1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
|
{
"question": [
"is there a specific genetic variation that can cause someone to live longer? please make your answer accessible to a non-expert"
],
"answer": [
"Yes, certain genetic variations have been associated with longer lifespans. For example, variations in the APOE, FOXO3A, and EXO1 genes have been linked to longevity. However, it's important to note that these genes don't guarantee a longer life, as longevity is influenced by a combination of genetic, environmental, and lifestyle factors."
],
"contexts": [
[
"Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.Genomic analysis of longevity offers the potential to illuminate the biology of human aging.Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA).We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated.We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD.Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.",
"DIFFERENT GENETIC MODELS OF EXCEPTIONAL LONGEVITYWe used the whole genome sequences of these two subjects to test different hypotheses about the genetics of exceptional longevity.These non-exclusive hypotheses and the results of the analyses are described in the sections that follow.We also used the genome sequences of these two subjects to test different genetic models of exceptional longevity.The insulin pathway, caloric restriction, and lipid metabolism significantly influence lifespan in other organisms including the mouse, fly, and worm (Christensen et al., 2006) and have provided natural candidates for the genetics of human exceptional longevity.Our analysis shows that while the man had several of the noted longevity variants in metabolic genes, particularly FOXO3A, the woman was homozygous only for one variant in HSP70 that is also common in the population.No additional novel coding SNPs in these putative genes were discovered, and the different genetic profiles of these candidate genes in the two supercentenarians suggest that not all of the genetic variants associated with exceptional longevity to-date are necessary to achieve such survival, and even if some of these variants may have a role in longevity there are likely many more yet to be discovered.This suggests that the metabolic hypothesis may be just one of the many paths to exceptional lifespan.It is also likely that environmental factors and possibly the genetic ancestry may influence the likelihood of an individual to live long ages directly or by interacting with the genetic background.The NECS has shown that the chance of male and female siblings of centenarians to live past 100 can be 8 and 17 times higher than the risk in the general population (Perls et al., 2002).Consistent with this observation, our data suggest that the genetic contribution increases with older and older ages as the limit of lifespan is approached (Sebastiani et al., 2012).The male supercentenarian included in this study had strong longevity in his family.Although we do not have information about the family history of the female supercentenarian, she has living offspring who are approaching their nineties in good health and are currently enrolled in the NECS.The heterogeneity of the results herein suggest that sequencing additional exceptionally old individuals of different genetic ancestry and possibly their family members will provide the critical information to understand roles of common and rare genetic determinants of exceptional longevity and healthspan.The nature and contribution of genetic variation to exceptional longevity remains unclear, particularly the role for undiscovered rare genetic variants with large effects and/or the presence of many common genetic variants with small effects (Bloss et al., 2010).Exceptional longevity is typically characterized by strong familiality (Perls et al., 2000(Perls et al., , 2002;;Atzmon et al., 2005;Schoenmaker et al., 2006) as well as a marked delay in disability (Terry et al., 2008) and, as human lifespan is approached at about age 110 years, many such individuals compress not only disability but also age-related diseases (Andersen et al., 2011).Studies of centenarians have provided strong evidence to support the hypothesis that a genetic contribution to human exceptional longevity is decisive, although only a small number of genetic variants with modest effects have been irrefutably linked to this phenotype (Schachter et al., 1994;Barzilai et al., 2003;Christensen et al., 2006;Wheeler and Kim, 2011).The technology of next generation sequencing provides a tool to generate data that may eventually provide an answer (Metzker, 2009).",
"Genetics of Interspecies Variation in Genome Instability and LongevityThe influence of genetics in longevity is most obvious when we consider the dramatic life span differences among species.Whereas a nematode worm can live no longer than approximately 30 days, a human can live to 100 years.It is generally assumed that such species-specific differences, which are far larger than the also-not-inconsiderable intraspecies variations in life span, reflect major",
"IntroductionWorldwide human populations have shown an increase in mean life expectancy in the past two centuries (Oeppen & Vaupel, 2002).This is mainly because of environmental factors such as improved hygiene, nutrition, and health care.The large variation in healthy lifespan among the elderly has prompted research into the determinants of aging and lifespan regulation.The genetic contribution to human lifespan variation was estimated at 25-30% in twin studies (Gudmundsson et al., 2000;Skytthe et al., 2003;Hjelmborg et al., 2006).The most prominent genetic influence is observed in families in which the capacity to attain a long lifespan clusters (Perls et al., 2000;Schoenmaker et al., 2006).Exceptional longevity can be reached with a low degree of age-related disability (Christensen et al., 2008;Terry et al., 2008), raising the question whether protective mechanisms against disease exist in long-lived subjects.In most experimentally modified animal model systems, single-gene mutations in many different genes have major life extension effects (Fontana et al., 2010;Kenyon, 2010).However, natural human and animal longevity is presumed to be a complex trait (Finch & Tanzi, 1997).In humans, both candidate gene and genome-wide genetic association approaches have been applied in an attempt to identify longevity loci.The frequency of genetic variants has been typically compared between nonagenarian cases and young controls, revealing loci at which genetic variants may contribute to a higher or lower probability of survival into old age.The initial candidate gene studies aimed at finding human longevity genes were dominated by contradictory results (Christensen et al., 2006).The more consistent evidence obtained by repeated observation in independent cohort studies for association with longevity has so far only been observed for three loci, the apolipoprotein E (APOE) locus (Schachter et al., 1994;Christensen et al., 2006), the FOXO3A locus (Willcox et al., 2008;Flachsbart et al., 2009;Pawlikowska et al., 2009;Soerensen et al., 2010), and the AKT1 locus (Pawlikowska et al., 2009).Thus, despite the expectation that longevity would be influenced by many genetic variants with small effect sizes, the effect of variants has consistently been shown in only three genes.",
"Clear 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",
"Living 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.Living 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.",
"The DNA of over 500,000 people was read to reveal the specific 'genetic fingerprints' of each participant.Then, after asking each of the participants how long both of their parents had lived, Timmers et al. pinpointed 12 DNA regions that affect lifespan.Five of these regions were new and had not been linked to lifespan before.Across the twelve as a whole several were known to be involved in Alzheimer's disease, smoking-related cancer or heart disease.Looking at the entire genome, Timmers et al. could then predict a lifespan score for each individual, and when they sorted participants into ten groups based on these scores they found that top group lived five years longer than the bottom, on average.",
"The search for the genetic determinants of extreme human longevity has been challenged by the phenotype's rarity and its nonspecific definition by investigators.To address these issues, we established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort.We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years).The analyses identified new rare variants in chromosomes 4 and 7 associated with extreme survival and with reduced risk for cardiovascular disease and Alzheimer's disease.The results confirm the importance of studying truly rare survival to discover those combinations of common and rare variants associated with extreme longevity and longer health span.The search for the genetic determinants of extreme human longevity has been challenged by the phenotype's rarity and its nonspecific definition by investigators.To address these issues, we established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort.We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years).The analyses identified new rare variants in chromosomes 4 and 7 associated with extreme survival and with reduced risk for cardiovascular disease and Alzheimer's disease.The results confirm the importance of studying truly rare survival to discover those combinations of common and rare variants associated with extreme longevity and longer health span.",
"Longevity Genes-A Special CaseDemographers are fascinated by the possibility that one or more genes might determine the rate of decline in multiple organ systems.Several such genes have been identified in other species (Vaupel et al., 1998).These genes are sometimes called gerontogenes or longevity genes.The discovery of one or more genes that act as aging \"clocks\" in humans would be a major breakthrough for genetics.However, the mere existence of such genes would not have a major effect on demographic research.For example, a mutation in a longevity gene that was present in 0.1 percent of the population would still be rare (probably less than 1 percent) among centenarians. 19Such a genotype would not explain much about survival to the oldest ages.Therefore, in order to be important for demographic research, there would have to be common polymorphisms associated with large differences in survival.Vaupel has estimated that there could be hundreds of genotypes with frequencies of 5-10 percent that lower death rates by 5-10 percent (Vaupel, personal communication).",
"Here, we review advances in genomic analysis within and across species to help refine the genetic foundations of age-associated diseases and longevity.As such, independent evolutionary occurrences of this species-specific lifespan change can empower comparative approaches to refine the shared mechanisms associating with longevity phenotypes.These evolutionary-refined gene sets can then be leveraged to focus statistical analysis within human cases of extreme longevity to discover core mechanisms of regulation.",
"IntroductionHuman longevity is influenced by multiple genetic and environmental factors.Approximately 25-32% of the overall variation in adult lifespan is because of genetic variation that becomes particularly important for survival at advanced age (Hjelmborg et al., 2006).Epidemiological studies have revealed that long-lived individuals (LLI), that is, people surviving to the 95th percentile of the respective birth cohort-specific age distributions (Gudmundsson et al., 2000), frequently show a favorable ('healthy') course of the aging process, with the absence or a delayed onset of agerelated diseases (Hitt et al., 1999).Hence, the LLI offer the key to elucidate the molecular mechanisms underlying the 'healthy aging' phenotype (Perls, 2006).",
"IntroductionApproximately 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.",
"Unraveling the heritability of human longevity was one of the first problems faced by geneticists.Just over a century ago, Mary Beeton and Karl Pearson [1] described a resemblance among relatives for the duration of life.A short time later, Yule [2] and Fisher [3] proved that the correlation is to be expected if lifespan is influenced by what had recently been termed 'genes' [4].Indeed, a century of correlation studies have established that something on the order of 30-50% of the total variation in human life span is attributable to genetic variation [5].Despite the wealth of diversity, specific genes contributing to this variation have proven notoriously difficult to identify.Sample size and issues of shared environment limit family-based methods such as linkage analysis, where rough genomic positions of important genetic variants are identified by comparing a small number of exceptionally long-lived people in defined pedigrees."
]
],
"task_id": [
"D53462CE61F52F7D31BB627998F4D75A"
]
}
|
