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

Muntané, Gerard; Farré, Xavier; Rodríguez Pérez, Juan Antonio, 1985-; Pegueroles Queralt, Maria Cinta; Hughes, David; Magalhães, João Pedro de; Gabaldón Estevan, Juan Antonio, 1973-; Navarro i Cuartiellas, Arcadi, 1969-

doi:http://dx.doi.org/10.1093/molbev/msy105

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

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Muntané G, Farré X, Rodríguez JA, Pegueroles C, Hughes DA, de Magalhães JP et al. Biological processes modulating longevity across primates: a phylogenetic genome-phenome analysis. Mol Biol Evol. 2018 Aug 1;35(8):1990-2004. DOI: 10.1093/molbev/msy105

Abstract

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.