Genetic determinants of human health span and life span: progress and new opportunities

Abstract

We review three approaches to the genetic analysis of the biology and pathobiology of human aging. The first and so far the best-developed is the search for the biochemical genetic basis of varying susceptibilities to major geriatric disorders. These include a range of progeroid syndromes. Collectively, they tell us much about the genetics of health span. Given that the major risk factor for virtually all geriatric disorders is biological aging, they may also serve as markers for the study of intrinsic biological aging. The second approach seeks to identify allelic contributions to exceptionally long life spans. While linkage to a locus on Chromosome 4 has not been confirmed, association studies have revealed a number of significant polymorphisms that impact upon late-life diseases and life span. The third approach remains theoretical. It would require longitudinal studies of large numbers of middle-aged sib-pairs who are extremely discordant or concordant for their rates of decline in various physiological functions. We can conclude that there are great opportunities for research on the genetics of human aging, particularly given the huge fund of information on human biology and pathobiology, and the rapidly developing knowledge of the human genome.

Figure 1. Visual Presentation of the Frequency Trends of Favorable Genotypes with Exceptional Longevity

This trend was obtained in ∼400 Ashkenazi Jewish subjects over age 95 and ∼600 subjects between ages 60–95 [76,87]. While these genotypes were assessed cross-sectionally in groups between ages ∼60–110, it is important to realize that marked selection occurs during the life course. One also should be aware of the fact that very few subjects achieve centenarian status. Of many polymorphic candidate loci, only subjects homozygous for CETP VV, APOC-3 CC, and ADIPOQ del/del genotypes are markedly and significantly enriched among centenarians (see details in text). To be considered a favorable longevity genotype, a monotonic increase should be observed among age groups. This criterion helps to exclude false-positive associations that occur only in one age group but that do not exhibit trends among sequential age groups. Genotypes with unchanged frequencies among age groups serve as partial controls for genotypic distribution and stratification tests. The analysis of such patterns is useful for the identification of candidate “longevity genes.”

Figure 2. The Stages Needed in Order to Support the Association of a Genotype with Longevity

While Figure 1 demonstrates how to obtain genotypes in genes that are important for the assurance of longevity, the verification of such genotypes requires additional analyses. First, one should seek evidence of a relevant biological phenotype. These may include in vitro and in vivo functional assays that demonstrate appropriate alterations in genes and the determination of plasma or tissue levels of substances that reflect an intermediate phenotype. Second, one should ideally develop lines of evidence demonstrating that a given genotype is protective against common diseases of aging, i.e., that the genotypes also modulate health span. These various steps should help to establish genetic factors contributing to exceptional longevity. As such, they should serve as major clues to the pathogenesis of common diseases of aging, thus providing rational strategies of prevention (see text).