Evolutionary and genetic aspects of human longevity
Many individuals do not age healthily, resulting in growing economic and healthcare challenges. Understanding the factors that contribute to healthy aging has become increasingly important. Interestingly, a small percentage of people seem to avoid the detrimental effects of aging and live longer than their peers, in part due to their genetics. My dissertation focused on identifying rare genetic variants associated with longevity and exploring the evolutionary history of known longevity genes.In part I, I analyzed whole exome sequencing data from a large German longevity cohort. In chapter 1, I focused on autophagy-related genes and identified a potential pro-longevity variant in ATG2A. This rare variant seems to increase levels of the ATG2A, potentially promoting longevity. In chapter 2, I expanded the analysis to all exome-wide variation and found that genes involved in mTOR signaling, including RPS6, FLCN, and SIK3, were significantly overrepresented. This suggests that the nutrient-sensing mTOR pathway, known to regulate lifespan in model organisms, may play a similar role in humans. These findings could provide potential targets for therapeutic interventions aimed at promoting healthy aging.Part II of my dissertation explored the evolutionary history of known longevity variants, investigating their population origins and the effects of selection. Longevity variants generally had distinct evolutionary trajectories, but shared common demographic patterns, with substantial differences in allele frequencies between early European populations. Western hunter-gatherers had higher frequencies of non-longevity alleles, while the first farmers had more pro-longevity alleles. Additionally, higher farmer ancestry in present-day Europeans was associated with an increased likelihood of becoming long-lived. These insights highlight the potential of integrating evolutionary history into modern approaches to health and aging.
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