The genetics of extreme longevity: lessons from the new England centenarian study

Abstract

The New England Centenarian Study (NECS) was founded in 1994 as a longitudinal study of centenarians to determine if centenarians could be a model of healthy human aging. Over time, the NECS along with other centenarian studies have demonstrated that the majority of centenarians markedly delay high mortality risk-associated diseases toward the ends of their lives, but many centenarians have a history of enduring more chronic age-related diseases for many years, women more so than men. However, the majority of centenarians seem to deal with these chronic diseases more effectively, not experiencing disability until well into their nineties. Unlike most centenarians who are less than 101 years old, people who live to the most extreme ages, e.g., 107+ years, are generally living proof of the compression of morbidity hypothesis. That is, they compress morbidity and disability to the very ends of their lives. Various studies have also demonstrated a strong familial component to extreme longevity and now evidence particularly from the NECS is revealing an increasingly important genetic component to survival to older and older ages beyond 100 years. It appears to us that this genetic component consists of many genetic modifiers each with modest effects, but as a group they can have a strong influence.

Keywords: centenarians; compression of morbidity; genetic of longevity; genetic variation; heritability of longevity.

Figure 1

Examples of familial clusters of exceptional longevity. The small pedigree on the left (A) shows a sibship of three centenarians, with youngest age at death of 100 years. The pedigree on the right (B) shows a larger sibship of eight, with two centenarians (ages at death 101 and 106 years), three nonagenarians (ages 91, 93, and 94), and three siblings who live past the age of 80. Squares and circles represent males and females, diagonal bars represent deceased subjects. Numbers below nodes are birth years, last age at contact, and death year. For living subjects, the death year is not available (NA). Red triangles denote probands enrolled in the New England Centenarian Study.

Figure 2

Initial hypothesis on the genetic basis of exceptional longevity.

Figure 3

Examples of two similar genetic risk profiles that are highly predictive of exceptional longevity and a cluster of profiles that include the two profiles. The x-axis displays the 281 SNPs, sorted by the significance of the association with exceptional longevity. The y-axis represents the posterior probability of exceptional longevity given the nested sets of SNPs. The two genetic risk profiles in the top panel represent the pattern of risk for varying combinations of genotypes of the 281 SNPs that we found associated with exceptional longevity. The two plots are not exactly the same, meaning that the two subjects have some different alleles of the 281 SNPs. However, the similar pattern of risk means that they essentially have the same genetic basis for exceptional longevity and were assigned to the same cluster displayed in the bottom panel.

Figure 4

Revised hypothesis for the prevalences of disease and longevity (or protective) associated variants with increasing age at very old ages.