Understanding the Determinants of Exceptional Longevity

Researchers and the lay public often ask how much of aging, or of age-related disease, is due to genetic factors, which we generally cannot influence, and how much is due to health-related behaviors and interventions, which we can influence. This question has been addressed from many points of view, ranging from evolutionary biology to genetic epidemiology. Clearly, the more that successful aging is due to environmental factors, the more likely it is that we have the power to determine our health and vitality in old age. On the other hand, if environmental influences explain much of the variability in healthy aging, it seems a daunting task to sort out the many environmental, genetic, and stochastic factors and interactions that affect how we age (1). A Scandinavian study of twins (2) calculated the heritability of average life expectancy to be 20% to 30%. In other words, environmental differences accounted for at least 70% of the variations in age at death for the sets of twins studied, the oldest of whom were in their mid- to late 80s. If average humans are born with an average set of genetic polymorphisms, it will be differences in their habits and environments that explain the variability in their life expectancy. Supporting this idea is a study of Seventh Day Adventists (3) indicating that optimal health-related behaviors add 10 years to average life expectancy. Given that in the United States, 75% of persons are overweight and one third are obese (4), far too many persons still use tobacco (5), and far too few persons regularly exercise (6), it is no wonder that our average life expectancy is about 10 years less than our average set of genes can achieve for us. The heterogeneity of how people age represents a broad spectrum of the importance of environmental, genetic, and stochastic determinants of survival. The persons at the extremes of longevitypersons with a progeroid syndrome and those who live to extreme old agemight achieve those extremes through factors that are, individually or in combination, rare. The progeroid syndromes mimic premature aging in numerous ways, including early development of cataracts, aged skin, and cardiovascular disease. One such condition is the Werner syndrome, the underlying cause of which is a single gene mutation. The gene involved, the Werner (WRN) gene, is a DNA helicase that catalyzes DNA unwinding. At the molecular level, persons with the Werner syndrome have substantial genomic instability, with prevalent chromosome breaks, translocations, and large deletions (7). The cause of another progeroid syndrome, the HutchinsonGilford syndrome, was recently found to be a single mutation in the Lamin A gene (8, 9). At the other extreme are centenarians, who outlive those who are relatively predisposed to age-related fatal illnesses. Centenarians are less likely to have environmental and genetic exposures that contribute to death at earlier ages. This phenomenon, called demographic selection, is exemplified by the fact that the apolipoprotein E 4 allele, associated with heart disease and Alzheimer disease, is rare in centenarians, whereas the prevalence of an alternative allele, 2, is relatively high (10). Richard Cutler, in what is now a classic paper in gerontology (11), proposed that persons who achieve extreme old age do so in great part because they have genetic variations that affect the basic mechanisms of aging and that result in a uniform decreased susceptibility to age-associated diseases. Our studies and those of others researching the oldest old have noted that persons who achieve extreme old age probably lack many of the variations (the disease genes) that substantially increase risk for premature death by predisposing persons to various fatal diseases, both age-associated and nonage-associated (12). More controversial is the idea that genetic variations might confer protection against the basic mechanisms of aging or age-related illnesses (the longevity-enabling genes) (13). The progressive selecting out of more and more genetically fit persons of very old age lays the foundation for a simpler model for sorting out the genetics of aging and longevity. Centenarians may be rare because a complex set of environmental and genetic variables must coexist for such survival to occur. The Familiality of Exceptional Longevity To further explore the genetic aspects of exceptional old age, we recently studied 444 centenarian pedigrees containing 2092 siblings (14). We compared sibling death rates and survival probabilities with national U.S. death rates and survival probabilities according to the Social Security Administration's life table for the cohort born in 1900. Compared with the 1900 birth cohort, the siblings of centenarians maintained a lifelong reduction in risk for death of approximately one half, even through very old age. Siblings may share environmental and behavioral factors early in life that may have strong effects throughout life. It would make sense that some of these effects are primarily responsible for the shared survival advantage up to middle age. Some of these effects might not become evident until after middle age. However, in general, environmental characteristicssuch as socioeconomic status, lifestyle, and region of residenceare likely to diverge as siblings grow older. Thus, if the survival advantage of the siblings of centenarians is mainly due to environmental factors, that advantage should decline with age. In contrast, the stability of relative risk for death across a wide age range suggests that the advantage is due more to genetic than to environmental factors. Whereas death rates reflect the current intensity of death at a moment in time, survival probability reflects the cumulative experience of death up to that moment in a cohort's life history. Thus, a relatively constant advantage from moment to moment (as seen in the relative death rates) translates into an increasing survival advantage over a lifetime (as seen in the relative survival probabilities). This increase is seen in the Table, which shows the relative survival probabilities of the male and female siblings of centenarians at various ages. Table. Relative Survival Probabilities of Siblings of Centenarians Compared with the U.S. 1900 Birth Cohort By the age of 100 years, the relative survival probability is 8.2 for female siblings of centenarians and 17 for male siblings. From the analysis of death rates, we know that the siblings' survival advantage does not increase as the siblings age. Rather, the siblings' relative probability of survival is a cumulative measure and reflects their lifelong survival advantage over the general population born around the same time. The marked increase in relative survival probability and sustained survival advantage in extreme old age could be consistent with the forces of demographic selection, in which genes or environmental factors (or both) that predispose to longevity win out over those that are associated with premature or average mortality. The substantially higher relative survival probability values for men at older ages might reflect the fact that male mortality rates are substantially higher than female mortality rates at these ages and, thus, that men gain a greater advantage from beneficial genotypes than women do. Another possibility is that men require an even greater, and thus more rare, combination of genetic and environmental factors to achieve extreme age than women do (15). Either possibility could explain why men make up only 15% of centenarians. Although men make up a small proportion of centenarians, they tend to be better off than their female counterparts in terms of both physical and cognitive function (13). At first, this seems paradoxical because so many more women achieve extreme old age. One explanation may be that compared with women, men must be in particularly good condition to achieve extreme old age. Women, on the other hand, seem to be physiologically stronger in old age and more likely than men to be able to live with chronic illnesses and disabilities. These observations may indicate a demographic crossover in which women are better off than men in younger old age and men, although fewer in number, are functionally better off in extreme old age. The underlying reasons that women generally live longer than men and, at least before menopause, are substantially less likely to develop heart disease and stroke are unclear. Estrogen, which has been suggested to be a powerful antioxidant, has been implicated as an important reason (16). Another possible reason is that women, because of menses, are relatively iron deficient compared with men for a 30- to 40-year period (17). Iron is a critical catalyst in mitochondrial production of free radicals as a byproduct of metabolism (18); perhaps a reduction in available iron leads to less free-radical production (19). For example, iron deficiency has been associated with significant reductions in levels of oxidized low-density lipoprotein cholesterol, an essential component of atherosclerotic plaque production (20). In addition, diets high in heme have been associated with significantly increased risk for heart disease (21). Genes Predisposing to Exceptional Longevity The discovery of genetic variations that explain even 5% to 10% of the variation in survival to extreme old age could yield important clues about the cellular and biochemical mechanisms that affect basic mechanisms of aging and susceptibility to age-associated diseases. Until recently, only one genetic variation had been replicated to show an association with exceptional longevity, but even that finding may vary according to ethnicity and other, unknown sources of stratification. Schachter and colleagues (10) noted that the apolipoprotein E 4 allele becomes markedly less frequent with advancing age. One of its counterparts, the 2 allele, becomes more frequent with advancing age in white persons. Presumabl