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

Ukraintseva, Svetlana

Yashin, Anatoliy

Arbeev, Konstantin

Kulminski, Alexander

Akushevich, Igor

Wu, Deqing

Joshi, Gaurang

Land, Kenneth C

Stallard, Eric

Netherlands

2017-06-05T19:13:09Z

2017-06-05T19:13:09Z

2016-02

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.

https://www.ncbi.nlm.nih.gov/pubmed/26306600

10.1007/s10522-015-9600-1

1573-6768

https://hdl.handle.net/10161/14816

eng

Springer Science and Business Media LLC

Biogerontology

10.1007/s10522-015-9600-1

Age-specific influence

Aging

Complex disease

Conditional effects

Epistasis

Genetic risk factors

Gene–environment interaction

Longevity

Physical senescence

Trade-offs

Age Distribution

Aging

Alleles

Gene Frequency

Genetic Predisposition to Disease

Genetic Variation

Humans

Longevity

Models, Genetic

Risk Factors

Survival Rate

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

Journal article

Arbeev, Konstantin|0000-0002-4195-7832

Land, Kenneth C|0000-0002-9551-7314

https://www.ncbi.nlm.nih.gov/pubmed/26306600

109

127

1

Center for Population Health & Aging

Duke

Duke Cancer Institute

Duke Population Research Center

Duke Population Research Institute

Institutes and Centers

Institutes and Provost's Academic Units

Physics

Sanford School of Public Policy

School of Medicine

Social Science Research Institute

Staff

Trinity College of Arts & Sciences

University Institutes and Centers

Published

17