Puzzling role of genetic risk factors in human longevity: "risk alleles" as pro-longevity variants

Abstract

Complex diseases are major contributors to human mortality in old age. Paradoxically, many genetic variants that have been associated with increased risks of such diseases are found in genomes of long-lived people, and do not seem to compromise longevity. Here we argue that trade-off-like and conditional effects of genes can play central role in this phenomenon and in determining longevity. Such effects may occur as result of: (i) antagonistic influence of gene on the development of different health disorders; (ii) change in the effect of gene on vulnerability to death with age (especially, from "bad" to "good"); (iii) gene-gene interaction; and (iv) gene-environment interaction, among other factors. A review of current knowledge provides many examples of genetic factors that may increase the risk of one disease but reduce chances of developing another serious health condition, or improve survival from it. Factors that may increase risk of a major disease but attenuate manifestation of physical senescence are also discussed. Overall, available evidence suggests that the influence of a genetic variant on longevity may be negative, neutral or positive, depending on a delicate balance of the detrimental and beneficial effects of such variant on multiple health and aging related traits. This balance may change with age, internal and external environments, and depend on genetic surrounding. We conclude that trade-off-like and conditional genetic effects are very common and may result in situations when a disease "risk allele" can also be a pro-longevity variant, depending on context. We emphasize importance of considering such effects in both aging research and disease prevention.

Keywords: Age-specific influence; Aging; Complex disease; Conditional effects; Epistasis; Genetic risk factors; Gene–environment interaction; Longevity; Physical senescence; Trade-offs.

Fig. 1

Trade-off-like and conditional effects of genes on health and aging related traits might explain why genetic “risk factors” for major diseases do not always compromise longevity

Fig. 2

Simplified illustration of potential consequences of the antagonistic change in effect of genotype on vulnerability to death with age: from increasing the relative vulnerability in middle life to decreasing it at oldest old ages (85+) (not actual data; for empirical examples see references in the text). a Population frequency of some “risk” genotypes may change non-monotonically (U-shape-like) with age: first decreasing towards middle-old ages, and then increasing towards extreme ages (e.g., De Benedictis et al. ; Yashin et al. ; Bergman et al. 2007). b Intersection of survival functions for carriers of different genotypes may occur, so that genotype with initially negative effect on survival may have positive effect later in life, at oldest old ages (e.g., Yashin et al. 2001, 2015)

Fig. 3

A hypothetical example of the change in G × E interaction over time. The G × E determines the “norm of reaction”—the range of possible phenotypic manifestations of a genotype across different environments. It can contribute to situations in which the genotype behaves as a risk factor for a disease in one environment, but as neutral or protective factor in another environment