associated with extreme longevity in humans, particularly among centenarians [5]. Additionally, specific variants at the FOXO3 locus have been identified that respond to cellular stress, which may contribute to their role in promoting longevity [8].",
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              "text": "27 Willcox, B. J. et al. 2008 FOXO3A genotype is\nstrongly associated with human longevity. Proc. Natl\nAcad. Sci. USA 105, 13 98713 992. ( doi:10.1073/\npnas.0801030105 )\n28 Flachsbart, F., Caliebe, A., Kleindorp, R., Blanche, H.,\nvon Eller-Eberstein, H., Nikolaus, S., Schreiber, S. &\nNebela, A. 2009 Association of FOXO3A variationwith human longevity conrmed in GermanGenomics of human longevity P . E. Slagboom et al. 41",
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              "text": "3. Willcox BJ, Donlon TA, He Q et al (2008) FOXO3A genotype is\nstrongly associated with human longevity. Proc Natl Acad Sci\nUSA 105(37):1398713992. doi: 10.1073/pnas.0801030105\n4. Anselmi CV, Malovini A, Roncarati R et al (2009) Association of\nthe FOXO3A locus with extreme longevity in a southern Italian\ncentenarian study. Rejuvenation Res 12(2):95104. doi: 10.1089/\nrej.2008.0827\n5. Flachsbart F, Caliebe A, Kleindorp R et al (2009) Association of\nFOXO3A variation with human longevity conrmed in German",
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              "text": "are, in fact, part of the same insulin/IGF1/GH pathway(Fig. 1) that modulates lifespan across organisms (Ke-nyon, 2010). A strong association between FOXO3 and\nhuman longevity has been reported (Willcox et al., 2008)and subsequently validated in other populations (forreview, see Kenyon, 2010). FOXO3 was also associatedAGING GENES AS TARGETS FOR DRUG DISCOVERY 95",
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              "text": "Biogerontology 11:28797\n117. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, et al. 2008. FOXO3A genotype is strongly associated\nwith human longevity. Proc. Natl. Acad. Sci. USA 105:1398792\n118. Soerensen M, Dato S, Christensen K, McGue M, Stevnsner T, et al. 2010. Replication of an association\nof variation in the FOXO3A gene with human longevity using both case-control and longitudinal data.\nAging Cell 9:101017\n119. Mardis ER. 2011. A decades perspective on DNA sequencing technology. Nature 470:198203",
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              "text": "FOXO3 locus is associated with extreme longevity in humans (centenarians) [2, \n58, 59].\nNRF/SKN-1 activates the expression of genes involved in protecting the cell in \nresponse to ROS, toxins, and metabolic changes through mTOR and insulin/IGF \nsignaling, and it is also dysregulated later in life [60, 61]. Increasing the levels of \nL. Garca-Velzquez and C. Arias",
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              "text": "A. 2003;100:406671. https://doi.org/10.1073/pnas.2628028100.\n 24. van den Akker EB, Deelen J, Slagboom PE, Beekman M. Exome and whole genome \nsequencing in aging and longevity. Adv Exp Med Biol. 2015;847:12739. https://doi.\norg/10.1007/978-1-4939-2404-2_6.\n 25. Flachsbart F, etal. Association of FOXO3A variation with human longevity confirmed in \nGerman centenarians. Proc Natl Acad Sci U S A. 2009;106:27005. https://doi.org/10.1073/\npnas.0809594106.\nA. Garca-Venzor and E. A. Mandujano-Tinoco",
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              "text": "X.L.,  2009.  Genetic  association  of  FOXO1A  and  FOXO3A  with  longevity  trait  in\nHan  Chinese  populations.  Hum.  Mol.  Genet.  18,  48974904.\nLunetta,  K.L.,  DAgostino  Sr.,  R.B.,  Karasik,  D.,  Benjamin,  E.J.,  Guo,  C.Y.,  Govindaraju,\nR.,  Kiel,  D.P.,  Kelly-Hayes,  M.,  Massaro,  J.M.,  Pencina,  M.J.,  Seshadri,  S.,  Murabito,\nJ.M.,  2007.  Genetic  correlates  of  longevity  and  selected  age-related  phenotypes:",
              "title": "2011 - A genome-wide association study confirms APOE as the major gene influencing.pdf",
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              "text": "theFOXO3 locus is not surprising, since this locus was previously\nreported in the longevity GWA study from the CHARGE con-\nsortium\n7, from which many cohorts are included in these meta-\nanalyses. So far, three functional longevity-associated variants\nhave been identi ed at the FOXO3 locus (rs2802292, rs12206094,\nand rs4946935). For all of them, an allele-speci c response to\ncellular stress was observed. Consistently, the longevity-associated\nalleles of all three variants were shown to induce FOXO3",
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              "text": "exceptional longevity with no significant genetic contribution. Interestingly, the \nauthors found that FOXO3A, a longevity allele, may not be related to healthy aging \nphenotype [29].\nAging is a complex process usually accompanied by the onset of different dis-\neases like neurodegenerative disorders (Alzheimers disease and Parkinsons dis-\nease), cardiovascular illnesses, and cancer. The study of the genetic basis of these \naging-related diseases is another approach in the study of the genomic basis of",
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              "text": "centenarians. Proc Natl Acad Sci USA 106(8):27002705. doi: 10.\n1073/pnas.0809594106\n6. Li Y, Wang WJ, Cao H et al (2009) Genetic association of\nFOXO1A and FOXO3A with longevity trait in Han Chinese\npopulations. Hum Mol Genet 18(24):48974904. doi: 10.1093/\nhmg/ddp459\n7. Soerensen M, Dato S, Christensen K et al (2010) Replication of\nan association of variation in the FOXO3A gene with human\nlongevity using both case-control and longitudinal data. AgingCell 9(6):10101017. doi: 10.1111/j.1474-9726.2010.00627.x",
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              "content": "The environment interacts with genes to influence aging through several mechanisms:\n\n1. **Signaling Pathways and Gene Expression**: Environmental factors can trigger signaling pathways and modulate gene expression, impacting aging. For example, certain genes have varying effects on lifespan depending on environmental factors like diet [1].\n\n2. **Epigenetic Modifications**: Environmental factors can lead to changes in DNA methylation, acetylation, or deacetylation of histones, which are epigenetic modifications that influence gene expression. These changes can result in cellular damage and accelerated aging, such as the shortening of telomeres [2], [6].\n\n3. **Epigenetics as a Link**: Epigenetic modifications provide a potential link between the environment, disease, and aging. This suggests that specific environmental factors might directly induce specific epigenetic changes, which could be targeted for interventions aimed at improving healthspan or promoting healthy aging [3].\n\n4. **Physiological Capacity and Longevity**: Environmental factors, along with protective genetic alleles, contribute to an individual's physiological capacity, indirectly determining healthy lifespan and longevity. For instance, caloric restriction and smoking have opposite effects on the rate of aging [4].\n\n5. **Plasticity of Aging**: Aging is a plastic process that can be manipulated by both genetic and environmental factors. Understanding these interactions can help identify targets for anti-aging therapies, potentially through diet, lifestyle, and pharmacological interventions [5], [10].\n\nOverall, the interaction between the environment and genes is complex and involves multiple pathways and mechanisms that collectively influence the aging process.",
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              "text": "Several studies show the influence of the environment on the ageing process [24]. \nEnvironmental factors may affect homeostasis and lead to the development of dis-\neases, thus affecting the quality of life in older age [25]. They also produce cellular \ndamage, which causes an accelerated shortening of the telomeres at the genetic \nlevel, accompanied by changes in DNA methylation, acetylation or deacetylation \nof histones, among others. Altogether, these changes induce an aberrant gene",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "changes are generated during the aging process. For a long time it\nhas been believed that epigenetic modications occurring during\naging may depend on environmental factors. This idea is attractive\nbecause, if true, epigenetics could provide a link between the\nenvironment, disease and aging. It also opens the possibility of\ntargeted intervention aimed, for example, at improving healthspan\nor healthy aging. Thus, the rst question is whether specic\nenvironmental factors can directly induce specic epigenetic",
              "title": "2009 - The role of epigenetics in aging and age-related diseases.pdf",
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              "text": "In addition, environmental factors influence the\norganism s ability to withstand the increase in entropy\nwith aging: for example, caloric restriction and\nsmoking can exert opposite effects on the rate ofaging (Colman et al. 2009 ; Fraser and Shavlik 2001 ).\nBoth protective alleles and a benevolent environment\ncontribute to excess physiological capacity, which in\nturn indirectly determines an individual s healthy life\nspan and longevity (Martin et al. 2007 ). The well-",
              "title": "2011 - How pleiotropic genetics of the musculoskeletal system.pdf",
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              "text": "to humans through ge-netic manipulations for numerous legal, ethical, andtechnical reasons. If we could understand how the envi-ronment modulates these aging-related genes, we mightbe able to create antiaging therapies applicable to hu-mans, potentially through diet, lifestyle, and even phar-macological interventions. Therefore, understanding ge-nome-environment interactions in the context of agingcan be a powerful approach to identify attractive targetsfor drug design.",
              "title": "2012 - Genome-Environment Interactions That Modulate.pdf",
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              "text": "ing human life span have been identified [2,3]. At the\nsame time, there is a growing realization that environ-\nmental factors are major contributors to aging and age-\nassociated illness. Epigenetics is the study of chemical\nmodifications of the genome, heritable by cell progeny,\nand it has been an attractive target for studies of aging\nand environmentally influenced disease. Several groups\nhave shown differences in DNA methylation - a covalent",
              "title": "2015 - Age and sun exposure-related widespread.pdf",
              "version": "v0",
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            "metadata": {
              "text": "al., 2009; Stanfel et al., 2009). Many of these genesmodulate the response to environmental signals, such asfood availability, and act in signaling pathways that ifunderstood can be targeted (Fig. 1). The genetic regula-tion of aging is therefore an emerging field with multipleapplications in the human nutrition, cosmetic, and phar-maceutical industries.\nAGING GENES AS TARGETS FOR DRUG DISCOVERY 91",
              "title": "2012 - Genome-Environment Interactions That Modulate.pdf",
              "version": "v0",
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            "metadata": {
              "text": "standing the cause and mechanisms of aging is imperative in\nassisting to suppress age-related diseases and promote healthylongevity. It is well-known that aging is influenced by a combin-\nation of genetic and environmental factors. Previous twin stud-\nies have shown that the genetic contribution to general human\nlongevity is about 2030% [ 4,5], whereas environmental factors\nin human aging and longevity still account for the largest effect.\nEpigenetic factors influence the regulation of gene expres-",
              "title": "2016 - Progress on the role of DNA methylation in aging.pdf",
              "version": "v0",
              "chunk_order": 4,
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            "metadata": {
              "text": "known to affect the function of epigenetic regulators, this may be an example of how aging interacts\nwith our genome to inuence AD development.",
              "title": "2018 - Genomics New Light on Alzheimer?s.pdf",
              "version": "v0",
              "chunk_order": 95,
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              "text": "consequently the incidence of age-related diseasessuch as heart disease, cancer, and neurodegenerativediseases, is projected to increase considerably in thecoming decades. Findings from model organisms haverevealed that aging is a surprisingly plastic processthat can be manipulated by both genetic and environ-mental factors. Here we review a broad range of find-ings in model organisms, from environmental to ge-netic manipulations of aging, with a focus on thosewith underlying gene-environment interactions",
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              "content": "Senescent cells are cells that have stopped dividing and have entered a state of permanent growth arrest. They are characterized by an altered metabolism and the secretion of pro-inflammatory factors, a phenomenon known as the senescence-associated secretory phenotype (SASP) [1], [3]. These cells accumulate in tissues over time and are resistant to apoptosis, meaning they are not easily cleared from the body [9].\n\nSenescent cells contribute to aging and age-related diseases in several ways. They impact the tissue environment by secreting inflammatory cytokines, proteases, and growth factors, which can lead to chronic inflammation and tissue dysfunction [3], [4]. This chronic inflammation is a significant factor in the development of age-related degenerative diseases [1], [4]. Additionally, senescent cells can alter the tissue microenvironment, promoting the degeneration of organs and stem cell niches, and potentially stimulating cancer cell growth [6].\n\nThe accumulation of senescent cells is associated with various age-related pathologies, such as atherosclerosis, osteoarthritis, and Alzheimer's disease [5], [9]. Recent studies have shown that clearing senescent cells can prevent or delay tissue dysfunction and extend health span, highlighting their causative role in aging [5].",
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              "text": "senescence, exhausting the ability for a tissue to regenerate after injury, impacting mitochondrial function,and inducing protein aggregation. Senescent cells have altered metabolism, and they can secreteproinammatory factors and alter the local tissue environment, thereby contributing to aging andage-related degenerative diseases. In addition, stem cell function can be impacted by DNA damage by bothcell autonomous and nonautonomous mechanisms. Proper function of mitochondria is dependent upongenome",
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              "text": "[87] and the accumulation of senescent cells in human\ntissues with age has been implicated as a driver of aging-\nrelated diseases. Indeed, pharmacological approaches\ntargeting senescent cells, like senolytics, are a major and\ntimely area of research that could result in human clin-\nical applications [ 5,88]. It is imperative that we fully\nunderstand and deconstruct cellular senescence in order\nto target aging-related diseases. We hope that CellAge\nwill help researchers understand the role that CS plays",
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              "text": "An important source of inflammatory signals in aged organ-\nisms is thought to be the accumulation of senescent cells across\ntissues [ 5,7]. Indeed, accumulating evidence has shown that\nsenescent cells are characterized by a senescence-associatedsecretory phenotype [ 810], which includes a panoply of\npro-inflammatory cytokines, proteases, growth factors and\nmetabolites [ 10,11]. The impact of senescent cells on age-related\ninflammation, and their potential role as a target for pro-",
              "title": "2022 - Functional genomics of inflamm-aging.pdf",
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              "text": "senescent cells [150]. SASP factors exert their functions in either an autocrine or a \nparacrine manner and are responsible for the induction of the chronic inflammation \nand cell proliferation that contributes to cell dysfunction and cancer. Thus, the accu-\nmulation of senescent cells in tissue is closely associated with aging-related dis-\neases. Recently, it was determined that senescent fibroblasts significantly increase \nthe expression of HLA-E, which inhibits the receptor NKG2A in killer cells, and",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "atherosclerosis, osteoarthritis, sarcopenia, ulcer formation, cancer, and Alzheimer disease, which\nis suggestive of a causative role. However, the most convincing evidence that senescent cells causeaging comes from recent genetic (85) and pharmacologic studies (86) revealing that clearance of\nsenescent cells can prevent or delay tissue dysfunction and extend health span.\nSenescent cells induce autocrine, as well as paracrine, signaling by secretion of proinamma-",
              "title": "2018 - Nuclear Genomic Instability.pdf",
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              "text": "senescence can deplete both stem (5153) and stromal\n(10,11) cell pools. Moreover, because senescent cellspersist, they have the ability to alter the tissue micro-environment, and can therefore also promote the degen-eration of organs and stem cell niches (14,46). Finally,\nsenescent cells secrete factors such as matrix metallopro-\nteinase-3 (MMP-3), which favors extra-cellular matrixremodeling, promotes defects in epithelial cell dierentia-tion and stimulates cancer cell growth (46,54,55).",
              "title": "2007 - Two faces of p53 aging and tumor suppression.pdf",
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              "text": "potential role of senescence in in vivo  aging and disease has been difficult to assess and somewhat controversial  \n[146]. However, recent studies have shown that senescent cells accumulate in normal arterial tissue over the \nlifespan of humans  [147, 148]. Likewise, the accumulation of senescent cells has been reported in diseased \ntissues, such as atherosclerotic plaques  [149] and abdominal aortic aneurysms  [150]. Baker et al.  showed that",
              "title": "2015 - Cellular and Molecular Biology of Aging Endothelial Cells.pdf",
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              "text": "51. Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. 2007. Accumulation of senescent cells in mitotic tissue\nof aging primates. Mech. Ageing Dev. 128:3644\n52. Boyle J, Kill IR, Parris CN. 2005. Heterogeneity of dimer excision in young and senescent human dermal\nbroblasts. Aging Cell 4:24755\n53. Seluanov A, Mittelman D, Pereira-Smith OM, Wilson JH, Gorbunova V. 2004. DNA end joining\nbecomes less efcient and more error-prone during cellular senescence. PNAS 101:762429",
              "title": "2018 - Nuclear Genomic Instability.pdf",
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              "text": "in many accelerated-aging mouse models and in a plethora of human age-associated pathologies,\nincluding osteoporosis, atherosclerosis, glomerular disease, diabetic venous ulcers, chronic ob-structive pulmonary disease and emphysema, osteoarthritis, herniated intervertebral discs, and\nvascular calcication (112). Senescent cells are resistant to apoptosis and accumulate exponen-\ntially with age as a consequence of inefcient clearance. Unlike apoptotic tissues, senescent tissues\n436 VermeijHoeijmakersPothof",
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              "text": "wound healing [ 8], and immune clearance [ 9,10]. By\ncontrast, the gradual accumulation and chronic\npersistence of senescent cells with time promotes dele-\nterious effects that are considered to accelerate deterior-\nation and hyperplasia in aging [ 11]. Senescent cells\nsecrete a cocktail of inflammatory and stromal regula-\ntorsdenoted as the senescence-associated secretory\nphenotype, or SASP which adversely impact neighbor-\ning cells, the surrounding extracellular matrix, and other",
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              "content": "Yes, there are known lifestyle interventions that can positively impact genes related to aging. Dietary interventions, such as dietary restriction (DR) and calorie restriction, have been shown to alter patterns of DNA methylation and induce long-lasting changes in gene expression that improve health during aging and extend lifespan [1], [8]. These interventions can modify the epigenome, which is linked to the biology of aging [5]. Additionally, glucose restriction has been shown to extend human cellular lifespan through SIRT1-mediated epigenetic and genetic mechanisms [7].",
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              "text": "Dietary interventions, including starvation and protein\ndeprivation, can also alter patterns of DNA methyla-\ntion, potentially in a long-lasting manner [42, 43],\nincluding transgenerationally [26, 44].\nDietary, genetic and pharmacological interventions\nthat improve health during aging and extend lifespan\ninduce long-lasting changes in gene expression that\nmediate their effects. Here we have asked if and how\nage-related DNA methylation, transcription and lipid",
              "title": "2017 - Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism.pdf",
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              "text": "Longev. Heal. 2, 10 (2013).\n7. Kreienkamp Ret al.Doubled lifespan and patient-like pathologies in progeria mice fed high-fat diet. \nAging Cell18, e12852 (2019). [PubMed: 30548460] \n8. Heilbronn LK & Ravussin E Calorie restriction and aging: review of the literature and implications \nfor studies in humans. Am. J. Clin. Nutr. 78, 361369 (2003). [PubMed: 12936916] \n9. Liang Yet al.Calorie restriction is the most reasonable anti-ageing intervention: a meta-analysis of",
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              "text": "a medical intervention), without changing the fundamental rateof organismal aging. Nevertheless, it does seem that manyso-called longevity genes, as well as dietary restriction,\nappear to extend not only life span, but also health span\n(Kauffman et al., 2010; Luo et al., 2010 ). In that regard, it does\nappear that it is possible to experimentally slow the rate of aging.\nStill, in each case, aging does continue on as if there is some",
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              "text": "As we describe above, a small but growing number ofinterventions has been shown to reproducibly increase\nlifespan in laboratory animals and, in a few cases, to also\ndelay or reverse age-related declines in multiple organsystems. These healthy aging interventions could, in prin-\nciple, be tested to determine whether they also increase\nlifespan and promote healthspan in dogs (Table 1). There\nare several questions that immediately present themselves\nwhen considering the design of a healthy aging interven-",
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              "text": "be linked to the biology of stem cell quiescence and self-renewal.\nAlthough genetic and environmental interventions have clearly\nproven to be effective in prolonging life span, we postulate thatthose interventions, as well as the rejuvenating interventions\ndescribed above, are, in fact, acting primarily to modify theepigenome. Consistent with this, genetic interventions directlytargeting the epigenome can extend life span ( Greer et al.,\n2010 ). Studying aging and rejuvenation through the lens of",
              "title": "2012 - Aging, Rejuvenation, and Epigenetic.pdf",
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              "text": "During the past century, remarkable progress has been \nmade in unveiling the mechanisms of aging. Genetic and molecular pathways that regulate healthspan and lifespan have been identified in various model organisms, provid-ing a rich knowledge base (Longo etal. 2015; Lopez-Otin etal. 2013, 2016; Singh etal. 2019). However, the focus on",
              "title": "2020 - Mitonuclear genomics and aging.pdf",
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              "text": "205. Li, Y.; Tollefsbol, T.O. p16INK4a Suppression by Glucose Restriction Contributes to Human Cellular Lifespan Extension through\nSIRT1-Mediated Epigenetic and Genetic Mechanisms. PLoS ONE 2011 ,6, e17421. [CrossRef]\n206. Daniel, M.; Tollefsbol, T.O. Epigenetic linkage of aging, cancer and nutrition. J. Exp. Biol. 2015 ,218, 5970. [CrossRef]\n207. Kapahi, P .; Kaeberlein, M.; Hansen, M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Res. Rev. 2017 ,\n39, 314. [CrossRef]",
              "title": "2021 - Epigenetics of Aging and Aging-Associated Diseases.pdf",
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              "text": "as diabetes, cancer and neurodegenerative disorders\n[1, 2]. Environmental and genetic interventions can\nameliorate the effects of aging, with nutrition,\nnutrient-sensing signaling networks and metabolism\nplaying evolutionarily conserved roles [1, 3 5]. Diet-\nary restriction (DR), in which food intake is reducedwhile avoiding malnutrition, extends lifespan in di-\nverse model and non-model organisms [3, 6]. DR\ninduces a remarkably broad-spectrum improvement in",
              "title": "2017 - Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism.pdf",
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              "text": "53. Mair W & Dillin A Aging and survival: the genetics of life span extension by dietary restriction. \nAnnu. Rev. Biochem. 77, 727754 (2008). [PubMed: 18373439] \n54. Masoro EJCaloric restriction-induced life extension of rats and mice: a critique of proposed \nmechanisms. Biochim. Biophys. Acta1790, 10401048 (2009). [PubMed: 19250959] \n55. Weindruch R, Walford RL, Fligiel S & Guthrie D The retardation of aging in mice by dietary",
              "title": "2021 - Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.pdf",
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              "text": "In addition to genes associated with aging, research has\nfocused on identifying genes associated with the life-\nextending effects of CR. One method is to identify genesthat decrease or cancel out the life-extending effects of CRwhen mutated (Gems et al., 2002; Bishop and Guarente,2007). More than 100 such genes have been identified inmodel organisms (D. Wuttke, C. Vora, J. P. de Magalhes,unpublished observations). The growth hormone receptor(GHR) is the only gene so far identified in mammals that",
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              "content": "The 'epigenetic clock' is a molecular biomarker of aging that is based on the DNA methylation levels of specific CpG sites. These methylation patterns are highly correlated with an individual's chronological age, with a robust correlation coefficient of approximately 0.9 for individuals aged between 20 and 100 years [1]. The epigenetic clock serves as a reliable predictor of biological age, which refers to how well a person's body functions compared to their chronological age [2]. \n\nIn aging research, the epigenetic clock is used to estimate the biological age of cells, tissues, or organs by analyzing the methylation levels of select CpGs, often referred to as clock CpGs [8]. This estimated age, known as the epigenetic age, can indicate different aging rates between individuals with the same chronological age, providing insights into the biological basis of aging [9]. The epigenetic clock has been applied in various studies to understand the relationship between epigenetic aging and factors such as metabolism, and it is considered one of the most promising molecular estimators of biological age [6], [8].",
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              "text": "vided one of the most reliable aging biomarkers. An epigenetic clock is a group of \nCpG sites with particular methylation patterns that are highly related to the chrono-\nlogical age of an individual. This correlation is very robust (r=0.9) for individuals \nbetween 20 and 100years. The epigenetic clock is a breakthrough discovery that \nwill allow novel experimental approaches to understand the biological basis of \naging [113]. For example, by using the epigenetic clock as a measure of cellular",
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              "text": "Epigenetic Clock\nChronological age is the number of years a person has lived, and biological or phys-\niological age refers to a measure of how well your body functions compared to your \nchronological age. Biological age is influenced by multiple factors (genes, lifestyle, \nbehavior, environment, among others) and correlates with mortality and health sta-\ntus. The epigenetic clock is one potentially reliable predictor of biological age.",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "Background\nEpigenetic clocks are sets of CpG dinucleotides whose DNA methylation (DNAm) can\nbe used to accurately predict a person s chronological age [ 1]. In recent years, various\nepigenetic clocks have been developed [ 25]. Well-known examples are the clocks de-\nveloped by Hannum et al., trained on blood samples and containing 71 CpGs [ 2], and\nHorvath, a multi-tissue predictor consisting of 353 CpGs [ 3]. A popular application of",
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              "text": "An EpigeneticClock\nThe aging transcriptome could be used to gauge the physiological \nage of worms, and in that way serve as an epigenetic clock revealing \nhow much of life span has been spent and how much remains (23). \nMiddle-aged worms show an aging transcriptome half-way between \nthe aging expression profiles of young and old worms. This provides \nan independent way to assess the age of an animal independent of \nits life span. This is important as there are at least 2 explanations to",
              "title": "2021 - Career Retrospective Tom Johnson?Genetics, Genomics.pdf",
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              "text": "The epigenetic aging clock measures the sum of all the age-related \npathways affecting cellular physiology in old age. The aging epigen-\netic clock is heavily enriched for germline- and intestinal-expressed \ngenes, but lack muscle- and neuronal-expressed genes (23, 25). \nExpression changes in the germline and intestine were expected as \nthere are massive changes in the morphology of gonad at the end of \nfertility and the intestine in old age. The aging transcriptome pro-",
              "title": "2021 - Career Retrospective Tom Johnson?Genetics, Genomics.pdf",
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              "text": "etic mouse aging and may be used to inform future studies in other model organisms and humans \nfocused on studying the relationship between epigenetic aging and metabolism.\nIntroduction\nEpigenetic clocks are widely used molecular biomarkers of aging (Horvath and Raj, 2018). These \nDNA methylation (DNAm) age predictors are based on the methylation levels of select CpGs that are RESEARCH ARTICLE\n*For correspondence: \nkmozhui@uthsc.edu\nCompeting interest: See page \n22\nFunding: See page 22",
              "title": "2021 -Mozhui- Epigenetic aging.pdf",
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              "text": "etic mouse aging and may be used to inform future studies in other model organisms and humans \nfocused on studying the relationship between epigenetic aging and metabolism.\nIntroduction\nEpigenetic clocks are widely used molecular biomarkers of aging (Horvath and Raj, 2018). These \nDNA methylation (DNAm) age predictors are based on the methylation levels of select CpGs that are RESEARCH ARTICLE\n*For correspondence: \nkmozhui@uthsc.edu\nCompeting interest: See page \n22\nFunding: See page 22",
              "title": "2021 - Genetic loci and metabolic states associated with murine epigenetic aging.pdf",
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              "text": "estimators epigenetic clocks; telomere length; transcriptomic-, proteomic-, and \nmetabolomic-based estimators; and composite biomarkers concluded that the epi-\ngenetic clock is the most promising molecular estimator of biological age [26]. \nEpigenetic age estimators are sets of CpGs (also known as clock CpGs) that are \ncoupled with a mathematical algorithm to estimate the age of a DNA source, such \nas cells, tissues, or organs. This estimated age, also referred to as epigenetic age or",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "proved epigenetic clock. It should be noted that building\na biological age predictor is difficult since there is no\nclear definition of biological age. Nevertheless, one of\nthe essential features of biological age is its ability to in-\ndicate the different ageing rates between individuals with\nthe same chronological age. A previous study has re-\nported a number of CpG sites that show variation in the\nlongitudinal changing rates between individuals [ 40].",
              "title": "2019 - Improved precision of epigenetic clock.pdf",
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              "text": "ranging from 0.15 to 0.19 [ 8,9]. Individuals with epigenetic clock estimates greater than\ntheir chronological age display age acceleration and have been shown to be at a\ngreater risk of all-cause mortality and multiple adverse health outcomes [ 10]. Conse-\nquently, identification of genetic and environmental contributors to the variation in\nthese measures in populations has become a major goal in the field [ 11].\nThe first generation of epigenetic aging clocks used penalized regression models to",
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              "content": "Researchers use model organisms like yeast and worms to study human aging due to their simpler genomes, short lifespans, and the ease with which they can be genetically and environmentally manipulated. These characteristics make them ideal for identifying and characterizing genes and signaling pathways involved in aging [3]. \n\nYeast, specifically Saccharomyces cerevisiae, is a highly informative model for aging studies because of its genetic tools and the ability to measure aging through replicative or chronological lifespan assays [2], [5]. Yeast has been extensively used to identify genes and interventions responsible for lifespan extension, providing insights into the aging processes of all eukaryotic organisms [10].\n\nSimilarly, the nematode Caenorhabditis elegans is another widely used model organism in biogerontology. Researchers study these organisms to understand whether the aging process is evolutionarily conserved and to what degree mechanisms in these simpler organisms can be indicative of aging mechanisms in humans [1], [6]. These model organisms help explore both genetic and environmental determinants of lifespan, contributing to hypotheses surrounding extended lifespan and healthspan [7].",
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              "text": "the nematode Caenorhabditis elegans , and the budding yeast \nSaccharomyces cerevisiae , have emerged as the most widely \nused and, hence, best characterized, model organisms in bio-\ngerontology. \n When considering the use of simple eukaryotes to study \naging and age-related disease, it is pertinent to ask whether, and to what degree, the aging process is evolutionarily con-\nserved. Does a yeast cell age by the same mechanism(s) as a",
              "title": "2007 - Longevity Genomics Across Species.pdf",
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              "text": "Studies on the aging of mammals are rather limited by the long life\nspan of the commonly used model organisms. Thus, both nonverte-brate and invertebrate organisms, with their shorter life span and ease\nof genetic and environmental manipulations, gained popularity amongresearchers in the aging field as experimental models for aging studies.\nAmong them, budding yeast or Saccharomyces cerevisiae is a highly in-\nformative organismal model for aging studies with its genetic tools,",
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              "text": "Abstract\nCellular models such as yeasts are a driving force in biogerontology studies. Their simpler genome, short lifespans and vast\ngenetic and genomics resources make them ideal to characterise pro-ageing and anti-ageing genes and signalling pathways.Over the last three decades, yeasts have contributed to the understanding of fundamental aspects of lifespan regulation\nincluding the roles of nutrient response, global protein translation rates and quality, DNA damage, oxidative stress,",
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              "text": "usually chosen for convenience rather than for specific features \napplicable to human aging. Hence, choosing the suitable animal model to answer the specific question we aim to understand is \nof high importance in these types of studies. Among the most \nprevalent aging model organisms are Saccharomyces cerevisiae , \nCaenorhabditis elegans, Drosophila melanogaster, and Mus mus -\nculus . As a single-celled organism, S. cerevisiae is easily grown,",
              "title": "2018 - Genomic Instabilities, Cellular Senescence, and Aging In Vitro, In Vivo and Aging-Like Human Syndromes.pdf",
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              "text": "mammalian genes that affect aging than any other model organism. Aging in yeast is assayed primarily by\nmeasurement of replicative or chronological life span. Here, we review the genes and mechanisms implicated\nin these two aging model systems and key remaining issues that need to be addressed for their optimization.",
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              "text": "be more exaggerated in more distantly related species (such \nas the worm and mouse models). There are, however, simi -\nlarities between aged humans and aged model organisms; \nthey all tend to have decreasing overall fitness, and there -\nfore, studies using model organisms continue as they may \nbe at least indicative of some aging mechanisms in humans.\nExtensions to life span in model organisms are mostly \nassociated with disruption to fundamental metabolic path -",
              "title": "2012 - Genomics and Successful Aging Grounds for Renewed.pdf",
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              "text": "eukaryote model organisms, namely yeast, worms, ies,and sh, as well as mice and rats, to explore both genetic\nand environmental determinants of lifespan. While these\nshort-lived models have each yielded a number of fasci-\nnating ndings and insights into hypotheses surrounding\nextended lifespan and healthspan, they may also haveconstrained this complex, multifactorial eld to areas in\nwhich they are best suited, most notably short-term inter-",
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              "text": "et al., 2010 ). These effects require an intact germline, andTable 2. Repositories and Tools for Aging Research\nModels Description Link/Reference\nYeast Saccharomyces genome database http://www.yeastgenome.org/\npublished lifespan data http://lifespandb.sageweb.org/ (McCormick et al., 2015 )\nWilcoxon rank sum test to test signicance of lifespan\ndifferenceshttp://data.kaeberleinlab.org/scripts/ranksum.php\nyeast outgrowth data analyzer (YODA) for chronological\nlifespan assayshttp://yoda.sageweb.org/",
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              "text": "for molecular biological studies on aging. Although material \nfrom humans should be employed where possible, for prac- \ntical reasons animal model systems like rats and mice are \nindispensible. There is evidence that, provided their health sta- \ntus and husbandry is optimal, rodents age much in the same \nway as humans do (Burek 1978). For studying certain funda- \nmental processes, such as the occurrence of various types of \nDNA rearrangement, lower organisms and cell lines can also",
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              "text": "short life span, and fully sequenced genome (20 ,21). Despite being uni-\ncellular, yeast has been an excellent model to identify and characterize\nconserved basic biological processes, including aging. Yeast has beenextensively used to identify genes and interventions responsible for lifespan extension and to gain insights into the aging processes of all eu-\nkaryotic organisms. In parallel, over the years, studies on invertebrate\norganisms, such as Drosophila melanogaster (flies) and Caenorhabditis",
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              "content": "Yes, there are promising anti-aging therapies being developed based on genetic research. Several approaches are being explored:\n\n1. **Senolytic Drugs**: Research has shown that abolishing senescent cells through genetic manipulation or senolytic drugs can significantly halt biological aging in mice. Trials are underway to test the ability of senolytics to postpone age-associated pathologies in humans [3].\n\n2. **Genetic Discoveries in Aging**: A number of genes capable of altering the aging process have been identified in animal models and even in humans. This area of research is promising as it explores the association of multiple alleles with human exceptional longevity [6].\n\n3. **Manipulation of Aging-Related Genes**: There is potential in manipulating aging-related genes through diet, lifestyle, and pharmaceuticals to improve human health and develop drugs against age-related diseases such as cancer, heart disease, type 2 diabetes, obesity, and neurodegenerative diseases [8].\n\nThese developments indicate that genetic research is paving the way for potential anti-aging therapies.",
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              "text": "need to develop approaches and therapies targeting theaging process and age-related diseases (Butler et al.,2008). Delaying the process of aging, even slightly,would have profound social, medical and economic ben-efits (Olshansky et al., 2006; Butler et al., 2008). Forexample, slowing aging by a mere 7 years would cutmortality of age-related diseases by half at every age.Therefore, the potential benefits from research on thebasic biology and genetics of aging are unparalleled interms of improving quality",
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              "text": "raises the possibility of therapies to slow aging.  Therefore the discoveryof a gerontogene with even very rare mutations that increased longevitywould cause speculation about future trends in mortality.    However, thediscovery of such a gene would be relevant only to long-term (and, there-fore, very speculative) projections.\nProspective Epidemiologic Surveys that Include Genetic Information\nSome epidemiologic cohort studies of populations have collected",
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              "text": "Interestingly, when senescent cells are abolished either through genetic manipulation or via senolytic\ndrugs, biological aging is signicantly halted in mice [ 53,54]. Therefore, trials are now under way to\ntest the ability of senolytics to postpone age-associated pathologies in humans [ 55]. Notably, multi-\nple drugs are being pursued that either directly or indirectly impact DNA repair or the consequenceof DNA damage.\nFuture Prospects: Developing Interventions through DNA Repair",
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              "text": "5. Goldman DP, etal. Substantial health and economic returns from delayed aging may warrant \na new focus for medical research. Health Aff (Millwood). 2013;32(10):1698705.\n 6. Esplin ED, Oei L, Snyder MP.Personalized sequencing and the future of medicine: discov-\nery, diagnosis and defeat of disease. Pharmacogenomics. 2014;15(14):177190.\n 7. Marian AJ.Clinical applications of molecular genetic discoveries. Transl Res. 2016;168:614.",
              "title": "2020 - Clinical Genetics and Genomics of Aging.pdf",
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              "text": "J.L. Kirkland, Barriers to the Preclinical Development of Therapeutics that Target\nAging Mechanisms, J. Gerontol. A Biol. Sci. Med Sci. 71 (11) (2016) 1388 1394 .\n[2]D.J. Baker, B.G. Childs, M. Durik, M.E. Wijers, C.J. Sieben, J. Zhong, R.A. Saltness,\nK.B. Jeganathan, G.C. Verzosa, A. Pezeshki, K. Khazaie, J.D. Miller, J.M. van\nDeursen, Naturally occurringp16(Ink4a)-positive cells shorten healthy lifespan,\nNature 530 (7589) (2016) 184 189.",
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              "text": "series of recent breakthroughs, a number of genes capable ofaltering the aging process as a whole  or at least to a largedegree  have been identified in animal models and even a fewin humans (Finch & Ruvkun, 2001; de Magalhes, 2005; Kenyon,2005). Furthermore, multiple alleles have been examined fortheir association with human exceptional longevity (Vijg & Suh,2005). This is a fascinating and important area of research, yetthere are now so many genes being associated with aging andlongevity that keeping",
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              "text": "pharmaceutical and other interventions for human aging based on research that starts with the genomic information required to sustain adaptation, and thus health, in older fruit flies [36-39].   \n \nNaturally, any such genomic short-cut to reverse-engineering the evolution of slowed aging from fruit flies to humans is fraught with potential for error.  Such \nevolutionarily deep orthologies are sure to supply",
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              "text": "century. Manipulation of aging-related genes by diet,lifestyle, and pharmaceuticals could dramatically im-prove human health and could be used to develop drugsagainst age-related diseases such as cancer, heart dis-ease, type 2 diabetes, obesity, and neurodegenerativediseases. The hundreds of aging-related genes and genesrelated to CR already identified offer enormous oppor-tunities for target discovery (Fig. 2). Although aging-related genes cannot be modified in humans, under-standing how these can be",
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              "text": "[7] Hughes, S.E., Evason, K., Xiong, C., Kornfeld, K. Genetic and \npharmacological factors that influence reproductive aging in nema-\ntodes. PLoS Genet.  2007 , 3: e25. \n[8] Vijg, J., Campisi, J. Puzzles, promises and a cure for ageing. Na-\nture 2008 , 454: 1065-1071. \n[9] Rolland, Y., Czerwinski, S., Abellan Van Kan, G., Morley, J.E., \nCesari, M., Onder, G., Woo, J., Baumgartner, R., Pillard, F., Boirie, \nY., Chumlea, W.M., Vellas, B. Sarcopenia: its assessment, etiol-",
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              "text": "for the aging process during the 20th Century. Thissituation poses a fundamental challenge to anti-aging\nmedicine: how to develop effective therapies for a\ngenomically complex pathology. We propose such astrategy. As a rst step, we recommend the use of modelsystems in which signicant genetic intervention is not\nproscribed or impractical. Second, we propose that work",
              "title": "2002 - Pharmacology, Genomics, and the Evolutionary Biology.pdf",
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              "content": "Caloric restriction and diet have significant impacts on the genetics of aging through various mechanisms:\n\n1. **Gene Expression and Lifespan Extension**: Caloric restriction (CR) has been shown to delay age-related gene-expression changes in mice and, to some extent, in flies. This suggests that CR may influence the genetic pathways associated with aging, potentially contributing to lifespan extension [4].\n\n2. **Epigenetic and Post-Translational Mechanisms**: In calorie-restricted rats, transcriptome analysis indicates that CR involves epigenetic and post-translational mechanisms, which are implicated in neuroprotection and aging. These mechanisms may alter genome function to promote increased health and lifespan [3], [5].\n\n3. **mTOR Pathway**: Caloric restriction is associated with decelerating mTOR-driven aging, which is a significant pathway involved in cellular growth and metabolism. By modulating this pathway, CR may influence the genetic regulation of aging processes [5].\n\n4. **Genomic and Epigenetic Approaches**: Nutritional modulation, including caloric restriction, can impact aging through genomic and epigenetic approaches. This suggests that diet can influence the genetic and epigenetic landscape, potentially affecting the aging process [6].\n\nOverall, caloric restriction and diet can modulate genetic pathways and mechanisms that are crucial for aging, potentially leading to increased lifespan and improved health during aging.",
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              "text": "caloric restriction. Physiol. Genom. 17, 307 315.Van Remmen, H., Ward, W.F., Sabia, R.V ., Richardson, A., 1995. Gene\nexpression and protein degradation. In: Masoro, E.J. (Ed.), Handbook ofPhysiology. Section 11: Aging. Oxford University Press, New York, pp.\n171234.\nWeindruch, R., Walford, R.L., 1982. Dietary restriction in mice beginning at\n1 year of age: effect on life-span and spontaneous cancer incidence.Science 215, 1415 1418.S.R. Spindler / Mechanisms of Ageing and Development 126 (2005) 960 966 966",
              "title": "2005 - Rapid and reversible induction of the longevity, anticancer.pdf",
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              "text": "extension by dietary restriction.   Annu Rev Biochem  2008,\n77:727-54.\n8. Harper JM, Leathers CW, Austad SN: Does caloric restriction\nextend life iin wild mice?   Aging Cell  2006, 5:441-9.\n9. Forster MJ, Morris P, Sohal RS: Genotype and age influence the\neffect of caloric intake  on mortality in mice.   FASEB J  2003,\n17:690-2.\n10. Spindler SR, Mote PL: Screening candidate longevity therapeu-\ntics using gene-e xpression arrays.   Gerontology  2007, 53:306-21.",
              "title": "2009 - Genes and gene expression modules associated with caloric.pdf",
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              "text": "analysis in calorie-restricted rats implicates epigenetic and post-translational\nmechanisms in neuroprotection and aging. Genome Biol. 2015;16:285.\n21. Gillespie ZE, Pickering J, Eskiw CH. Better living through chemistry: caloric\nrestriction (CR) and CR mimetics alter genome function to promote\nincreased health and lifespan. Front Genet. 2016;7:142.\n22. Jiang T, Liebman SE, Lucia MS, Phillips CL, Levi M. Calorie restriction modulates\nrenal expression of sterol regulatory element binding proteins, lipid",
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              "text": "Calorie restriction, a dietary regimen that extends \nthe lifespan of numerous organisms, also delays the \nmajority of age-related gene-expression changes in \nmice and, to a certain extent, in flies45,50. It is currently \nunclear whether the effect of calorie restriction on gene \nexpression underlies its beneficial effect on lifespan or is merely a consequence thereof. Findings in yeast suggest \nthat there may be a causal link: Sir2 not only facilitates \nheterochromatin and promotes DNA stability, but is",
              "title": "2007 - The role of nuclear architecture.pdf",
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              "text": "Transcriptome analysis in calorie-restricted rats implicates epigenetic and post-\ntranslational mechanisms in neuroprotection and aging. Genome Biol. 16,2 8\n(2015).\n204. M. V. Blagosklonny, Calorie restriction: Decelerating mTOR-driven aging from cells to or-\nganisms (including humans). Cell Cycle 9, 683 688 (2010).\n205. D. K. Ingram, G. S. Roth, Calorie restriction mimetics: Can you have your cake and eat it,\ntoo? Ageing Res. Rev. 20,4 662 (2015).",
              "title": "2016 - Epigenetics and aging.pdf",
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              "text": "life-span extension by calorie restriction in Saccharomyces cerevisiae. Science\n289:21262128.\nMair W, Goymer P, Pletcher SD, and Partridge L (2003) Demography of dietary\nrestriction and death in Drosophila. Science 301:17311733.\nMasoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev\n126:913922.\nMathers JC (2006) Nutritional modulation of ageing: genomic and epigenetic ap-\nproaches. Mech Ageing Dev 127:584589.\nMeric-Bernstam F and Gonzalez-Angulo AM (2009) Targeting the mTOR signaling",
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              "text": "Keywords: Caloric restriction; Short-term; Longevity; Cancer; Microarray; Affymetrix\nAging is widely assumed to result from the gradual age-\nrelated accumulation of essentially irreversible moleculardamage. In this context, CR is often viewed as preventing orslowing the accumulation of such damage, thereby slowingthe process of aging ( Bokov et al., 2004 ). This view is\nintuitively appealing, as it provides a straightforwardexplanation for the stochastic nature of aging and the onset",
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              "text": "of short- and long-term caloric restriction effects in the liver of agingmice. Proc. Natl. Acad. Sci. U.S.A. 98, 10630 10635.Capstick, F., Brooks, B.A., Burns, C.M., Zilkens, R.R., Steinbeck, K.S.,\nYue, D.K., 1997. Very low calorie diet (VLCD): a useful alternative inthe treatment of the obese NIDDM patient. Diab. Res. Clin. Pract. 36,\n105111.\nChen, H., 2004. Gene expression by the anterior pituitary gland: effects of\nage and caloric restriction. Mol. Cell. Endocrinol. 222, 21 31.",
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