Identifying Genes Responsible for Human Longevity Relative to Other Primates
We humans are unusually long-lived for our size, as compared to other mammals. This is particularly noticeable in comparison to our nearest primate relatives. Since our exceptional longevity among primates arose only comparatively recently in evolutionary time, coincident with intelligence, culture, and modernity, it is thought feasible to identify genetic changes likely involved in this process. That effort proceeds in tandem with more theoretical considerations regarding how it is that natural selection produced this gain in species life span, such as the Grandmother hypothesis, and the two lines of work can inform one another as they progress.
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. 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.
To our knowledge, this is the first systematic report providing direct evidence of gene-phenotype evolution of aging-related traits in primates. Genes and biological processes reported in this study could be added to the list of genes that increase lifespan when overexpressed or mutated (gerontogenes) and represent a valuable resource for examination of new candidate interventions that mimic gene evolution associated with natural changes in lifespan. Although our results may reflect local adaptive responses of species to their environment, we observed nonrandom association of gene evolution with pathways mainly related to wound healing, coagulation, and many cardiovascular processes. This would make sense from a biological perspective, since flexible and adjustable control of coagulation mechanisms is required for species that live longer.