Longevity 1

Description

Longevity, or extended life span, is a complex trait, determined by multiple genes as well as by environmental factors. Longevity has been associated with a locus on chromosome 4 (LGV1). Longevity has also been associated with a locus on chromosome 6q21 (LGV2; 606460).

See also 502000 for a discussion of aging related to changes in mitochondrial DNA.

Inheritance

A pioneering study by Pearl and Pearl (1934) found strong correlations in a group of nonagenarians with the long-lived phenotypes of their ancestors. In a follow-up of this study, Abbott et al. (1974) examined the survival curves of the offspring of nonagenarians and demonstrated that long-lived parents clearly had longer-lived children. However, the influences were not symmetric: the father-daughter effect was weakest, whereas the mother-son effect was strongest.

Jarvik et al. (1960) found tighter concordance of ages at death in monozygotic twins than in dizygotic twins (3 years vs more than 6 years).

Cutler (1975) estimated the evolutionary rate of increase in maximum life span potential along the ancestral-descendant sequence of hominids leading to modern man, and inferred that this rate may have been achieved by allelic substitution at a relatively small number of loci. Schachter et al. (1993) proposed that reverse genetics approaches might permit identification of some of these loci. They suggested sib-pair analysis applied to nonagenarian and centenarian sibs combined with association studies.

Herskind et al. (1996) studied the heritability of longevity in a population-based study of 2,872 Danish twin pairs born between 1870 and 1900. The most parsimonious explanation of the data was provided by a model that included genetic dominance (nonadditive genetic effects caused by interaction between gene loci) and nonshared environmental factors (environmental factors that are individual-specific and not shared in a family). The heritability of longevity was estimated to be 0.26 for males and 0.23 for females. This was an expansion of the study reported by McGue et al. (1993).

Gudmundsson et al. (2000) used a comprehensive population-based computerized genealogy database to examine multigenerational relationships among those who lived to the 95th percentile in Iceland. They found that first-degree relatives of those living to the 95th percentile were almost twice as likely to live to the 95th percentile compared with controls. Furthermore, they developed an algorithm, which they named the Minimum Founder Test (MFT), to examine the degree of relatedness of any population-based list of individuals to estimate whether a trait has a familial component. The data indicated that there is a significant genetic component to longevity. In addition, age-specific death rates were significantly lower in the offspring of long-lived parents compared with controls, especially after age 70.

Hypothesizing that surviving to extreme old age entails a substantial familial predisposition for longevity, Perls et al. (2002) analyzed the pedigrees of 444 centenarian families in the United States. These pedigrees included 2,092 sibs of centenarians, whose survival was compared with 1900 birth cohorts survival data from the U.S. Social Security Administration. The sibs of centenarians experienced a mortality advantage throughout their lives relative to the U.S. 1900 cohort. Female sibs had death rates of all ages about one-half the national level; male sibs had a similar advantage at most ages, although diminished somewhat during adolescence and young adulthood. Relative survival probabilities for these sibs increased markedly at older ages. Compared with the U.S. 1900 cohort, male sibs of centenarians were at least 17 times as likely to attain age 100 themselves, whereas female sibs were at least 8 times as likely.

Hjelmborg et al. (2006) examined how the genetic influence on human life span varies with age by studying Swedish, Finnish, and Danish same-sex monozygotic and dizygotic twin pairs born between 1870 and 1910, comprising 9,272 male twins and 11,230 female twins followed until 2003-2004. The survival data indicated that past age 60 years, survival increased each year that the cotwin survived, with a greater effect in monozygotic compared to dizygotic twins. Moreover, having a cotwin surviving to old age substantially and significantly increased the chance of reaching the same old age. The findings suggested that genetic influences on life span are minimal prior to age 60 but increase thereafter.

Pathogenesis

Seropositivity for cytomegalovirus (CMV) is 1 of the parameters of the 'immune risk profile' associated with mortality in longitudinal studies of the elderly and may accelerate immunosenescence. Derhovanessian et al. (2010) compared immune responses to CMV in 97 middle-aged offspring of long-lived families with those of their partners, who represented the general population. They observed a reduction in the frequency of naive T cells and an accumulation of CD45RA (see PTPRC; 151460)-reexpressing and late-differentiated memory T cells, but higher C-reactive protein (CRP; 123260) levels, in CMV-seropositive controls compared with CMV-seropositive offspring of long-lived families. T-cell proliferative responses to CMV antigens tended to be detectable and stronger in offspring of long-lived families compared with controls. Derhovanessian et al. (2010) proposed that individuals genetically predisposed to longevity are less susceptible to the characteristic CMV-associated age-driven immune alterations associated with immunosenescence.

Mapping

Substantial evidence supports the familial aggregation of exceptional longevity. Clustering for this phenotype in some families suggests the existence of a genetic component. Puca et al. (2001) conducted a genomewide scan for loci predisposing to longevity. The study included 308 individuals belonging to 137 sibships in which a minimum age of 98 years for at least 1 member of the sibship was used as the criterion for inclusion in the study. Using a nonparametric analysis, they found significant evidence for linkage to chromosome 4 at D4S1564 (4q25) with a maximum lod score of 3.65 (P = 0.044). The linkage was corroborated by a parametric analysis.

Associations Pending Confirmation

Longevity represents the evasion of mortality. Susceptibility or resistance to common multifactorial pathologies as an influence on life span is discussed in those entries; for example, coronary heart disease (see 607339), stroke (see 601367), cancer (e.g., colorectal; see 114500), and diabetes (see 125853).

Longevity has been associated with polymorphisms in several genes, including YTHDF2 (610640) and IGF1R (147370). In a review of genetic determinants of human longevity, Christensen et al. (2006) pointed out that variants of apolipoprotein E (APOE; 107741) on chromosome 19q13 had been found to be consistently associated with survival and longevity.

Tanaka et al. (1998) reported that a mitochondrial 5178C-A transversion, which results in a met-to-leu substitution in the MTND2 gene (516001), was found much more frequently in Japanese centenarians than in blood donor controls. The authors postulated that certain mitochondrial mutations may protect against development of adult-onset diseases. Mitochondrial DNA polymorphisms associated with longevity were described in a Finnish population by Niemi et al. (2003). See also 502000 for a discussion of aging related to changes in mitochondrial DNA.

Bonafe et al. (2002) reported that a gln192-to-arg polymorphism in the PON1 gene (Q192R; 168820.0001) on chromosome 7q21 was associated with longevity in Italian centenarians.

In a screen comparing allele frequencies of 6,500 SNPs located in approximately 5,000 genes between samples of young and elderly European Americans, Kammerer et al. (2003) identified a 2073A-G SNP in exon 14 of the AKAP10 gene (604694) on chromosome 17p11, resulting in an ile646-to-val (I646V) substitution. The frequency of the SNP differed significantly between young and old persons in both males (P = 0.03) and females (P = 0.009). Subsequent analysis of an independent sample indicated that the val variant was associated with a statistically significant decrease in the length of the electrocardiogram PR interval. An in vitro binding assay revealed that the ile variant bound approximately 3-fold weaker to the PKA RI-alpha isoform than the val variant. This decreased affinity resulted in alterations in the subcellular distribution of the recombinantly expressed PKA RI-alpha isoform. Kammerer et al. (2003) concluded that alterations in PKA RI-alpha subcellular localization caused by variation in DAKAP2 may have a negative health prognosis in the aging population that may be related to cardiac dysfunction, and that age-stratified samples appeared to be useful for screening SNPs to identify functional gene variants that have an impact on health.

Barzilai et al. (2003) reported that homozygosity for the val405 allele (VV genotype) of an ile405-to-val polymorphism in the CETP gene (I405V; 118470.0004) on chromosome 16q21 was associated with longevity in Ashkenazi Jewish probands and their offspring. Probands with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations.

Balistreri et al. (2004) reported that an asp299-to-gly (D299G) allele in the TLR4 gene (603030.0001) on chromosome 9q32-q33 was overrepresented in 55 very old Sicilian men (mean age, 100 years) compared to controls.

Evolution

Like other mammals, humans have an apparent maximum life span potential, namely, about 120 years. All homeothermic species have a species-specific metabolic rate that is negatively correlated with maximum life span potential. Schachter et al. (1993) examined the 'disposable soma theory,' which suggests a central role of energy metabolism in determining life span. The theory is based on several considerations, including the following: most deaths in natural populations, except for humans, arise from accidental causes, not related to aging; long-term survival depends upon somatic maintenance and maintenance processes are energetically costly; it is disadvantageous to invest a greater fraction of metabolic resources in long-term survival than is necessary for the organism to survive in reasonably good condition through its natural expectation of life in the wild.

Kaplan and Robson (2002) observed that 2 striking differences between humans and our closest living relatives, chimpanzees and gorillas, are the size of our brains (larger by a factor of 3 or 4) and our life span (longer by a factor of about 2). They theorized that these 2 distinctive features of humans are products of coevolutionary selection. The large human brain is an investment with initial costs and later rewards, which coevolved with increased energy allocations to survival. They suggested that their theory helped explain life history variation among primates and its extreme evolution in humans. Kaplan and Robson (2002) introduced and applied a general formal demographic model for constrained growth and evolutionary tradeoffs in the presence of life cycle transfers between age groups in a population.

Animal Model

Calorie restriction can extend life span in a variety of species including mammals, flies, nematodes, and yeast. The Sir2 gene (604479) is known to be involved in life span determination and calorie restriction in yeast. In nematodes, increased Sir2 can extend life span. Rogina and Helfand (2004) reported that Sir2 is directly involved in the calorie-restriction life span-extending pathway in Drosophila. They demonstrated that an increase in Drosophila Sir2 extends life span, whereas a decrease in Sir2 blocks the life span-extending effect of calorie reduction or Rpd3 (601241) mutations. These data led Rogina and Helfand (2004) to propose a genetic pathway by which calorie restriction extends life span and to provide a framework for genetic and pharmacologic studies of life span extension in metazoans.

Chen et al. (2009) provided evidence that the Cisd2 gene (611507) is involved in mammalian life span control. In mice, Cisd2 was primarily localized in the mitochondria and associated with the outer mitochondrial membrane. Cisd2-null mice showed early senescence and shortened life span compared to wildtype mice. Features included prominent eyes, protruding ears, corneal opacities and degeneration, thinner bones and hair, and decreased muscle mass, which are all consistent with premature aging. Tissue from mutant mice showed progressive mitochondrial breakdown and dysfunction accompanied by autophagic cell death, which preceded nerve and muscle degeneration. Mitochondria isolated from the mutant mice showed a defect in respiration. Together, the phenotype was suggestive of premature aging with some features of Wolfram syndrome (WFS; 222300). The findings also suggested that Wolfram syndrome-2 (604928) is in part a mitochondria-mediated disorder. Chen et al. (2009) also noted that the human CISD2 gene maps to chromosome 4q22-q24, close to a region implicated in human longevity.

Studies of the genetic requirements for life span extension by dietary restriction in the nematode C. elegans have implicated a number of key molecules in this process, including the nutrient-sensing target of rapamycin (TOR; see 601231) pathway and the Foxa transcription factor PHA4, homologous to FOXA1 (602294). Given its involvement in regulating nutrient intake and energy balance, the endocannabinoid system is an excellent candidate for a metabolic signal that coordinates the organismal response to dietary restriction and maintains homeostasis when nutrients are limited. Despite this, a direct role for endocannabinoid signaling in dietary restriction or life span determination had not been demonstrated, in part due to the apparent absence of endocannabinoid signaling pathways in model organisms that are amenable to life span analysis (summary by Lucanic et al., 2011). N-acylethanolamines (NAEs) are lipid-derived signaling molecules, which include the mammalian endocannabinoid arachidonoyl ethanolamide. N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD; 612334) catalyzes the last step in NAE biosynthesis, while the hydrolytic enzyme fatty acid amide hydrolase (FAAH; 602935) inactivates NAE molecules. Lucanic et al. (2011) identified NAEs in C. elegans and showed that NAE abundance is reduced under dietary restriction and that NAE deficiency is sufficient to extend life span through a dietary restriction mechanism requiring PHA4. Conversely, dietary supplementation with the nematode NAE eicosapentaenoyl ethanolamide not only inhibited dietary restriction-induced life span extension in wildtype worms, but also suppressed life span extension in a TOR pathway mutant. Lucanic et al. (2011) concluded that their study demonstrated a role for NAE signaling in aging and indicated that NAEs represent a signal that coordinates nutrient status with metabolic changes that ultimately determine life span.