A Trend Towards Increased Proteostasis in Longer-Lived Mammalian Species

Researchers here report on a broad comparison of protein sequences across many mammalian species, conducted in order to search for small differences between individual proteins that correlate with species life span. They find that humans, as one of the longer-lived mammals, already have most of these differences present across most of the the population. Further, the nature of these differences between proteins, meaning the specific functions of differing proteins in cell metabolism, is argued to support the hypothesis that quality control processes responsible for maintaining protein structure and removing damaged proteins make a sizable contribution to species differences in life span.

A key mechanism that may contribute to differences in lifespan between species is the maintenance of the proteostasis network. Protein stability or proteostasis refers to the capacity to protect protein structures and functions against environmental stressors, including aging. In fact, dysfunction of the protein quality control mechanisms is a hallmark of aging and there is substantial evidence linking proteostasis and longevity. For instance, improved protein stability is determinant for longevity in exceptionally long-lived mollusks and in the naked mole-rat, the longest-living rodent. In addition, interventions that enhance proteome stability can improve health or increase lifespan in model organisms, such as pharmacological chaperones that have been investigated as potential therapeutic targets to reduce the adverse effects of misfolding of aging-related proteins.

A mammalian-wide study of the genomic underpinnings of lifespan has never been carried out with the combined goals of identifying individual mutations linked to longevity; analyzing the functional properties of their genes and the pathways in which they take part; and studying how the stability of proteins coded by these genes may differentiate long- and short-lived species. Here, we performed the largest phylogeny-based genome-phenotype analysis to date, focusing on the detection of individual mutations and genes that underlie the enormous variation of lifespan in mammals. We report the discovery of more than 2,000 longevity-related genes and show that, overall, they present a trend towards increased protein stability in long-lived organisms. In addition, we successfully show that our findings enhance the interpretation of the results of longevity genome-wide association studies that have been carried out in humans.

We discovered a total of 2,737 single amino acid differences (AA) in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance. These genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 AA showed a significant association with maximum lifespan in a phylogenetic test. Interestingly, most of the detected AA positions do not vary in extant human populations (81.2%) or have allele frequencies below 1% (99.78%). Consequently, almost none of these putatively important variants could have been detected by genome-wide association studies. Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected, successfully demonstrating for the first time that comparative genomics can be used to enhance interpretation of human genome-wide association studies. Finally, we show that the human longevity-associated proteins are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.

Link: https://doi.org/10.1093/molbev/msab219

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