The quest for genetic determinants of human longevity: challenges and insights
TL;DR: Large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress in human studies of longevity.
Abstract: Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.
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TL;DR: It is proposed that inflammaging can be flanked by anti-inflammaging as major determinants not only of immunosenescence but eventually of global aging and longevity.
1,747 citations
TL;DR: Research by demographers, epidemiologists and other biomedical researchers suggests that further progress is likely to be made in advancing the frontier of survival — and healthy survival — to even greater ages.
Abstract: Human senescence has been delayed by a decade. This finding, documented in 1994 and bolstered since, is a fundamental discovery about the biology of human ageing, and one with profound implications for individuals, society and the economy. Remarkably, the rate of deterioration with age seems to be constant across individuals and over time: it seems that death is being delayed because people are reaching old age in better health. Research by demographers, epidemiologists and other biomedical researchers suggests that further progress is likely to be made in advancing the frontier of survival — and healthy survival — to even greater ages.
876 citations
TL;DR: Long-lived men presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls, several of these aging phenotypes were associated with FOXO3A genotype.
Abstract: Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.
856 citations
Cites background from "The quest for genetic determinants ..."
...The study of longevity may be affected by small genetic effect sizes, population stratification artifact, population heterogeneity, lack of sufficient numbers of long-lived study participants, and other problems (3, 4, 41)....
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...Few replications have been observed across populations, with the exception of the APOE gene (3)....
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...There are many biologically plausible candidate genes for human longevity but only one finding has so far been widely replicated in multiple populations, that of the APOE gene (3)....
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TL;DR: This study investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provided evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age, and confirmed the initial discovery in the Japanese sample.
Abstract: The human forkhead box O3A gene (FOXO3A) encodes an evolutionarily conserved key regulator of the insulin–IGF1 signaling pathway that is known to influence metabolism and lifespan in model organisms A recent study described 3 SNPs in the FOXO3A gene that were statistically significantly associated with longevity in a discovery sample of long-lived men of Japanese ancestry [Willcox et al (2008) Proc Natl Acad Sci USA 105:13987–13992] However, this finding required replication in an independent population Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research Our study extended the initial finding observed in Japanese men to women and indicates that both genders were likely to be equally affected by variation in FOXO3A Replication in a French centenarian sample generated a trend that supported the previous results Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans
555 citations
Cites background from "The quest for genetic determinants ..."
...Although numerous case-control candidate studies have been performed and associations of the longevity phenotype with biologically plausible genes have been described, results from these experiments have proven difficult to validate (5)....
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...However, this requirement may sometimes be difficult to achieve when polygenic traits, such as human longevity, are analyzed for which only modest or weak effects are predicted (5)....
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...The selection of appropriate controls for genetic longevity research is a matter of concern (5, 14)....
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TL;DR: The mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals, and compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.
Abstract: Aging constitutes the key risk factor for age-related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which "protective genes" are carried by long-lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin-like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.
495 citations
Cites background from "The quest for genetic determinants ..."
...Human longevity and healthy aging are complex phenotypes influenced by environmental (diet, physical activity, health habits, and psychosocial factors) and genetic factors (Herskind et al., 1996; Christensen et al., 2006; Bishop & Guarente, 2007)....
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References
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TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
Abstract: The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
8,669 citations
TL;DR: The identification of the genetic basis of complex human diseases such as schizophrenia and diabetes has proven difficult as mentioned in this paper, and Risch and Merikangas proposed that they can best accomplish this goal by combining the power of the human genome project with association studies.
Abstract: The identification of the genetic basis of complex human diseases such as schizophrenia and diabetes has proven difficult. In their Perspective, Risch and Merikangas propose that we can best accomplish this goal by combining the power of the human genome project with association studies, a method for determining the basis of a genetic disease.
5,143 citations
TL;DR: The beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
Abstract: In this paper we extend the “network theory of aging,” and we argue that a global reduction in the capacity to cope with a variety of stressors and a concomitant progressive increase in proinflammatory status are major characteristics of the aging process. This phenomenon, which we will refer to as “inflamm-aging,” is provoked by a continuous antigenic load and stress. On the basis of evolutionary studies, we also argue that the immune and the stress responses are equivalent and that antigens are nothing other than particular types of stressors. We also propose to return macrophage to its rightful place as central actor not only in the inflammatory response and immunity, but also in the stress response. The rate of reaching the threshold of proinflammatory status over which diseases/disabilities ensue and the individual capacity to cope with and adapt to stressors are assumed to be complex traits with a genetic component. Finally, we argue that the persistence of inflammatory stimuli over time represents the biologic background (first hit) favoring the susceptibility to age-related diseases/disabilities. A second hit (absence of robust gene variants and/or presence of frail gene variants) is likely necessary to develop overt organ-specific age-related diseases having an inflammatory pathogenesis, such as atherosclerosis, Alzheimer's disease, osteoporosis, and diabetes. Following this perspective, several paradoxes of healthy centenarians (increase of plasma levels of inflammatory cytokines, acute phase proteins, and coagulation factors) are illustrated and explained. In conclusion, the beneficial effects of inflammation devoted to the neutralization of dangerous/harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging.
3,763 citations
TL;DR: Calculations based on Swedish mortality data suggest that standard methods overestimate current life expectancy and potential gains in life expectancy from health and safety interventions, while underestimating rates of individual aging, past progress in reducing mortality, and mortality differentials between pairs of populations.
Abstract: Life table methods are developed for populations whose members differ in their endowment for longevity. Unlike standard methods, which ignore such heterogeneity, these methods use different calculations to construct cohort, period, and individual life tables. The results imply that standard methods overestimate current life expectancy and potential gains in life expectancy from health and safety interventions, while underestimating rates of individual aging, past progress in reducing mortality, and mortality differentials between pairs of populations. Calculations based on Swedish mortality data suggest that these errors may be important, especially in old age.
2,271 citations
TL;DR: The findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.
Abstract: Ageing is a fundamental, unsolved mystery in biology. DAF-16, a FOXO-family transcription factor, influences the rate of ageing of Caenorhabditis elegans in response to insulin/insulin-like growth factor 1 (IGF-I) signalling. Using DNA microarray analysis, we have found that DAF-16 affects expression of a set of genes during early adulthood, the time at which this pathway is known to control ageing. Here we find that many of these genes influence the ageing process. The insulin/IGF-I pathway functions cell non-autonomously to regulate lifespan, and our findings suggest that it signals other cells, at least in part, by feedback regulation of an insulin/IGF-I homologue. Furthermore, our findings suggest that the insulin/IGF-I pathway ultimately exerts its effect on lifespan by upregulating a wide variety of genes, including cellular stress-response, antimicrobial and metabolic genes, and by downregulating specific life-shortening genes.
2,120 citations