Healthy at 100: Genetic factors and phenotypes associated with healthy aging and longevity

Background. Healthy aging and longevity are distinct phenotypes that describe an individual’s health span and life span, respectively. Both are complex phenotypes that are influenced by lifestyle, environment, and genetics. Using Super-Seniors, individuals aged 85 years and older and free of major chronic disease, and mid-life controls, I investigated whether Super-Seniors have an overall decreased genetic susceptibility and increased resilience to age- related diseases. Results. Using lifestyle, health, and genetic data, I compared the phenotypic and genetic characteristics of Super-Seniors to mid-life controls. Super-Seniors performed well on geriatric tests when compared to other long-lived populations, and an even more select group of Super-Seniors who survived 10 years after their initial recruitment still exhibited high function and good health. Super-Senior parents also exceeded the life expectancy for their era by a decade, and female Super-Seniors had an older age of last fertility, and were more likely to have had a child at ≥40 years.Exome sequencing of two centenarian brothers suggested that long-lived individuals do not carry a decreased burden of common complex disease variants. Instead, protective buffering variants that attenuate the effects of deleterious variants may play a role in healthy aging. In an analysis of buffering candidates, Super-Seniors were less likely than controls to carry an APOEε4 allele or a haptoglobin HP2 allele, and I identified 3 potential gene-gene interactions. In a network analysis of candidate buffering genes, lipid and cholesterol metabolism was a common theme. Further exploring the potential for protective factors in the Super-Seniors, I looked for evidence of allele-specific expression among disease genes, however no differences between groups were found. Conclusions. Super-Seniors are cognitively and physically high functioning individuals who have evaded major age-related chronic diseases into old age. The familiality of long lifespan of the parents of Super-Seniors supports the hypothesis that heritable factors contribute to this desirable phenotype. Although Super-Seniors did not appear to carry a decreased burden of disease-associated variants, there was some evidence that they may carry protective factors. The Super-Seniors are a phenotypically healthy group in which to look for further genetic markers of healthy aging and longevity.