title: 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.
authors: Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University, Durham, NC, 27708, USA. svo@duke.edu.|Duke Cancer Institute, Duke University, Durham, NC, 27708, USA. svo@duke.edu.
authors: Svetlana
authors: S
authors: Ukraintseva
authors: Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University, Durham, NC, 27708, USA.|Duke Cancer Institute, Duke University, Durham, NC, 27708, USA.
authors: Anatoliy
authors: A
authors: Yashin
authors: Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University, Durham, NC, 27708, USA.
authors: Konstantin
authors: K
authors: Arbeev
authors: Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University, Durham, NC, 27708, USA.
authors: Alexander
authors: A
authors: Kulminski
authors: Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University, Durham, NC, 27708, USA.
authors: Igor
authors: I
authors: Akushevich
authors: Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University, Durham, NC, 27708, USA.
authors: Deqing
authors: D
authors: Wu
authors: University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
authors: Gaurang
authors: G
authors: Joshi
authors: Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University, Durham, NC, 27708, USA.
authors: Kenneth C
authors: KC
authors: Land
authors: Biodemography of Aging Research Unit, Center for Population Health and Aging, Social Science Research Institute, Duke University, Durham, NC, 27708, USA.
authors: Eric
authors: E
authors: Stallard
mesh_terms: D017677:Age Distribution; D000375:Aging / Q000235:genetics*; D000483:Alleles; D005787:Gene Frequency / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008957:Models, Genetic; D012307:Risk Factors; D015996:Survival Rate
keywords: Age-specific influence; Aging; Complex disease; Conditional effects; Epistasis; Genetic risk factors; Gene–environment interaction; Longevity; Physical senescence; Trade-offs