Low Genetic Risk for Coronary Artery Disease underlies Multigenerational Longevity and Healthy Aging
Sant' Anna Barbosa Ferreira, P.; Trompet, S.; Slagboom, E. P.; Deelen, J.; Beekman, M.; Berg, N. v. d.
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Descendants of exceptionally long-lived families have a delayed onset of their first chronic disease. We therefore hypothesize that one of the key features explaining healthy survival up to high ages is the absence of chronic disease risk alleles. Using the LLS and Leiden85+ multigenerational cohorts and Polygenic Scores (PGS) for chronic diseases, we showed that an increasing number of long-lived ancestors is additively associated with lower genetic risk for coronary artery disease (CAD). We further showed that a lower PGS for CAD explains up to 20% of the delay in cardiovascular disease incidence in long-lived families. Finally, we constructed a novel cholesterol-metabolism-PGS, based on gene-annotation enrichment analysis, that predicted time to all-cause mortality in two 90+ study populations. Our findings demonstrate that the absence of chronic disease risk alleles is one key-feature linked to longevity and that alleles linked to cholesterol metabolism are a key component in healthy aging trajectories.
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