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Large-scale genome-wide association studies (GWAS) strongly suggest that most traits and diseases have a polygenic component. This observation has motivated the development of disease-specific "polygenic scores (PGS)" that are weighted sums of the effects of disease-associated variants identified from GWAS that correlate with an individual's likelihood of expressing a specific phenotype. Although most GWAS have been pursued on disease traits, leading to the creation of refined "Polygenic Risk Scores" (PRS) that quantify risk to diseases, many GWAS have also been pursued on extreme human longevity, general fitness, health span, and other health-positive traits. These GWAS have discovered many genetic variants seemingly protective from disease and are often different from disease-associated variants (i.e., they are not just alternative alleles at disease-associated loci) and suggest that many health-positive traits also have a polygenic basis. This observation has led to an interest in "polygenic longevity scores (PLS)" that quantify the "risk" or genetic predisposition of an individual towards health. We derived 11 different PLS from 4 different available GWAS on lifespan and then investigated the properties of these PLS using data from the UK Biobank (UKB). Tests of association between the PLS and population structure, parental lifespan, and several cancerous and non-cancerous diseases, including death from COVID-19, were performed. Based on the results of our analyses, we argue that PLS are made up of variants not only robustly associated with parental lifespan, but that also contribute to the genetic architecture of disease susceptibility, morbidity, and mortality., (© 2024. The Author(s).)

Backgrounds and Aims: Several genes are known to contribute to the levels and metabolism of HDL-C, however, their protective effects in cardiovascular disease (CVD), healthy aging, and longevity are complex and poorly understood. It is also unclear if these genes predict longitudinal HDL-C change. We aimed to identify loci influencing HDL-C change., Methods: We performed a genome-wide association study (GWAS) with harmonized HDL-C and imputed genotype in three family-based studies recruited for exceptional survival (Long Life Family Study), from community-based (Framingham Heart Study) and enriched for CVD (Family Heart Study). In 7738 individuals with at least 2 visits, we employed a growth curve model to estimate the random linear trajectory parameter of age-sex-adjusted HDL-C for each person. GWAS was performed using a linear regression model on HDL-C change accounting for kinship correlations, population structure, and differences among studies., Results: We identified a novel association for HDL-C with GRID1 (p = 5.43 × 10 -10 ), which encodes a glutamate receptor channel subunit involved in synaptic plasticity. Seven suggestive novel loci (p < 1.0 × 10 -6 ; MBOAT2, LINC01876-NR4A2, NTNG2, CYSLTR2, SYNE2, CTXND1-LINC01314, and CYYR1) and a known lipid gene (ABCA10) showed associations with HDL-C change. Two additional sex-specific suggestive loci were identified in women (DCLK2 and KCNJ2). Several of these genetic variants are associated with lipid-related conditions influencing cardiovascular and metabolic health, have predictive regulatory function, and are involved in lipid-related pathways., Conclusions: Modeling longitudinal HDL-C in prospective studies, with differences in healthy aging, longevity and CVD risk, contributed to gene discovery and provided insights into mechanisms of HDL-C regulation., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: We hypothesize that mechanisms associated with extended reproductive age may overlap with mechanisms for the selection of genetic variants that slow aging and decrease risk for age-related diseases. Therefore, the goal of this analysis is to search for genetic variants associated with delayed age of menopause (AOM) among women in a study of familial longevity., Methods: We performed a meta-analysis of genome-wide association studies for AOM in 1,286 women in the Long Life Family Study (LLFS) and 3,151 women in the Health and Retirement Study, and then sought replication in the Framingham Heart Study (FHS). We used Cox proportional hazard regression of AOM to account for censoring, with a robust variance estimator to adjust for within familial relations., Results: In the meta-analysis, a single nucleotide polymorphism (SNP) previously associated with AOM reached genome-wide significance (rs16991615; HR = 0.74, P = 6.99 × 10). A total of 35 variants reached >10 level of significance and replicated in the FHS and in a 2015 large meta-analysis (ReproGen Consortium). We also identified several novel SNPs associated with AOM including rs3094005: MICB, rs13196892: TXNDC5 | MUTED, rs72774935: SSBP2 | ATG10, rs9447453: COL12A1, rs114298934: FHL2 | NCK2, rs6467223: TNPO3, rs9666274 and rs10766593: NAV2, and rs7281846: HSPA13., Conclusions: This work indicates novel associations and replicates known associations between genetic variants and AOM. A number of these associations make sense for their roles in aging., Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A420.

Importance: Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care., Objective: To explore sex differences in genetic associations with longevity., Design Setting and Participants: This population-based case-control study used sex-specific genome-wide association study and polygenic risk score (PRS) analyses to examine sex differences in genetic associations with longevity. Five hundred sixty-four male and 1614 female participants older than 100 years were compared with a control group of 773 male and 1526 female individuals aged 40 to 64 years. All were Chinese Longitudinal Healthy Longevity Study participants with Han ethnicity who were recruited in 1998 and 2008 to 2014., Main Outcomes and Measures: Sex-specific loci and pathways associated with longevity and PRS measures of joint effects of sex-specific loci., Results: Eleven male-specific and 11 female-specific longevity loci ( P < 10 -5 ) and 35 male-specific and 25 female-specific longevity loci (10 -5 ≤ P < 10 -4 ) were identified. Each of these loci's associations with longevity were replicated in north and south regions of China in one sex but were not significant in the other sex ( P = .13-.97), and loci-sex interaction effects were significant ( P < .05). The associations of loci rs60210535 of the LINC00871 gene with longevity were replicated in Chinese women ( P = 9.0 × 10 -5 ) and US women ( P = 4.6 × 10 -5 ) but not significant in Chinese and US men. The associations of the loci rs2622624 of the ABCG2 gene were replicated in Chinese women ( P = 6.8 × 10 -5 ) and European women ( P = .003) but not significant in both Chinese and European men. Eleven male-specific pathways (inflammation and immunity genes) and 34 female-specific pathways (tryptophan metabolism and PGC-1α induced) were significantly associated with longevity ( P < .005; false discovery rate < 0.05). The PRS analyses demonstrated that sex-specific associations with longevity of the 4 exclusive groups of 11 male-specific and 11 female-specific loci ( P < 10 -5 ) and 35 male-specific and 25 female-specific loci (10 -5 ≤ P < 10 -4 ) were jointly replicated across north and south discovery and target samples. Analyses using the combined data set of north and south showed that these 4 groups of sex-specific loci were jointly and significantly associated with longevity in one sex ( P = 2.9 × 10 -70 to 1.3 × 10 -39 ) but not jointly significant in the other sex ( P = .11 to .70), while interaction effects between PRS and sex were significant ( P = 4.8 × 10 -50 to 1.2 × 10 -16 )., Conclusion and Relevance: The sex differences in genetic associations with longevity are remarkable, but have been overlooked by previously published genome-wide association studies on longevity. This study contributes to filling this research gap and provides a scientific basis for further investigating effects of sex-specific genetic variants and their interactions with environment on healthy aging, which may substantially contribute to more effective and targeted individualized health care for male and female elderly individuals., Competing Interests: Conflict of Interest Disclosures: Dr Bai reported grants from the Natural Science Foundation of China during the conduct of the study. Dr Ni reported grants from the National Basic Research Program of China during the conduct of the study. Dr Slagboom reported grants from government during the conduct of the study. Dr Gottschalk reported serving as a consultant for Zinfandel Pharmaceuticals Inc outside the submitted work and was supported by National Institute on Aging grant RO1 AG040370. No other disclosures were reported.

Objectives: To investigate the association between mortality and heritability of a rescaled Fried frailty index, the Scale of Aging Vigor in Epidemiology (SAVE), to determine its value for genetic analyses., Design: Longitudinal, community-based cohort study., Setting: The Long Life Family Study (LLFS) in the United States and Denmark., Participants: Long-lived individuals (N = 4,875, including 4,075 genetically related individuals) and their families (N = 551)., Measurements: The SAVE was administered to 3,599 participants and included weight change, weakness (grip strength), fatigue (questionnaire), physical activity (days walked in prior 2 weeks), and slowness (gait speed); each component was scored 0, 1, or 2 using approximate tertiles, and summed (range 0 (vigorous) to 10 (frail)). Heritability was determined using a variance component-based family analysis using a polygenic model. Association with mortality in the proband generation (N = 1,421) was calculated using Cox proportional hazards mixed-effect models., Results: Heritability of the SAVE was 0.23 (P < .001) overall (n = 3,599), 0.31 (P < .001) in probands (n = 1,479), and 0.26 (P < .001) in offspring (n = 2,120). In adjusted models, higher SAVE scores were associated with higher mortality (score 5-6: hazard ratio (HR) = 2.83, 95% confidence interval (CI) = 1.46-5.51; score 7-10: HR = 3.40, 95% CI = 1.72-6.71) than lower scores (0-2)., Conclusion: The SAVE was associated with mortality and was moderately heritable in the LLFS, suggesting a genetic component to age-related vigor and frailty and supporting its use for further genetic analyses., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Objectives: To determine, in a sample of Ashkenazi Jewish aged 95 and older, whether there is a compression of morbidity similar to what has been reported in other cohorts with exceptional longevity., Design: Case-control study., Setting: Longevity Genes Project (LGP) and New England Centenarian Study (NECS)., Participants: LGP (n = 439, mean age 97.8 ± 2.8) and NECS (n = 1,498, mean age 101.4 ± 4.0) participants with exceptional longevity and their respective younger referent cohorts (LGP, n = 696; NECS, n = 302)., Measurements: Self- and proxy reports of age of onset of cancer, cardiovascular disease, diabetes mellitus, hypertension, osteoporosis, and stroke., Results: Long-lived individuals from LGP and NECS had later age of onset of cancer, cardiovascular disease, diabetes mellitus, hypertension, and osteoporosis than their respective younger reference groups. The risk of overall morbidity was lower in participants with exceptional longevity than in younger participants (NECS men: relative risk (RR) = 0.12, women: RR = 0.20; LGP men: RR = 0.18, women: RR = 0.24). The age at which 20% of each of the groups with exceptional longevity experienced specific diseases was between 18 and 24 years later than in the reference groups, stratified according to sex., Conclusion: The similar extension of health span and compression of morbidity seen in NECS and LGP participants with exceptional longevity further validates the utility of these rare individuals for the study of factors that delay or prevent a broad spectrum of diseases otherwise associated with mortality and disability., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.

Chromosomal telomere length shortens with repeated cell divisions. Human leukocyte DNA telomere length (LTL) has been shown to shorten during aging. LTL shortening has correlated with decreased longevity, dementia, and other age-associated processes. Because LTL varies widely between individuals in a given age group, it has been hypothesized to be a marker of biological aging. However, the principal basis for the variation of human LTL has not been established, although various studies have reported heritability. Here, we use a family-based study of longevity to study heritability of LTL in 3037 individuals. We show that LTL is shorter in older individuals, and in males, and has a high heritability (overall h(2) = 0.54). In the offspring generation, who are in middle-life, we find an ordinal relationship: persons more-closely-related to elderly probands have longer LTL than persons less-closely-related, who nonetheless have longer LTL than unrelated spouses of the offspring generation. These results support a prominent genetic underpinning of LTL. Elucidation of such genetic bases may provide avenues for intervening in the aging process., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Rationale: Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury., Objective: Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease., Methods and Results: We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R-like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34(+) cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle., Conclusions: Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes., (© 2015 American Heart Association, Inc.)

Case control studies of nonagenarians and centenarians provide evidence that long-lived individuals do not differ in the rate of disease associated variants compared to population controls. These results suggest that an enrichment of novel protective variants, rather than a lack of disease associated variants, determine the genetic predisposition to exceptionally long lives. Using data from the Long Life Family Study (LLFS), we sought to replicate these findings and extend them to include a larger number of disease-specific risk alleles. To accomplish this goal, we built a genetic risk score for each of four age-related disease groups: Alzheimer's disease, cardiovascular disease and stroke, type 2 diabetes, and various cancers and compared the distribution of these scores between older participants of the LLFS, their offspring and their spouses. The analyses showed no significant differences in distribution of the genetic risk scores for cardiovascular disease and stroke, type 2 diabetes, or cancer between the groups, while participants of the LLFS appeared to carry an average 1% fewer risk alleles for Alzheimer's disease compared to spousal controls and, while the difference may not be clinically relevant, it was statistically significant. However, the statistical significance between familial longevity and the Alzheimer's disease genetic risk score was lost when a more stringent linkage disequilibrium threshold was imposed to select independent genetic variants.

Background: Longevity-associated genes may modulate risk for age-related diseases and survival. The Healthy Aging Index (HAI) may be a subphenotype of longevity, which can be constructed in many studies for genetic analysis. We investigated the HAI's association with survival in the Cardiovascular Health Study and heritability in the Long Life Family Study., Methods: The HAI includes systolic blood pressure, pulmonary vital capacity, creatinine, fasting glucose, and Modified Mini-Mental Status Examination score, each scored 0, 1, or 2 using approximate tertiles and summed from 0 (healthy) to 10 (unhealthy). In Cardiovascular Health Study, the association with mortality and accuracy predicting death were determined with Cox proportional hazards analysis and c-statistics, respectively. In Long Life Family Study, heritability was determined with a variance component-based family analysis using a polygenic model., Results: Cardiovascular Health Study participants with unhealthier index scores (7-10) had 2.62-fold (95% confidence interval: 2.22, 3.10) greater mortality than participants with healthier scores (0-2). The HAI alone predicted death moderately well (c-statistic = 0.643, 95% confidence interval: 0.626, 0.661, p < .0001) and slightly worse than age alone (c-statistic = 0.700, 95% confidence interval: 0.684, 0.717, p < .0001; p < .0001 for comparison of c-statistics). Prediction increased significantly with adjustment for demographics, health behaviors, and clinical comorbidities (c-statistic = 0.780, 95% confidence interval: 0.765, 0.794, p < .0001). In Long Life Family Study, the heritability of the HAI was 0.295 (p < .0001) overall, 0.387 (p < .0001) in probands, and 0.238 (p = .0004) in offspring., Conclusion: The HAI should be investigated further as a candidate phenotype for uncovering longevity-associated genes in humans.

Objectives: Studies of health and longevity require accurate age reporting. Age misreporting among older adults in the United States is common., Methods: Participants in the Long Life Family Study (LLFS) were matched to early-life census records. Age recorded in the census was used to evaluate age reporting in the LLFS. The study population was 99% non-Hispanic white., Results: About 88% of the participants were matched to 1910, 1920, or 1930 U.S. censuses. Match success depended on the participant's education, place of birth, and the number of censuses available to be searched. Age at the time of the interview based on the reported date of birth and early-life census age were consistent for about 89% of the participants, and age consistency within 1 year was found for about 99% of the participants., Discussion: It is possible to match a high fraction of older study participants to their early-life census records when detailed information is available on participants' family of origin. Such record linkage can provide an important source of information for evaluating age reporting among the oldest old participants. Our results are consistent with recent studies suggesting that age reporting among older whites in the United States appears to be quite good.

Exceptional longevity is associated with substantial heritability. The ε4 allele in apolipoprotein E and the linked G allele in rs2075650 of TOMM40 have been associated with increased mortality and the ε2 allele with decreased mortality, although inconsistently. Offspring from long-lived families and spouse controls were recruited at 3 sites in the United States and Denmark. We used generalized estimating equations to compare the likelihood of carrying risk alleles in offspring (n = 2307) and spouse controls (n = 764), adjusting for age, sex, level of education, and family membership. The likelihood of carrying an APOE ε4 allele or a G allele in rs2075650 was lower (odds ratio [OR], 0.75; p = 0.005 and OR, 0.70; p = 0.002) and the likelihood of carrying an APOE ε2 allele was higher (OR, 1.5; p = 0.007) among family members in the offspring generation than among their spouse controls. Our findings support the hypothesis that both reduction in the frequency of the ε4 allele and increase in the frequency of the ε2 allele contribute to longevity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Given previous evidence of familial predisposition for longevity, we hypothesized that siblings and parents of supercentenarians (age >or= 110 years) were predisposed to survival to very old age and that, relative to their birth cohorts, their relative survival probabilities (RSPs) are even higher than what has been observed for the siblings of centenarians., Methods: Mean age at death conditional upon survival to ages 20 and 50 and survival probabilities from ages 20 and 50 to higher ages were determined for 50 male and 56 female siblings and 54 parents of 29 supercentenarians. These estimates were contrasted with comparable estimates based on birth cohort-specific mortality experience for the United States and Sweden., Results: Conditional on survival to age 20 years, mean age at death of supercentenarians' siblings was approximately 81 years for men and women. Compared with respective Swedish and U.S. birth cohorts, these estimates were 17%-20% (12-14 years) higher for the brothers and 11%-14% (8-10 years) higher for the sisters. Sisters had a 2.9 times greater probability and brothers had a 4.3 times greater probability of survival from age 20 to age 90. Mothers of supercentenarians had a 5.8 times greater probability of surviving from age 50 to age 90. Fathers also experienced an increased survival probability from age 50 to age 90 of 2.7, but it failed to attain statistical significance., Conclusions: The RSPs of siblings and mothers of supercentenarians revealed a substantial survival advantage and were most pronounced at the oldest ages. The RSP to age 90 for siblings of supercentenarians was approximately the same as that reported for siblings of centenarians. It is possible that greater RSPs are observed for reaching even higher ages such as 100 years, but a larger sample of supercentenarians and their siblings and parents is needed to investigate this possibility.

Attaining age 100 is a rare event in industrialized nations, occurring in 1 person per 10,000 in the population. Becoming a centenarian does not appear to be rare because the individual genetic or behavioral factors (such as specific genetic polymorphisms or lack of specific toxic exposures) that enable such longevity are rare, but rather because having the adequate combination of these factors is rare.

Background: A small percentage of centenarians, about 15-25%, are functionally cognitively intact. Among those who are not cognitively intact at 100, approximately 90% delayed the onset of clinically evident impairment at least until the average age of 92 yr., Objective: To review current and past findings related to the prevalence and incidence of dementia amongst the exceptionally long-lived., Methods: Findings from the various centenarian studies, world-wide, are reviewed., Results: Neuropsychological and neuropathological correlations thus far suggest that there are centenarians who demonstrate no evidence of neurodegenerative disease. There also appear to be centenarians who despite the substantial presence of neuropathological markers of Alzheimer's disease did not meet clinical criteria for having dementia, thus suggesting the existence of cognitive reserve. Epigenic studies suggest a significant familial component to these survival advantages., Conclusion: Centenarians are of scientific interest as a human model of relative resistance to dementia.

Centenarians represent an extreme of life expectancy. They achieve their exceptional longevity in part by lacking genetic variations linked to premature death. Pedigree studies have shown a substantial familial component in the ability to survive to extreme old age, and a recent study demonstrated a locus on chromosome 4 linked to exceptional longevity, indicating the likely existence of at least one longevity-enabling gene in humans. The children of centenarians have markedly reduced relative risks for age-related diseases, particularly heart disease, hypertension, and diabetes, and are a promising model for genetic and phenotypic studies of 1) aging slowly relative to the general population and 2) the delay of and perhaps escape from important age-related diseases. These studies and those of other mammals and lower organisms show great promise for the delineation of important environmental and genetic determinants of aging well.

Centenarians exist at the extreme of life expectancy and are rare. A number of pedigree and molecular genetic studies indicate that a significant component of exceptional longevity is genetically influenced. Furthermore, the recent discovery of a genetic locus on chromosome 4 indicates the powerful potential of studying centenarians for genetic factors that significantly modulate aging and susceptibility to age-related diseases. These studies include siblings and children of centenarians. Siblings have a significantly increased propensity to achieve exceptional old age and have half the mortality risk of their birth cohort from young adulthood through extreme old age. The children of centenarians are emerging as a promising model for the genetic and phenotypic study of aging relatively slowly and the delay and perhaps escape of important age-related diseases.

How we age as individuals is no doubt a complex interaction of genetic and environmental factors. Studies of certain populations with optimal environments and health-related behaviors, as well as twin studies, suggest that the average set of genetic variations should facilitate the average person's ability to live to around age 85. Average life expectancies are lower than this because we generally fight survival advantage with bad health habits that can lead to premature aging, chronic illness, and death at a significantly younger age. Centenarians on the other hand live 15-25 years beyond what the average collection of us are able to achieve. Many of them have a history of aging relatively slowly, and either markedly delaying or even escaping lethal diseases associated with aging (Alzheimer's disease, stroke, cancer, cardiovascular disease, and diabetes). In order to live to such old age, centenarians are less likely to have genetic and environmental exposures that would cause at least lethal diseases at younger ages. Demographic selection is the drop out within a cohort, of genotypes linked to age-related lethal diseases and premature mortality as the cohort achieves older and older age. The result is a very old cohort that lacks these genotypes relative to younger age groups. Recent pedigree and molecular genetic studies indicate that scientists can use this selection to their advantage in discerning genotypes that play important roles in delaying or escaping diseases such as Alzheimer's disease, and in slowing the aging process.

To live beyond the octogenarian years, population and molecular genetic studies of centenarian sibships indicate that genetic factors play an increasingly important role as the limit of life span is approached. These factors are likely to influence basic mechanisms of aging that in turn broadly influence susceptibility to age-related illnesses. Lacking genetic variations that predispose to disease as well as having variations that confer disease resistance (longevity enabling genes) are probably both important to achieving exceptional old age. The AGE (aging, genetics, environment) nomogram is introduced as an illustrative construct for understanding the influence of environmental and genetic factors on survival to various ages, depending on variations in the hypothesized relative importance of genes and environment to longevity. The rapid rise in the incidence of centenarians could indicate that many more people than we originally thought have the optimal set of genetic factors necessary to get to 100 and beyond. Recent studies indicate the likelihood that such factors will be elucidated in the near future.

Centenarians disprove the ageist myth "the older you get, the sicker you get"; they live 90-95% of their very long lives in excellent health, only to experience illnesses in the very last few years of their lives. Thus, it appears that in order to live to 100, one must age relatively slowly and markedly delay and/or escape age-associated diseases. How they achieve such a survival advantage is still a mystery though it is becoming increasingly clear that a substantial genetic advantage plays a role in their ability to live 20-25 years beyond average life expectancy. Current genetic studies of centenarian sibships may yield the identity of some of these genes in the near future. Identifying such genes may yield new information about how people age differently and what modulates differences in susceptibilities to various diseases associated with aging.

Substantial evidence supports the familial aggregation of exceptional longevity. The existence of rare families demonstrating clustering for this phenotype suggests that a genetic etiology may be an important component. Previous attempts at localizing loci predisposing for exceptional longevity have been limited to association studies of candidate gene polymorphisms. In this study, a genome-wide scan for such predisposing loci was conducted by using 308 individuals belonging to 137 sibships demonstrating exceptional longevity. By using nonparametric analysis, significant evidence for linkage was noted for chromosome 4 at D4S1564 with a MLS of 3.65 (P = 0.044). The analysis was corroborated by a parametric analysis (P = 0.052). These linkage results indicate the likelihood that there exists a gene, or genes, that exerts a substantial influence on the ability to achieve exceptional old age. 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.

Noteworthy data is emerging to support the existence of longevity-enabling genes. Our observations of the relationship between reproductive fitness and longevity among centenarians support theories that posit strong selective forces in the determination of how fast humans age and their susceptibility to diseases associated with ageing. Current data support the idea that there is no selective advantage for humans to have a lifespan of approximately 100 years. Rather, getting to such a very old age may be a by-product of longevity-enabling genes that maximize the length of time during which women can bear children, and during which they can increase the survival probabilities of their children and grandchildren. We thus review the literature pertaining to the relationship between reproductive fitness and longevity.

With the ample gene sequence information that has become available with the human genome project virtually completed, it has become possible to identify functional gene variants and their frequencies in elderly populations with different aging-related characteristics. Such a genetic epidemiological approach could lead to new insights with respect to the basic mechanisms of aging and longevity as well as the identification of new targets to prevent or retard some of the late-age adverse effects. Using our recently developed two-dimensional gene scanning (TDGS) technology platform we demonstrate the feasibility of this approach by screening two different populations of centenarians for polymorphic variation in the BRCA1 breast cancer susceptibility gene, one of the many genes involved in genome maintenance. The initial results obtained with this approach suggest differences in BRCA1 genotype frequencies between the centenarian populations and controls.

Four families highly clustered for extreme longevity are described here, representing the first report of clustering for this phenotype. Families such as these may prove to be helpful in the further understanding of the genetic contribution to achieving exceptional longevity.

Objective: To determine the prevalence of cognitive disability as a function of advanced age and gender in elderly nursing home and community-dwelling populations. Since cognitive dysfunction is associated with increased mortality, we hypothesized that selective survival results in a decreased prevalence of cognitive disability in the oldest old., Design: Cohort study. An analysis of 6-month longitudinal data obtained from a national probability sample of older persons in 260 nursing homes (n = 1951) and 2-year-longitudinal data obtained from a sample of community-dwelling older persons (n = 2947)., Measures: In the nursing home sample, the primary outcome measure was cognitive performance score. In the community sample, cognitive performance was determined using the results of three orientation questions and assessment of decision-making ability. Cognitive performance and subsequent survival, controlling for various disease states and demographic factors, were examined in three age cohorts of men and women (ages 65-79, 80-89, 90-99)., Results: In the nursing home sample, the cognitive performance of very old men (> or = 90 years) was better than that of younger men (aged 80-89 years, P < 0.05) and very old women (age > or = 90 years, P = 0.001). Among 80-89-year-olds with poor cognitive performance, the 6-month mortality rate was higher in men than in women (38% vs 19%, P = 0.001). However, the mortality rates of men and women with good cognitive performance were not statistically different in any age group. Proportional-hazards regression analysis demonstrated that poor cognitive performance remained a powerful predictor of death among men aged 80-89 years with a relative risk of 2.7 (95% Cl, 1.19-3.17; P = 0.0006) after controlling for covariates. Results from the community sample lent support to our findings: within each age group, mortality rates for men and women with intact cognitive performance were not statistically different. However, in the two older age groups, the mortality rates of subjects with impaired cognitive performance were significantly greater for men than for women (P < 0.01 for both age groups)., Conclusions: Decreased cognitive performance is significantly associated with mortality among elderly men. Survival by men who have relatively intact cognitive function results in a population of oldest men, those aged 90-99 years, with cognitive performance scores better than younger men or similarly-aged women. The same selective survival phenomenon was not observed among women. Thus, there may be less cognitive disability among very old men than previously expected.