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

Abstract

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.

Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing

“…SMC4 is known to inhibit cellular senescence in replicating cells [61,62]. Additional eQTL colocalization results for IEAA include CD46, a regulator of the complement system and T-cell function [63,64], and the lipid transporter gene ATP8B4, which contains variants that have been reported in relation to centenarian status in Italians and Alzheimer's disease [65,66].…”

The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity

“…Many studies have attempted to grasp the complexity of the genetics of human longevity [128,129,130,131,132,133]: recent findings suggest that alleles associated with this phenotype are population-specific and, at the same time, that the achievement of extreme longevity is modulated by mechanisms shared among populations [134,135,136]. One of the most relevant loci identified by many studies (if not all) is the APOE gene.…”

Exceptionally Long-Lived Individuals (ELLI) Demonstrate Slower Aging Rate Calculated by DNA Methylation Clocks as Possible Modulators for Healthy Longevity

“…A unique group of aging individuals termed centenarians serves as a healthy aging model, outliving the age of 100, with mostly intact cognition and physical health [1][2][3]. Such exceptionally long-lived individuals (ELLI) are the focus of many studies around the world [4][5][6][7][8][9][10][11][12], and this group is now being studied in Israel as well. Our newly established cohort of ELLI is part of the Israeli Multi-Ethnic Centenarian Study (IMECS), which aims to elucidate the mechanisms of their healthy aging process.…”