Genetics of longevity

—Recent studies on the genetics of aging in the yeast Saccharomyces cerevisiae, the roundworm Caenorhabditis elegans, and the fruit fly Drosophila melanogaster have converged revealing the central role of metabolic capacity and resistance to stress in determining life span. Signal transduction has emerged from these studies as an important molecular mechanism underlying longevity. In their broad features, the results obtained in these genetic models are applicable to the dietary restriction paradigm in mammals, suggesting a general significance. It will be of interest to determine whether many of the molecular details will also pertain. The examination of centenarian populations for the frequency of certain alleles of pertinent genes may provide insights into the relevance of the conclusions of studies in invertebrates to human aging. These population genetic studies can be augmented by mechanistic studies in transgenic mice.     

The genetics of exceptional human longevity

There is a substantial distinction to be made between the genetics of aging and the genetics of exceptional longevity. Twin studies suggest that the average set of genetic variations facilitates the average human's ability to live well into their octogenarian years. Other studies indicate that taking full advantage of this average set results in spending the majority of those years in good health. However, many people counteract such genetic endowment with poor health habits, resulting in a substantially lower average life expectancy and relatively more time spent in poor health. To live beyond the octogenarian years, life-span experiments in lower organisms and mammals and population and molecular genetic studies of centenarian sibships suggest that genetic factors play an important role in exceptional longevity. These factors are likely to influence basic mechanisms of aging, which in turn broadly influence susceptibility to age-related illnesses. Lacking genetic variations that predispose to disease, and having variations that confer disease resistance (longevity enabling genes), are probably both important to such a remarkable survival advantage. Recent studies indicate the likelihood that such factors will be elucidated in the near future.     

Lifestyle factors of people with exceptional longevity

OBJECTIVES: To assess lifestyle factors including physical activity, smoking, alcohol consumption, and dietary habits in men and women with exceptional longevity. DESIGN: Retrospective cohort study. SETTING: A cohort of community‐dwelling Ashkenazi Jewish individuals with exceptional longevity defined as survival and living independently at age 95 and older. PARTICIPANTS: Four hundred seventy‐seven individuals (mean 97.3±2.8, range 95–109; 74.6% women) and a subset of participants of the National Health and Nutrition Examination Survey (NHANES) I (n=3,164) representing the same birth cohort as a comparison group. MEASUREMENTS: A trained interviewer administrated study questionnaires to collect information on lifestyle factors and collected data on anthropometry. RESULTS: People with exceptional longevity had similar mean body mass index (men, 25.4±2.8 kg/m² vs 25.6±4.0 kg/m², P=.63; women, 25.0±3.5 kg/m² vs 24.9±5.4 kg/m²; P=.90) and a similar proportion of daily alcohol consumption (men, 23.9 vs 22.4, P=.77; women, 12.1 vs 11.3, P=.80), of regular physical activity (men: 43.1 vs 57.2; P=.07; women: 47.0 vs 44.1, P=.76), and of a low‐calorie diet (men: 20.8 vs 21.1, P=.32; women: 27.3 vs 27.1, P=.14) as the NHANES I population. CONCLUSION: People with exceptional longevity are not distinct in terms of lifestyle factors from the general population, suggesting that people with exceptional longevity may interact with environmental factors differently than others. This requires further investigation.     

Mitochondrial genomes and exceptional longevity in a Chinese population: the Rugao longevity study

Genetic variants of whole mitochondrial DNA (mtDNA) that predispose to exceptional longevity need to be systematically identified and appraised. Here, we conducted a case-control study with 237 exceptional longevity subjects (aged 95–107) and 444 control subjects (aged 40–69) randomly recruited from a “longevity town”—the city of Rugao in China—to investigate the effects of mtDNA variants on exceptional longevity. We sequenced the entire mtDNA genomes of the 681 subjects using a next-generation platform and employed a complete mtDNA phylogenetic analytical strategy. We identified T3394C as a candidate that counteracts longevity, and we observed a higher load of private nonsynonymous mutations in the COX1 gene predisposing to female longevity. Additionally, for the first time, we identified several variants and new subhaplogroups related to exceptional longevity. Our results provide new clues for genetic mechanisms of longevity and shed light on strategies for evaluating rare mitochondrial variants that underlie complex traits.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-015-9750-8) contains supplementary material, which is available to authorized users.     

Association of exceptional parental longevity and physical function in aging

Offspring of parents with exceptional longevity (OPEL), who are more likely to carry longevity-associated genotypes, may age more successfully than offspring of parents with usual survival (OPUS). Maintenance of physical function is a key attribute of successful aging. While many genetic and non-genetic factors interact to determine physical phenotype in aging, examination of the contribution of exceptional parental longevity to physical function in aging is limited. The LonGenity study recruited a relatively genetically homogenous cohort of Ashkenazi Jewish (AJ) adults age 65 and older, who were defined as either OPEL (having at least one parent who lived to age 95 or older) or OPUS (neither parent survived to age 95). Subjective and objective measures of physical function were compared between the two groups, accounting for potential confounders. Of the 893 LonGenity subjects, 365 were OPEL and 528 were OPUS. OPEL had better objective and subjective measures of physical function than OPUS, especially on unipedal stance (p = 0.009) and gait speed (p = 0.002). Results support the protective role of exceptional parental longevity in preventing decline in physical function, possibly via genetic mechanisms that should be further explored.     

血清促甲状腺素升高的遗传倾向与超高寿相关

一些临床研究表明,随着年龄的增长甲状腺功能逐渐减退,而这与抗甲状腺抗体水平或与年龄相关的其它疾病无关.我们先前已证实.促甲状腺素(TSH)随年龄增长而升高这一现象已扩展至寿命超长群体.由于血清TSH升高可能反映了甲状腺功能的减退,因而我们推测寿命超长者的甲状腺激素分泌可能减少.此外,我们最近报道在Ashkenazi犹太百岁老人和年轻对照者中,血清TSH和FT4呈显著负相关.说明甲状腺激素的反馈调节可导致相对(亚临床)甲状腺功能减退.     

Association between subjective well-being and exceptional longevity in a longevity town in China: a population-based study

To examine the associations of cognitive and emotional facets (measured by life satisfaction [LS], positive affect [PA], negative affect [NA], and affect balance [AB]) of subjective well-being (SWB) with exceptional longevity (EL), we conducted a population-based study with 463 EL individuals (95+, EL group) recruited from a longevity town of Rugao, China (N = 755, with a response rate of 71.6 %), and 926 elderly individuals (60–69, elderly/control group). The population-based controls were sampled from the resident registry according to the gender ratio of the EL group. We found that the EL group had significantly higher levels of LS (30.74 vs. 28.93), PA (3.91 vs. 3.67), and AB (7.89 vs. 7.40) and a lower level of NA (1.02 vs. 1.27) than the elderly group. Multivariate logistic regression analysis revealed that higher levels of LS, PA, AB, and NA were significantly associated with EL, with odds ratios (ORs) of 1.98 (95 % CI, 1.36–2.89), 2.35 (95 % CI, 1.59–3.48), 2.56 (95 % CI, 1.75–3.75), and 0.50 (95 % CI, 0.33–0.74), respectively. Stratification analysis showed that the associations were significant in the healthy subsample, with the following ORs: LS = 2.31, PA = 2.53, AB = 3.05, and NA = 0.39. In conclusion, SWB, with high cognitive and emotional facets, was associated with EL in the healthy Rugao population. The findings imply that interventions that aim to improve elderly individuals’ SWB may promote their quality of life and, ultimately, EL.     

Plasma HDL levels highly correlate with cognitive function in exceptional longevity

BACKGROUND: Families of centenarians have high levels of plasma high-density lipoprotein (HDL) cholesterol, which may have neurological as well as cardiovascular protective effects during aging. Because plasma HDL level declines progressively with aging, we examined whether centenarians with higher plasma HDL levels have better cognitive function. METHODS: Total plasma cholesterol, low-density lipoprotein (LDL) cholesterol, HDL, triglycerides, and apolipoprotein levels were measured in a group of centenarians (N = 139; older than 95 years) and were correlated with their cognitive function (measured by Mini-Mental State Examination [MMSE]). RESULTS: Plasma HDL levels correlated significantly with MMSE (r =.32; p <.0001). Each decrease in plasma HDL tertile (74.9 +/- 2.1, 50.6 +/- 0.5, and 36.8 +/- 1.0 mg/dl) was associated with a significant decrease in MMSE (23.4 +/- 1.5, 17.7 +/- 1.8, and 12.4 +/- 1.8; p <.04 for each plasma HDL tertile). As expected, increased plasma apolipoprotein A-I and decreased plasma triglyceride levels were also correlated with a significantly superior cognitive function. Biological markers of hydration and nutritional status did not differ between the groups with the higher or lower plasma HDL or MMSE. CONCLUSIONS: These data demonstrate that cognitive dysfunction in centenarians is associated with a progressive decline in plasma HDL concentrations. This underscores the protective effects of increased plasma HDL and its role in maintaining superior cognition in longevity.     

Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study

Centenarians represent a rare phenotype appearing in roughly 10–20 per 100,000 persons in most industrialized countries but as high as 40–50 per 100,000 persons in Okinawa, Japan. Siblings of centenarians in Okinawa have been found to have cumulative survival advantages such that female centenarian siblings have a 2.58-fold likelihood and male siblings a 5.43-fold likelihood (versus their birth cohorts) of reaching the age of 90 years. This is indicative of a strong familial component to longevity. Centenarians may live such extraordinarily long lives in large part due to genetic variations that either affect the rate of aging and/or have genes that result in decreased susceptibility to age-associated diseases. Some of the most promising candidate genes appear to be those involved in regulatory pathways such as insulin signaling, immunoinflammatory response, stress resistance or cardiovascular function. Although gene variants with large beneficial effects have been suggested to exist, only APOE, an important regulator of lipoproteins has been consistently associated with a longer human lifespan across numerous populations. As longevity is a very complex trait, several issues challenge our ability to identify its genetic influences, such as control for environmental confounders across time, the lack of precise phenotypes of aging and longevity, statistical power, study design and availability of appropriate study populations. Genetic studies on the Okinawan population suggest that Okinawans are a genetically distinct group that has several characteristics of a founder population, including less genetic diversity, and clustering of specific gene variants, some of which may be related to longevity. Further work on this population and other genetic isolates would be of significant interest to the genetics of human longevity.     

Normal and pathological cardiac aging. Apropos of an exceptional case of longevity]

Born in Arles on February 21st 1875, Madame J. C. was the oldest registered human being. She died on August 4th 1997 at the age of 122 years, the record for longevity probably for a long moment. Based on this unique case and a review of the literature, the authors describe the mechanical, physiological and clinical aspects of normal cardiac ageing. The diseases of the elderly which accelerate the process of physiological ageing are then reviewed. With its participation in left ventricular hypertrophy, left atrial dilatation and the increase in valvular stress, the decreased elasticity of the great arteries seems to be the essential factor.     

Functional status of centenarians in Tokyo, Japan: developing better phenotypes of exceptional longevity

BACKGROUND: Centenarians are sometimes said to be representative of lifelong healthy aging. Whether they are, in fact, examples of healthy aging remains a subject of debate. The existence of heterogeneity in functional status has been reported repeatedly in previous studies of centenarians. However, there is as yet no standardized classification system with which to describe their functional phenotype. METHODS: As part of a dynamic cohort study, we studied 304 centenarians (65 men and 239 women) living in Tokyo. Their functional status (sensory, physical, and cognitive), which we used to represent their phenotype, was assessed and subsequently classified by standard assessment methods (simple questionnaire, Barthel index, Mini-Mental State Examination, and the Clinical Dementia Rating, respectively). RESULTS: We classified participants into 4 categories according to their functional status. Only 5 (2%) were classified as "Exceptional," with all of their functions graded as excellent, and 56 (18%) were "Normal," exhibiting maintenance of fine cognitive and physical functions. One hundred sixty-seven (55%) were "Frail," exhibiting impairment of either cognitive or physical functions, and the remaining 76 (25%) were "Fragile," exhibiting deterioration of both physical and cognitive functions. CONCLUSIONS: The relationships between biochemical marker, mortality rates, lifestyle, and functional phenotypes demonstrated by this classification method indicate that the system is reliable to address the functional status of extremely old persons. Thus, this framework would be a useful tool for exploring the factors that contribute to exceptional longevity as well as those that help to maintain the functional status of the extremely old population.     

High polygenic risk score for exceptional longevity is associated with a healthy metabolic profile

GeroScience - Healthy metabolic measures in humans are associated with longevity. Dysregulation leads to metabolic syndrome (MetS) and negative health outcomes. Recent exceptional longevity (EL)...     

A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4

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.     

Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity

The SIR2/Sirt1 gene has been demonstrated as regulating lifespan in many model organisms, including yeast, Caenorhabditis elegans and rodents. These findings render the human homologue, SIRT1, a very plausible candidate as a modifier of human life expectancy. We therefore sought to investigate whether common allelic variation in the SIRT1 gene was associated with human longevity. Five single nucleotide polymorphisms (SNPs), distributed across the entire gene, including the promoter region, were genotyped in our extensive DNA collections of 1573 long-lived individuals (centenarians and nonagenarians) and matched younger controls. Four of the markers were haplotype-tagging SNPs (htSNPs) that defined five common haplotypes. No evidence for an association was detected between any of the tested SNPs and the longevity phenotype at the allele, genotype or haplotype levels. These findings, based on an htSNP approach, suggest that there is no noteworthy influence of SIRT1 sequence variation on exceptional human longevity in the German population. However, this does not rule out the possibility that allelic variants in direct regulators or downstream substrates of SIRT1 could play critical roles in extending lifespan in humans.     

Coevolution of exceptional longevity, exceptionally high metabolic rates, and mitochondrial DNA-coded proteins in mammals

Mammals' longevity is inversely related to mass-specific basal metabolic rate because the generation of reactive oxygen species constrains lifespan. Longevity increases with body mass because the latter is inversely related to mass-specific basal metabolic rates. In placental mammals the longevity residuals from the power laws that describe longevity as a function of mass-specific basal metabolic rates, or body mass, are positively correlated with the relative rates of evolution of cytochrome b, a generator of reactive oxygen species. Therefore, longevity is more accurately described as a function of both mass-specific basal metabolic rate and the relative rate of cytochrome b evolution. The longevity residuals from the power law that describe longevity as a function of body mass are positively correlated with the relative rate of evolution of most other mtDNA-coded proteins. In taxa with very high rate of cytochrome b evolution exceptional longevity is associated with an increase, rather than the predicted decrease, of basal metabolic rates. These finding are compatible with the hypothesis that, in placental mammals, the accelerated evolution of mtDNA-coded proteins, allowed the extension of lifespan by selecting mutations that reduce the generation of reactive oxygen species, mostly by increasing internal proton leak, that accelerates mitochondrial electron transport.     

Insights on aging and exceptional longevity from longitudinal data: novel findings from the Framingham Heart Study

Age trajectories of physiological indices contain important information about aging-related changes in the human organism and therefore may help us understand human longevity. The goal of this study is to investigate whether shapes of such trajectories earlier in life affect the residual life span distribution. We used longitudinal limited access data from seven physiological indices and life spans of respective individuals collected in the Framingham Heart Study (FHS). These include: diastolic blood pressure (DBP), pulse pressure (PP), body mass index (BMI), serum cholesterol (SCH), blood glucose (BG), hematocrit (HC), and pulse rate (PR). We developed a method for assigning individuals to groups of potentially long-lived (PLL) and potentially medium-lived (PML) groups using age trajectories of physiological indices at the age interval between 40 and 60 years. The analysis shows that the longevity of individuals who survived to age of 65 depends on the behavior of the physiological indices between 40 and 60 years of age.     

The exceptional longevity of an egg-laying mammal, the short-beaked echidna (Tachyglossus aculeatus) is associated with peroxidation-resistant membrane composition

The echidna Tachyglossus aculeatus is a monotreme mammal from Australia that is exceptionally long-living. Its documented maximum lifespan of 50 years is 3.7 times that predicted from its body mass. Other exceptionally long-living mammals (naked mole-rats and humans) are known to have peroxidation-resistant membrane composition, raising the question about echidnas. Phospholipids were extracted from skeletal muscle, liver and liver mitochondria of echidnas and fatty acid composition measured. As with other exceptionally long-living mammals, membrane lipids of echidna tissues were found to have a lower content of polyunsaturates and a higher content of monounsaturates than predicted for their body size. The peroxidation index (=peroxidation susceptibility) calculated from this membrane composition was lower-than-expected for their body size, indicating that the cellular membranes of echidnas would be peroxidation-resistant. Additionally when the calculated peroxidation index was plotted against maximum lifespan, the echidna values conformed to the relationship for mammals in general. These findings support the membrane pacemaker theory of aging and emphasise the potential importance of membrane fatty acid composition in aging and in the determination of maximum longevity.