Biological processes modulating longevity across primates: a phylogenetic genome-phenome analysis

Aging is a complex process affecting different species and individuals in different ways. Comparing genetic variation across species with their aging phenotypes will help understanding the molecular basis of aging and longevity. Although most studies on aging have so far focused on short-lived model organisms, recent comparisons of genomic, transcriptomic, and metabolomic data across lineages with different lifespans are unveiling molecular signatures associated with longevity. Here, we examine the relationship between genomic variation and maximum lifespan across primate species. We used two different approaches. First, we searched for parallel amino-acid mutations that co-occur with increases in longevity across the primate linage. Twenty-five such amino-acid variants were identified, several of which have been previously reported by studies with different experimental setups and in different model organisms. The genes harboring these mutations are mainly enriched in functional categories such as wound healing, blood coagulation, and cardiovascular disorders. We demonstrate that these pathways are highly enriched for pleiotropic effects, as predicted by the antagonistic pleiotropy theory of aging. A second approach was focused on changes in rates of protein evolution across the primate phylogeny. Using the phylogenetic generalized least squares, we show that some genes exhibit strong correlations between their evolutionary rates and longevity-associated traits. These include genes in the Sphingosine 1-phosphate pathway, PI3K signaling, and the Thrombin/protease-activated receptor pathway, among other cardiovascular processes. Together, these results shed light into human senescence patterns and underscore the power of comparative genomics to identify pathways related to aging and longevity.This work was supported by Ministerio de Ciencia e Innovación, Spain (BFU2012-38236 and BFU2015-68649-P (MINECO/FEDER, UE) to AN), by Direcció General de Recerca, Generalitat de Catalunya (2014SGR1311 and 2014SGR866 to A.N., and 2014BP-B00157 to G.M.), by the Spanish National Institute of Bioinfomatics of the Instituto de Salud Carlos III (PT13/0001/0026), by “Unidad de Excelencia María de Maeztu”, funded by the MINECO (ref: MDM-2014-0370), and by FEDER (Fondo Europeo de Desarrollo Regional)/FSE (Fondo Social Europeo