{
  "question": [
    "What are the main genetic factors that influence aging?",
    "How do genes affect the aging process in humans?",
    "What lifestyle choices can help slow down genetic aging?",
    "How do scientists study the genetics of aging in animals?",
    "Are there specific genes that have been linked to longer lifespans?"
  ],
  "answer": [
    "The main genetic factors that influence aging include genes such as APOE, FOXO3A, HLA-DQA1/DRB1, LPA, CHRNA3/5, CDKN2A/B, SH2B3, and MTP. These genes are associated with various biological processes such as metabolism, insulin signaling, and DNA damage and repair. Polymorphisms in these genes have been associated with longevity and healthy aging.",
    "Genes influence the aging process in humans by governing levels of physiological capacity, repair, and turnover. They indirectly determine potential longevity. Genetic factors can explain about 20-25% of the variability of human survival to the mid-eighties. Certain genes, such as APOE and FOXOA3, have been associated with long life. However, aging is a complex process that involves the interactions of multiple genes with each other and the environment. It's also important to note that aging is likely a highly polygenic trait, meaning it's probably influenced by many genes.",
    "Lifestyle choices that can help slow down genetic aging include mindful changes in behavior, reducing environmental exposure, healthy food and supplement use, weight loss, and regular exercise. A Mediterranean diet containing fruits, whole grains, fiber, antioxidants, soy protein, and healthy fats is also suggested. Additionally, giving up smoking and increasing educational attainment can positively correlate with lifespan.",
    "Scientists study the genetics of aging in animals by using various animal models, including yeast, worms, flies, and mice. These models are genetically manipulated to investigate lifespan and age-related diseases. Techniques such as genotyping, genetic analysis, and forward genetic approaches are used to identify specific genes and molecular pathways related to aging. In some cases, cross-breeding of different strains is performed to identify aging-relevant genetic determinants. Additionally, in vivo studies are conducted to test the effect of certain manipulations or treatments on the whole organism.",
    "Yes, specific genes have been linked to longer lifespans. These include the apolipoprotein E gene (APOE), the forkhead box O3A (FOXO3A) gene, and the AKT1 locus. Other genes associated with longevity include HLA-DQA1/DRB1 and LPA. However, these genes account for only a small portion of the genetic contribution to longevity."
  ],
  "contexts": [
    [
      "\t\n\nGenomic 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.",
      "\t\n\nRecent developments on the genetics of aging can be seen as several streams of effort.In general, humans show a relatively modest (<50%) heritability of life spans (results obtained from twin studies discussed below).The apoE polymorphisms are remarkable for their influence on both cardiovascular disease and Alzheimer disease.In contrast, rare mutant genes with high penetrance cause these same diseases but with early onset and a major shortening of the life span.Shortlived laboratory models (fruit flies, nematodes, mice) are yielding rapid advances, with the discovery of mutants that increase life spans in association with altered metabolism, which leads to questions on the physiological organization of aging processes.Although these early findings do not show that a conserved genetic program actually controls aging processes across animal phylogeny, it is striking how frequently findings of metabolic rate, insulin signaling, and free radicals have emerged from very different approaches to aging in nematodes and mammals, for example.These findings hint that the genetic control of life span was already developed in the common ancestor of modern animals so that subsequent evolution of life spans was mediated by quantitative changes in the control of metabolism through insulin and the production of free radicals.",
      "\tIntroduction\n\nWith the development of human genomics research, a large number of studies of the genetics of longevity have been conducted.Scientists from various countries have proposed many different theories concerning the mechanisms of aging from different perspectives, involving oxidative stress, energy metabolism, signal transduction pathways, immune response, etc. [1,2].These mechanisms interact with each other and are influenced by heredity to some degree [2,3].The identification of longevity-related biological markers is critical to an indepth understanding of the mechanisms of carrier protection against common disease and/or of the retardation of the process of aging.",
      "\tINTRODUCTION\n\nHuman aging is affected by genes, life style, and environmental factors.The genetic contribution to average human aging can be modest with genes explaining 20-25% of the variability of human survival to the mid-eighties (Herskind et al., 1996;Fraser and Shavlik, 2001).By contrast, genetic factors may have greater impact on survival to the ninth through eleventh decades (Tan et al., 2008).Notably, exceptional longevity is rare and may involve biological mechanisms that differ from those implicated in usual human aging.",
      "\t\n\nBefore the advent of NGS technologies, several scientists were interested in the study of allele variants associated with aging, but they were limited by the lack of aging rate biomarkers.Now with NGS technologies, these biomarkers have been emerged such as the epigenetic clock that is described in the DNA methylation sequencing section of this chapter.In this post-genomic era, different strategies have been developed in order to understand the genetic factors involved in aging [17].One strategy used is the study of aging in extreme longevity groups of people, called centenarians.Centenarians are a group that can reach an age above 100 years and has an incidence of 1 every 10,000 people [18].In a pioneering study using extreme longevity people (308 individuals belonging to 137 sibships showing extreme longevity), genome-wide scan analysis identified a region on chromosome 4 associated with extreme longevity [19] that corresponds to the microsomal transfer protein (MTP) [20], which is associated with abetalipoproteinemia and hypobeta lipoproteinemia in humans [21,22].Another approach to study the genetic factors involved in longevity consists in assessing allele frequencies from people of different ages, looking for those polymorphisms (SNPs) with enhanced allele frequencies in high-longevity individuals.Those alleles with diminished frequencies in aged individuals may be associated with age-related diseases.Using this approximation, an SNP that shifts isoleucine to valine was identified in the PKA-anchoring protein (AKAP2) gene.This polymorphism is associated with reduced longevity and cardiac disease [23].Genome-wide association studies (GWAS) have confirmed only three loci that affect longevity: FOXO3A, APOE, and an intergenic locus on chromosome 5q33.3[24][25][26].\tIndividual Genotype\n\nIndividual differences in biological ageing may be due in part to the specific variations of the genotype but also genome-environment interactions [21,37].The maintenance of genomic stability and integrity is considered an essential factor required for cell viability and the overall longevity of an organism.The accumulation of physical damage is one of the leading causes of the ageing process.When considering oxidative damage as one of the causes of the damage of genetic material, these changes alter vital processes, such as replication, transcription, and translation, leading to genomic instability and personalized processes of ageing [38,39].\tInfluence of Genetic Factors in Ageing and Lifespan\n\nAgeing is defined as the decline of physiological functions in several tissues and organs inducing an increasing probability of death [17].The understanding of genetic factors involved in ageing has been limited due to the complexity of this process and the heterogeneity among individuals and even among tissues [18][19][20].Tissue cells adopt a senescent phenotype as a consequence of multiple intrinsic, extrinsic, and stochastic factors [21].The combination of these genetic factors is related to longevity and healthy ageing [22].Although this decline is somewhat predictable, some individuals show a much slower decline and get to live past the age of 100.Studies in these individuals showed polymorphisms in some genes which are associated with long life, such as APOE and FOXO3.However, these associations have not been consistent across different populations, suggesting that ageing is rather polygenic [23].",
      "\t\n\nInvolvement of genes in a wide range of fundamental biological processes suggests also a broad role of these genes in regulating the aging-related phenotypes.",
      "\t\n\nM 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).",
      "\t\n\nIn 2021, Science published a special issue entitled \"125 Questions: Exploration and Discovery.\" One of these 125 questions was \"Can we stop ourselves from aging? \"The U.S. National Institute on Aging (NIA) at the National Institutes of Health (NIH) states that \"aging is associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes.\" Although geneticists and epidemiologists have long debated the relative importance of the role played by genotype or the environment in the development of age-related diseases, it is apparent that both can play substantial roles in this process [6,7].However, most etiological studies have concentrated on the role of genotype and have considered the environment to play a secondary role.Nevertheless, an analysis of GBD data showed that nearly 50% of deaths worldwide are attributable to environmental exposure, primarily exposure to airborne particulates (including household air pollution and occupational exposure; 14% of all deaths), smoking and secondhand smoke (13%), plasma sodium concentrations (6%), and alcohol consumption (5%) [8].In contrast, a recent analysis of 28 chronic diseases in identical twins showed that the genetic-related risks of developing one of five age-related diseases were 33.3%, 10.6%, 36.3%, 19.5%, and 33.9% for AD, PD, CAD, COPD, and T2DM, respectively, with a mean of only 26% [9].The results of over 400 genome-wide association studies (GWASs) have also elucidated that the heritability of degenerative diseases is only approximately 10% [10,11].Consequently, nongenetic drivers, such as environmental factors, are now recognized as major risk factors for age-related diseases.The contributions of environmental factors to the development of age-related diseases can be revealed by analyses of all of the factors to which individuals are exposed in their life and the relationships between these exposures and age-related diseases [12,13].",
      "\tTranslational\n\nA LTHOUGH there is much debate about the processes driving human aging, there is little doubt that genetic influences play a significant role (1).Humans clearly live very much longer than the currently favored laboratory models of aging, and such interspecies differences in reproductively 'fit' life span must have an inherited genetic foundation.Within human populations, environmental and behavioral exposures are important but at least a quarter of life expectancy variation in twin or family studies is attributable to inherited genetic or epigenetic factors (2).Age-related conditions such as type 2 diabetes, myocardial infarction, common cancers, and Alzheimer's disease (AD) typically have onsets after the fourth decade of life; \"successful\" agers delay these onsets until relatively late in life (3).Many aging traits and diseases show moderate heritability, including cardiovascular disease (CVD) (4) and impaired physical functioning (5), independent of known environmental risk factors.",
      "\t\n\nMany factors contribute to aging, including genes.This is the first article in a 10-part series that highlight some of what is known about the influence of genes on aging and emerging treatment options that may slow down or potentially reverse the aging process.The series will address \\genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown.Underpinning these factors are wear and tear on cells and aging as a result of inability to repair or replace these affected cells.These topics have been addressed in research, health magazines, and even by talk show hosts.There is even a LongevityMap website addressing significant and nonsignificant genetic association studies in aging across the human genome (http://genomics.senescence.info/longevity/).The series will address a scientific and clinical approach to genome-related aging topics.",
      "\t\n\nThe 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 chter 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.",
      "\t\n\nStudies in various models have revealed that genetic differences and somatic mutations underlie longevity, but non-genetic contributions also play a major role (Cournil and Kirkwood, 2001).Calorie restriction (Bordone and Guarente, 2005), lowering of basal metabolic rate (Ruggiero et al., 2008), upregulated stress response (Migliaccio et al., 1999), restoration of mi-tonuclear protein balance (Houtkooper et al., 2013), and reduced fertility (Westendorp and Kirkwood, 1998) have all been shown to correlate with lifespan extension.These observations illuminate the role of ''epi''-genetic mechanisms in modulating longevity pathways.",
      "\tIntroduction\n\nApproximately 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 gele 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 chter 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.",
      "\tThe mechanisms that underlie healthy agingparticularly, the cognitive as-\n\npectsremain poorly understood. Research suggests that genetics play a significant role in determining an individuals\nsusceptibility or resilience to cognitive decline and dementia\n(Harris and Deary 2011; Ridge et al. , 2013). Identification of precise genetic factors involved would provide insight into\n\nCell Reports 32, 108091, September 1, 2020  2020 The Author(s). 1\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ll\nOPEN ACCESS\n\nReport\n\nFigure 1.",
      "\tGenAge: the aging gene database Philosophy and overview of resources\n\nIt is undisputed that genetic factors influence aging.In a remarkable series of recent breakthroughs, a number of genes capable of altering the aging process as a whole -or at least to a large degree -have been identified in animal models and even a few in humans (Finch & Ruvkun, 2001;de Magalhes, 2005;Kenyon, 2005).Furthermore, multiple alleles have been examined for their association with human exceptional longevity (Vijg & Suh, 2005).This is a fascinating and important area of research, yet there are now so many genes being associated with aging and longevity that keeping track of them all is becoming increasingly more difficult.Moreover, it is necessary now to study not only individual genes but their interactions with each other and with the environment, and how together genes give rise to a given phenotype: the so-called systems biology approach.To help researchers address these issues we created GenAge, a database of genes related to longevity and/or aging.",
      "\t\n\nI 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.",
      "\t\n\nHuman lifespan variation is mainly determined by environmental factors, whereas the genetic contribution is 25-30% and expected to be polygenic.Two complementary fields go hand in hand in order to unravel the mechanisms of biological aging: genomic and biomarker research.Explorative and candidate gene studies of the human genome by genetic, transcriptomic, and epigenomic approaches have resulted in the identification of a limited number of interesting positive linkage regions, genes, and pathways that contribute to lifespan variation.The possibilities to further exploit these findings are rapidly increasing through the use of novel technologies, such as next-generation sequencing.Genomic research is progressively being integrated with biomarker studies on aging, including the application of (noninvasive) deep phenotyping and omics data -generated using novel technologies -in a wealth of studies in human populations.Hence, these studies may assist in obtaining a more holistic perspective on the role of the genome in aging and lifespan regulation.\t\nHuman lifespan variation is mainly determined by environmental factors, whereas the genetic contribution is 25-30% and expected to be polygenic.Two complementary fields go hand in hand in order to unravel the mechanisms of biological aging: genomic and biomarker research.Explorative and candidate gene studies of the human genome by genetic, transcriptomic, and epigenomic approaches have resulted in the identification of a limited number of interesting positive linkage regions, genes, and pathways that contribute to lifespan variation.The possibilities to further exploit these findings are rapidly increasing through the use of novel technologies, such as next-generation sequencing.Genomic research is progressively being integrated with biomarker studies on aging, including the application of (noninvasive) deep phenotyping and omics data -generated using novel technologies -in a wealth of studies in human populations.Hence, these studies may assist in obtaining a more holistic perspective on the role of the genome in aging and lifespan regulation."
    ],
    [
      "\t\n\nRecent developments on the genetics of aging can be seen as several streams of effort.In general, humans show a relatively modest (<50%) heritability of life spans (results obtained from twin studies discussed below).The apoE polymorphisms are remarkable for their influence on both cardiovascular disease and Alzheimer disease.In contrast, rare mutant genes with high penetrance cause these same diseases but with early onset and a major shortening of the life span.Shortlived laboratory models (fruit flies, nematodes, mice) are yielding rapid advances, with the discovery of mutants that increase life spans in association with altered metabolism, which leads to questions on the physiological organization of aging processes.Although these early findings do not show that a conserved genetic program actually controls aging processes across animal phylogeny, it is striking how frequently findings of metabolic rate, insulin signaling, and free radicals have emerged from very different approaches to aging in nematodes and mammals, for example.These findings hint that the genetic control of life span was already developed in the common ancestor of modern animals so that subsequent evolution of life spans was mediated by quantitative changes in the control of metabolism through insulin and the production of free radicals.",
      "\t\nAging is a complex process affecting different species and individuals in different ways.Comparing genetic variation across species with their aging phenotypes will help understanding the molecular basis of aging and longevity.Although most studies on aging have so far focused on short-lived model organisms, recent comparisons of genomic, transcriptomic, and metabolomic data across lineages with different lifespans are unveiling molecular signatures associated with longevity.Here, we examine the relationship between genomic variation and maximum lifespan across primate species.We used two different approaches.First, we searched for parallel amino-acid mutations that co-occur with increases in longevity across the primate linage.Twenty-five such amino-acid variants were identified, several of which have been previously reported by studies with different experimental setups and in different model organisms.The genes harboring these mutations are mainly enriched in functional categories such as wound healing, blood coagulation, and cardiovascular disorders.We demonstrate that these pathways are highly enriched for pleiotropic effects, as predicted by the antagonistic pleiotropy theory of aging.A second approach was focused on changes in rates of protein evolution across the primate phylogeny.Using the phylogenetic generalized least squares, we show that some genes exhibit strong correlations between their evolutionary rates and longevity-associated traits.These include genes in the Sphingosine 1-phosphate pathway, PI3K signaling, and the Thrombin/protease-activated receptor pathway, among other cardiovascular processes.Together, these results shed light into human senescence patterns and underscore the power of comparative genomics to identify pathways related to aging and longevity.\t\n\nAging is a complex process affecting different species and individuals in different ways.Comparing genetic variation across species with their aging phenotypes will help understanding the molecular basis of aging and longevity.Although most studies on aging have so far focused on short-lived model organisms, recent comparisons of genomic, transcriptomic, and metabolomic data across lineages with different lifespans are unveiling molecular signatures associated with longevity.Here, we examine the relationship between genomic variation and maximum lifespan across primate species.We used two different approaches.First, we searched for parallel amino-acid mutations that co-occur with increases in longevity across the primate linage.Twenty-five such amino-acid variants were identified, several of which have been previously reported by studies with different experimental setups and in different model organisms.The genes harboring these mutations are mainly enriched in functional categories such as wound healing, blood coagulation, and cardiovascular disorders.We demonstrate that these pathways are highly enriched for pleiotropic effects, as predicted by the antagonistic pleiotropy theory of aging.A second approach was focused on changes in rates of protein evolution across the primate phylogeny.Using the phylogenetic generalized least squares, we show that some genes exhibit strong correlations between their evolutionary rates and longevity-associated traits.These include genes in the Sphingosine 1-phosphate pathway, PI3K signaling, and the Thrombin/protease-activated receptor pathway, among other cardiovascular processes.Together, these results shed light into human senescence patterns and underscore the power of comparative genomics to identify pathways related to aging and longevity.",
      "\tINTRODUCTION\n\nHuman aging is affected by genes, life style, and environmental factors.The genetic contribution to average human aging can be modest with genes explaining 20-25% of the variability of human survival to the mid-eighties (Herskind et al., 1996;Fraser and Shavlik, 2001).By contrast, genetic factors may have greater impact on survival to the ninth through eleventh decades (Tan et al., 2008).Notably, exceptional longevity is rare and may involve biological mechanisms that differ from those implicated in usual human aging.",
      "\t\n\nAdditional 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.",
      "\t\n\nInvolvement of genes in a wide range of fundamental biological processes suggests also a broad role of these genes in regulating the aging-related phenotypes.\t\n\nAging is an extremely complex process associated with interplay of genetic, biochemical, and metabolic factors in an organism in a given environment.Although genetic studies of various animal models suggest that even a single-gene mutation can remarkably extend lifespan (Kenyon 2005;Johnson 2006) and, thus, modulate aging, no such genes are revealed in humans so far.Given that a human organism is a much more complex system than a model organism (Christensen et al. 2006), it is evident that genetic effects on the aging process should be mediated via coordinate action of a large number of inter-related processes (Kirkwood 2011).Coordinated function is rather relevant to complex biological (Soltow et al. 2010;Slagboom et al. 2011) and genetic (Bloss et al. 2011) networks than to individual genes.\t\n\nEven more disappointing result is that some genes predisposing to geriatric diseases discovered by GWAS appear to be not correlated with human longevity (Beekman et al. 2010;Deelen et al. 2011).This result questions whether findings obtained from GWAS may provide insights into the bio-genetic mechanisms underlying a healthy lifespan.In fact, this finding is very surprising because (1) genetic studies of non-human species have discovered numerous genes predisposing to aging-related processes (Cutler and Mattson 2006;Vijg and Suh 2005;Kenyon 2005;Johnson 2006;Greer and Brunet 2008), (2) nongenetic association studies show that the long-living individuals are typically in better health compared to the short-living individuals (Barzilai et al. 2003;Willcox et al. 2008b;Willcox et al. 2008a;Evert et al. 2003), and (3) candidate-gene studies (but not GWAS) document that the same genes can affect diseases and lifespan (Koropatnick et al. 2008;Kulminski et al. 2011).This is an apparent paradox which has to be carefully examined.A prominent geneticist and evolutionary biologist T. G. Dobzhansky asserts that \"nothing in biology makes sense except in the light of evolution. \"Evolution primarily maximizes fitness of individuals of reproductive age.The classical evolutionary biological theory of aging claims that aging occurs because of decline in the force of natural selection with age (Kirkwood and Austad 2000).Then, according to that theory, aging-related (senescent) phenotypes with post-reproductive manifestation are non-adaptive and subject to stochastic variation.Therefore, at a first glance evolution should not be relevant to senescent phenotypes (apart so-called grandmother hypothesis; Hawkes et al. 1998).Such phenotypes, however, can be caused by reproductive-age-related risk factors making, thus, evolution to be relevant to them (Vijg and Suh 2005;Di Rienzo and Hudson 2005;Drenos and Kirkwood 2010).",
      "\t\n\nGenes do not drive the aging process but by governing the levels of excess physiological capacity, repair, and turnover they indirectly determine potential longevity.There are no genes that specifically drive longevity but there are genes that govern biological processes that increase the likelihood of survival to reproductive maturity.The variations in excess physiological capacity, repair, and turnover accounts for the variations found in longevity both within and between species.\t\n\nThe studies in lower animals made in recent years that have led to the view that genes are involved in aging have not revealed a reversal or arrest of the inexorable expression of molecular disorder that is the hallmark of aging.These studies are more accurately interpreted to have impact on our understanding of longevity determination because all of the experimental results have altered biological variables before the aging process begins.None of these studies in invertebrates has demonstrated that the manipulation of genes has slowed, stopped, or reversed recognized biomarkers of the aging process.",
      "\t\n\nAgeing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death.Some individuals delay, escape or survive much of this age-related decline and live past age 100.Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times.However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations.Therefore, ageing is probably a highly polygenic trait.In humans, it is important to also consider differences in age-related decline that occur within and among tissues.Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time.Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing.Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association.The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing.New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.\t\nAgeing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death.Some individuals delay, escape or survive much of this age-related decline and live past age 100.Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times.However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations.Therefore, ageing is probably a highly polygenic trait.In humans, it is important to also consider differences in age-related decline that occur within and among tissues.Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time.Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing.Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association.The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing.New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.",
      "\tIV. Genome-Environment Interactions as Targets for Dietary Interventions and Drug Discovery\n\n\"[It's] possible that we could change a human gene and double our life span. \"-CynthiaKenyon (Duncan, 2004) According to the GenAge database of aging-related genes (http://genomics.senescence.info/genes/),more than 700 genes have been identified that regulate lifespan in model organisms (de Magalha es et al., 2009a).Many of these genes and their associated pathways-such as the insulin/IGF1/GH pathway-have been shown to affect longevity across different model organisms (Kenyon, 2010).Therefore, at least some mechanisms of aging are evolutionarily conserved and may have potential therapeutic applications (Baur et al., 2006).For example, evidence suggests the use of lowered IGF signaling (e.g., by targeting IGF receptors) to treat certain age-related diseases such as cancer (Pollak et al., 2004), Alzheimer's disease (Cohen et al., 2009), and autoimmune diseases (Smith, 2010).Moreover, a number of genes and pathways associated with longevity and CR are part of nutrient-sensing pathways that also regulate growth and development, including the insulin/IGF1/GH pathway (Narasimhan et al., 2009;Stanfel et al., 2009).Many of these genes modulate the response to environmental signals, such as food availability, and act in signaling pathways that if understood can be targeted (Fig. 1).The genetic regulation of aging is therefore an emerging field with multiple applications in the human nutrition, cosmetic, and pharmaceutical industries.\t\n\nThe remarkable discoveries of the past 2 decades showing that single genes can regulate aging in model organisms demonstrate that aging can be genetically manipulated (Finch and Ruvkun, 2001;Kenyon, 2010).Hundreds of genes that modulate longevity have now been identified in model organisms (de Magalha es et al., 2009a).In some cases (e.g., in worms), mutations in single genes can extend lifespan by almost 10-fold (Ayyadevara et al., 2008).Nonetheless, aging is a complex process that derives not from single genes but from the interactions of multiple genes with each other and with the environment.Evidence from animal systems shows a major impact of the environment on aging, yet environmental manipulations of aging act through genes and proteins, usually by triggering signaling pathways and modulating gene expression.In fact, some genes have been shown in model organisms to have varying effects on lifespan depending on diet (Heikkinen et al., 2009).Genes that can regulate aging in model organisms cannot be directly applied to humans through genetic manipulations for numerous legal, ethical, and technical reasons.If we could understand how the environment modulates these aging-related genes, we might be able to create antiaging therapies applicable to humans, potentially through diet, lifestyle, and even pharmacological interventions.Therefore, understanding genome-environment interactions in the context of aging can be a powerful approach to identify attractive targets for drug design.",
      "\tTranslational\n\nA LTHOUGH there is much debate about the processes driving human aging, there is little doubt that genetic influences play a significant role (1).Humans clearly live very much longer than the currently favored laboratory models of aging, and such interspecies differences in reproductively 'fit' life span must have an inherited genetic foundation.Within human populations, environmental and behavioral exposures are important but at least a quarter of life expectancy variation in twin or family studies is attributable to inherited genetic or epigenetic factors (2).Age-related conditions such as type 2 diabetes, myocardial infarction, common cancers, and Alzheimer's disease (AD) typically have onsets after the fourth decade of life; \"successful\" agers delay these onsets until relatively late in life (3).Many aging traits and diseases show moderate heritability, including cardiovascular disease (CVD) (4) and impaired physical functioning (5), independent of known environmental risk factors.",
      "\t\n\nMany factors contribute to aging, including genes.This is the first article in a 10-part series that highlight some of what is known about the influence of genes on aging and emerging treatment options that may slow down or potentially reverse the aging process.The series will address \\genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown.Underpinning these factors are wear and tear on cells and aging as a result of inability to repair or replace these affected cells.These topics have been addressed in research, health magazines, and even by talk show hosts.There is even a LongevityMap website addressing significant and nonsignificant genetic association studies in aging across the human genome (http://genomics.senescence.info/longevity/).The series will address a scientific and clinical approach to genome-related aging topics.",
      "\tGenAge: the aging gene database Philosophy and overview of resources\n\nIt is undisputed that genetic factors influence aging.In a remarkable series of recent breakthroughs, a number of genes capable of altering the aging process as a whole -or at least to a large degree -have been identified in animal models and even a few in humans (Finch & Ruvkun, 2001;de Magalhes, 2005;Kenyon, 2005).Furthermore, multiple alleles have been examined for their association with human exceptional longevity (Vijg & Suh, 2005).This is a fascinating and important area of research, yet there are now so many genes being associated with aging and longevity that keeping track of them all is becoming increasingly more difficult.Moreover, it is necessary now to study not only individual genes but their interactions with each other and with the environment, and how together genes give rise to a given phenotype: the so-called systems biology approach.To help researchers address these issues we created GenAge, a database of genes related to longevity and/or aging.\t\n\nAlthough the models data set comprises all genes (to our knowledge) shown by the time of the latest update to statistically increase longevity or alter the aging process in a noticeable way, in the human data set we try to evaluate whether a given intervention is affecting the aging process itself or not.For example, many mutations may increase longevity by decreasing the incidence of specific diseases, rather than by altering the basic process of aging (de Magalhes et al ., 2005a(de Magalhes et al ., , 2005b)).Therefore, the human data set is not merely an extension of the work conducted in model organisms and of its bibliography, but a manually selected list of the most pertinent human aging candidate genes, each presented with a higher annotation level.We cite studies on whether the functions of aging-associated genes in model organisms are conserved in their human orthologues.Likewise, we cite flaws in previous studies based on new published observations, although we have a neutral stance on conflicting findings from different research groups.Our policy is to cite all conflicting reports and let visitors make their own decisions on how to interpret them.By contrast, each entry in GenAge model organisms has only one reference: the first publication reporting an association of the gene with longevity or aging.Moreover, one of the latest enhancements in the human data set was the inclusion of Gene Ontology annotation.Gene Ontology terms and annotation files were obtained from the Gene Ontology Consortium website (http://www.geneontology.org/ ) and provide an additional layer of description for the gene products in a cellular context (Ashburner et al ., 2000).",
      "\t\n\nAgeing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death.Some individuals delay, escape or survive much of this age-related decline and live past age 100.Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times.However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations.Therefore, ageing is probably a highly polygenic trait.In humans, it is important to also consider differences in age-related decline that occur within and among tissues.Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time.Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing.Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association.The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing.New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.\t\nAgeing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death.Some individuals delay, escape or survive much of this age-related decline and live past age 100.Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times.However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations.Therefore, ageing is probably a highly polygenic trait.In humans, it is important to also consider differences in age-related decline that occur within and among tissues.Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time.Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing.Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association.The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing.New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future."
    ],
    [
      "\t\n\nGenomic 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.\t\nGenomic 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.",
      "\t\n\nRecent developments on the genetics of aging can be seen as several streams of effort.In general, humans show a relatively modest (<50%) heritability of life spans (results obtained from twin studies discussed below).The apoE polymorphisms are remarkable for their influence on both cardiovascular disease and Alzheimer disease.In contrast, rare mutant genes with high penetrance cause these same diseases but with early onset and a major shortening of the life span.Shortlived laboratory models (fruit flies, nematodes, mice) are yielding rapid advances, with the discovery of mutants that increase life spans in association with altered metabolism, which leads to questions on the physiological organization of aging processes.Although these early findings do not show that a conserved genetic program actually controls aging processes across animal phylogeny, it is striking how frequently findings of metabolic rate, insulin signaling, and free radicals have emerged from very different approaches to aging in nematodes and mammals, for example.These findings hint that the genetic control of life span was already developed in the common ancestor of modern animals so that subsequent evolution of life spans was mediated by quantitative changes in the control of metabolism through insulin and the production of free radicals.",
      "\tIntroduction\n\nWith the development of human genomics research, a large number of studies of the genetics of longevity have been conducted.Scientists from various countries have proposed many different theories concerning the mechanisms of aging from different perspectives, involving oxidative stress, energy metabolism, signal transduction pathways, immune response, etc. [1,2].These mechanisms interact with each other and are influenced by heredity to some degree [2,3].The identification of longevity-related biological markers is critical to an indepth understanding of the mechanisms of carrier protection against common disease and/or of the retardation of the process of aging.",
      "\t\n\nSomatic 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].\tConclusions and Perspectives\n\nThe advent of new technologies has allowed the identification of conserved pathways involved in the aging process, as well as the association of genomic variants with human longevity.Nevertheless, heritability of human longevity has been estimated from 20% to 30%, reinforcing the fact that external factors such as diet, environment, and physical activity play a critical role in the human life span.",
      "\t\n\nM 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).\t\nLiving to a late age without suffering any major health problems is a genetically influenced trait.To identify the genes contributing to this important phenotype, a 10 cM genome screen was performed in 95 pairs of male fraternal twins concordant for healthy aging.Individuals meeting these criteria were defined as those attaining the age of 70 free of cardiovascular disease (coronary surgery, diabetes, heart attack, and stroke) and prostate cancer.Six chromosomal regions were identified with logarithm of odds (LOD) scores greater than 1.2 ( p , .01).A region on chromosome 4 at marker D4S1564 produced a LOD score of 1.67; this was the same marker previously linked to extreme longevity segregating as an autosomal dominant trait in centenarian families.Our results provide independent evidence that a locus on the long arm of chromosome 4 is associated with better physical aging and/or longevity.",
      "\t\n\nMany factors beside genetics influence how long a person will live and our lifespan cannot be read from our DNA alone.Nevertheless, Timmers et al. had hoped to narrow down their search and discover specific genes that directly influence how quickly people age, beyond diseases.If such genes exist, their effects were too small to be detected in this study.The next step will be to expand the study to include more participants, which will hopefully pinpoint further genomic regions and help disentangle the biology of ageing and disease.",
      "\tIntroduction\n\nThe 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).",
      "\t\n\nIn 2021, Science published a special issue entitled \"125 Questions: Exploration and Discovery.\" One of these 125 questions was \"Can we stop ourselves from aging? \"The U.S. National Institute on Aging (NIA) at the National Institutes of Health (NIH) states that \"aging is associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes.\" Although geneticists and epidemiologists have long debated the relative importance of the role played by genotype or the environment in the development of age-related diseases, it is apparent that both can play substantial roles in this process [6,7].However, most etiological studies have concentrated on the role of genotype and have considered the environment to play a secondary role.Nevertheless, an analysis of GBD data showed that nearly 50% of deaths worldwide are attributable to environmental exposure, primarily exposure to airborne particulates (including household air pollution and occupational exposure; 14% of all deaths), smoking and secondhand smoke (13%), plasma sodium concentrations (6%), and alcohol consumption (5%) [8].In contrast, a recent analysis of 28 chronic diseases in identical twins showed that the genetic-related risks of developing one of five age-related diseases were 33.3%, 10.6%, 36.3%, 19.5%, and 33.9% for AD, PD, CAD, COPD, and T2DM, respectively, with a mean of only 26% [9].The results of over 400 genome-wide association studies (GWASs) have also elucidated that the heritability of degenerative diseases is only approximately 10% [10,11].Consequently, nongenetic drivers, such as environmental factors, are now recognized as major risk factors for age-related diseases.The contributions of environmental factors to the development of age-related diseases can be revealed by analyses of all of the factors to which individuals are exposed in their life and the relationships between these exposures and age-related diseases [12,13].",
      "\tIV. Genome-Environment Interactions as Targets for Dietary Interventions and Drug Discovery\n\n\"[It's] possible that we could change a human gene and double our life span. \"-CynthiaKenyon (Duncan, 2004) According to the GenAge database of aging-related genes (http://genomics.senescence.info/genes/),more than 700 genes have been identified that regulate lifespan in model organisms (de Magalha es et al., 2009a).Many of these genes and their associated pathways-such as the insulin/IGF1/GH pathway-have been shown to affect longevity across different model organisms (Kenyon, 2010).Therefore, at least some mechanisms of aging are evolutionarily conserved and may have potential therapeutic applications (Baur et al., 2006).For example, evidence suggests the use of lowered IGF signaling (e.g., by targeting IGF receptors) to treat certain age-related diseases such as cancer (Pollak et al., 2004), Alzheimer's disease (Cohen et al., 2009), and autoimmune diseases (Smith, 2010).Moreover, a number of genes and pathways associated with longevity and CR are part of nutrient-sensing pathways that also regulate growth and development, including the insulin/IGF1/GH pathway (Narasimhan et al., 2009;Stanfel et al., 2009).Many of these genes modulate the response to environmental signals, such as food availability, and act in signaling pathways that if understood can be targeted (Fig. 1).The genetic regulation of aging is therefore an emerging field with multiple applications in the human nutrition, cosmetic, and pharmaceutical industries.\t\n\nWith an aging population, there is a great and urgent need to develop approaches and therapies targeting the aging process and age-related diseases (Butler et al., 2008).Delaying the process of aging, even slightly, would have profound social, medical and economic benefits (Olshansky et al., 2006;Butler et al., 2008).For example, slowing aging by a mere 7 years would cut mortality of age-related diseases by half at every age.Therefore, the potential benefits from research on the basic biology and genetics of aging are unparalleled in terms of improving quality of life and health.Although much debate remains regarding the molecular causes of aging, findings from model organisms show that aging is surprisingly plastic and can be manipulated by both genetic and environmental factors (Finch and Ruvkun, 2001;Kenyon, 2010).In principle, therefore, it is possible to manipulate human aging.Unlocking this capacity to manipulate aging in people would result in unprecedented human health benefits, and it opens new opportunities for industry.",
      "\t\n\nA better understanding of pathways that contribute at middle age to the divergence of healthy and unhealthy ageing humans may be substantiated by in depth studies of the cells and tissues of longevity family members in the context of their genomic background.",
      "\tRelevance to nurse practitioner practice\n\nCurrently, there is no cure for genetic variants associated with rapid aging, but novel agents that may slow down the aging process are being tested.The authors of this article advocate individual participation in association studies of aging and pharmacologic risk mitigation or reversal of symptoms for those with known genetic disease risk.Direct to consumer epigenetic biological aging tests and telomere length tests are available; but they are not approved by the Food and Drug Administration.Health care providers may want to consider the simple but key clinical and personal changes, suggested above, to enhance DNA health, wellness, and longevity.Simple mindful changes in behavior, environmental exposure, food/supplement use, weight loss, and regular exercise can reduce adduct exposure damage and impact telomere length, potentially increasing longevity.A Mediterranean diet containing fruits and whole grains along with fiber, antioxidants, soy protein, and healthy fats (from avocados, fish, flax, and walnuts) is suggested to reduce DNA adducts and protect telomeres.In light of our current pandemic, focus on population health, and restrictions to health care access, especially in rural communities, health care providers could incorporate these lifestyle and dietary principles in telehealth visits with patients to reduce disease risk and optimize healthy aging.\t\n\nMany factors contribute to aging, including genes.This is the first article in a 10-part series that highlight some of what is known about the influence of genes on aging and emerging treatment options that may slow down or potentially reverse the aging process.The series will address \\genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown.Underpinning these factors are wear and tear on cells and aging as a result of inability to repair or replace these affected cells.These topics have been addressed in research, health magazines, and even by talk show hosts.There is even a LongevityMap website addressing significant and nonsignificant genetic association studies in aging across the human genome (http://genomics.senescence.info/longevity/).The series will address a scientific and clinical approach to genome-related aging topics.",
      "\t[PubMed: 18208581]\n3. de Magalhes JP, Wuttke D, Wood SH, Plank M & Vora C Genome-environment interactions that\nmodulate aging: Powerful targets for drug discovery. Pharmacol. Rev. 64, 88101 (2012). [PubMed:\n22090473]\n4. McDaid AFet al.Bayesian association scan reveals loci associated with human lifespan and linked\nbiomarkers. Nat. Commun. 8, 15842 (2017). [PubMed: 28748955]\n5. Fontana L & Partridge L Promoting health and longevity through diet: From model organisms to\nhumans. Cell 161, 106118 (2015). [PubMed: 25815989]\n6.",
      "\t\n\nStudies in various models have revealed that genetic differences and somatic mutations underlie longevity, but non-genetic contributions also play a major role (Cournil and Kirkwood, 2001).Calorie restriction (Bordone and Guarente, 2005), lowering of basal metabolic rate (Ruggiero et al., 2008), upregulated stress response (Migliaccio et al., 1999), restoration of mi-tonuclear protein balance (Houtkooper et al., 2013), and reduced fertility (Westendorp and Kirkwood, 1998) have all been shown to correlate with lifespan extension.These observations illuminate the role of ''epi''-genetic mechanisms in modulating longevity pathways.",
      "\tThe mechanisms that underlie healthy agingparticularly, the cognitive as-\n\npectsremain poorly understood. Research suggests that genetics play a significant role in determining an individuals\nsusceptibility or resilience to cognitive decline and dementia\n(Harris and Deary 2011; Ridge et al. , 2013). Identification of precise genetic factors involved would provide insight into\n\nCell Reports 32, 108091, September 1, 2020  2020 The Author(s). 1\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ll\nOPEN ACCESS\n\nReport\n\nFigure 1.",
      "\t\n\nWith modern genomic technologies and largescale data analysis methods, it is possible to sift through the genes of populations to find the loci that act to postpone aging. [3]There are uncertainties with the comparison of populations with different rates of aging.However, it is superior to experimental designs that only consider age-dependence or dietary-response, without determining causal mechanisms."
    ],
    [
      "\t\n\nWhen considering the advantages and disadvantages of dogs as a model for geroscience research, it is useful to note that the vast majority of mammalian studies on the basic biology of aging are performed in a relatively small number of inbred mouse strains.Typical average lifespan for most of these mouse strains is approximately 2-3 years, and animals are generally kept in highly controlled, pathogen-free facilities and fed one of a small number of standard, refined mouse chow diets.A majority of laboratory-aged mice die from cancers, many of which are not commonly occurring in human populations.Although there have been recent efforts to define comprehensive measures of frailty and healthspan in aging mice (Parks et al. 2012;Richardson et al. 2016), consensus is still lacking, and functional measures of key organ systems are rarely utilized by the broader field.For example, changes in cardiac and cognitive/behavioral function are rarely assessed in studies of aging mice, but are obviously important components of human aging.As we discuss below, the challenges of the mouse as an aging model underscore the value of studying aging in companion dogs.In the following paragraphs, we expand on some of the additional features of companion dogs that make them uniquely well suited for geroscience research.",
      "\t\n\nStudies on the aging of mammals are rather limited by the long life span of the commonly used model organisms.Thus, both nonvertebrate and invertebrate organisms, with their shorter life span and ease of genetic and environmental manipulations, gained popularity among researchers in the aging field as experimental models for aging studies.Among them, budding yeast or Saccharomyces cerevisiae is a highly informative organismal model for aging studies with its genetic tools, short life span, and fully sequenced genome (20,21).Despite being unicellular, yeast has been an excellent model to identify and characterize conserved basic biological processes, including aging.Yeast has been extensively used to identify genes and interventions responsible for life span extension and to gain insights into the aging processes of all eukaryotic organisms.In parallel, over the years, studies on invertebrate organisms, such as Drosophila melanogaster (flies) and Caenorhabditis elegans (worms), and certain vertebrate models, such as mice, zebrafish, naked mole rats, and, most recently, African turquoise killifish, have also provided invaluable information to help us understand the complexity of the process of aging and the influence of overlapping pathways on the outcome (22,23).",
      "\tAfter specific tissues (brain regions and hind\nlimbs) were dissected immediately upon sacrifice,\nAging Clin Exp Res\n\ncarcasses were preserved in buffered formalin until comprehensive pathological examinations were completed. Genotyping and genetic analyses\nMice that began the phenotyping procedure in each of the 3\nage groups were genotyped at 96 microsatellite markers\n[1317]. Distortions in the frequency of alleles with aging\nwere detected by Chi-squared tests conducted for each\nlocus.",
      "\tExperimental Goals and Significance\nThe experimental goal of the work performed in this dissertation was to identify\nspecific gene(s) and molecular pathways underlying HSC aging in two commonly used\nstrains of inbred mice using a forward genetic approach.",
      "\t\n\nCross-breeding of N. furzeri strains with different life spans is currently being performed in our laboratory and should enable the identification of quantitative trait loci and facilitate cloning of aging-relevant genetic determinants.The present study illustrates the challenges that will have to be addressed in an N. furzeri genome project that we would like to establish in order to make maximal use of this fish species as a vertebrate model for aging research.",
      "\t\n\nMost studies in this area have been performed in the classical animal models of aging, such as C. elegans, yeast, and rodents (mice and rats); however, in this chapter we have attempted to include only representative studies in humans, which were performed in samples of skeletal muscle, heart, and brain obtained from elderly individuals.\tAnimal Models for HGPS\n\nIn recent years, animal models have been at the forefront of aging research, making important contributions to a better understanding of this process at the organismal level.Some animals have been preferred in aging research, ranging from invertebrate (Caenorhabditis elegans and Drosophila melanogaster) to mammal species (murine and primate species).Nonetheless, scientists preferably chose mouse models for the study of age-related diseases for various reasons: (a) mice are closely related to humans, with nearly 99% of human orthologous in mice; (b) their relatively short lifespan and small size allow surveillance of the aging process within a pertinent time frame and make their housing less expensive; (c) the feasibility of performing genetic manipulations facilitates the engineering of transgenic strains (gain-and loss-of function mice) that model premature aging disorders.In this section, we describe the major HGPS mouse models previously developed (see Table 10.1 for details).",
      "\tJournal of Theoretical Biology 12:1245. Hughes, K. A., and B. Charlesworth. 1994. A genetic analysis of senescence in Drosophila. Nature 367:6466. Hutchinson, E. W., and M. R. Rose. 1990. Quantitative genetic analysis of Drosophila stocks\nwith postponed aging. Pages 6687 in D. E. Harrison, ed. Genetic Effects on Aging II. Caldwell, NJ: Telford. Kannisto, V., J. Lauristen, and J. W. Vaupel. 1994. Reduction in mortality at advanced ages: Several decades of evidence from 27 countries. Population Development Review 20:793810. 580\n\n\n\nA P P L I C AT I O N S\nKennedy, B. K., and L. Guarente. 1996.\tGenetic analysis of aging in Saccharomyces cerevisiae. Trends in Genetics 12:355359. Khazaeli, A. A., S. D. Pletcher, and J. W. Curtsinger. 1998. The fractionation experiment:\nReducing heterogeneity to investigate age-specific mortality in Drosophila. Mechanics of\nAgeing and Development 16:301317. Khazaeli, A. A., W. Van Voorhies, and J. W. Curtsinger. 2005. The relationship between life\nspan and adult body size is highly strain-specific in Drosophila melanogaster. Experimental\nGerontology 40:37785. Kim, S. K. 2007. Common aging pathways in worms, flies, mice and humans. Journal of\nExperimental Biology 210:16071612. Kirkwood, T. B. L. 1977. Evolution of aging. Nature 270:301304.",
      "\tIn Vivo\n\nIn vivo studies can further test the effect of a manipulation or treatment, either targeted or scattered, on the whole organism.Most of these biological models offer many advantages over humans, for instance, their basic biology and genomes are well documented and are easier to manipulate genetically.Furthermore, they have much shorter life spans than humans, enabling longitudinal studies, while ethical issues, long natural life span, environmental influences, genetic heterogeneity, and various other limiting factors complicate the use of human subjects in aging research.Regardless of the advantages listed earlier and the eminent contribution to our understanding of the aging process, the use of animal models in aging studies has its own limitations.Aging is not a simple process, and there is no genuine agreement about what it is and how to define it (14,15), despite the agreement on being a multifactorial and complex phenomenon.Additionally, there is conflicting evidence about aging as a process that is similar across all organisms or particular to each species (15,16).Therefore, it is important to draw attention to the fact that animal models are usually chosen for convenience rather than for specific features applicable to human aging.Hence, choosing the suitable animal model to answer the specific question we aim to understand is of high importance in these types of studies.Among the most prevalent aging model organisms are Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus.As a single-celled organism, S. cerevisiae is easily grown, manipulated, and observed; together with a well-characterized genome that bares much resemblance to bigger and more complex organisms, this model organism among others is a convenient platform for the study of the aging phenotype.Another important model system for studying a range of biological processes, including aging, is the nematode C. elegans.C. elegans has a short adult life span of ~2 weeks and a well-documented anatomy which is visible using a microscope.This enables easy observations of aging-related changes in the whole organism, in specific tissues and organs, and even on molecular and cellular levels (17)(18)(19)(20)(21).The classic genetic model organism, D. melanogaster, is also used FiGURe 1 | Key elements in the DNA damage response (DDR) pathway.In case of double-strand breaks (DSB), the DNA damage sensor MRN complex recruits the protein kinase ATM which activates H2AX at the damaged site.H2AX connects to MDC1, and this complex amplifies the activity of the MRN complex which, in a positive feedback, amplifies the ATM activity and the dispersal of H2AX along the chromosome.MDC1 and 53BP1 further mediates the activation of CHK2 which carries the signal to distant locations on the genome.For single-strand breaks (SSB), the protein kinase ATR is activated and amplified by the 9-1-1 complex and TOPBP1, which also mediates the activation of CHK1.The signaling pathway cascades toward the key factors p53 and CDC25.When the lesion is repaired, the DDR complexes are dismantled (2,4,9). in the study of aging.Studies conducted in these flies have identified single gene mutations that influence their life span.One of the strengths of Drosophila as a model organism is the capability to illustrate how genes that have an established role in regulating organismal life span particularly influence cellular and tissue function, how they work together, and how their tissue-specific functions might be linked (22)(23)(24)(25).That said, Drosophila is far from being a good model for human aging as they share only 60% of the human genome.A better similarity is achieved with M. musculus, the mouse.It is the most commonly used model in biological research for various reasons.Mice are small, have a short generation time, and an accelerated life span which means they are not expensive and require only little space and time, compared to larger animal models.Another important reason is the fact that the mouse genome is well documented and can be easily manipulated.In addition, they are biologically similar to humans, exhibiting many of the same diseases and conditions.Nevertheless, mice do not develop several important age-related diseases naturally (e.g., atherosclerosis and diabetes), a fact that limits their potential as an aging model.All the organisms described earlier are short-lived, which is one of their desired traits as model organisms.However, that may not be appropriate for the study of human aging.Thus, in recent years there have been more studies conducted on non-model long-living organisms such as the naked mole rats and bats, which may be more appropriate models in understanding healthy human aging.The naked mole rat (Heterocephalus glaber) is a very important non-model organism in cancer and aging studies.This subterranean, mouse-sized, eusocial rodent is known as the longest-living rodent, living 4-17 years in the wild and with captive individuals demonstrating exceptional longevity that exceeds 30 years (26)-almost an order of magnitude longer than mice.Moreover, until a few years ago no cancer cases were reported in NMRs, and researchers failed to induce tumorigenesis, placing this rodent as a novel model for cancer studies.Bats are the second most speciose mammalian order after rodents.Little brown bats (Myotis) are the smallest bats (3-30 g) with the highest longevity records (Myotis myotis live for 37.1 years and M. brandti live for 41 years).Nevertheless, longevity is generally high in all bat lineages, which makes them an interesting model in biogerontology.One of the most interesting non-model organisms adopted for aging research is the Bowhead whale (Balaena mysticetus), which is estimated to be the longest-living mammal, reaching the age of ~200 years and also one of the biggest species, with length and weight of 20 m and 100 tons (6,27).Bowhead whales live in arctic environment and are well adapted to these harsh surroundings.They are considered to be resistance to cancer and age-related diseases, and thus, though research is very technically complicated, the study of Bowhead whale in the context of longevity could improve our understanding of molecular mechanisms of healthy aging (27).",
      "\t\n\nOur own work has taken a different tack: we have attempted to determine whether mutations with differential effects on aging may be present within the many available populations of laboratory-adopted inbred mice.The goal is not so much to clone these genes-if indeed they existbecause positional cloning strategies of this kind require many thousands of animals and would be extremely expensive using an assay, age at death, that is itself so costly.Instead, the goal has been to use gene mapping methods to test hypotheses about aging and to develop new animal models that will be useful for testing well-specified hypotheses about the molecular basis for age-dependent changes.In the absence of a validated battery of biomarkers of aging, we (like most others) have reluctantly decided to use mouse life span as a crude surrogate for aging itself, reasoning that genetic alleles that extend life span well beyond the median for the tested population may be operating via an influence on aging itself.Work conducted using recombinant inbred mouse stocks (Gelman et al., 1988;de Haan and Van Zant, 1999) has suggested that life-span differences between pairs of inbred mouse lines might reflect the influence of as few as 4-7 polymorphic loci, providing some basis for hope that some of these would have an effect large enough to be detected by a genome scan experiment involving 300-1,200 mice.",
      "\t\n\nThe present study offers certain alternatives relative to studies using clinical samples by employing inbred mouse strains.The use of inbred mice achieves several advantages such as isogenicity and genomewide homozygosity among individuals within a strain, which significantly reduces gene expression variability between individuals.This variability was confounding in the aging human study (18).Aging mouse models have been used, for example, to evaluate global gene expression changes in skeletal muscle (35).One of the primary findings with aged skeletal muscle suggested that stress-response genes, including heat shock-response and oxidative stress-inducible genes, were upregulated.A similar study focusing on retinal tissue also found an upregulation in stressresponse genes with age (25).While both of these previous studies used C57BL/6J (B6) mice, there was a common agedependent upregulation of stress-response genes across different tissues.",
      "\tJournal of Theoretical Biology 12:1245. Hughes, K. A., and B. Charlesworth. 1994. A genetic analysis of senescence in Drosophila. Nature 367:6466. Hutchinson, E. W., and M. R. Rose. 1990. Quantitative genetic analysis of Drosophila stocks\nwith postponed aging. Pages 6687 in D. E. Harrison, ed. Genetic Effects on Aging II. Caldwell, NJ: Telford. Kannisto, V., J. Lauristen, and J. W. Vaupel. 1994. Reduction in mortality at advanced ages: Several decades of evidence from 27 countries. Population Development Review 20:793810. 580\n\n\n\nA P P L I C AT I O N S\nKennedy, B. K., and L. Guarente. 1996.\tGenetic analysis of aging in Saccharomyces cerevisiae. Trends in Genetics 12:355359. Khazaeli, A. A., S. D. Pletcher, and J. W. Curtsinger. 1998. The fractionation experiment:\nReducing heterogeneity to investigate age-specific mortality in Drosophila. Mechanics of\nAgeing and Development 16:301317. Khazaeli, A. A., W. Van Voorhies, and J. W. Curtsinger. 2005. The relationship between life\nspan and adult body size is highly strain-specific in Drosophila melanogaster. Experimental\nGerontology 40:37785. Kim, S. K. 2007. Common aging pathways in worms, flies, mice and humans. Journal of\nExperimental Biology 210:16071612. Kirkwood, T. B. L. 1977. Evolution of aging. Nature 270:301304.",
      "\t\n\n(ii) Uncertainties exist as to the most suitable model systems for molecular biological studies on aging.Although material from humans should be employed where possible, for practical reasons animal model systems like rats and mice are indispensible.There is evidence that, provided their health status and husbandry is optimal, rodents age much in the same way as humans do (Burek 1978).For studying certain fundamental processes, such as the occurrence of various types of DNA rearrangement, lower organisms and cell lines can also be employed.Various aspects of mammalian development and differentiation have been revealed in such model systems, which could facilitate the interpretation of observed phenomena and their relevance to the aging process.However, in these cases results obtained cannot be extrapolated directly to the human situation with respect to physiological consequences.",
      "\tTo identify genes and molecular\npathways regulating memory capabilities during aging, here we\nperform a forward systems genetic analysis on an aged cohort of\nstrains from the BXD GRP. 2. Methods\n2.1. Animals\nMale and female mice were group housed (2e5 per cage) and\nmaintained in colony housing (12-hour light/dark cycle) with ad\nlibitum access to food and water.",
      "\t\n\nTaking advantage of the long-range contiguity of the N. furzeri reference sequence, we set out to study whether aging-related genes show positional gene enrichment (PGE) in sgrs.To this end, we identified aging-related DEGs in three tissues (brain, liver, and skin) by applying two different approaches: (1) we compared young versus old MZM-0410 (5 weeks versus 39 weeks, corresponding to 10% versus 75% of maximum lifespan), and (2) we compared GRZ versus MZM-0410 at 12 weeks.As aging rates differ between these strains (Terzibasi et al., 2008), the same chronological age in the second approach corresponds to 50% of the maximum lifespan in GRZ and 24% in MZM-0410 (Data S4A-S4G).",
      "\tFor example, investigators funded by\nNIH National Institute on Aging have been working assiduously for years using a complex 4-way\nmouse F2 intercross to understand how a multitude of interventions affect longevity\n\nAccepted Article\n\n(www.nia.nih.gov/research/dab/interventions-testing-program-itp). Scientists at three sites have\nsystematically phenotyped ~15,000 animals using a range of diets, pharmaceuticals, and\nsupplements. Fortunately, they had the foresight to save tails, and the genetic component is now\nbeing bolted on at a cost of about $20/animala bargain given the cost of obtaining longevity data.",
      "\t\n\nVarious animal models have been critical for uncovering key pathways related to aging.Genetically tractable models such as yeast have been used to investigate both replicative lifespan, measured by the maximum number of mitotic divisions a cell can undergo, and chronological lifespan, measured by the length of time a cell can survive in a post-mitotic state (Kaeberlein et al., 2007).Other studies have taken advantage of the short lifespans of worms and flies (Brandt and Vilcinskas, 2013;Tissenbaum, 2012).Studies in these models have contributed greatly to the field but cannot fully recapitulate the complex nature of human aging, particularly with respect to age-related diseases and the decline of healthspan.Therefore, vertebrate models such as mice have been utilized, taking advantage of genetic proximity to humans and the availability of gene knockout and premature aging models (Quarrie and Riabowol, 2004).Unfortunately, mouse lifespan is too long for efficient laboratory studies of normal aging, creating the need for alternative short-lived vertebrate models such as the African turquoise killifish (Nothobranchius furzeri) (Harel et al., 2015) which lives for 4-6 months and recapitulates many of the age-related pathological changes found in humans.",
      "\t\n\nInstead, we recommend the use of organisms that have had their aging slowed or postponed, but that do not merely have life \"stretching\", unlike cooled poikilotherms.That is, we propose that aging studies normally be based on the comparison of normal healthy animals with an experimental group that lives even longer, with increased total biological activity, from reproduction to locomotion to metabolic work.Such organisms exist among Drosophila stocks, including some of the mutants with increased lifespan and the selectively bred populations."
    ],
    [
      "\t\nGenomic 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.\t\n\nGenomic 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.",
      "\t\n\nStudies 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].",
      "\t\n\nSomatic 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].",
      "\t\n\nsmall number of genes or interventions are known to increase life span in different model organisms.A selection of these are shown here.\t\nUnbiased genome-wide studies of longevity in S. cerevisiae and C. elegans have led to the identification of more than one hundred genes that determine life span in one or both organisms.Key pathways have been uncovered linking nutrient and growth factor cues to longevity.Quantitative measures of the degree to which aging is evolutionary conserved are now possible.A major challenge for the future is determining which of these genes play a similar role in human aging and using that information to develop therapies toward age-associated diseases.\t\n\nUnbiased genome-wide studies of longevity in S. cerevisiae and C. elegans have led to the identification of more than one hundred genes that determine life span in one or both organisms.Key pathways have been uncovered linking nutrient and growth factor cues to longevity.Quantitative measures of the degree to which aging is evolutionary conserved are now possible.A major challenge for the future is determining which of these genes play a similar role in human aging and using that information to develop therapies toward age-associated diseases.",
      "\t\n\nThe only two genes associated with human longevity that have been replicated in multiple populations are FOXO3A and APOE [11,12,15,26,28 -31].The effect sizes of these two genes for longevity are small with odds ratios of 1.26 and 1.45 for survival to age 100 in replicate studies for FOXO3A and APOE, respectively [10,29].These genes account for only a small portion of the genetic contribution to longevity measured through family heritability studies [4,5].Therefore, much of the heritability of lifespan remains to be explained.",
      "\t\n\nIn 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.",
      "\t\nClear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives.To identify such longevity alleles, we performed the largest genomewide linkage scan thus far reported.Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in fifteen study centers of eleven European countries as part of the Genetics of Healthy Ageing (GEHA) project.In the joint linkage analyses we observed four regions that\t\n\nClear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives.To identify such longevity alleles, we performed the largest genomewide linkage scan thus far reported.Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in fifteen study centers of eleven European countries as part of the Genetics of Healthy Ageing (GEHA) project.In the joint linkage analyses we observed four regions that",
      "\t\nLiving to a late age without suffering any major health problems is a genetically influenced trait.To identify the genes contributing to this important phenotype, a 10 cM genome screen was performed in 95 pairs of male fraternal twins concordant for healthy aging.Individuals meeting these criteria were defined as those attaining the age of 70 free of cardiovascular disease (coronary surgery, diabetes, heart attack, and stroke) and prostate cancer.Six chromosomal regions were identified with logarithm of odds (LOD) scores greater than 1.2 ( p , .01).A region on chromosome 4 at marker D4S1564 produced a LOD score of 1.67; this was the same marker previously linked to extreme longevity segregating as an autosomal dominant trait in centenarian families.Our results provide independent evidence that a locus on the long arm of chromosome 4 is associated with better physical aging and/or longevity.",
      "\tIntroduction\n\nThe 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).",
      "\t\nIn animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent.The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex.Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction.Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small.Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology.Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death.By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.\t\n\nIn animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent.The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex.Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction.Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small.Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology.Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death.By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.\tGENETIC STUDIES OF HUMAN LONGEVITY\n\nGenetic and genomic studies into longevity have been performed based on a hypothesis, referred to as a candidate gene approach.Alternatively, explorative genome-wide analyses have been applied in which genetic variation and gene transcription across the complete genome are being studied for associations with longevity and related traits.Genetic studies into human disease and longevity include candidate gene approaches, genome-wide association studies (GWASs) and genome-wide linkage studies.",
      "\t\n\nThe 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 chter 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.",
      "\tIntroduction\n\nApproximately 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 gele 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 chter 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.",
      "\t\n\nThe only two genes associated with human longevity that have been replicated in multiple populations are FOXO3A and APOE [11,12,15,26,28 -31].The effect sizes of these two genes for longevity are small with odds ratios of 1.26 and 1.45 for survival to age 100 in replicate studies for FOXO3A and APOE, respectively [10,29].These genes account for only a small portion of the genetic contribution to longevity measured through family heritability studies [4,5].Therefore, much of the heritability of lifespan remains to be explained.",
      "\t\n\nMost 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]."
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