Impact of demography and population dynamics on the genetic architecture of human longevity

The study of the genetics of longevity has been mainly addressed by GWASs that considered subjects from different populations to reach higher statistical power. The "price to pay" is that population‐specific evolutionary histories and trade‐offs were neglected in the investigation of gene‐environment interactions. We propose a new “diachronic” approach that considers processes occurred at both evolutionary and lifespan timescales. We focused on a well‐characterized population in terms of evolutionary history (i.e. Italians) and we generated genome‐wide data for 333 centenarians from the peninsula and 773 geographically‐matched healthy individuals. Obtained results showed that: (i) centenarian genomes are enriched for an ancestral component likely shaped by pre‐Neolithic migrations; (ii) centenarians born in Northern Italy unexpectedly clustered with controls from Central/Southern Italy suggesting that Neolithic and Bronze Age gene flow did not favor longevity in this population; (iii) local past adaptive events in response to pathogens and targeting arachidonic acid metabolism became favorable for longevity; (iv) lifelong changes in the frequency of several alleles revealed pleiotropy and trade‐off mechanisms crucial for longevity. Therefore, we propose that demographic history and ancient/recent population dynamics need to be properly considered to identify genes involved in longevity, which can differ in different temporal/spatial settings.