{
  "question": [
    "Why is it so diffuclut to map gene loci that control aging in humans?",
    "what causes the aging process",
    "What genes are associated with aging?",
    "what genetic factor are associated with aging",
    "which genes are involved in the aging process"
  ],
  "answer": [
    "Mapping gene loci that control aging in humans is difficult due to several reasons. Firstly, aging is a complex phenotype influenced by multiple genes and numerous different pathophysiological processes and diseases. Secondly, any common variation in genes associated with aging probably has a small effect, requiring large studies for identification. Thirdly, human studies face issues like environmental heterogeneity, genetic diversity, and lack of birth matched controls. Lastly, the influence of environmental factors and human-specific confounders like psychosocial, economic, and cultural factors can potentially mask purely biological aging mechanisms, making the analysis more difficult.",
    "The aging process is caused by a combination of factors including genetic influences, environmental conditions, and stochastic processes. It involves the accumulation of molecular damage, mutations, incomplete repair, and genetic programs. Other factors include wear and tear on cells, 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. Aging is also associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes.",
    "The genes associated with aging include the apolipoprotein E gene (APOE), the forkhead box O3A (FOXO3A) gene, HLA-DQA1/DRB1, LPA, CHRNA3/5, CDKN2A/B, SH2B3, and AKT1. Other genes involved in processes like growth and development, energy metabolism, oxidative stress, genomic stability maintenance, and neurocognition are also associated with aging.",
    "Several genetic factors are associated with aging. These include the APOE, FOXO3A, and CHRNA3/5 genes, as well as the CDKN2A/B, SH2B3, and MTP genes. Other factors include the HLA-DQA1/DRB1 and LPA regions, and the AKAP2 gene. Additionally, genes highly expressed in the brain, genes involved in neural development and function, and genes associated with autophagy have been linked to aging.",
    "The genes involved in the aging process include daf-16, daf-2, BAZ2B, HMGB4, NOC2L, RAI1, SIK1, SMARCA2, SPZ1, TBP, TRIP13, ZKSCAN1, DBH, TPO, LSS, GPER, HCRTR2, ATG2A, NEDD4L, PSMB1, UBXN4, USP6, EEF1A2, ITGB2, TUBB2C, WRN, ABCA7, AZGP1, CD36, DEGS2, PI4KA, SOAT2, APOE, LDLR, CDKN2B, RBM38, IGF1R, FOXO3, SNCA, NAP1L4, GAB2, QKI, and many others."
  ],
  "contexts": [
    [
      "Recent 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.",
      "FUTURE DIRECTIONS: HIGHER RESOLUTION DATA VIA HIGHER THROUGHPUT ASSAYS  One inescapable conclusion of the aggregate results of genome-wide studies of aging to date (see summary Table 1) is that we have not come close to saturating the number of potentially lifespan-altering genes in any organism.This is in no small part because directly generating survival curves is a relatively time-consuming process in most model organisms using current methods.There are several possible ways to address this.One way that has been tried is by attempting to find surrogate phenotypes [72,73,126] that can be screened more rapidly, or even scored under selection.Another is mining candidates from the many whole-genome expression profiles.Results to date with these have been very fruitful, but have not suggested that these methods alone will rapidly saturate our search for lifespan-and healthspan-altering genes in tractable model organisms.",
      "Chromosome mapping of genes that were differentially expressed in mice of different ages and/or in response to CR revealed a wide distribution of genes with some physical clustering of responsive genes within the genome.The latter findings are consistent with the concept that aging is a complex process and that evolutionary adaptations to aging, if they exist, may or may not involve geographic clustering of functionally related genes.",
      "Genetic linkage studies of long-lived human families identified a longevity locus while candidate gene approaches have been used to identify and confirm the association between specific variants in the FOXO3A gene and human longevity [3\u20137]. Genome-wide association studies have also been used to identify the association of APOE with life  123 Aging Clin Exp Res  span and have yielded insights into potential biological pathways and processes related to aging. Despite these successes, several problems are inherent in human longevity studies including potentially high degrees of environmental heterogeneity, genetic diversity, and lack of birth matched controls, among others [8].",
      "The aging process most certainly is under highly polygenic controls\u2026 This should not discourage us from pursuing a search for those loci which may be of profound importance to human aging as it ordinarily occurs in most human beings.",
      "In most experimentally modified animal model systems, single-gene mutations in many different genes have major life extension effects (Fontana et al., 2010;Kenyon, 2010).However, natural human and animal longevity is presumed to be a complex trait (Finch & Tanzi, 1997).In humans, both candidate gene and genome-wide genetic association approaches have been applied in an attempt to identify longevity loci.The frequency of genetic variants has been typically compared between nonagenarian cases and young controls, revealing loci at which genetic variants may contribute to a higher or lower probability of survival into old age.The initial candidate gene studies aimed at finding human longevity genes were dominated by contradictory results (Christensen et al., 2006).The more consistent evidence obtained by repeated observation in independent cohort studies for association with longevity has so far only been observed for three loci, the apolipoprotein E (APOE) locus (Schachter et al., 1994;Christensen et al., 2006), the FOXO3A locus (Willcox et al., 2008;Flachsbart et al., 2009;Pawlikowska et al., 2009;Soerensen et al., 2010), and the AKT1 locus (Pawlikowska et al., 2009).Thus, despite the expectation that longevity would be influenced by many genetic variants with small effect sizes, the effect of variants has consistently been shown in only three genes.",
      "1993), and gene expression microarrays (Pletcher et al. 2002). Given the ambiguities and limitations of large-effect mutant studies of aging, discussed earlier, those publications do not provide very useful evidence with respect to the question of the number of loci that affect aging. At present, the best answer to the question of the number of genes controlling aging is many (Rose and Long 2002), in keeping with the original expectations of evolutionary biologists. However, studies of the genetics of the experimental evolution of aging are now amenable to the application of genomic methods.",
      "Accepted Article  \u00a9 2013 The Authors Aging Cell \u00a9 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland over 90 years and 1,955 controls between 55 and 80 years did not reveal genome-wide significant loci (Newman et al., 2010) and neither did the analyses of all-cause mortality and survival free of major disease in this cohort (Walter et al., 2011).A smaller Dutch study of 403 nonagenarians and 1,670 controls younger than 65 years identified the APOE gene as a mortality locus (Deelen et al., 2011), which was confirmed in a German study of 763 long-lived individuals and 1,085 younger controls (Nebel et al., 2011) and a longitudinal study of 1,606 Danes showed that the effect size of this association increases at the highest ages (Jacobsen et al., 2010).Apparently, the influence of the common genetic variation on longevity is small which requires large meta-GWA studies for identification.Alternatively, rare genetic variants may play a more important role in longevity.Since the previous linkage studies showed contradictory results potentially due to heterogeneity in the longevity phenotype, it is expected that longevity is influenced by many private rare variants.",
      "Ageing is complex and takes a long time to study -a lifetime in fact.This makes it difficult to discern its causes, among the countless possibilities based on an individual's genes, behaviour or environment.While thousands of regions in an individual's genetic makeup are known to influence their risk of different diseases, those that affect how long they will live have proved harder to disentangle.Timmers et al. sought to pinpoint such regions, and then use this information to predict, based on their DNA, whether someone had a better or worse chance of living longer than average.",
      "Several explanations are possible for the lack of genomewide significant findings.First, mortality is arguably 1 of the most complex phenotypes, and several trajectories toward extreme old age have been identified (Evert et al., 2003).Multiple genes could mediate the aging process but would have their effects through numerous different patho-physiological processes and diseases that act as intermediate factors on the pathway to death (de Magalhaes et al., 2010).Therefore, any common variation in genes associated with aging probably has a small effect.",
      "Second, the largely negative findings of this and other studies contrast with the intriguing animal studies of longevity.Very large effects of single genes on lifespan have indeed been observed in laboratory animals, but humans often have several homologues of these genes which might significantly differ in function or compensate for mutated genes through redundant mechanisms (Kuningas et al., 2008).This could explain why our top findings did not include genes in these pathways found in animal models.Animal models also represent genetically homogenous populations and are exposed to controlled environmental influences.The lack of replication of animal model findings in humans suggests that the use of knockout animals may not provide the optimal approach to understanding the variation in survival in humans as interactions with environmental factors may obscure the associations and prevent the identification of loci in humans.",
      "The lack of success in the identification of genes related to aging in humans may be due to the complexity of the phenotype.One approach to investigate aging and longevity is to compare frequencies of genetic variants between nonagenarians or centenarians and the general population.This approach led to the discovery of an association between APOE (Deelen et al., 2011;Ewbank, 2007;Gerdes et al., 2000) and more recently FOXO3A (Anselmi et al., 2009;Flachsbart et al., 2009;Li et al., 2009a;Pawlikowska et al., 2009;Willcox et al., 2008) and human aging and longevity.However, a recent genome-wide association study (GWAS) of individuals reaching the age of 90 or older failed to identify genome-wide significant variants (Newman et al., 2010).",
      "In addition to timing differences, a small proportion of genes (10%-15%) exhibit opposite trends of expression changes with age in humans and macaques (Supplemental Fig. S13).Interestingly, such differences are ;1.5 times more common in aging than in development, an observation consistent with the lower strength of purifying selection on the gene regulation at old age (discussed below).These differences could also reflect extreme shifts in developmental timing between species, as well as technical artifacts.Future studies, using additional species and alternative methodology, are needed to address this issue.",
      "1993), and gene expression microarrays (Pletcher et al. 2002). Given the ambiguities and limitations of large-effect mutant studies of aging, discussed earlier, those publications do not provide very useful evidence with respect to the question of the number of loci that affect aging. At present, the best answer to the question of the number of genes controlling aging is many (Rose and Long 2002), in keeping with the original expectations of evolutionary biologists. However, studies of the genetics of the experimental evolution of aging are now amenable to the application of genomic methods.",
      "The 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 \u02dces 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.",
      "TRANSLATION OF LONGEVITY MODEL ORGANISMS AND CORE AGING PATHWAYS  Genetic studies on lifespan have proven to be challenging.While longevity is a defining trait for a given species, the lifespan of individuals is of limited heritability, making analyses more difficult.Exceptional human life span, although a rare phenotype, is likely multifactorial; refined analyses are required to obtain statistically robust genomic signatures of longevity (Zhang et al., 2020) and these have proven elusive.Unlike laboratory models, the effect of environmental variance cannot be controlled in human studies, potentially masking purely biological aging mechanisms.Even laboratory models cannot replicate the complex \"environment\" of humans; it includes psychosocial, economic, and cultural factors, rather than strictly biological.These human-specific confounders are difficult or impossible to target in traditional model organisms.Despite these limitations, experimentally tractable model organisms have proven invaluable in deciphering the purely genetic contribution to lifespan, including genes and pathways conserved across the tree of life.",
      "ANALYSIS OF HUMAN VARIATION IN THE GENETIC CONTROL OF LONGEVITY  Heritability studies have convincingly demonstrated that at least some fraction of human lifespan is heritable.In tandem, large-scale genome-wide association studies (GWAS) have identified numerous loci associated with age-related traits (Buniello et al., 2019).While genetic studies have functionally shown an inverse effect of multiple age-related, diseaseassociated variants on lifespan regulation, the number of well-replicated longevity-conferring variants remains limited to variants in APOE (ApoE \u03b52), and more recently, CDKN2A/B and IL6 (see Table 1).To date, studies in humans have been hampered by the specific phenotype definitions used, sample sizes of the extreme phenotypes, and modest heritability of the longevity-related traits (Breitbach et al., 2019).This is due to the complex interplay of biological and social factors involved in human aging, as well as the limited power of GWAS, which require sampling thousands of subjects to achieve statistical significance (Breitbach et al., 2019).Genetic studies of aging have also been hindered by an inconsistent use of definitions of aging (reviewed in Baghdadi et al., 2020).The two main ways of conducting research on the genetics of longevity in human populations are by studying (i) the lifespan (continuous trait, years lived) and (ii) the longevity (dichotomous trait, i.e., being among the longest-lived individuals within a specific population).These complexities have limited the resolution and capability of broad association studies of human longevity.Importantly, these genomic analyses focus on a shift of survival in a population; these variables may be genetically distinct from the mechanisms establishing potential for longevity overall (Figure 1A).We argue that an understanding of this shift in lifespan as well as genetic mechanisms of regulating a species specific 'set points' (Figure 1B) will aid in the conceptual distinction of aging and longevity in humans.",
      "With 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.",
      "Most of the human candidate gene studies were performed in cross-sectional designs (Box 1 and Fig. 1), comparing allele frequencies of potential longevity loci between highly aged individuals and young controls.The candidate gene studies based on single genes have pointed a role for genes involved in, e.g., GH/insulin/IGF-1 signaling, immune regulation, and lipoprotein metabolism (Supporting Information Table S1), although most of these results have not (yet) been confirmed in sufficient independent studies.The most convincing human longevity loci today are APOE and FOXO3A which have frequently been associated with longevity in cross-sectional studies (see for a review [26]) and survival in prospective studies [27][28][29] (Fig. 3).APOE encodes the protein apolipoprotein E which seems to play a role in e.g., lipoprotein metabolism, cognitive function, and immune regulation [30].FOXO3A encodes the protein forkhead box O3 which acts as a transcription factor for many different genes involved in processes like apoptosis and oxidative stress [31].",
      "Conclusions and prospects  Over 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."
    ],
    [
      "There are multiple definitions of the aging process.Aging may be perceived as the random, systemic loss of molecular fidelity that, after reproductive maturity, accumulates to levels that eventually exceed tissue repair, turnover, or maintenance capacity (Hayflick 2004).The underlying molecular mechanisms of aging remain a subject of debates (de Magalhaes et al. 2009): tissue deterioration might not be programmed, being just a function of increase in entropy (Hayflick 2004).No genes are necessary to drive a stochastic process; however, there are genes that act to prevent an organism from destruction and disorganization.It may be due to the absence of specific disease-causing alleles or due to the presence of favorable alleles (Halaschek-Wiener et al. 2009).These genes may inhibit entropy, regulate inflammation, maintain DNA repair (such as telomere maintenance factors), or provide antioxidant functions (e.g., antagonists of reactive oxygen species).As healthy cells adapt to degeneration, differential expression of genes with age may indicate a transcriptional response to aging rather than a deleterious mechanism of aging per se (de Magalhaes et al. 2009).It might be postulated that there exist alleles that confer a pleiotropic effect on structure and function during aging (Lunetta et al. 2007).These alleles should regulate the ability of an organism to withstand challenging endogenous and exogenous influences.",
      "Why does ageing evolve? The intrinsic decline in function that occurs during ageing appears to be caused by the accumulation of damage, particularly at the molecular level.As far as we know, no genes have evolved specifically because they cause damage to accumulate, and the evolution of ageing can therefore be understood only as a side-effect of other causes of evolutionary change.The mechanisms by which ageing can evolve were first elucidated by J.B.S. Haldane [14], P.B. Medawar [15] and G.C. Williams [16].Extrinsic hazards from disease, predation and accidents mean that even potentially immortal organisms will die.Genetic effects that become apparent only later in life encounter a reduced force of natural selection, because not all their bearers will survive to express them.Haldane pointed out that late-onset genetic diseases in humans, such as Huntington's disease, encounter only weak selection, because most reproduction is complete by the age of onset [14].Ageing could therefore result from the accumulation under mutation pressure of age-specific, deleterious mutations.In addition, if some mutations have pleiotropic effects, with beneficial effects in youth, such as high fecundity, but also with a higher subsequent rate of ageing, then they could be incorporated into the population by natural selection, which will act more strongly on the early, beneficial effect.Thus, variation in the rate of ageing would result from the readjustment of a tradeoff between youthful benefits and the subsequent rate of ageing.Both processes imply that faster ageing will evolve where the extrinsic hazard to adults is greatest, a hypothesis in general supported by the data [1,2,17].",
      "A. Theories  In looking back at the development of aging studies, we can see that it did not follow a straight or logical course.On the contrary, it can be compared with the flow of several convergent streams winding in their course.To date, numerous proposals have been made for the paradigm of aging.These include Hayflick's contributions (153) on programmed cellular incapacitation derived from flbroblast studies, a decrease in immunologic response, deleterious endocrinological changes, nuclear somatic gene mutation, mitochondrial somatic gene mutation, oxygen free radical damage to proteins and nucleic acids, molecular instabilities, molecular cross-linking, glycation reactions, and so on.There is little doubt that many of these factors contribute to the overall aging, but what are primary causes, and what are secondary outcomes?",
      "Ageing Is Adjusted by Genetic, Environmental, and Stochastic Processes  Enough evidence suggests that ageing is the result of different events such as molecular damage, mutations, incomplete repair, genetic programs, and continued development, among others [16].These events, in turn, are caused by genetic factors, environmental conditions, and even stochastic factors, which are mentioned below in this chapter.",
      "Different stochastic theories of ageing focus on specific mechanisms that may lead to ageing.The catastrophic error theory poses that the accumulation of errors in protein synthesis causes damage in cell function.The theory of cross-linking holds this process between proteins and other macromolecules responsible for ageing, while the theory of free radicals suggests that ageing is the result of inadequate protection against cell and tissue damage by free radicals and oxidative stress throughout life.Finally, the wear-and-tear theory poses that the cumulative damage that eventually leads to ageing and death is, in fact, the result of the continuous functioning of vital processes, during which stochastic errors gradually arise.",
      "Introduction  Aging is a natural and irreversible process characterized by a progressive decay in physiological, biochemical, and structural functions of individuals.Aging is a multifactorial process that can be affected by two main factors: environmental and genetic.Environmental factors are nutrition, pathologies, pollution exposure, physical activity, and microbiota, while genetic factors are issues that have been associated with antioxidant and DNA damage responses, the fidelity of genetic information transfer, the efficiency of protein degradation, the extent of cellular responsiveness to stress, the mechanisms of epigenetic regulation, and the ability to elongate telomeres.All of them can determine how fast we age.Traditionally, aging studies had used several model organisms, from yeast to mammals, especially rodents (rats and mice).Most of the studies are made under controlled conditions, where only a few variables are observed, and the subjects are members of the same strain with the same genetic backgrounds or the same mutations.The information that so far has been obtained about aging has helped us to describe different factors that influence this process and that are the fundamental concepts of the various theories of aging.However, these theories do not fully explain the aging process in the different models of aging study.This is the case of the study of aging in humans, where it is very difficult to control the environmental and genetic variables.That is why issues haven't been solved such as the following: How does time influence aging?When do we start to age?How do we know we are old?Is it possible to delay aging?Those and more questions are the cornerstones for aging studies.Biological aging has been associated with the decrease in the repair and regeneration capacity of tissues and organs; it is a time-dependent process.This reduction can be observed by an increase in the acquisition of diseases and functional and reproductive disability, which eventually lead to death.On the other hand, it has been observed that in humans, people with the same chronological age exhibit different trajectories in the decrease of physiological functions associated with biological aging and what complicates the understanding of the molecular and physiological phenomena that drive the complex and multifactorial processes that underlie biological aging in humans.",
      "The 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.",
      "Aging does not happen in a vacuum.Aging must be the result of changes that occur in molecules that have existed at one time with no age changes.It is the state of these pre-existing molecules that governs longevity determination.The pre-existing state is, as I have already described, maintained by repair and turnover systems that themselves eventually succumb to irreparable age changes.Longevity determination is the state of all molecules prior to succumbing to irreparable loss of molecular structure.",
      "Biological aging is more than simply the occurrence of random changes in molecules.It also includes the role of the many repair systems found within cells.Thus, a more complete, but less concise, explanation of the first causes of aging in biological systems is the following:",
      "U  nderstanding the deleterious processes that cause aging has been a human endeavor ever since we figured out that we grew old and that we didn't like it.Many hypotheses have been proposed to explain the root cause of aging (1).One broad-based hypothesis is that generalized homeostatic failure leads to age-related decline.Although notions of time-and use-related deterioration may be applicable to mechanical objects, they fall short as analogies to biological systems because energy input should theoretically maintain living systems indefinitely.Yet, despite the regenerative potential of biological organisms, progressive deterioration accompanies postmaturational aging.That the organism's repair capabilities cannot keep up with wear and tear is, according to evolutionary theory, explained by the inevitable declining force of natural selection with age.According to this reasoning, there is no selective advantage to maintaining somatic cells in perfect order much beyond reproductive maturation (1).Hence, a long life depends on the timing of maturation and the quality of somatic cell maintenance.",
      "Wear and tear on the DNA often has been touted as a possible basis for our progressive age-related decline.Supporting this notion is the work of de Boer et al. (2) reported on page 1276 of this week's issue.They reveal important evidence for imperfect genome maintenance of DNA damage as a possible causal factor in aging.Harman, with his \"free radical theory of aging\" (3), was the first to propose that metabolic by-products called reactive oxygen species (ROS) continually damage cellular macromolecules, including DNA.Incomplete repair of such damage would lead to its accumulation over time and eventually result in age-related deterioration.A number of observations support the free radical theory, including the discovery that dietary restriction delays aging and extends life-span in a wide range of rodents and other species, possibly by reducing free radical damage.The notion that genomic DNA could be a major target of continual free radical attack over time is supported by the recent observation that genetic lesions accumulate with age and that dietary restriction reduces this accumulation in rodents (4).In addition, deletion of p66 shc , a signaling protein that maintains oxidant levels, increases resistance to oxidative damage and extends the life-span of mice (5).",
      "Instead, aging is expected to be a pervasive failure of adaptation across most, if not all, of the physiological mechanisms that sustain survival and reproduction among young individuals. For this reason, evolutionary biologists have generally been skeptical of proposals that attribute \u201cthe cause of aging\u201d to any one physiological mechanism or gene for aging or programmed death. Although common genetic pathways might be identified that contribute to aging among a variety of organisms (cf.",
      "Background  Aging is a complex process characterized by the progressive degeneration of a healthy phenotype and correlated with a decline in the ability to withstand cellular stress and damage.The subject of investigation for decades, the underlying molecular genetic causes of and responses to aging remain an area of active study.Research from model systems has characterized a range of physiological and molecular phenotypes associated with aging.These include genomic instability caused by accumulation of DNA damage, dysregulation of repair mechanisms, and telomere attrition; epigenetic alterations; dysregulation of transcription; loss of proteostasis; cellular senescence; and deregulated nutrient sensing, metabolic pathways, and energy use (reviewed in [1]).Separating causation from correlation between these phenotypes and aging remains a challenge, however.",
      "Introduction  Understanding what actually causes ageing remains admittedly a fundamental and fascinating problem in biology [1].Experimental data accumulated in the last three decades have led to the identification of various environmental and genetic factors, as well as chemical substances that influence lifespan in divergent eukaryotic species [1,2].Organisms normally age faster and hence live shorter under stress conditions that can lead to the generation of DNA mutations and, often as a consequence of mutations, damaged cytoplasmic constituents (including injured proteins, lipids, carbohydrates and organelles).Such types of damage can interfere with cellular functioning; thereby, they should be eliminated by effective repair and self-cleaning mechanisms to maintain cellular homeostasis.These mechanisms include DNA repair pathways, molecular chaperons, as well as the proteasome-ubiquitin system and lysosome-mediated autophagy, the main forms of cellular self-degradation [3].This has led to the attractive model that the gradual, lifelong accumulation of unrepaired cellular damage drives the ageing process and determines the incidence of age-related fatal diseases [4,5].",
      "In conclusion, aging may not be primarily due to damage accumulating from the basic biochemical reactions that make up life but rather the result of the developmental program or of changes brought about by it.Our hypothesis is that the timing of development regulates the rate of aging among mammals, with a subset of developmental mechanisms determining the pace and causing most agerelated changes.Maybe people change as they grow old due to the same mechanisms that drive changes throughout the earlier stages in life.",
      "Instead, aging is expected to be a pervasive failure of adaptation across most, if not all, of the physiological mechanisms that sustain survival and reproduction among young individuals. For this reason, evolutionary biologists have generally been skeptical of proposals that attribute \u201cthe cause of aging\u201d to any one physiological mechanism or gene for aging or programmed death. Although common genetic pathways might be identified that contribute to aging among a variety of organisms (cf.",
      "In 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].",
      "Introduction  The fundamental manifestation of the aging process is a progressive decline in the functional maintenance of tissue homeostasis and an increasing propensity to degenerative diseases and death [1].It has attracted significant interest to study the underlying mechanisms of aging, and many theories have been put forward to explain the phenomenon of aging.There is an emerging consensus that aging is a multifactorial process, which is genetically determined and influenced epigenetically by environment [2].Most aging theories postulate a single physiological cause of aging, and likely these theories are correct to a certain degree and in certain aspects of aging.",
      "Many 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.",
      "Trying to explain aging in terms of a singular process would be in conflict with evolutionary theory.Even if loss of genome sequence integrity was the most conserved cause of aging, already active in the first replicators (Vijg, 2007), natural selection would allow a multitude of mutations with late adverse effects to accumulate in the germline, many of which would be positively selected for because of their beneficial effects early in life (Williams, 1957), In this respect, somatic mutation accumulation could be a conserved, inevitable cause of aging but superposed on multiple other processes that usually cause the earlier demise of an individual."
    ],
    [
      "Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.",
      "Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.",
      "Recent 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.",
      "Studies revealed from 300 to 750 genes related to longevity that are critically involved in a variety of life activities, such as growth and development, energy metabolism, oxidative stress, genomic stability maintenance, and neurocognition [4].These candidate genes include mainly APOE, a gene involved in lipoprotein metabolism [5,6].Others are those involved in cell cycle regulation, cell growth and signal transduction, the maintenance of genome stability, and the endocrine-related pathway [7][8][9].In addition, the candidates for longevity encompass genes related to drug metabolism, the ones involved in protein folding, stabilization, and degradation, as well those related to coagulation and regulation of circulation [10], etc.In most cases, these genes or their polymorphic sites were examined in multiple population replication studies, which discovered certain longevity-associated genes or pathways [4][5][6][7][8][9][10].",
      "Additional association studies with these families and replication of these results with an independent data set should facilitate the positional cloning of a gene that influences the ability to age well and achieve exceptional longevity.Identification of the genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.",
      "Somatic mutations with the inherited gene variations of each individual cumulatively or synergistically influence the health span and life span [11].Very few genetic variants have been associated with human longevity, but those found include the transcription factor FOXO3 gene, the APOE/TOMM40 and the CDKN2B/ ANRIL loci, which are associated with Alzheimer's disease and cellular senescence [12][13][14].In fact, the heritability for human longevity has been estimated to be approximately 20-30%, according to studies of twins, suggesting that external factors such as diet, environment, physical activity and microbiomes are important factors that influence the health span [14][15][16].The increase in the rate of retrotranscription reflects genome deregulation, creating additional mutations, DNA damage, and other forms of genome instability.For instance, the expression of several families of retrotransposable elements increases with age, as observed in mouse skeletal muscle and human fibroblasts, particularly the long interspersed nuclear element-1 (L1 LINE) [17,18].",
      "Before 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].",
      "Unbiased 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.",
      "Involvement of genes in a wide range of fundamental biological processes suggests also a broad role of these genes in regulating the aging-related phenotypes.",
      "Gene associations with age-related traits found using longitudinal study data.",
      "In most experimentally modified animal model systems, single-gene mutations in many different genes have major life extension effects (Fontana et al., 2010;Kenyon, 2010).However, natural human and animal longevity is presumed to be a complex trait (Finch & Tanzi, 1997).In humans, both candidate gene and genome-wide genetic association approaches have been applied in an attempt to identify longevity loci.The frequency of genetic variants has been typically compared between nonagenarian cases and young controls, revealing loci at which genetic variants may contribute to a higher or lower probability of survival into old age.The initial candidate gene studies aimed at finding human longevity genes were dominated by contradictory results (Christensen et al., 2006).The more consistent evidence obtained by repeated observation in independent cohort studies for association with longevity has so far only been observed for three loci, the apolipoprotein E (APOE) locus (Schachter et al., 1994;Christensen et al., 2006), the FOXO3A locus (Willcox et al., 2008;Flachsbart et al., 2009;Pawlikowska et al., 2009;Soerensen et al., 2010), and the AKT1 locus (Pawlikowska et al., 2009).Thus, despite the expectation that longevity would be influenced by many genetic variants with small effect sizes, the effect of variants has consistently been shown in only three genes.",
      "The lack of success in the identification of genes related to aging in humans may be due to the complexity of the phenotype.One approach to investigate aging and longevity is to compare frequencies of genetic variants between nonagenarians or centenarians and the general population.This approach led to the discovery of an association between APOE (Deelen et al., 2011;Ewbank, 2007;Gerdes et al., 2000) and more recently FOXO3A (Anselmi et al., 2009;Flachsbart et al., 2009;Li et al., 2009a;Pawlikowska et al., 2009;Willcox et al., 2008) and human aging and longevity.However, a recent genome-wide association study (GWAS) of individuals reaching the age of 90 or older failed to identify genome-wide significant variants (Newman et al., 2010).",
      "Thus, substantially more work is needed in this area to establish whether longevity is driven by nuclear genomic stability.Diverse and unexpected bits of evidence support a relationship.For example, a disproportionate number of genes identified in unbiased and targeted genome-wide association studies (GWASs) as associated with longevity are involved in genome maintenance (75).One study involved age of natural menopause in \u223c70,000 women and led to the identification of 44 genetic variants associated with early or late menopause, a strong biomarker of healthy TIFs (telomere dysfunction-induced foci): co-localization of multiple DNA damage response factors and repair proteins on uncapped telomeric DNA aging (76).Approximately two-thirds of these are associated with genome maintenance genes.Seven of ten significantly associated pathways are involved in DNA repair.The highly significant overrepresentation of DNA repair pathways indicates an intimate connection between genome maintenance and aging phenotypes.From unrelated studies, we know that reduced expression of the repair endonuclease ERCC1-XPF causes accelerated aging (3), whereas ERCC1 is one of the top genes under positive selective pressure in the longest-lived mammalian species, the bowhead whale (77).Intriguingly, hepatocytes from old rats have impaired NER, whereas caloric restriction, which extends longevity, restored the NER capacity of old rats to that of youthful levels (42).In a human interventional study, brief caloric restriction increased NER capacity in PBMCs of individuals who had low NER prior to dietary intervention (78).Therefore, increased DNA repair capacity could promote longevity and may even prove amenable to improvement.",
      "In addition to aging-and CR-related genes, another source of candidate genes and pathways for drug design are human longevity-associated genes (Barzilai and Shuldiner, 2001;Browner et al., 2004;Kenyon, 2010).Dozens of genes have now been associated with human longevity (de Magalha \u02dces et al., 2009a), although only a handful of genes have been shown to have consistent effects across populations.",
      "Genes/loci identified by genome-wide association studies of longevity and lifespan traits.",
      "The genetic basis of human longevity has so far been primarily investigated by association studies.Most results from these experiments have been difficult to confirm in independent samples, probably owing to the modest heritability, multifactorial nature, and heterogeneity of the phenotype (Christensen et al., 2006).To date, variation in only two genes has been identified, which has an effect on longevity in various populations: (i) the apolipoprotein E gene (APOE) (Scha \u00a8chter et al., 1994;Christensen et al., 2006) and (ii) the forkhead box O3A (FOXO3A) gene in the insulin-IGF1 signaling (IIS) pathway (Willcox et al., 2008;Flachsbart et al., 2009).Given the apparent lack of susceptibility candidates, it is conceivable that other genetic factors influence the function or expression of genes relevant for human longevity.",
      "Since many alleles will fit the two patterns just described, it follows that we expect many genetic and biochemical mechanisms of aging.There are some experiments that have attempted to estimate the number of genes involved in aging, particularly in Drosophila.Quantitative genetic estimates of gene number have probably been subject to artifacts, [6,8] and are highly imprecise.Molecular genetic estimates using 2-D gels [3] and high-density geneexpression arrays [12] indicate the involvement of at least 300 genetic loci in Drosophila aging, and that estimate is highly conservative.For now, the best conclusion is probably that many genes are involved in aging in fruit flies.Vertebrates are unlikely to have fewer genes involved in aging, in view of their larger genomes.",
      "GenAge consists of several searchable data sets.Considering the extraordinary discoveries in the genetics of aging in model organisms, GenAge includes a data set of genes associated with longevity and/or aging in model organisms.We consider a given gene for inclusion in GenAge if genetic manipulations of the gene result in noticeable changes in the aging phenotype and/or longevity.Most genes in GenAge are from the four typical model organisms: mice, worms, fruit flies and yeast (Table 1).Strikingly, homologues of many genes -such as insulin receptors and sirtuins -have been shown to regulate aging in model organisms separated by large evolutionary distances (Kenyon, 2005;Liu et al ., 2005;Smith et al ., 2008).Moreover, we have shown that genes associated with aging and/or longevity in model organisms are evolutionary conserved in terms of having more homologues than predicted by chance (Budovsky et al ., 2007(Budovsky et al ., , 2008) ) and exhibiting slower molecular evolution rates (de Magalh\u00e3es & Church, 2007).Therefore, it is now clear that at least some genes identified in model organisms may be relevant to human aging.",
      "Gene associations with age-related traits found using longitudinal study data.",
      "Most of the human candidate gene studies were performed in cross-sectional designs (Box 1 and Fig. 1), comparing allele frequencies of potential longevity loci between highly aged individuals and young controls.The candidate gene studies based on single genes have pointed a role for genes involved in, e.g., GH/insulin/IGF-1 signaling, immune regulation, and lipoprotein metabolism (Supporting Information Table S1), although most of these results have not (yet) been confirmed in sufficient independent studies.The most convincing human longevity loci today are APOE and FOXO3A which have frequently been associated with longevity in cross-sectional studies (see for a review [26]) and survival in prospective studies [27][28][29] (Fig. 3).APOE encodes the protein apolipoprotein E which seems to play a role in e.g., lipoprotein metabolism, cognitive function, and immune regulation [30].FOXO3A encodes the protein forkhead box O3 which acts as a transcription factor for many different genes involved in processes like apoptosis and oxidative stress [31]."
    ],
    [
      "Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.",
      "Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.",
      "Recent 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.",
      "Background: 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.",
      "Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality.Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively.We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function.Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs.A polygenic score for GrimAge acceleration showed strong associations with adiposityrelated traits, educational attainment, parental longevity, and C-reactive protein levels.Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.",
      "INTRODUCTION  Human aging is affected by genes, life style, and environmental factors.The genetic contribution to average human aging can be modest with genes explaining \u223c20-25% 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.",
      "Before 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].",
      "Even 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).",
      "On the other hand, the same evolutionary-motivated strategy suggesting to focus on more heterogeneous phenotypes (as opposite to more homogenous) can be highly beneficial for unraveling genetic predisposition to fundamental mechanisms of intrinsic biological aging and, consequently, to geriatric diseases.Indeed, aging is associated with systemic remodeling of an organism's functioning which increases chances of virtually all geriatric disorders (Franco et al. 2009;Franceschi et al. 2000;Martin et al. 2007;Cutler and Mattson 2006).Experiments with laboratory animals (Johnson 2006) and heritability estimates in humans (Christensen et al. 2006;Iachine et al. 1998) show that aging can be genetically regulated (Finch and Tanzi 1997;Martin et al. 2007;Vaupel 2010).Accordingly, yielding insights in genetic predisposition to aging-related processes in an organism could be a major breakthrough in preventing and/or ameliorating not one geriatric trait, but perhaps a major subset of such traits (Martin et al. 2007) that can greatly advance progress in solving the problem of extending healthy lifespan in humans.",
      "In conclusion, we performed a genome-wide association study of longevity-related phenotypes in individuals of European, East Asian and African American ancestry and identified the APOE and GPR78 loci to be associated with these phenotypes in our study.Moreover, our gene-level association analyses highlight a role for tissue-specific expression of genes at chromosome 5q13.3,12q13.2,17q21.31,and 19q13.32 in longevity.Genetic correlation analyses show that our longevity-related phenotypes are genetically correlated with several disease-related phenotypes, which in turn could help to identify phenotypes that could be used as potential biomarkers for longevity in future (genetic) studies.",
      "M OST genetic studies involved with aging have focused on identifying genes contributing to particular diseases.More recently, it has been recognized that it is also valuable to examine genetic factors related to diseasefree or healthy aging (1,2).Utilizing twins from the National Academy of Sciences-National Research Council (NAS-NRC) twin panel, we have demonstrated that healthy physical aging is under a significant degree of genetic influence, with a heritability over 50% (3).Our definition of healthy aging focused principally on freedom from cardiovascular disease, and has received considerable support in the more recent literature.Brand and colleagues (4) reported that parental age at death was a significant predictor of coronary heart disease death in the Framingham offspring study and concluded that familial similarities for age at death may be mediated through shared coronary heart disease risk factors.Frederiksen and colleagues (5) reported that increased parental life was associated with a reduction in odds ratio for their children to have diabetes, ischemic heart disease, heart failure, stroke, and hypertension.We have found that better midlife lipid levels and blood pressures were associated with increased parental longevity in the National Heart, Lung, and Blood Institute twin study (6).Centenarian siblings and offspring, besides having increased longevity, have been shown to have better health and better cardiovascular risk factor profiles (7)(8)(9)(10).",
      "The lack of success in the identification of genes related to aging in humans may be due to the complexity of the phenotype.One approach to investigate aging and longevity is to compare frequencies of genetic variants between nonagenarians or centenarians and the general population.This approach led to the discovery of an association between APOE (Deelen et al., 2011;Ewbank, 2007;Gerdes et al., 2000) and more recently FOXO3A (Anselmi et al., 2009;Flachsbart et al., 2009;Li et al., 2009a;Pawlikowska et al., 2009;Willcox et al., 2008) and human aging and longevity.However, a recent genome-wide association study (GWAS) of individuals reaching the age of 90 or older failed to identify genome-wide significant variants (Newman et al., 2010).",
      "Human longevity and healthy aging show moderate heritability (20%-50%).We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death.No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p \u03fd 5 \u03eb 10 \u03ea8 ).We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p \u03fd 10 \u03ea5 ).These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease.In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings.These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.",
      "Introduction  The recent, remarkable extension of life expectancy is largely attributed to the postponement of mortality at old age (Vaupel, 1997(Vaupel, , 2010)).The years of life gained in the older population residing in developed nations are a success story of public health measures and improved health care.In addition to such external factors, longevity and healthy aging consistently show a modest heritability between 20% and 50% and aging-associated genetic research may provide further insights into the mechanisms of aging (Herskind et al., 1996;McGue et al., 1993;Reed and Dick, 2003).It has been postulated that genes involved in pathways associated with aging identified in animal models, such as insulin-like growth factor (IGF)-insulin signaling, regulation of lipoprotein metabolism, the mTOR pathway, and the oxidative stress response may also influence survival to old or even exceptionally old age in humans (Christensen et al., 2006;Kenyon, 2010;Vellai et al., 2003).However, in humans, common variants within genes involved in these pathways have not been consistently associated with lifespan (Chris-tensen et al., 2006;Kenyon, 2010;Kuningas et al., 2008;Vijg and Suh, 2005).",
      "Human longevity and healthy aging show moderate heritability (20%-50%).We conducted a meta-analysis of genome-wide association studies from 9 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for 2 outcomes: (1) all-cause mortality, and (2) survival free of major disease or death.No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p \u03fd 5 \u03eb 10 \u03ea8 ).We found 14 independent SNPs that predicted risk of death, and 8 SNPs that predicted event-free survival (p \u03fd 10 \u03ea5 ).These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer's disease.In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings.These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity.",
      "Many 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.",
      "The genetic basis of human longevity has so far been primarily investigated by association studies.Most results from these experiments have been difficult to confirm in independent samples, probably owing to the modest heritability, multifactorial nature, and heterogeneity of the phenotype (Christensen et al., 2006).To date, variation in only two genes has been identified, which has an effect on longevity in various populations: (i) the apolipoprotein E gene (APOE) (Scha \u00a8chter et al., 1994;Christensen et al., 2006) and (ii) the forkhead box O3A (FOXO3A) gene in the insulin-IGF1 signaling (IIS) pathway (Willcox et al., 2008;Flachsbart et al., 2009).Given the apparent lack of susceptibility candidates, it is conceivable that other genetic factors influence the function or expression of genes relevant for human longevity.",
      "Introduction  Approximately 25-30% of the variation in adult lifespan is attributable to genetic factors that become more important with increasing age and exert their strongest effects in nonagenarians and centenarians (Go \u00a8gele et al., 2010;Hjelmborg et al., 2006).As yet, however, only a few genetic variants have been found consistently to influence longevity.The first to be discovered was the e4 allele of the apolipoprotein E (APOE) gene, a mortality factor that predisposes to both Alzheimer's and cardiovascular diseases (Corder et al., 1993; Panza et al., 2004).APOE e4 is the only variant with a reportedly large adverse effect upon survival at advanced age (Scha \u00a8chter et al., 1994), and this association has been replicated in several populations (Christensen et al., 2006).Variation in the human forkhead box O3A gene (FOXO3A), in contrast, has been found to be associated with the ability to live long, an effect corroborated by studies in Japanese, German, Italian, US-American, Jewish, Chinese and Danish populations (Anselmi et al., 2009;Flachsbart et al., 2009;Li et al., 2009;Pawlikowska et al., 2009;Soerensen et al., 2010;Willcox et al., 2008).More recently, we have identified exonuclease 1 (EXO1) as a potential novel longevity gene (Nebel et al., 2009).All three genes were detected through candidate-gene approaches.",
      "GenAge: the aging gene database Philosophy and overview of resources  It 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 Magalh\u00e3es, 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.",
      "I NCREASES in longevity of the general population world- wide are an unprecedented phenomenon with significant health and social impact.Although environmental factors have led to an increase in life span, there is ample evidence that genetic factors are involved in extreme longevity both in humans (1-7) and in other organisms (8).The protective genetic factors that lead to longevity are likely to involve fundamental processes of aging that may be different from those associated with early mortality or premature onset of age-related diseases in younger individuals.The mechanisms of aging in humans are far from understood, but available evidence suggests that several pathways-inflammation, oxidative stress and stress responses, cellular senescence, DNA damage and repair, and the growth hormone or insulinlike growth factor and insulin (GH, IGF, INS) axis-may play key roles (9)(10)(11)(12).Model organisms suggest that inhibiting the GH, IGF, or INS axis, which is involved in regulating cell proliferation, cell death, wound repair, and metabolism, may promote longevity by reducing oxidative stress and slowing the rate of cell replication and the accumulation of somatic-cell DNA mutations (13).There is also evidence for other important pathways such as the heatshock proteins and heat-shock factors that are highly conserved across species and play a role in prolongevity transcription pathways.Clinical and epidemiological investigations, including candidate gene studies, have suggested that inflammation pathways may affect life span and risk of age-related conditions such as cardiovascular disease (CVD) and its risk factors (14)(15)(16)(17)(18)(19).A combination of multiple genetic variants may be required for an individual to achieve exceptional longevity, which may account in part for its rarity."
    ],
    [
      "Indicative biological pathways associated with the candidate aging genes",
      "Fig. 2 Significant biological processes associated with the candidate aging genes",
      "Following are examples of the identified genes and experimental or GWAS link between these genes and aging.On the list of the 25 top genes, NAP1L4 encodes a member of the nucleosome assembly protein (NAP) family, which interacts with both core and linker histones, and shuttles between the cytoplasm and nucleus, suggesting a role as histone chaperone.Histone protein levels decline during aging, and dramatically affect chromatin structure.Remarkably, the lifespan can be extended by manipulations that reverse the age-dependent changes to chromatin structure, indicating the pivotal role of chromatin structure in aging [32].In another example, gene expression of NAP1L4 increases with age in the skin tissue [33].Findings of GWAS link a number of the identified genes to age-related disorders, such as GAB2 and late onset Alzheimer's disease [86], and QKI and coronary heart disease/myocardial infarction [79].Interestingly, GWAS reports also link QKI to successful aging [87].",
      "Examples of biological candidate genes with pleiotropic functions, which are involved in aging in general and in musculoskeletal aging in particular, are numerous: (a) in addition to the IGF-1 and vitamin D genes, estrogen metabolism pathway genes, including estrogen receptors and aromatase (CYP19), are associated with fat-free mass (Walsh et al. 2005) and BMD (Shearman et al. 2004), prostate and breast cancer (Gallicchio et al. 2006), and cardiovascular disease risk (Shearman et al. 2003).",
      "In-depth analysis of the age-regulated genes revealed that multiple genes in the DNA damage response pathway were upregulated with age including those that function in non-homologous end-joining repair (mre11, rad50, Ku80 and mus308) and in translesion DNA synthesis (mus205 and DNApol-eta) [44][45][46].Genes that encoded enzymes with antioxidant properties, such as the thioredoxin reductase Trxr-1, and antioxidant genes involved in glutamate metabolism, such as GlnRS, isoQC and QC, were also upregulated with age [47][48][49][50].We also observed increased age-associated expression of chaperone genes (Cct1, Cct4, Cct5, Cct6, Hsc70-4) and the unfolded protein response transcription factor Xbp1, consistent with an induction of the unfolded protein response [51][52][53].Under stress conditions, there is a translational switch that favors production of stressrelated proteins while decreasing translation of other proteins [54].Paralogs of canonical translation factors such as NAT1 and Rack1, which were both upregulated, promote this switch to cap-independent translation [55,56].Notably, Rheb, which is downregulated with age, positively regulates ribosome production and capdependent translation by activating the mechanistic target of rapamycin (mTOR) kinase pathway [57].Thus, decreased Rheb levels during aging could decrease mTOR pathway activity, which extends lifespan and is protective against age-related pathology [58].Together, these data suggest that multiple genes are induced in aging photoreceptors to mitigate the effects of oxidative stress, protein misfolding and DNA damage.",
      "CellAge vs human orthologues of longevity-associated model organism genes  To understand how senescence is linked to the genetics of aging processes, we looked at the intersection of CellAge genes and the 869 genes in the human orthologues of model organisms' longevity-associated genes (LAGs) dataset, collected based on quantitative changes in lifespan [34].Like CellAge, where genes are classified based on whether their upregulation induces, inhibits, or has an unknown impact on CS, the longevity orthologues dataset also provides information on the effect of upregulation of its genes, namely whether it promotes (pro, 421) or inhibits (anti, 448) longevity (Additional file 1: Table S7; Additional file 2: Fig. S2).",
      "Using network biology, we implicated the CellAge genes in various processes, particularly cell division and immune system processes.We used network topology to identify potential regulators of CS and bottlenecks that could impact various downstream processes if deregulated.Indeed, we identified 11 genes that have already been shown to contribute towards CS, which will be added to future versions of CellAge.Finally, we experimentally verified 26 genes that induce CS morphology or biomarkers when knocked down in human mammary fibroblasts.Of these, 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) were strong hits in inducing a senescent phenotype.",
      "Results: We develop CellAge (http://genomics.senescence.info/cells),a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses.Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes.Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates.We also build cellular senescence protein-protein interaction and co-expression networks.Clusters in the networks are enriched for cell cycle and immunological processes.Network topological parameters also reveal novel potential cellular senescence regulators.Using siRNAs, we observe that all 26 candidates tested induce at least one marker of senescence with 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) decreasing cell number, activating p16/p21, and undergoing morphological changes that resemble cellular senescence.Conclusions: Overall, our work provides a benchmark resource for researchers to study cellular senescence, and our systems biology analyses reveal new insights and gene regulators of cellular senescence.",
      "Genomics-a fundamental basis for understanding skin aging  In the last decade, genomic tools such as gene chips have been widely developed.This accomplishment has provided us with deeper insights into the molecular events underlying skin aging. 137Gene expression profiling has led to identification of pathways affected by aging, and this information has led to the development of new strategies to enable better skin repair and antiaging benefits. 138ene expression patterns were examined in sun-protected (buttocks) and sun-exposed skin (extensor forearm) from 10 young (age 19 to 20 years) and 10 older women (age 63 to 67 years) to examine gene expression profiles associated with chronologic skin aging and photoaging.Chronologic and photoaging were both associated with downregulation of the biologic process of lipid synthesis.In particular, genes involved in cholesterol and fatty acid synthesis were downregulated, as were genes associated with epidermal differentiation, including keratin filaments and cornified envelope components.An upregulation of the biologic processes of inflammatory response and wound healing, the molecular functions of cytokine activity and protease activity and the cellular component theme of extracellular matrix was also observed in both skin aging types.Elastin gene expression was upregulated with aging only in the photodamaged arm and remained unchanged in the sunprotected buttock.This finding corresponds to the histopathologic findings that show typical elastotic changes, the \"solar elastosis,\" in photoaged skin. 139urther studies conducted to investigate changes in gene expression during skin aging have been performed on naturally aged human foreskin obtained from children and elderly men.Some of the mechanisms proposed to be involved in the induction of aging comprise disturbed lipid metabolism, altered insulin and STAT3 signalling, upregulation of apoptotic genes partly due to the deregulation of FOXO1, downregulation of members of the jun and fos family, differential expression of cytoskeletal proteins (eg, keratin 2A, 6A, and 16A), extracellular matrix components (eg, PI3, S100A2, A7, A9, SPRR2B), and proteins involved in cell-cycle control (eg, CDKs, GOS2). 140Similar results have been presented by a study related to aging of skeletal muscle. 141n a previous study, we proposed that one of the factors significantly involved in the initiation of aging might be the physiologic decline of hormones occurring with age.Human SZ95 sebocytes in vitro treated with hormone levels that can be found in 60 year-old women produce less lipids than sebocytes treated with a hormone mixture representing that found in the serum of 20 year-old women. 6A differential gene expression between SZ95 sebocytes under the 20 and 60 year-old hormone mixture detected differentially expressed genes that are involved in biologic processes such as DNA repair and stability, mitochondrial function, oxidative stress, cell cycle and apoptosis, ubiquitin-induced proteolysis, and transcriptional regulation. 139,140A comparison of these results with data obtained from the aged kidney 142 identified key genes that may be of great importance for global aging.The most significantly altered signalling pathway was that of TGF-\u03b2.A disturbed function of this cascade has been also  c-Fos, which heterodimerize to form the activator protein 1 (AP-1) complex.AP-1 is a key regulator of skin aging, because it induces the expression of the MMP family and inhibits type I procollagen gene expression through interference with TGF-\u03b2 signalling pathway.It has been postulated that MAP kinases may be activated by excess production of reactive oxygen species (ROS) that occurs with advanced age and may be superimposed by extrinsic factors such as ultraviolet irradiation.Excess ROS production also leads to accumulation of cellular damage, which includes oxidation of DNA resulting in mutations, oxidation of proteins leading to reduced function, and oxidation of membrane lipids resulting in reduced transport efficiency and altered transmembrane signalling.IL, interleukin; NF-\u03baB, nuclear factor-\u03baB; TGF-\u03b2, transforming growth factor-\u03b2; TSP-1, thrombospondin-1; TSP-2, thrombospondin-2; VEGF, vascular endothelial growth factor.associated with tumorigenesis, such as in pancreatic, prostate, intestine, breast, and uterine cancer.",
      "Analysis of prior research (Online Resource 5) shows that the revealed genes can be explicitly involved in other key biological processes in an organism whose role is known to be changing with aging.Specifically, ten genes (BAZ2B, HMGB4, NOC2L, RAI1, SIK1, SMARCA2, SPZ1, TBP, TRIP13, and ZKSCAN1) regulate transcription which is believed to be disrupted when an organism is getting older (Roy et al. 2002).The DBH, TPO, and LSS genes are involved in synthesis of catecholamine, thyroid, and vitamin D hormones, respectively.The GPER binds estrogen and HCRTR2 binds orexin-A and orexin-B neuropeptid hormones.Hormonal deregulation with aging is considered to be one of the major components of senescent processes in an organism (Barzilai and Gabriely 2010).Five genes (ATG2A, NEDD4L, PSMB1, UBXN4, and USP6) are involved in degradation of proteins through ubiquitin-proteasome and the lysosomal/autophagic system.Dysfunction of this system leads to accumulation of damaged proteins in an organism that is associated with aging (Koga et al. 2011).Protein degradation through ubiquitin-mediated proteolysis plays an important role in cell-cycle regulation (Reed 2003).The PSMB1, SIK1, TRIP13, and TTN genes in the revealed set coordinate cell cycle.Cell cycle is linked with the aging-related processes in humans through a gradual increase in cell division errors in all tissues in an organism (Ly et al. 2000).Five genes (EEF1A2, DBH, ITGB2, TUBB2C, and WRN) take part in regulation of apoptosis which plays an important role in the aging process and tumorigenesis (Salvioli et al. 2008).Seven genes (ABCA7, AZGP1, CD36, DEGS2, LSS, PI4KA, and SOAT2) are involved in lipid metabolism which plays one of the key roles in human longevity and healthy aging (Barzilai et al. 2003).",
      "Genes that are age-regulated in all tissues would reveal genes involved in core mechanisms that underlie cellular ageing.Zahn et al. [63] discovered genetic pathways that show common age regulation in human kidney, brain and muscle.They used microarrays to analyse expression in 81 skeletal muscle samples from patients aged 16 -86 years and found 250 age-regulated muscle genes [63].Similar to the ageing expression profile for the kidney, the overall expression behaviour of this set of age-regulated muscle genes correlated with the physiological as well as chronological age of the muscle sample.Next, they compared their muscle-ageing results to previously published data on kidney and brain ageing of similarly large sample size [56,60].Although most of the age-related changes were tissue specific, they found evidence for common age regulation of six genetic pathways in all three tissues.Specifically, there is an overall increase in expression of the extracellular matrix genes, the ribosomal genes, the cell growth genes and the complement activation genes in all three tissues.Increased overall expression of the extracellular matrix and complement activation gene sets with advancing age may contribute to widespread fibrosis and inflammation in the elderly.There is an overall decrease in expression of the chloride transport genes and the electron transport genes in all three tissues.Decreased overall expression of electron transport chain genes with age might support the mitochondrial free-radical theory of ageing [67], as free-radical generation by mitochondria would preferentially damage the electron transport chain protein complexes.Decreased expression of the electron transport genes (encoded in the nucleus) might be caused by feedback regulation from damage to the electron transport chain protein complexes [63].However, it is also possible that increased oxidative damage occurs as a consequence of the decreased expression of the electron transport chain genes.In addition, an increasing number of studies in model organisms have critically challenged the mitochondrial free-radical theory of ageing [68].",
      "Discussion  Aging studies from model organisms such as yeast, worms, and flies have repeatedly shown that changes in the expression of certain genes have an effect upon longevity.Although similar aging processes are likely to operate across multiple species [30], it has been much more difficult to identify longevity candidate genes in human studies [30].A key question in human aging is to what extent a signature of aging may be detectable across tissues.Until now there has been a lack of large transcriptional profiles from the same human individuals in multiple tissues.The MuTHER study provides insight into the human aging process by interrogating the largest multiple human tissue gene expression resource to identify genes in which expression was affected by chronological age.The analysis of the skin and adipose tissues samples identified several hundred genes responsive to changes in chronological age.However, the 43 shared genes in skin and adipose tissue showed a single common identifiable pathway related to the stress response.From over 1,800 transcripts that have altered expression with age in skin and adipose tissues, 14 also had age-related differential expression in brain.The limited overlap in these two experiments may partly reflect the smaller sample size of the brain expression dataset, the differences in age range between the studies (16 to 83 years for brain samples; 39 to 85 years for MUTHER samples), or the inclusion of males in the brain samples.But it may also imply, as other studies have suggested, that the effects of age on gene transcription are tissue specific [6,31,32].This hypothesis was supported by the comparison with known related aging genes from the GenAge database, which identified an overlap for a small number of aging-related genes with our data.The GenAge database was the result of a meta-analysis using age-related expression profiles from human brain, kidney, and skeletal muscle, and several expression profiles from mouse and rat; no adipose tissue or skin samples were included (Additional file, Table 1 in [7]).The limited overlap between these datasets supports the idea that molecular signatures of aging reflect predominantly a tissue-specific transcriptional response.The lack of age-related genes in transformed LCLs, suggest that the transformation to immortalize a cell line may mask or even remove the age-related signatures in gene expression.The transformation of primary B lymphocytes into LCLs requires infection by the Epstein-Barr virus which has the effect of disrupting the p53 signaling pathway in order to induce growth and survival [33].Joehanes et al. [15] identified only five genes with age-associated expression in LCLs, including p53 itself (TP53).Although the authors attribute the lack of age-affected genes to their small sample size (n=50) and narrow age range, our analysis with a much larger sample size found even fewer age-related changes, suggesting a lack of detectable aging signature in LCLs.The analysis in the subset of fresh lymphocytes suggested an age influence in fresh lymphocytes may potentially be detectable with a larger sample size.",
      "Genes Whose Expression Decreased with Age.Of the 26 genes that decreased expression with age in control mice, 23% are involved in DNA replication and the cell cycle (Table 2).Most of these have a negative effect on cell growth and division.Among these, the product of phosphatase and tensin homolog (Pten) gene is a tumor suppressor that induces cell-cycle arrest through inhibition of the phosphoinositide 3-kinase pathway (28).B cell translocation gene 2 (Btg2) is a tumor suppressor that increases expression in response to DNA damage (29).The murine gene product of the amino-terminal enhancer of split (Aes) is a potent corepressor of gene expression and cellular proliferation (30).Calcium-binding protein A11 (S100a10) binds to and regulates the activity of annexin II, which is involved in the transduction of calcium-related mitogenic signals (31).Insulin-like growth factor (IGF) binding protein 1 (Igfbp1) plays an important role in the negative regulation of the IGF-1 system, a stimulator of mitogenesis (32).",
      "daf-16 dependent genes  Among the 52 genes that we have tested, 29 genes act almost completely in a daf-16 dependent manner, to regulate lifespan (Table 2).One of the genes identified was daf-2 (Y55D5A_391.b).This serves as a proof of principle that our screen is effective in identification of aging genes.",
      "Several 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.",
      "Hundreds of genes in several pathways act as regulators of ageing (1,32).However, analysis of DrugAge and other HAGR databases has revealed that the overlap between the targets of lifespan-extending drugs and known ageing related genes is modest (31).This indicates that most ageing-related pathways have yet to be targeted pharmacologically; DrugAge may aid in guiding further assays.This was recently demonstrated in one study where machine learning was used to predict whether a compound would increase lifespan in worms using data from Dru-gAge.The best model had 80% prediction accuracy and the top hit compounds could broadly be divided into compounds affecting mitochondria, inflammation, cancer, and gonadotropin-releasing hormone (33).",
      "Top 25genes co-expressed with aging related genes",
      "Aging-related gene prediction and putative transcriptional mechanisms  GeneFriends was used to identify genes related to aging.A seed list of genes known to be consistently overexpressed with age in mammals was used [18].In total, 1119 genes were co-expressed with the aging seed list at p <10 -6 ; Table 1 shows the top 25 genes.Many of these genes have been associated with age-related diseases.Several other genes that have been shown to play a role in aging such as lysosomal-associated membrane protein-2 Lamp2 [19] (p = 5.68 -30 ), Fas [20] (p = 2.70 -31 ) and growth hormone receptor Ghr [21] (p = 1.34 -19 ) also showed a significant co-expression.Anxa2, Anxa3 and Anxa4 also show a low p-value (p < 10 -25 ) as well as several S100 calcium binding proteins which have been shown to interact with annexins [22].",
      "Genetic studies have shown that aging can be slowed in mutants that are defective in a wide range of cellular processes (such as mitochondrial function, chromatin regulation, insulin signaling, transcriptional regulation, and genome stability).This indicates that aging is a complex process driven by diverse molecular pathways and biochemical events.As such, a powerful approach to study aging is to use systems biology, which allows a multitude of factors affecting aging to be analyzed in parallel.For example, DNA microarrays and gene expression chips have been used to perform a genome-wide analysis of changes in gene expres-sion in old age.Extensive studies in Caenorhabditis elegans and Drosophila melanogaster have identified hundreds of ageregulated genes (Hill et al. 2000;Zou et al. 2000;Lund et al. 2002;Pletcher et al. 2002;Murphy et al. 2003).Several studies have described age-regulated genes in the muscle and brain of mice (Lee et al. 1999(Lee et al. , 2000) ) and the retina and muscle of humans (Yoshida et al. 2002;Welle et al. 2003Welle et al. , 2004).These age-regulated genes may serve as markers of aging, enabling one to assess physiological age independently of chronological age.Analysis of the functions of these age-regulated genes has identified specific biochemical mechanisms that change toward the end of life.",
      "Age-Regulated Genes Involved in Reproductive Capacity.Decline in reproductive capacity is an age-related phenotype, and the reproductive system seems to play an important role in longevity (22).For example, signals from germ cells can affect lifespan in C. elegans (23).In our study, we observed decreased RNA levels for several genes involved in reproduction (Fig. 3).These include two genes that encode members of the Acp family.The Acp from male flies stimulates female egg-laying and facilitates storage of sperm in the female genital tract (24).In addition, two ESTs showing age-regulated decrease of transcript levels represent different genes with homology to Arabidopsis MALE STERIL-  In Northern analysis, the ratios were calculated by dividing mRNA levels at 25-, 40-, and 50-day time points by those at 3-day time points after normalization with mRNA levels of the control gene rp49.Ratios in microarray analysis are provided from each of the duplicate experiments for comparison.ITY 2 (MS2; ref. 25), a gene involved in gametogenesis.Furthermore, an EST with homology to peanut, a member of the septin family (26), is down-regulated in older flies.This downregulation may reflect a decrease in spermatogenesis."
    ]
  ]
}