{
  "question": [
    "What recent discoveries have been made about the genetics of aging?",
    "How do epigenetic changes affect aging?",
    "What is the role of the gene FOXO3 in longevity?",
    "How does the environment interact with genes to influence aging?",
    "What are senescent cells and how do they contribute to aging?"
  ],
  "answer": [
    "Recent discoveries in the genetics of aging include the identification of numerous genes that can alter the aging process in animal models and humans. Genetic research has also found that immune-related pathways might be critically involved in aging. Specific genes, such as the apoE polymorphisms, have been found to influence both cardiovascular disease and Alzheimer's disease. Additionally, whole-genome sequencing in centenarians has revealed genetic variants associated with longevity. Studies have also shown that aging can be influenced by the interactions of multiple genes with each other and the environment.",
    "Epigenetic changes significantly influence the aging process. These changes occur at various levels, including alterations in DNA methylation, histone modifications, and noncoding RNA expression. They can lead to altered gene expression, reactivation of transposable elements, and genomic instability. These changes can also influence lifespan, with diet and environmental factors potentially altering epigenetic information. Importantly, these changes can be partially or fully reversible, suggesting potential avenues for therapeutic intervention in aging and age-associated diseases.",
    "FOXO3, a transcription factor, is associated with lifespan extension in various species, including humans. It is regulated by the insulin/IGF signaling pathway, the nutrient sensor AMPK, and stress. This gene controls the expression of genes involved in stress response, metabolism, immunity, and neuronal function. The FOXO3 variant has been associated with extreme longevity in humans, particularly in centenarians. It's also involved in the response to DNA damage and apoptosis. However, the exact molecular mechanisms affecting longevity require further study.",
    "The environment interacts with genes to influence aging through various factors such as diet, lifestyle, and exposure to certain elements. Environmental factors can trigger signaling pathways and modulate gene expression, which in turn can affect the aging process. For instance, diet can influence aging trajectories in humans, with early nutrition affecting late-life diseases. Environmental factors like caloric restriction and smoking can also impact the rate of aging. Furthermore, environmental exposure to elements like airborne particulates, smoking, and alcohol consumption can contribute to age-related diseases. Understanding these genome-environment interactions can help in the development of anti-aging therapies and interventions.",
    "Senescent cells are cells that have permanently stopped dividing but remain metabolically active. They are a hallmark of aging and accumulate in tissues over time. Senescent cells contribute to aging and age-related diseases through several mechanisms. They secrete pro-inflammatory factors and proteases that can alter the local tissue environment, promoting chronic inflammation and inducing senescence in healthy cells. This can lead to tissue dysfunction, chronic disease, and a decrease in the regenerative potential of stem cells. Additionally, senescent cells are resistant to apoptosis, leading to their accumulation and disruption of the tissue microenvironment."
  ],
  "contexts": [
    [
      "\t\n\nRecent developments on the genetics of aging can be seen as several streams of effort.In general, humans show a relatively modest (<50%) heritability of life spans (results obtained from twin studies discussed below).The apoE polymorphisms are remarkable for their influence on both cardiovascular disease and Alzheimer disease.In contrast, rare mutant genes with high penetrance cause these same diseases but with early onset and a major shortening of the life span.Shortlived laboratory models (fruit flies, nematodes, mice) are yielding rapid advances, with the discovery of mutants that increase life spans in association with altered metabolism, which leads to questions on the physiological organization of aging processes.Although these early findings do not show that a conserved genetic program actually controls aging processes across animal phylogeny, it is striking how frequently findings of metabolic rate, insulin signaling, and free radicals have emerged from very different approaches to aging in nematodes and mammals, for example.These findings hint that the genetic control of life span was already developed in the common ancestor of modern animals so that subsequent evolution of life spans was mediated by quantitative changes in the control of metabolism through insulin and the production of free radicals.",
      "\t\n\nBackground: Genetic research on longevity has provided important insights into the mechanism of aging and aging-related diseases.Pinpointing import genetic variants associated with aging could provide insights for aging research.\t\nBackground: Genetic research on longevity has provided important insights into the mechanism of aging and aging-related diseases.Pinpointing import genetic variants associated with aging could provide insights for aging research.Methods: We performed a whole-genome sequencing in 19 centenarians to establish the genetic basis of human longevity.Results: Using SKAT analysis, we found 41 significantly correlated genes in centenarians as compared to control genomes.Pathway enrichment analysis of these genes showed that immune-related pathways were enriched, suggesting that immune pathways might be critically involved in aging.HLA typing was next performed based on the whole-genome sequencing data obtained.We discovered that several HLA subtypes were significantly overrepresented.Conclusions: Our study indicated a new mechanism of longevity, suggesting potential genetic variants for further study.\tIntroduction\n\nWith the development of human genomics research, a large number of studies of the genetics of longevity have been conducted.Scientists from various countries have proposed many different theories concerning the mechanisms of aging from different perspectives, involving oxidative stress, energy metabolism, signal transduction pathways, immune response, etc. [1,2].These mechanisms interact with each other and are influenced by heredity to some degree [2,3].The identification of longevity-related biological markers is critical to an indepth understanding of the mechanisms of carrier protection against common disease and/or of the retardation of the process of aging.",
      "\t\nAging is a complex process affecting different species and individuals in different ways.Comparing genetic variation across species with their aging phenotypes will help understanding the molecular basis of aging and longevity.Although most studies on aging have so far focused on short-lived model organisms, recent comparisons of genomic, transcriptomic, and metabolomic data across lineages with different lifespans are unveiling molecular signatures associated with longevity.Here, we examine the relationship between genomic variation and maximum lifespan across primate species.We used two different approaches.First, we searched for parallel amino-acid mutations that co-occur with increases in longevity across the primate linage.Twenty-five such amino-acid variants were identified, several of which have been previously reported by studies with different experimental setups and in different model organisms.The genes harboring these mutations are mainly enriched in functional categories such as wound healing, blood coagulation, and cardiovascular disorders.We demonstrate that these pathways are highly enriched for pleiotropic effects, as predicted by the antagonistic pleiotropy theory of aging.A second approach was focused on changes in rates of protein evolution across the primate phylogeny.Using the phylogenetic generalized least squares, we show that some genes exhibit strong correlations between their evolutionary rates and longevity-associated traits.These include genes in the Sphingosine 1-phosphate pathway, PI3K signaling, and the Thrombin/protease-activated receptor pathway, among other cardiovascular processes.Together, these results shed light into human senescence patterns and underscore the power of comparative genomics to identify pathways related to aging and longevity.",
      "\t\n\nBefore the advent of NGS technologies, several scientists were interested in the study of allele variants associated with aging, but they were limited by the lack of aging rate biomarkers.Now with NGS technologies, these biomarkers have been emerged such as the epigenetic clock that is described in the DNA methylation sequencing section of this chapter.In this post-genomic era, different strategies have been developed in order to understand the genetic factors involved in aging [17].One strategy used is the study of aging in extreme longevity groups of people, called centenarians.Centenarians are a group that can reach an age above 100 years and has an incidence of 1 every 10,000 people [18].In a pioneering study using extreme longevity people (308 individuals belonging to 137 sibships showing extreme longevity), genome-wide scan analysis identified a region on chromosome 4 associated with extreme longevity [19] that corresponds to the microsomal transfer protein (MTP) [20], which is associated with abetalipoproteinemia and hypobeta lipoproteinemia in humans [21,22].Another approach to study the genetic factors involved in longevity consists in assessing allele frequencies from people of different ages, looking for those polymorphisms (SNPs) with enhanced allele frequencies in high-longevity individuals.Those alleles with diminished frequencies in aged individuals may be associated with age-related diseases.Using this approximation, an SNP that shifts isoleucine to valine was identified in the PKA-anchoring protein (AKAP2) gene.This polymorphism is associated with reduced longevity and cardiac disease [23].Genome-wide association studies (GWAS) have confirmed only three loci that affect longevity: FOXO3A, APOE, and an intergenic locus on chromosome 5q33.3[24][25][26].",
      "\t\n\nUnbiased genome-wide studies of longevity in S. cerevisiae and C. elegans have led to the identification of more than one hundred genes that determine life span in one or both organisms.Key pathways have been uncovered linking nutrient and growth factor cues to longevity.Quantitative measures of the degree to which aging is evolutionary conserved are now possible.A major challenge for the future is determining which of these genes play a similar role in human aging and using that information to develop therapies toward age-associated diseases.\t\nUnbiased genome-wide studies of longevity in S. cerevisiae and C. elegans have led to the identification of more than one hundred genes that determine life span in one or both organisms.Key pathways have been uncovered linking nutrient and growth factor cues to longevity.Quantitative measures of the degree to which aging is evolutionary conserved are now possible.A major challenge for the future is determining which of these genes play a similar role in human aging and using that information to develop therapies toward age-associated diseases.",
      "\t\n\nEven more disappointing result is that some genes predisposing to geriatric diseases discovered by GWAS appear to be not correlated with human longevity (Beekman et al. 2010;Deelen et al. 2011).This result questions whether findings obtained from GWAS may provide insights into the bio-genetic mechanisms underlying a healthy lifespan.In fact, this finding is very surprising because (1) genetic studies of non-human species have discovered numerous genes predisposing to aging-related processes (Cutler and Mattson 2006;Vijg and Suh 2005;Kenyon 2005;Johnson 2006;Greer and Brunet 2008), (2) nongenetic association studies show that the long-living individuals are typically in better health compared to the short-living individuals (Barzilai et al. 2003;Willcox et al. 2008b;Willcox et al. 2008a;Evert et al. 2003), and (3) candidate-gene studies (but not GWAS) document that the same genes can affect diseases and lifespan (Koropatnick et al. 2008;Kulminski et al. 2011).This is an apparent paradox which has to be carefully examined.A prominent geneticist and evolutionary biologist T. G. Dobzhansky asserts that \"nothing in biology makes sense except in the light of evolution. \"Evolution primarily maximizes fitness of individuals of reproductive age.The classical evolutionary biological theory of aging claims that aging occurs because of decline in the force of natural selection with age (Kirkwood and Austad 2000).Then, according to that theory, aging-related (senescent) phenotypes with post-reproductive manifestation are non-adaptive and subject to stochastic variation.Therefore, at a first glance evolution should not be relevant to senescent phenotypes (apart so-called grandmother hypothesis; Hawkes et al. 1998).Such phenotypes, however, can be caused by reproductive-age-related risk factors making, thus, evolution to be relevant to them (Vijg and Suh 2005;Di Rienzo and Hudson 2005;Drenos and Kirkwood 2010).",
      "\t\n\nIn this light, we pursued a genomic study of an alternate but related aging phenotype-healthy aging-in order to expose its potential to uncover genetic factors for protection against age-associated disease.It is important to differentiate longevity from our healthy aging phenotype, which, as we have defined it for our healthy aging cohort (Wellderly), attempts to understand the genetics of disease-free aging in humans without medical interventions.Toward this end, we performed whole-genome sequencing (WGS) of the Wellderly and compared their genetic characteristics to an ethnicity-matched population control.Our findings suggest that healthy aging is associated with a diseaseprotective genetic profile that overlaps with but differs from that observed in exceptional longevity cohorts.These findings include no enrichment of true longevity variants, a lower genetic risk from common susceptibility alleles for Alzheimer and coronary artery disease, and no decrease in the rate of rare pathogenic variants.We identify suggestive common and rare variant genetic associations that implicate genetic protection against cognitive decline in healthy aging.Our data are made available for the discovery of additional disease protective genetic factors by the research community.",
      "\t\n\nThe studies in lower animals made in recent years that have led to the view that genes are involved in aging have not revealed a reversal or arrest of the inexorable expression of molecular disorder that is the hallmark of aging.These studies are more accurately interpreted to have impact on our understanding of longevity determination because all of the experimental results have altered biological variables before the aging process begins.None of these studies in invertebrates has demonstrated that the manipulation of genes has slowed, stopped, or reversed recognized biomarkers of the aging process.",
      "\tGENETIC ANALYSIS OF LONGEVITY, OF AGING, AND OF AGE-SENSITIVE TRAITS IN MICE\n\nBiogerontology has just begun to benefit from the attention and skills of professional geneticists.Geneticists can attack problems of aging from several related but fundamentally distinct directions.Studies of rare mutations at individual loci, such as the Werner's syndrome locus WRN, whose mutant form produces, in middle-aged people, several of the diseases typically not seen until old age, can give attractive points of entry into the pathophysiology of age-related diseases.In mice there are now four reports of mutations-two naturally occurring and two artificially produced-that lead to impressive increases in mean and maximal longevity (Miskin and Masos, 1997;Brown-Borg et al., 1996;Miller, 1999;Migliaccio et al., 1999), and thus provide extremely valuable models for testing mechanistic ideas and the control of aging.Some of these, such as the dw/dw and df/df dwarfing mutations that affect levels of growth hormone and thyroid hormone, provide clues to endocrine-dependent pathways that could regulate age effects in multiple cells and tissues.The recent report (Migliaccio et al., 1999) that mouse life span can be extended by an induced mutation that diminishes cell susceptibility to apoptotic death after injury should stimulate new inquiries into the effects of altered cell turnover on age-dependent changes.Each of these mutations, however, is exceptionally rare in natural populations; despite their effect on longevity, perhaps mediated by a direct effect on aging, each of the mutations is likely to have, overall, a negative effect on reproductive success and thus fail to become fixed in natural mouse populations.\t\n\nAny discovery about the biological determinants of the rate of aging raises the possibility of therapies to slow aging.Therefore the discovery of a gerontogene with even very rare mutations that increased longevity would cause speculation about future trends in mortality.However, the discovery of such a gene would be relevant only to long-term (and, therefore, very speculative) projections.",
      "\t\n\nThe remarkable discoveries of the past 2 decades showing that single genes can regulate aging in model organisms demonstrate that aging can be genetically manipulated (Finch and Ruvkun, 2001;Kenyon, 2010).Hundreds of genes that modulate longevity have now been identified in model organisms (de Magalha es et al., 2009a).In some cases (e.g., in worms), mutations in single genes can extend lifespan by almost 10-fold (Ayyadevara et al., 2008).Nonetheless, aging is a complex process that derives not from single genes but from the interactions of multiple genes with each other and with the environment.Evidence from animal systems shows a major impact of the environment on aging, yet environmental manipulations of aging act through genes and proteins, usually by triggering signaling pathways and modulating gene expression.In fact, some genes have been shown in model organisms to have varying effects on lifespan depending on diet (Heikkinen et al., 2009).Genes that can regulate aging in model organisms cannot be directly applied to humans through genetic manipulations for numerous legal, ethical, and technical reasons.If we could understand how the environment modulates these aging-related genes, we might be able to create antiaging therapies applicable to humans, potentially through diet, lifestyle, and even pharmacological interventions.Therefore, understanding genome-environment interactions in the context of aging can be a powerful approach to identify attractive targets for drug design.",
      "\t\n\nHere, we review advances in genomic analysis within and across species to help refine the genetic foundations of age-associated diseases and longevity.As such, independent evolutionary occurrences of this species-specific lifespan change can empower comparative approaches to refine the shared mechanisms associating with longevity phenotypes.These evolutionary-refined gene sets can then be leveraged to focus statistical analysis within human cases of extreme longevity to discover core mechanisms of regulation.",
      "\t\n\nStudies in various models have revealed that genetic differences and somatic mutations underlie longevity, but non-genetic contributions also play a major role (Cournil and Kirkwood, 2001).Calorie restriction (Bordone and Guarente, 2005), lowering of basal metabolic rate (Ruggiero et al., 2008), upregulated stress response (Migliaccio et al., 1999), restoration of mi-tonuclear protein balance (Houtkooper et al., 2013), and reduced fertility (Westendorp and Kirkwood, 1998) have all been shown to correlate with lifespan extension.These observations illuminate the role of ''epi''-genetic mechanisms in modulating longevity pathways.",
      "\t\n\nWith modern genomic technologies and largescale data analysis methods, it is possible to sift through the genes of populations to find the loci that act to postpone aging. [3]There are uncertainties with the comparison of populations with different rates of aging.However, it is superior to experimental designs that only consider age-dependence or dietary-response, without determining causal mechanisms.",
      "\tGenAge: the aging gene database Philosophy and overview of resources\n\nIt is undisputed that genetic factors influence aging.In a remarkable series of recent breakthroughs, a number of genes capable of altering the aging process as a whole -or at least to a large degree -have been identified in animal models and even a few in humans (Finch & Ruvkun, 2001;de Magalhes, 2005;Kenyon, 2005).Furthermore, multiple alleles have been examined for their association with human exceptional longevity (Vijg & Suh, 2005).This is a fascinating and important area of research, yet there are now so many genes being associated with aging and longevity that keeping track of them all is becoming increasingly more difficult.Moreover, it is necessary now to study not only individual genes but their interactions with each other and with the environment, and how together genes give rise to a given phenotype: the so-called systems biology approach.To help researchers address these issues we created GenAge, a database of genes related to longevity and/or aging.",
      "\tConclusions and prospects\n\nOver the past two decades the human aging field has built up the necessary resources to study the biology of aging and longevity by establishing human populations with a diversity of designs.Meta-analyses integrating genetic and phenotypic datasets have successfully identified variants associated with a range of age-related traits and diseases.Despite these accomplishments, the number of novel leads contributing to human lifespan regulation is limited.Although positive regions of linkage and suggestive GWAS hits have been reported, the field has not yet identified the loci that explain the clustering of longevity in families and the variation in biological aging rate in the population.As for animal models, down-signaling of the IIS and mTOR pathway appeared to be relevant in humans.These findings are being followed up by molecular and physiological profiling using skin, fat and muscle tissue of long-lived family members and controls.Human studies now also include the response of nutrient sensing systems to the application of dietary and physical challenges.",
      "\t\n\nAlthough many theories have tried to explain aging, only few experimental advances were made prior to the last two decades.Since then rapid progress in the genetics of aging has been made in invertebrate models such as C. elegans and D. melanogaster, demonstrating the existence of regulatory pathways that control the rate of aging in these organisms [1][2][3][4][5][6][7][8][9][10][11][12][13][14].They include the insulin-like pathway, the Jun kinase pathway and the Sir2 deacetylase pathway.Moreover, it was rapidly shown that some of these pathways are conserved from yeast to humans."
    ],
    [
      "\t\n\nIn summary, our data suggest that epigenetic mechanisms can be crucial for normal aging and be important players responsible for neuron-specifi c changes accumulated during this process.",
      "\t\n\nTogether, the examples above provide strong evidence that epigenetics-both DNA methylation and histone modifications-influence aging and that these impacts can differ between the sexes.The data from human DNA methylation studies suggest that alterations to the epigenome occur at a slower pace in females than in males.The data from model organisms are limited; additional studies will be needed to get a clear picture of how age-associated epigenetic changes might contribute to the sex-differences in aging observed.\tEpigenetics\n\nIn addition to increased DNA damage, mutations, and telomere attrition, large-scale epigenetic changes have been associated with increased age in a number of species.The epigenetic changes seen in old compared to young animals are quite diverse and include changes in histone modifications, DNA methylation, and levels of chromatin remodeling and modifying enzymes [for recent reviews see (63) or (64)].Heterochromatin, the silent form of chromatin required for proper centromere and telomere function and repression of transposable elements, is often lost during aging.Increased transcriptional noise associated with epigenetic changes during aging has been proposed to cause at least some of the degenerative phenotypes observed with increased age.While a variety of epigenetic changes occur with age, the relative importance of each of these changes and the impact of sex and genetic background on these changes is poorly understood.",
      "\t\n\nFigure1.Epigenetics of aging and aging-related diseases.During aging, various epigenetic alterations occur including accumulation of histone variants, changes in chromatin accessibility mediated by chromatin remodeling complexes, loss of histones and heterochromatin, imbalance of activating/repressing histone modifications and aberrant expression/activity of miRNAs.These deregulations can affect transcription and, subsequently, translation, as well as the stabilization or degradation of molecular components.Consequently, these aberrant epigenetic processes can promote morbidities, which are frequently observed in the elderly populations, including inflammation, cancer, osteoporosis, neurodegenerative diseases, and diabetes.\t\n\nFigure1.Epigenetics of aging and aging-related diseases.During aging, various epigenetic alterations occur including accumulation of histone variants, changes in chromatin accessibility mediated by chromatin remodeling complexes, loss of histones and heterochromatin, imbalance of activating/repressing histone modifications and aberrant expression/activity of miRNAs.These deregulations can affect transcription and, subsequently, translation, as well as the stabilization or degradation of molecular components.Consequently, these aberrant epigenetic processes can promote morbidities, which are frequently observed in the elderly populations, including inflammation, cancer, osteoporosis, neurodegenerative diseases, and diabetes.",
      "\t\nOver the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells.Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process.These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence.The end result of epigenetic changes during aging is altered local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability.Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the life span of the offspring.Several important conclusions emerge from these studies: rather than being genetically predetermined, our life span is largely epigenetically determined; diet and other environmental influences can influence our life span by changing the epigenetic information; and inhibitors of epigenetic enzymes can influence life span of model organisms.These new findings provide better understanding of the mechanisms involved in aging.Given the reversible nature of epigenetic information, these studies highlight exciting avenues for therapeutic intervention in aging and age-associated diseases, including cancer.\t\n\nOver the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells.Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process.These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence.The end result of epigenetic changes during aging is altered local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability.Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the life span of the offspring.Several important conclusions emerge from these studies: rather than being genetically predetermined, our life span is largely epigenetically determined; diet and other environmental influences can influence our life span by changing the epigenetic information; and inhibitors of epigenetic enzymes can influence life span of model organisms.These new findings provide better understanding of the mechanisms involved in aging.Given the reversible nature of epigenetic information, these studies highlight exciting avenues for therapeutic intervention in aging and age-associated diseases, including cancer.\t\n\nFig. 1.Overview of epigenetic changes during aging.In young individuals, the cells within each cell type have a similar pattern of gene expression, determined in large part by each cell having similar epigenetic information.During aging, the epigenetic information changes sporadically in response to exogenous and endogenous factors.The resulting abnormal chromatin state is characterized by different histone variants being incorporated, altered DNA methylation patterns, and altered histone modification patterns, resulting in the recruitment of different chromatin modifiers.The abnormal chromatin state in old cells includes altered transcription patterns and transcriptional drift within the population.The abnormal chromatin state in old cells also leads to new transposable elements being inserted into the genome and genomic instability, including DNA mutations.\tTRANSGENERATIONAL EPIGENETIC CHANGES THAT AFFECT AGING\n\nAccording to biological dogma, genetics governs all the inherited traits across generations, and epigenetic modifications are reset upon passage through the germ line.However, over the years, this notion was challenged when evidence of epigenetic inheritance through meiosis became acknowledged in certain processes, such as flower symmetry and color in plants, or coat color and size in mice (198,199).Recently, longevity mediated by histone methylation was shown to be epigenetically inherited for several generations (198), implicating transgenerational epigenetic inheritance for the first time in the regulation of life span.Deficiencies in either of the three components of H3 K4me3 methylase complex (ASH-2, WDR-5, or SET-2), in only the parental generation, resulted in life span extension in C. elegans in the three subsequent generations, in the absence of methylase deficiency in these offsprings.However, only the parents with the deficiencies in the H3 K4me3 regulatory complex, and not their wild-type long-lived offspring, had reduced global H3 K4me3 levels.Hence, altered histone methylation per se was not transgenerationally inherited.Instead, microarray analysis revealed that there were persistent changes in gene expression throughout the generations upon manipulation of the H3 K4me3 regulatory complex in the parents (198), which could potentially be responsible for the transgenerational inheritance of long life span.Further experimentation is needed to identify the pathways responsible for the transgenerational inheritance of longevity and to explore whether this epigenetic memory is generalizable to other species.A useful approach to study the inheritance of aging phenotypes would be to follow the lead of a recent study examining epigenetic germ line inheritance of dietinduced obesity and insulin resistance in mice (200).This study used in vitro fertilization to ensure exclusive inheritance through the gametes and showed that the parental high-fat diet renders the offspring more susceptible to developing obesity and diabetes.It is tempting to speculate that this novel mode of inheritance may illustrate how epigenetics could have contributed to evolution, whereby the ancestors' environmental exposure determined the fate of the descendants.Given the intriguing nature of the subject, more studies will undoubtedly further explore this exciting direction in the near future.",
      "\tEpigenetic modifications, most commonly in the form of changes in the methylation\nstatus of DNA and biochemical modifications of core histones, have been linked to the\naging process and are increasingly recognized as part of normal and pathologic aging\nphysiology (Issa, 2003). Manel Estellers group studied the epigenetic profiles of 80\npairs of monozygotic twins ranging in age from 3-74 years old and found that older twins\nexhibited large differences in their overall content and distribution of 5-methylcytosine\nDNA and histone acetylation compared to young twins which were largely\nindistinguishable epigenetically (Fraga et al. , 2005).",
      "\t\n\nClearly, epigenetic changes are both responsive to and effectors of the aging process.With DNA damage and environmental stresses like inflammation leading to changes in chromatin, the epigenome clearly adapts to age-related changes in the genome and the local milieu.Perhaps the epigenome is a general sensor of cellular dysfunction, sensing metabolic and proteomic changes that accompany aging as well.However, the epigenome is also an effector of the aging process, enforcing different patterns of gene expression in old cells and young cells and, in many cases, resulting in cellular phenotypes associated with aging such as senescence and metaplasia (Martin, 2009).In that sense, the epigenome is rather like a lens through which genomic information is filtered (Figure 3), a lens that deteriorates with age because of both loss of integrity of genomic information and direct environmental stresses within and outside of the cell.Within the ''epigenome as lens'' metaphor, the process of rejuvenation is the restoration of a youthful state by actions on the epigenomic lens (Figure 3).The loss of integrity of the genomic information remains, but the rejuvenating interventions are sufficient to overcome and possibly reverse at least some of the agerelated epigenetic changes.Similarly, an altered epigenome and gene expression programs may also be able to reverse or compensate for some age-dependent biochemical changes, such as protein aggregation, macromolecular oxidation, and glycation, to maintain cellular functions (Douglas and Dillin, 2010).",
      "\tRole of Epigenetic Alterations\n\nA wide range of epigenetic alterations affects the cells during the life span, which may modulate vascular aging phenotypes. 138Epigenetic changes that may contribute to vascular aging processes involve alterations in DNA methylation patterns, posttranslational modification of histones, microRNAs (miRNAs), long noncoding RNAs, and chromatin remodeling.",
      "\tEpigenetics of aging\n\nIncreasing evidence supports a role for epigenetics in the biology of aging.X-inactivated genes in the mouse show an increased frequency of reactivation with aging, consistent with age-related epigenetic change [39,40].The frequency of epigenetic changes in mice may be one to two orders of magnitude greater than the rate of somatic DNA mutation [41].This fits with a role of epigenetics in late-onset disorders such as frailty, a syndrome of decreased resiliency and reserves, in which a mutually exacerbating cycle of declines across multiple systems results in negative energy balance, sarcopenia, and diminished strength and tolerance for exertion [42].Accumulation of DNA sequence changes might not occur at enough high rate during the lifespan to induce common disease, but epigenetic changes may occur at a frequency that could contribute to this effect.Very few studies have demonstrated epigenetic changes in humans with age due to technical and biosample limitations.A recent study has shown differences in local and global methylation by age by examining the similarity in methylation patterns between MZ twins aged 3 years old and MZ twins aged 50.Although these analyses were not in the same individuals (the same twins were not followed longitudinally), the similarity in methylation patterns between young twins compared to the dissimilar patterns among older twins argues strongly for age-related changes in the epigenome [43].Direct evidence comes from a recent study showing changes in DNA methylation in the same individual over time, described in more detail below.",
      "\tIntroduction\n\nEpigenetics is destined to change across the lifespan.Loss of global DNA methylation and promoter hypermethylation of several specific genes occur during aging.Epigenetics plays an important role in cellular senescence, human tumorigenesis, and several agerelated diseases (Fraga et al. 2007;Bollati et al. 2009;Kim et al. 2010;Choi et al. 2009;Moore et al. 2008;Rakyan et al. 2010;Chambers et al. 2007).Indeed, epigenomic alterations are now increasingly recognized as part of aging and its associated pathologic phenotype (Petronis 2010;Bellizzi et al. 2011).However, the role of epigenetics in the modulation of healthy aging and longevity has not been clearly studied in humans.",
      "\t\n\nEpigenetic changes linked to aging also impact specific diseases of aging, including cancer.While some age-associated epigenetic changes, such as increased abundance of histone modification H4K20me3 [10] and decreased H3K27me3 [38,39], may activate tumour suppressor mechanisms and prevent cancer, others may be tumour promoting.Like cancer, aged tissue has been reported to exhibit global DNA hypomethylation and more focal hypermethylation at CpG islands [10].Most notably, so-called bivalent gene promoters, marked with both activating H3K4me3 and repressing H3K27me3 (hence \"bivalent\") in embryonal stem (ES) cells, acquire DNA methylation in aged tissues and are also methylated and stably silenced in cancer [15][16][17][18][19].In ES cells, these bivalent-marked genes are thought to be poised for activation due to loss of the repressive H3K27me3 mark during stem and progenitor cell differentiation and development.By virtue of their pro-differentiation functions these genes tend to have tumour suppressor-like properties, meaning that their methylation and stable silencing may promote proliferation, self-renewal and malignancy.In the haematopoietic system, some CpG islands progressively increase methylation from young to old to neoplasia, namely myelodysplastic syndrome (MDS) and ultimately acute myeloid leukemia [40].Sf3b1, the mouse ortholog of a gene frequently mutated in human MDS, is methylated and underexpressed in aged mouse HSCs [36].Hence, age-associated methylation changes might predispose to transformation of aged cells by promoting silencing of tumour suppressor genes.\t\n\nAging is associated with changes to the epigenome [10,11].These changes include age-associated accumulation of histone variants, for example histone H3.3 in neurons and macroH2A in lung, liver and muscle, as well as other chromatin-associated proteins and changes to histone and DNA modifications [12][13][14].Aging also affects specific gene regulatory elements, such as enhancers, promoters and CpG islands [15][16][17][18][19][20][21][22][23].Underscoring the importance of such age-associated epigenetic changes, recent human studies have identified collections of specific CpGs whose age-associated change in methylation status in multiple tissues correlates strongly with chronological age.An advanced methylation age compared to actual chronological age is thought to reflect accelerated biological age and is linked to increased mortality [24][25][26][27][28].",
      "\t\n\nVasily V. Ashapkin and coworkers studied a direct relationship on how aging affects the epigenetic phenomenon.It has been established that hypermethylation of genes associated with promoter CpG islands, and hypomethylation of CpG poor genes, repeat sequences, transposable elements and intergenic genome sections occur during aging in mammals.Moreover, the methylation levels of certain CpG sites display strict correlation with age and can be used as \"epigenetic clock\" to predict biological age.Multi-substrate deacetylases SIRT1 and SIRT6 affect aging via locus-specific modulations of chromatin structure and activity of multiple regulatory proteins involved in aging.In addition, the random changes in DNA methylation or chromatin remodeling on aging lead to gradual increase in transcriptional noise introducing phenotypic variation among cells.Therefore, most likely based on the author's interpretation, such variation could become detrimental to tissue functioning, leading to highly variable progressive decline in organ functions during aging.Multiple data of age-dependent induction of NF-B regulated gene sets in various tissues suggest NF-B to be a master regulator of gene expression programs in mammalian aging.Vasily V. Ashapkin and coworkers summarized how the upregulation of multiple miRNAs occurs at mid age leading to downregulation of genes functionally involved in the control of intermediate metabolism, apoptosis, DNA repair, oxidative defense, and mitochondrial oxidative phosphorylation.Strong evidence shows that all epigenetic systems contribute to the life span control in various organisms.Similar to other cell systems, epigenome is prone to gradual degradation due to the genome damage, stressful agents and other aging factors.Critical analysis by Vasily V. Ashapkin et al., demonstrated that unlike mutations and other kinds of the genome damage, age-related epigenetic changes could be fully or partially reversed to a \"young\" aged state and requires more detailed analysis in the context of the aged associated genetic modification especially during the courses of the development and maturation of human diseases.",
      "\tEPIGENETIC REGULATION OF AGING\n\nIn addition to gene expression changes, the states of epigenetic modifications have emerged to be significantly important in modulating lifespan (see the accompanying review by Liu and Zhou in this issue [45]).Epigenetic modifications include DNA and histone modifications that are potentially heritable and reversible without changing the genetic code [46].With the application of recent high-throughput approaches, such as bisulfite sequencing, ChIP-seq or ChIPchip, etc. (Section 1), epigenetic controls have become wellrecognized as important regulatory mechanisms during the lifetime of an organism [46,47].For example, using the anti-O-GlcNAc ChIP-on-chip whole-genome tiling arrays on C.elegans, Love et al. [48] found 800 genes displaying differential cycling of O-GlcNAc which have functions closely related to aging.By examining DNA methylation at CpG sites throughout the human genome, Hernandez et al. [49] identified hundreds of CpG sites with levels of DNA methylation in the human brain highly correlated with chronological age.",
      "\tThe impact of epigenetic changes accumulated during aging on the aging phenotype\n\nA key question about the role of epigenetics in aging is whether epigenetic changes accumulated during aging have a causal role in establishing the aging phenotype or if the two phenomena are unrelated.To settle this matter, it is important to consider the region in the genome/chromatin where these changes occur.Changes occurring in non-coding sequences will potentially have a smaller biological impact than those occurring in coding sequences as modifications of the latter type generally involve changes in gene expression.It is also important to consider the cells and tissues in which these occur because epigenetic patterns are celland tissue-specific so that changes occurring in a specific cell or tissue would not necessarily imply the same functional consequences in different cells or tissues.\tEpigenetic changes during ontogenic development and aging\n\nThe relationship between epigenetics and aging was proposed many years ago (Table 1).A pioneering study by Berdyshev et al. (1967) showed that genomic global DNA methylation decreases with age in spawning humpbacked salmon.Subsequently, Vanyushin et al. (1973) also detected a global loss of cytosine methylation during aging in rat brain and heart.More recently, Wilson et al. (1987) confirmed the gradual loss of DNA methylation with age in various mouse tissues and in human bronchial epithelial cells.Similarly, Fuke et al. (2004) recently found an agedependent decrease in global methylation levels in human leukocytes.The definitive corroboration on intra-individual epigenetic variation over time in humans, was recently provided in a longitudinal study of DNA methylation patterns in which successive DNA samples were collected more than 10 years apart in more than 100 individuals (Bjornsson et al., 2008)."
    ],
    [
      "\t\n\nForkhead box O3a (mFoxo3a) is a transcription factor that is characterized by a fork head DNA-binding domain and has been associated with longevity in humans as well as with several cancers.Similar to the situation with mSirt1, no daily rhythm in expression was detected, and no differences among the ages of mice was determined (Figure 4B).",
      "\tWillcox 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 confirmed in German\ncentenarians. Proc Natl Acad Sci USA 106(8):27002705. doi:10. 1073/pnas.0809594106\n6.",
      "\tCross-species, cross-condition comparisons reveal shared longevity gene-expression signatures\n\nBased upon the hypothesis that longevity may be mediated by common sets of target genes that are effectors of upstream signaling pathways, and that the transcriptional targets of FOXO are likely to include direct mediators of increased longevity, the gene expression profiles resulting from MnSOD over-expression in Drosophila were compared to those of genes regulated by daf-2 in a daf-16 dependent manner in C. elegans [74,75].Remarkably, comparison of MnSOD target genes (genes whose expression was altered at both time points) to those genes regulated by daf-2 in a daf-16 dependent manner [74] revealed 25 genes (Figure 7) out of 3,542 unique fly genes with a stringent worm ortholog that were upregulated in both conditions, and this overlap is non-random (p << 0.001; Additional data file 5).When the list of MnSODregulated genes was expanded to include those genes altered at the same chronological age, but not the same 'physiological age', five additional conserved genes (CG15099, Jra, PHGPx, n-syb, Hrb98DE) were identified (Additional data file 7).\tMnSOD-regulated targets downstream of dFOXO\n\nThe cross-species, cross-condition comparison described above was aimed at identifying genes and processes that broadly mediate lifespan and, hence, are robust signatures of longevity mechanisms.However, certain downstream targets of dFOXO may have been missed by a comparison of stringent orthologs.In order to identify species specific MnSODregulated targets that act downstream of dFOXO as well as potential lifespan promoting mechanisms that might be unique to Drosophila, the transcriptional profile of MnSOD over-expression was compared to those resulting from altered insulin signaling in Drosophila.These comparisons are described in Additional data file 10.",
      "\t\n\nAge-associated changes in transcriptional factors represent a critical aspect of aging [2].Some conserved pro-longevity factors are FOXO/DAF-16, NRF/SKN-1, HSF-1, XBP-1, REST/SPR-4, and p53/CEP-1.FOXO/DAF-16 promotes longevity in a variety of species from worms to humans, and it is regulated by the insulin/IGF signaling pathway, the nutrient sensor AMPK, and stress [56,57].This transcription factor controls the expression of genes involved in stress response, metabolism, immunity, and neuronal function in a variety of organisms, and interestingly, the FOXO3 locus is associated with extreme longevity in humans (centenarians) [2,58,59].",
      "\t\n\nIncreasing S-adenosylmethionine (SAM) synthesis by FOXO-dependent glycine N methyltransferase (Gnmt) extends the lifespan in Drosophila and thus overexpression of Gnmt increases longevity, cooperatively with Notes: These transcripts are significantly affected more than two-fold (>LogFC 1) dietary restriction and lowered IIS [137].We see a 6.3 LogFC (increase) in Gnmt in three week diapausing flies (Additional file 3: Dataset S1, Additional file 9: Table S4).Another gene implicated in Drosophila lifespan extension is Tequila a multiple-domain serine protease known to be upregulated during infection [138].These authors showed that knockdown of Tequila in insulin producing cells increases longevity, probably due to decreased systemic IIS.",
      "\t\n\nIn addition to testing genes known to be associated with age-related diseases and phenotypes for association with longevity, genes known to promote longevity in model organisms have been examined in human populations.Mutations in insulin or insulinlike signalling pathway genes have been shown to extend lifespan in Caenorhabditis elegans [20], Drosophila melanogaster [21,22] and mice [23,24].The insulin-signalling pathway negatively regulates the forkhead (FOXO) transcription factor [25].When insulin or insulin-like growth factor signalling is low, FOXO is activated and lifespan extension occurs [26].An overrepresentation of rare insulin-like growth factor I receptor (IGFIR) mutations has been observed in centenarians [27].These mutations are associated with reduced activity of IGFIR as measured in transformed lymphocytes [27].",
      "\tGiannakou, M., M. Goss, and L. Partridge. 2008. Role of dFOXO in lifespan extension by\ndietary restriction in Drosophila melanogaster: Not required, but its activity modulates the\nresponse. Aging Cell 7:187198. Gillespie, J. H. 1973. Natural selection with varying selection coefficients: A haploid model. Genetical Research 21:115120. Greenwood, M., and J. O. Irwin. 1939. Biostatistics of senility. Human Biology 11:123. Guarente, L., and C. Kenyon. 2000. Genetic pathways that regulate aging in model organisms. Nature 408:255262. Haldane, J. B. S. 1941. New Paths in Genetics. London: Allen and Unwin. Hamilton, W. D. 1966. The moulding of senescence by natural selection.",
      "\t\n\nMuch work has been done implicating FOXO3 as an ageing gene in model organisms (Kenyon et al., 1993;Hwangbo et al., 2004), however we found the association in humans at that locus may be driven by expression of SESN1 (admittedly a finding restricted to peripheral blood tissue).SESN1 is a gene connected to the FOXO3 promoter via chromatin interactions and is involved in the response to reactive oxygen species and mTORC1 inhibition (Donlon et al., 2017).While finemapping studies have specifically found genetic variation within the locus causes differential expression of FOXO3 itself (Flachsbart et al., 2017;Grossi et al., 2018), this does not rule out the effect of co-expression of SESN1.More powered tissue-specific expression data and experimental work on SESN1 vs. FOXO3 could elucidate the causal mechanism.For now, results from model organisms seem to leave the preponderance of evidence for FOXO3.",
      "\tHe, R. Chen, J. S. Grove,\nK. Yano, K. H. Masaki, D. C. Willcox, B. Rodriguez, and\n291\nBIBLIOGRAPHY\nJ. D. Curb. Foxo3a genotype is strongly associated with human longevity. Proceedings of the National Academy of Sciences,\n105(37):1398713992, Sep 2008. [370] David Withers, Edward Kawas, Luke McCarthy, Benjamin Vandervalk, and Mark Wilkinson. Semantically-guided workow construction in taverna: The sadi and biomoby plug-ins. Leveraging Applications of Formal Methods, Verification, and Validation,\npage 301312, 2010.",
      "\t\n\nSeveral of the genes we identify have previously been shown to influence lifespan in experiments on model organisms.For example, knockouts of the orthologs of APOE, LDLR, CDKN2B, and RBM38 in mice shortens their lifespan [24][25][26][27] , while knockout of IGF1R has the opposite effect 28 .Similarly, overexpression of the FOXO3 orthologue in Drosophila melanogaster 29 and the SNCA orthologue in Caenorhabditis elegans 30 have shown to extend their respective lifespans.Many of our genes are also enriched for pathways previously related to ageing in eukaryotic model organisms, including genomic stability, cellular senescence, and nutrient sensing 31 .For example, FOXO3 and IGF1R are well-known players modulating survival in response to dietary restriction 32 , but we also highlight genes involved in the response to DNA damage and apoptosis, such as CDKN2B, USP28, E2F2, and BCL3.In addition to hallmarks discovered in model organisms, our results suggest that haem metabolism may play a role in human ageing.This pathway includes genes involved in processing haem and differentiation of erythroblasts 33 .Although the enrichment is largely driven by genes linked to the LDLR locus, genes linked to other loci of interest (such as FOXO3, CDKN2B, LINC02513) are involved in similar biological pathways: myeloid differentiation, erythrocyte homeostasis, and chemical homeostasis.\t\n\nImportantly, the genes we have highlighted show natural variation in the human population and some of them show altered levels of expression with increasing age, which makes them good candidates for therapeutic intervention.However, colocalisation of gene expression could be due to pleiotropy rather than causality, and there is a need to validate the effects of genetic variants in experimental models to confirm their role in disease aetiology.For example, we have found life-extending variants colocalise with decreased expression of FOXO3 in blood, which itself becomes increasingly expressed with increasing age, but experiments suggest the gene has many protective functions including detoxification of reactive oxygen species and DNA damage repair 15 .The observed inverse relationship between healthy life and FOXO3 expression may reflect healthy individuals have less oxidative damage and require less FOXO3 to mitigate this damage.\t\n\nTo determine the age-related expression of the identified cisand trans-acting genes, we performed a look-up in the dataset of Peters et al. 14 .This large dataset contains the associations of genes with age in whole blood, so we limited ourselves to the cis-and trans-acting genes identified in the whole-blood datasets.We found that FOXO3 expression is increased with age in this dataset, which is in line with the life-extending variant decreasing expression (Supplementary Data 6).Moreover, one cis-(ILF3) and two trans-acting genes (E2F2 and PDZK1IP1) in the LDLR locus show a similar effect (i.e.increased or decreased expression with age combined with the life-extending variant decreasing or increasing expression, respectively).The most interesting, however, seems to be the LINC02513 locus, which showed multiple trans-acting genes to be strongly downregulated with age, while the lead life-extending variant increases expression.LEF1, CCR7, and ABLIM1 even belong to the most significantly affected genes in the whole transcriptomic dataset.This indicates that this long intergenic non-protein coding RNA may serve as a master regulator of age-related transcription in whole blood.",
      "\t\n\nIt is thought that inflammatory triggers during aging may induce the loss of muscle cells and myonuclei during the process of human aging through an apoptotic mechanism (9,30).Indeed, several genes known to play a role in the regulation of apoptosis are components of the upregulated genes in this signature.The forkhead box O3A (FOXO3A) is one such gene upregulated in the aged signature.FOXO3A activation has been shown to induce apoptosis by activating the expression of genes necessary for cell death (14,48).Recent studies have shown the influence of FOXO transcription factors in the transcriptional activation of the ubiquitin protein ligase atrogin-1 during fasting-and glucocorticoid-induced atrophy (45).Welle et al. ( 59) also found increased FOXO1 mRNA in aged muscle using standard microarray analysis.Another recent study has shown that nuclei of aged muscle contain more FOXO1 than those of young muscle (35), and another shows increased atrogin mRNA in aged rats (39).Thus the FOXO proteins may very well play a role in the loss of muscle mass or muscle nuclei with aging.",
      "\tGiannakou, M., M. Goss, and L. Partridge. 2008. Role of dFOXO in lifespan extension by\ndietary restriction in Drosophila melanogaster: Not required, but its activity modulates the\nresponse. Aging Cell 7:187198. Gillespie, J. H. 1973. Natural selection with varying selection coefficients: A haploid model. Genetical Research 21:115120. Greenwood, M., and J. O. Irwin. 1939. Biostatistics of senility. Human Biology 11:123. Guarente, L., and C. Kenyon. 2000. Genetic pathways that regulate aging in model organisms. Nature 408:255262. Haldane, J. B. S. 1941. New Paths in Genetics. London: Allen and Unwin. Hamilton, W. D. 1966. The moulding of senescence by natural selection.",
      "\tB. Prioritizing Targets for Drug Discovery and Network Approaches\n\nGenome analyses from CR, aging, and human longevity genes provide biological targets for drug discovery.Screening natural products, existing drugs, and chemical libraries for molecules that affect \"druggable\" targets associated with aging may lead to compounds of therapeutic value.Given the hundreds of genes associated with aging and CR, however, it is important to identify the most promising targets.Integrating information from different datasets can help prioritize candidates (Fig. 2).It is interesting to note the two genes shown in model organisms to be related with aging, associated with human longevity, and essential to CR effects: IGF1R and FOXO3 (Fig. 2).IGFR1 is part of the insulin/ IGF1/GH pathway, the down-regulation of which has been associated with life-extension in several model systems and, as mentioned above, is already a target of pharmacological interventions.The FOXO transcription factor FOXO3 is a homolog of dFOXO and of daf-16, in which mutations suppress the life-extending effects of daf-2 (Kenyon et al., 1993).FOXO transcription factors are, in fact, part of the same insulin/IGF1/GH pathway (Fig. 1) that modulates lifespan across organisms (Kenyon, 2010).A strong association between FOXO3 and human longevity has been reported (Willcox et al., 2008) and subsequently validated in other populations (for review, see Kenyon, 2010).FOXO3 was also associated AGING GENES AS TARGETS FOR DRUG DISCOVERY with insulin levels and prevalence of cancer, heart disease, and type 2 diabetes (Willcox et al., 2008).Further work is necessary to understand the modulation of FOXO3 and its molecular mechanisms affecting longevity, but it is a promising target for drug development.",
      "\t\n\nThe effect of reduced IIS signalling on lifespan extension in model systems is through changes in gene expression and especially genes orthologous to human FOXO transcription factor, HSF-1, a heat shock transcription factor, and NFE2L2 [25], a xenobiotic response factor.The initial human candidate longevity gene studies were dominated by contradictory results [26].The more consistent evidence obtained by repeated observation in independent cohort studies for association to longevity was found for the APOE locus and, more recently, the FOXO1 and 3 [27 -29] and AKT1 loci [30].The effect size of the association of the FOXO3 variant appears to vary with the age of the cases, being most prominent in centenarians.Other intriguing observations that need to be replicated but fit observations in humans at the phenotype level discussed above were made in the Ashkenazi Jewish Centenarian Study in which a higher serum thyroid-stimulating hormone level and TSHR genetic variation marked the centenarian population [31].Recently, an association with longevity was found for genetic variation in RNA-editing genes [32].",
      "\t\n\nStudies have shown that ageing is accompanied by increased insulin/IGF signalling (IIS).FOXO (forkheadrelated transcription factor) is a transcription factor downstream of IIS that transcriptionally regulates longevityrelated genes such as hsp (heat-shock factor), inhibits ageing-related genes, and participates in feedback control of IIS (Hwangbo et al. 2004).However, the transcriptional activity of FOXO can be inhibited by increased IIS in ageing Drosophila.Several classic landmark studies have revealed that reduced signalling by insulin-like peptides through loss of CHICO (a Drosophila insulin receptor substrate protein) (Clancy et al. 2001) or mutation of InR (a Drosophila gene insulin-like receptor) (Tatar et al. 2001) can increase the lifespan of D. melanogaster (Tatar et al. 2003).Therefore, FOXO is considered an important contributor to extreme The data are presented as the mean  SEM. ***P < 0.001 versus 3-day-old Drosophila.n = 100 per group Fig. 5 Relative mRNA expression of genes in the longevity-regulating pathway, the peroxisome pathway, and the mTOR-signalling pathway in 3-day-old/30-day-old Drosophila.The relative mRNA levels of the genes were normalized to the levels of tubulin and are expressed as the fold changes relative to the levels in the 3-day group.n = 6 per group.The data are presented as the mean  SEM. *P < 0.05, **P < 0.01 versus 3-day-old Drosophila Fig. 6 Relative mRNA expression of predicted genes in sub-network 1 of Fig. 3 in 3-day-old/30-day-old Drosophila.The relative mRNA levels of key genes were normalized to the levels of tubulin and are expressed as the fold changes relative to the levels in the 3-day group.n = 6 per group.The data are presented as the mean  SEM. *P < 0.05, **P < 0.01 versus 3-day-old Drosophila longevity and health.Akt1, Bsk, Cat and P38b are functionally crucial in the FOXO-signalling pathway.Moreover, food-finding latency is shortened in old D. melanogaster with increased IIS, leading to lower fat reserves and lower starvation resistance (Egenriether et al. 2015).It was confirmed that starvation resistance was significantly reduced in 30-day-old D. melanogaster strain w 1118 , indicating that the 30-day-old D. melanogaster strain w 1118 showed a tendency toward senescence.",
      "\tFOXO3A and EXO1\n\nThe recently confirmed longevity gene FOXO3A (Anselmi et al., 2009;Flachsbart et al., 2009;Li et al., 2009;Pawlikowska et al., 2009;Soerensen et al., 2010;Willcox et al., 2008) and the longevity candidate EXO1 (Nebel et al., 2009) yielded comparatively high P CCA values of 0.007 and 0.035, respectively, and were therefore far too large to qualify for follow-up in stage 2.",
      "\t\n\nIn addition to testing genes known to be associated with age-related diseases and phenotypes for association with longevity, genes known to promote longevity in model organisms have been examined in human populations.Mutations in insulin or insulinlike signalling pathway genes have been shown to extend lifespan in Caenorhabditis elegans [20], Drosophila melanogaster [21,22] and mice [23,24].The insulin-signalling pathway negatively regulates the forkhead (FOXO) transcription factor [25].When insulin or insulin-like growth factor signalling is low, FOXO is activated and lifespan extension occurs [26].An overrepresentation of rare insulin-like growth factor I receptor (IGFIR) mutations has been observed in centenarians [27].These mutations are associated with reduced activity of IGFIR as measured in transformed lymphocytes [27]."
    ],
    [
      "\tINTRODUCTION\n\nHuman aging is affected by genes, life style, and environmental factors.The genetic contribution to average human aging can be modest with genes explaining 20-25% of the variability of human survival to the mid-eighties (Herskind et al., 1996;Fraser and Shavlik, 2001).By contrast, genetic factors may have greater impact on survival to the ninth through eleventh decades (Tan et al., 2008).Notably, exceptional longevity is rare and may involve biological mechanisms that differ from those implicated in usual human aging.",
      "\t\n\nIn addition, environmental factors influence the organism's ability to withstand the increase in entropy with aging: for example, caloric restriction and smoking can exert opposite effects on the rate of aging (Colman et al. 2009;Fraser and Shavlik 2001).Both protective alleles and a benevolent environment contribute to excess physiological capacity, which in turn indirectly determines an individual's healthy life span and longevity (Martin et al. 2007).The wellrecognized increase in variability with aging reflects the precarious balance between the stochastic destruction, environmental influences, and correcting effect of genes responsible for repair.",
      "\tStochasticity in Aging\n\nAging has a strong nongenetic and apparently nonenvironmental component.The nongenetic, nonenvironmental component of life span is evident from studies of isogenic organisms aged in the same environment, because the animals have different life spans.For example, individual isogenic C. elegans aged on the same Petri dish can have an order of magnitude difference in life span (36).This nongenetic, nonenvironmental component is comprised of experimentally difficult-to-track variables including chance events centered around the partitioning of resources and epigenetic information between cells, accumulated molecular damage, and differences in the perception of environmental or biological signals (37).These differences can begin as early as gametogenesis (38,39).Importantly, these differences affect the biological program of gene expression.",
      "\tIndividual Genotype\n\nIndividual differences in biological ageing may be due in part to the specific variations of the genotype but also genome-environment interactions [21,37].The maintenance of genomic stability and integrity is considered an essential factor required for cell viability and the overall longevity of an organism.The accumulation of physical damage is one of the leading causes of the ageing process.When considering oxidative damage as one of the causes of the damage of genetic material, these changes alter vital processes, such as replication, transcription, and translation, leading to genomic instability and personalized processes of ageing [38,39].",
      "\t\nThe underlying cause of aging remains one of the central mysteries of biology.Recent studies in several different systems suggest that not only may the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues.This Review focuses on the emerging biology of rejuvenation through the lens of epigenetic reprogramming.By defining youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges.",
      "\t\n\nAging is an extremely complex process associated with interplay of genetic, biochemical, and metabolic factors in an organism in a given environment.Although genetic studies of various animal models suggest that even a single-gene mutation can remarkably extend lifespan (Kenyon 2005;Johnson 2006) and, thus, modulate aging, no such genes are revealed in humans so far.Given that a human organism is a much more complex system than a model organism (Christensen et al. 2006), it is evident that genetic effects on the aging process should be mediated via coordinate action of a large number of inter-related processes (Kirkwood 2011).Coordinated function is rather relevant to complex biological (Soltow et al. 2010;Slagboom et al. 2011) and genetic (Bloss et al. 2011) networks than to individual genes.\t\n\nInvolvement of genes in a wide range of fundamental biological processes suggests also a broad role of these genes in regulating the aging-related phenotypes.",
      "\t\n\nGenes significantly affected by age (P  0.05) in both the active and sedentary environment",
      "\t\n\nGenes do not drive the aging process but by governing the levels of excess physiological capacity, repair, and turnover they indirectly determine potential longevity.There are no genes that specifically drive longevity but there are genes that govern biological processes that increase the likelihood of survival to reproductive maturity.The variations in excess physiological capacity, repair, and turnover accounts for the variations found in longevity both within and between species.",
      "\t\n\nIn the most general terms, three types of environmental factors can influence human health during aging: physical, chemical, and biological.Physical factors include temperature and solar radiation.Chemical factors from natural and biological sources include trace toxins (asbestos, lead, tobacco smoke), but also trace morphogens that can cause subtle abnormalities in development.Biological factors include diet and infectious organisms, but also stress from social interactions.We know little about the concentrations of a vast number of bioactive substances that may be present sporadically in the environment.It seems fair to say that our concept of the environment will evolve rapidly with new technical developments and may come to include multigenerational effects.For example, in the case of diabetes, the maternal physiological state existing before pregnancy can influence fetal growth.Moreover, the ovary acquires its full stock of eggs in the fetus: thus, the egg cell from which all of our cells stem was exposed to the environment of our maternal grandmother (Finch and Loehlin, 1998).The depth of the transgenerational environment is a completely obscure aspect of human experience.",
      "\t\n\nIn 2021, Science published a special issue entitled \"125 Questions: Exploration and Discovery.\" One of these 125 questions was \"Can we stop ourselves from aging? \"The U.S. National Institute on Aging (NIA) at the National Institutes of Health (NIH) states that \"aging is associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes.\" Although geneticists and epidemiologists have long debated the relative importance of the role played by genotype or the environment in the development of age-related diseases, it is apparent that both can play substantial roles in this process [6,7].However, most etiological studies have concentrated on the role of genotype and have considered the environment to play a secondary role.Nevertheless, an analysis of GBD data showed that nearly 50% of deaths worldwide are attributable to environmental exposure, primarily exposure to airborne particulates (including household air pollution and occupational exposure; 14% of all deaths), smoking and secondhand smoke (13%), plasma sodium concentrations (6%), and alcohol consumption (5%) [8].In contrast, a recent analysis of 28 chronic diseases in identical twins showed that the genetic-related risks of developing one of five age-related diseases were 33.3%, 10.6%, 36.3%, 19.5%, and 33.9% for AD, PD, CAD, COPD, and T2DM, respectively, with a mean of only 26% [9].The results of over 400 genome-wide association studies (GWASs) have also elucidated that the heritability of degenerative diseases is only approximately 10% [10,11].Consequently, nongenetic drivers, such as environmental factors, are now recognized as major risk factors for age-related diseases.The contributions of environmental factors to the development of age-related diseases can be revealed by analyses of all of the factors to which individuals are exposed in their life and the relationships between these exposures and age-related diseases [12,13].",
      "\t\n\nIn this review, we give an overview of the major environmental factors that modulate aging in animals, in particular those with underlying gene-environment interactions with potential for improving human health and drug discovery.Moreover, we provide a snapshot of the relevance of these to human biology and to antiaging applications in diet, industry, pharmacy, and healthcare.\t\n\nThe remarkable discoveries of the past 2 decades showing that single genes can regulate aging in model organisms demonstrate that aging can be genetically manipulated (Finch and Ruvkun, 2001;Kenyon, 2010).Hundreds of genes that modulate longevity have now been identified in model organisms (de Magalha es et al., 2009a).In some cases (e.g., in worms), mutations in single genes can extend lifespan by almost 10-fold (Ayyadevara et al., 2008).Nonetheless, aging is a complex process that derives not from single genes but from the interactions of multiple genes with each other and with the environment.Evidence from animal systems shows a major impact of the environment on aging, yet environmental manipulations of aging act through genes and proteins, usually by triggering signaling pathways and modulating gene expression.In fact, some genes have been shown in model organisms to have varying effects on lifespan depending on diet (Heikkinen et al., 2009).Genes that can regulate aging in model organisms cannot be directly applied to humans through genetic manipulations for numerous legal, ethical, and technical reasons.If we could understand how the environment modulates these aging-related genes, we might be able to create antiaging therapies applicable to humans, potentially through diet, lifestyle, and even pharmacological interventions.Therefore, understanding genome-environment interactions in the context of aging can be a powerful approach to identify attractive targets for drug design.\tIV. Genome-Environment Interactions as Targets for Dietary Interventions and Drug Discovery\n\n\"[It's] possible that we could change a human gene and double our life span. \"-CynthiaKenyon (Duncan, 2004) According to the GenAge database of aging-related genes (http://genomics.senescence.info/genes/),more than 700 genes have been identified that regulate lifespan in model organisms (de Magalha es et al., 2009a).Many of these genes and their associated pathways-such as the insulin/IGF1/GH pathway-have been shown to affect longevity across different model organisms (Kenyon, 2010).Therefore, at least some mechanisms of aging are evolutionarily conserved and may have potential therapeutic applications (Baur et al., 2006).For example, evidence suggests the use of lowered IGF signaling (e.g., by targeting IGF receptors) to treat certain age-related diseases such as cancer (Pollak et al., 2004), Alzheimer's disease (Cohen et al., 2009), and autoimmune diseases (Smith, 2010).Moreover, a number of genes and pathways associated with longevity and CR are part of nutrient-sensing pathways that also regulate growth and development, including the insulin/IGF1/GH pathway (Narasimhan et al., 2009;Stanfel et al., 2009).Many of these genes modulate the response to environmental signals, such as food availability, and act in signaling pathways that if understood can be targeted (Fig. 1).The genetic regulation of aging is therefore an emerging field with multiple applications in the human nutrition, cosmetic, and pharmaceutical industries.\tIII. Diet, Health, and Aging\n\nThe previous examples of how diet can modulate aging (e.g., social insects and the dauer pathway) are extreme cases not observed in humans.There is evidence, however, that the environment, and diet in particular, can influence aging trajectories in humans.Such environmental influences can be observed from an early age with long-lasting effects.Early nutrition can affect latelife diseases, such as cardiovascular disease (Barker and Osmond, 1986) and mortality (Gluckman et al., 2008;Hanson and Gluckman, 2008).Likewise, infections in early life can increase inflammatory levels and, together with diet, contribute to late-life diseases (Finch, 2010).The specific genes and mechanisms involved are largely unknown, but these epidemiological studies clearly demonstrate that early life environment can affect aging, and these effects are most likely mediated by geneenvironment interactions.",
      "\t\nAs our society is growing older, the consequences of aging have begun to gain particular attention.Improvement of quality of life at old age and prevention of age-associated diseases have become the main focus of the aging research.The process of aging in humans is complex and underlies multiple influences, with the probable involvement of heritable and various environmental factors.In particular, hormones are decisively involved in the generation of aging.Over time, important circulating hormones decline due to a reduced secretion of the pituitary, the adrenal glands and the gonads or due to an intercurrent disease.Among them, serum levels of growth factors and sexual steroids show significant aging-associated changes.Within the scope of the Explorative Project 'Genetic aetiology of human longevity' supported by the German National Genome Research Network 2 (NGFN-2) an in vitro model of human hormonal aging has been developed.Human SZ95 sebocytes were maintained under a hormone-substituted environment consisting of growth factors and sexual steroids in concentrations corresponding to those circulating in 20-and in 60-year-old women.Eight hundred and ninety-nine genes showed a differential expression in SZ95 sebocytes maintained under the 20-and 60-year-old hormone mixture, respectively.Among them genes were regulated which are involved in biological processes which are all hallmarks of aging.The most significantly altered signaling pathway identified was that of the transforming growth factor-b (TGF-b).A disturbed function of this cascade has been associated with tumorigenesis, i.e. in pancreatic, prostate, intestine, breast, and uterine cancer.Interestingly, genes expressed in signaling pathways operative in age-associated diseases such as Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and amyotrophic lateral sclerosis (ALS) were also identified.These data demonstrate that skin and its appendages may represent an adequate model for aging research.Hormones interact in a complex fashion, and aging may be partly attributed to the changes in their circulating blood levels.Furthermore, a disturbed hormone status may partially act towards the manifestation of neurodegenerative diseases.Thus, these results could be a basis for an integrated and interdisciplinary approach to the analysis of the aging process.",
      "\tTranslational\n\nA LTHOUGH there is much debate about the processes driving human aging, there is little doubt that genetic influences play a significant role (1).Humans clearly live very much longer than the currently favored laboratory models of aging, and such interspecies differences in reproductively 'fit' life span must have an inherited genetic foundation.Within human populations, environmental and behavioral exposures are important but at least a quarter of life expectancy variation in twin or family studies is attributable to inherited genetic or epigenetic factors (2).Age-related conditions such as type 2 diabetes, myocardial infarction, common cancers, and Alzheimer's disease (AD) typically have onsets after the fourth decade of life; \"successful\" agers delay these onsets until relatively late in life (3).Many aging traits and diseases show moderate heritability, including cardiovascular disease (CVD) (4) and impaired physical functioning (5), independent of known environmental risk factors.",
      "\t\n\nMany factors contribute to aging, including genes.This is the first article in a 10-part series that highlight some of what is known about the influence of genes on aging and emerging treatment options that may slow down or potentially reverse the aging process.The series will address \\genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown.Underpinning these factors are wear and tear on cells and aging as a result of inability to repair or replace these affected cells.These topics have been addressed in research, health magazines, and even by talk show hosts.There is even a LongevityMap website addressing significant and nonsignificant genetic association studies in aging across the human genome (http://genomics.senescence.info/longevity/).The series will address a scientific and clinical approach to genome-related aging topics.",
      "\t[PubMed: 18208581]\n3. de Magalhes JP, Wuttke D, Wood SH, Plank M & Vora C Genome-environment interactions that\nmodulate aging: Powerful targets for drug discovery. Pharmacol. Rev. 64, 88101 (2012). [PubMed:\n22090473]\n4. McDaid AFet al.Bayesian association scan reveals loci associated with human lifespan and linked\nbiomarkers. Nat. Commun. 8, 15842 (2017). [PubMed: 28748955]\n5. Fontana L & Partridge L Promoting health and longevity through diet: From model organisms to\nhumans. Cell 161, 106118 (2015). [PubMed: 25815989]\n6.",
      "\tGenAge: the aging gene database Philosophy and overview of resources\n\nIt is undisputed that genetic factors influence aging.In a remarkable series of recent breakthroughs, a number of genes capable of altering the aging process as a whole -or at least to a large degree -have been identified in animal models and even a few in humans (Finch & Ruvkun, 2001;de Magalhes, 2005;Kenyon, 2005).Furthermore, multiple alleles have been examined for their association with human exceptional longevity (Vijg & Suh, 2005).This is a fascinating and important area of research, yet there are now so many genes being associated with aging and longevity that keeping track of them all is becoming increasingly more difficult.Moreover, it is necessary now to study not only individual genes but their interactions with each other and with the environment, and how together genes give rise to a given phenotype: the so-called systems biology approach.To help researchers address these issues we created GenAge, a database of genes related to longevity and/or aging."
    ],
    [
      "\tSenescence and apoptosis are thought to contribute\nto aging and age-related disorders by decreasing the proliferative potential of progenitor\nstem cells, altering tissue regenerative capacity, decreasing tissue function and by altered\ntissue architecture and microenvironment caused by altered gene expression and secretion of\ninflammatory cytokines, growth factors, and proteases (Campisi 2003; Coppe et al. 2008;\nGarfinkel et al. 1994; Krtolica and Campisi 2002; Kuilman et al. 2008; Novakova et al. 2010; Ohtani and Hara 2013).",
      "\tIntroduction\n\nReplicative cellular senescence was first described as an irreversible growth arrest triggered by the accumulation of cell divisions (Hayflick & Moorhead, 1961).Subsequently it has emerged as a potent tumor suppression mechanism, and recent evidence points to important connections with aging (Collado et al., 2007;Baker et al., 2011).Progression of both cancer and aging includes a significant epigenetic component, such as changes in DNA methylation and chromatin remodeling (Decottignies & d'Adda di Fagagna, 2011).",
      "\t\nAccumulation of senescent cells over time contributes to aging and age-related diseases.However, what drives senescence in vivo is not clear.Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals.Ercc1 -/ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome.Ercc1 -/ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice.As a consequence, senescent cells accumulated more rapidly in Ercc1 -/ mice compared to repair-competent animals.However, the levels of DNA damage and\t\n\nAccumulation of senescent cells over time contributes to aging and age-related diseases.However, what drives senescence in vivo is not clear.Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals.Ercc1 -/ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome.Ercc1 -/ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice.As a consequence, senescent cells accumulated more rapidly in Ercc1 -/ mice compared to repair-competent animals.However, the levels of DNA damage and",
      "\t\n\nCellular senescence is one of the hallmarks of aging [87] and the accumulation of senescent cells in human tissues with age has been implicated as a driver of agingrelated diseases.Indeed, pharmacological approaches targeting senescent cells, like senolytics, are a major and timely area of research that could result in human clinical applications [5,88].It is imperative that we fully understand and deconstruct cellular senescence in order to target aging-related diseases.We hope that CellAge will help researchers understand the role that CS plays in aging and aging-related diseases and contributes to the development of drugs and strategies to ameliorate the detrimental effects of senescent cells.\tBackground\n\nIn the 1960s, Leonard Hayflick and Paul Moorhead demonstrated that human fibroblasts reached a stable proliferative growth arrest between their fortieth and sixtieth divisions [1].Such cells would enter an altered state of \"replicative senescence,\" subsisting in a nonproliferating, metabolically active phase with a distinct vacuolated morphology [2].This intrinsic form of senescence is driven by gradual replicative telomere erosion, eventually exposing an uncapped free double-stranded chromosome end and triggering a permanent DNA damage response [3,4].Additionally, acute premature senescence can occur as an antagonistic consequence of genomic, epigenomic, or proteomic damage, driven by oncogenic factors, oxidative stress, or radiation [5].Initially considered an evolutionary response to reduce mutation accrual and subsequent tumorigenesis, the pleiotropic nature of senescence has also been positively implicated in processes including embryogenesis [6,7], wound healing [8], and immune clearance [9,10].By contrast, the gradual accumulation and chronic persistence of senescent cells with time promotes deleterious effects that are considered to accelerate deterioration and hyperplasia in aging [11].Senescent cells secrete a cocktail of inflammatory and stromal regulators-denoted as the senescence-associated secretory phenotype, or SASP-which adversely impact neighboring cells, the surrounding extracellular matrix, and other structural components, resulting in chronic inflammation, the induction of senescence in healthy cells, and vulnerable tissue [12,13].Mice expressing transgenic INK-ATTAC, which induces apoptosis of p16-positive senescent cells, also have increased lifespan and improved healthspan [14].It is, therefore, no surprise that in recent years gerontology has heavily focused on the prevention or removal of senescent cells as a means to slow or stop aging and related pathologies [15][16][17].\t\n\nBackground: Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases.Many genes play a role in cellular senescence, yet a comprehensive understanding of its pathways is still lacking.",
      "\tJ\nAm Geriatr Soc 45: 482-8. Campisi J (2005). Senescent cells, tumor suppression, and organismal aging: good\ncitizens, bad neighbors. Cell 120: 513-22. Chambers SM, Boles NC, Lin KY, Tierney MP, Bowman TV, Bradfute SB et al (2007a). Hematopoietic Fingerprints: An Expression Database of Stem Cells and Their Progeny. Cell Stem Cell 1: 578-591. 128\nChambers SM, Shaw CA, Gatza C, Fisk CJ, Donehower LA, Goodell MA (2007b). Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 5: e201. Chen DJ, Nirodi CS (2007).\tMany stimuli\nhave been shown to induce the senescence response including, but not limited to,\ntelomere erosion, certain types of DNA damage, such as DNA breaks and oxidative\nlesions, epigenetic changes to chromatin organization, as well as exposure to ionizing\nirradiation (Campisi, 2005; Wang et al. , 2006). There is increasing evidence that\nsenescent cells accumulate with age. Senescence-associated -galactosidase, an enzyme\ncommonly used as a marker to detect the senescent phenotype, was shown to increase\nwith age in various mammalian tissues (Krtolica and Campisi, 2002).",
      "\tDissecting the Role of Cellular Senescence\n\nAnother hallmark of the ageing process is the induction and accumulation of cells in a senescent state [2].Cellular senescence is characterised by a stable arrest of the cell cycle while maintaining viability and metabolic activity.Senescent cells are also known to activate what is known as the senescence-associated secretory phenotype (SASP), which is a plethora of secreted factors comprising pro-inflammatory cytokines, chemokines, growth factors and matrix remodelling enzymes [88,89].Beyond telomere attrition in the case of replicative senescence, cellular senescence can be induced by many other cellular stresses like oncogene activation, loss of tumour suppressors, oxidative stress, persistent DNA damage response, ionising radiation and cytotoxic chemicals [88,89].Cellular senescence is thought to primarily act as a potent cell-autonomous tumour-suppressive mechanism by preventing the expansion of pre-malignant cells.However, research over the past decade has revealed that cellular senescence is a pleiotropic phenotype that has many context-dependent paracrine effects mediated by the SASP, such as aiding in tissue regeneration or, paradoxically, promoting tumorigenesis and the acquisition of malignancy [88][89][90].",
      "\t\n\nHow might apoptosis and senescence be antagonistically pleiotropic and contribute to aging?In the case of apoptosis, this process clearly is beneficial because it culls damaged or defective cells from tissues.However, it also eventually depletes tissues of cells and/or depletes stem cell reserves.In the case of senescence, this process is beneficial because it prevents the proliferation of preneoplastic, damaged or defective cells.However, senescent cells persist and adopt an altered phenotype in conjunction with the senescence growth arrest (Krtolica & Campisi, 2002;Rinehart & Torti, 1997).This phenotype includes the secretion of degradative enzymes, cytokines and growth factors that can perturb the surrounding tissue, leading to a loss of tissue homeostasis and development of age related pathologies.",
      "\t\n\nSeveral representative applications merit an integrative genomics approach to aging.One application is to determine which molecular and cellular factors responsible for the process of cellular senescence also underlie functional cognitive decline.Cellular senescence is an anticancer and wound healing mechanism characterized by arrested cellular proliferation and secretion of pro-inflammatory cytokines, chemokines, growth factors, and proteases (the senescence associated secretory phenotype, or SASP).Senescent cells accumulate with age in many tissues, where the SASP promotes chronic inflammation and exacerbates age-associated degeneration and hyperplasia.Recent evidence suggests that neurological aging and neurodegeneration are accompanied by an accumulation of secretory cells in brain, suggesting that cellular senescence may contribute to brain aging [2] through a shared mechanism.Overlapping mechanisms can be detected using functional genomics studies of both the biology of cellular senescence and cognitive aging.",
      "\t\n\nMarkers of senescence are detected at higher levels in tissues of older mice, humans, and other primates, including skin, liver, pancreatic islets, bone marrow, intestine, kidney, ovary, heart, and retina tissues.Senescent cells have altered metabolism (83).They also secrete proinflammatory factors and proteases able to alter the local tissue environment (84), providing plausible mechanisms by which senescent cells could promote aging and age-related degenerative diseases.Indeed, senescent cells are found at sites of numerous tissue-specific, age-related diseases, including atherosclerosis, osteoarthritis, sarcopenia, ulcer formation, cancer, and Alzheimer disease, which is suggestive of a causative role.However, the most convincing evidence that senescent cells cause aging comes from recent genetic (85) and pharmacologic studies (86) revealing that clearance of senescent cells can prevent or delay tissue dysfunction and extend health span.\t\n\nOf note, senescent cells accumulate with age in mammals (51).Compelling evidence shows that BER (47), NER (52), and NHEJ (53) are reduced in senescent cells relative to earlier passage nonsenescent cells.Thus, DNA repair may be reduced in a subset of cells that increase in number as an organism ages.Furthermore, genotoxic stress and ex vivo culture conditions induce senescence of cells, which impacts measurement of DNA repair.New tools to measure DNA repair in vivo are needed to determine if diminution of repair occurs in all cells and cell types as an organism ages.",
      "\tCellAge--a database of cell senescence genes\n\nCell senescence, also known as cellular senescence (CS), is the irreversible cessation of cell division of normally prolif-erating cells.Senescent cells accumulate as an organism ages and may be an important contributor to ageing and agerelated disease (34).However, the connection between organismal ageing and CS remains controversial (35).CellAge (http://genomics.senescence.info/cells/) is a new database of CS-associated genes, built to elucidate mechanisms of CS and its role in ageing.It is described here for the first time.",
      "\t\n\nInterestingly, when senescent cells are abolished either through genetic manipulation or via senolytic drugs, biological aging is significantly halted in mice [53,54].Therefore, trials are now under way to test the ability of senolytics to postpone age-associated pathologies in humans [55].Notably, multiple drugs are being pursued that either directly or indirectly impact DNA repair or the consequence of DNA damage.",
      "\t\n\nIrreparably damaged cells may also enter senescence.Senescence occurs in response to various insults, including genotoxic (e.g., oxidative) stress, telomere erosion, and oncogenic and replicative stress, which often occur as a result of persistent DNA lesions (111).Cellular senescence is elevated in many accelerated-aging mouse models and in a plethora of human age-associated pathologies, including osteoporosis, atherosclerosis, glomerular disease, diabetic venous ulcers, chronic obstructive pulmonary disease and emphysema, osteoarthritis, herniated intervertebral discs, and vascular calcification (112).Senescent cells are resistant to apoptosis and accumulate exponentially with age as a consequence of inefficient clearance.Unlike apoptotic tissues, senescent tissues largely retain their function.Therefore, senescence is thought to be antagonistically pleiotropic: It is beneficial early in life during development and later in life during wound healing after injury, but it becomes deleterious late in life, as the tissue increasingly accumulates nondividing senescent cells, which disturb the tissue microenvironment (113).This disruption is primarily caused by the secretion of a range of proinflammatory cyto-and chemokines, a state that has been defined as the senescence-associated secretory phenotype (SASP) (103).Major SASP factors include IL1, IL6, IL8, and various matrix metalloproteases (MMPs), all of which individually are thought to drive aging and age-related diseases.Thus, DNA damage is a major determinant in controlling cell death, stem cell exhaustion, and cellular senescence, which are considered important events in the development of age-related pathology and aging.",
      "\t\n\nAnother group of studies concentrated on a classic in vitro model for aging: the replicative senescence of primary cultured cells.The process of cellular senescence was first described in a seminal study by Hayflick and Moorhead (1961), who observed that normal human fibroblasts were able to enter a state of irreversible growth arrest after serial cultivation in vitro, while cancer cells were able to proliferate indefinitely.They proposed that there were some factors whose gradual loss through cell proliferation limited the number of cell divisions and that this process could contribute to organismal aging.It is still not completely clear how the latter might occur, but two main processes have been suggested: the accumulation of senescent cells in tissues and the limitation of regenerative potential of adult stem cell pools (Fraga et al., 2007).Wilson and Jones (1983) first showed how global DNA methylation also decreased with the number of cell passages in cultures of diploid fibroblasts of mice, hamsters and humans, while immortal cell lines had stable levels of methylation.The greatest loss of methylation was observed in mouse cells, which survived the fewest divisions, implying that the rate of methylation loss may be correlated with functional senescence.",
      "\t\n\nSenescence primarily occurs in the G0/G1 phase of the cell cycle and is a vital tumor suppressive mechanism that prevents passing damaged DNA to daughter cells or potential neoplastic transformation of damaged cells [144,145].Since being first described by Leonard Hayflick as an in vitro phenomenon in human fibroblasts, the potential role of senescence in in vivo aging and disease has been difficult to assess and somewhat controversial [146].However, recent studies have shown that senescent cells accumulate in normal arterial tissue over the lifespan of humans [147,148].Likewise, the accumulation of senescent cells has been reported in diseased tissues, such as atherosclerotic plaques [149] and abdominal aortic aneurysms [150].Baker et al. showed that clearance of senescent cells reversed aged and diseased phenotypes in a mouse model of accelerated aging [151].This important study strongly suggested that there were phenotypic properties of senescent cells that were problematic to tissues, and potentially contribute to aging and chronic disease.",
      "\tConcluding remarks and future perspectives\n\nAging research has rapidly expanded over the past two decades, with studies ranging from lifespan-extending  [68,69,71].However, when their effect on cell death and senescence leads to stem cell loss and tissue degeneration, they might contribute to aging [66,67]."
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