Low genetic risk for coronary artery disease underlies multigenerational longevity and healthy aging.

Aging is a major risk factor for chronic diseases. Unlike the general population, members of long-lived families maintain exceptional health as they age, with over 10 years delayed onset of their first chronic disease. We therefore hypothesize that one of the key features explaining healthy survival up to high ages (longevity) is the absence of chronic disease risk alleles. We investigated this hypothesis in the Leiden Longevity Study, a cohort with data from more than 420 long-lived families in three generations and the Leiden 85-plus study. To analyze our data, we constructed a set of polygenic scores (PGS) covering the top diseases causing most deaths in the Netherlands. We showed that having an increasing number of long-lived ancestors is additively associated with lower genetic risk for coronary artery disease (CAD). Using accelerated failure time modelling, we further showed that a lower PGS for CAD explains up to 20% of the delay in cardiovascular disease incidence in descendants of 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 independent 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.