Abstract
Several studies have found that long-lived individuals do not appear to carry lower numbers of common disease-associated variants than ordinary people; it has been hypothesized that they may instead carry protective variants. An intriguing type of protective variant is buffering variants that protect against variants that have deleterious effects. We genotyped 18 variants in 15 genes related to longevity or healthy aging that had been previously reported as having a gene-gene interaction or buffering effect. We compared a group of 446 healthy oldest-old ‘Super-Seniors’ (individuals 85 or older who have never been diagnosed with cancer, cardiovascular disease, dementia, diabetes or major pulmonary disease) to 421 random population-based midlife controls. Cases and controls were of European ancestry. Association tests of individual SNPs showed that Super-Seniors were less likely than controls to carry an APOEε4 allele or a haptoglobin HP2 allele. Interactions between APOE/FOXO3, APOE/CRYL1, and LPA/CRYL1 did not remain significant after multiple testing correction. In a network analysis of the candidate genes, lipid and cholesterol metabolism was a common theme. APOE, HP, and CRYL1 have all been associated with Alzheimer’s Disease, the pathology of which involves lipid and cholesterol pathways. Age-related changes in lipid and cholesterol maintenance, particularly in the brain, may be central to healthy aging and longevity.
Highlights
Healthy aging is the ability to age successfully without succumbing to disease, with an emphasis on healthspan over lifespan [1]
APOE is an exception; genetic variation in this gene has been associated with longevity in multiple genome-wide association studies (GWAS) and candidate gene studies [1, 2]
We have assembled a list of genetic variants previously reported as having possible epistatic or buffering/buffered effects related to longevity in human studies. We examined these variants in individuals aged 85 years or older who had never been diagnosed with cancer, cardiovascular disease (CVD), diabetes, dementia, or major pulmonary disease; we call them the ‘Super-Seniors’ [9]
Summary
Healthy aging is the ability to age successfully without succumbing to disease, with an emphasis on healthspan over lifespan [1]. The genetics of healthy aging and longevity is complex, with few genetic associations replicating between studies. Long-lived individuals have been found to carry a burden of disease-associated variants comparable to that observed in typical individuals [4,5,6]. One possible explanation for their ability to remain in good health to advanced ages, and still carry deleterious variants, is the concept of genetic buffering. Genetic buffering is a type of epistatic interaction in which a favourable genotype attenuates the effect of one or more deleterious variants. In this model, long-lived individuals may carry harmful (buffered) variants without developing disease, as a result of carrying protective (buffering) variants. In a paper first suggesting the application of buffering to human longevity, Bergman and colleagues used changes in allele frequencies with age to show buffering of a deleterious LPA heterozygote by a buffering CETP VV genotype [7] in participants in the Longevity Genes Project [8]
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