Summary: Researchers have identified 2,000 genes in humans linked to longevity. The genes are associated with biological mechanisms that drive the prolongation of life in mammals, including DNA repair, coagulation, and immune response.
Source: UPF Barcelona
What determines the life expectancy of each species? This is a fundamental and highly complex question that has intrigued the field of research throughout history. From the evolutionary point of view, the major cause of these differences between species lies in their ecological adaptations. For example, life expectancy is longer in species adapted to living in trees, underground, or with large body mass, since all these adaptations reduce mortality by predation.
In the case of mammals, their life expectancy varies hugely, ranging from short-lived species like shrews and mice – which, with luck, reach two years of age – to long-living species like whales – which can live for up to two hundred years.
As for humans, we can potentially live for a hundred and twenty years, and on average we are all very long-lived. The keys to our long life expectancy, however, are still largely unknown. Until now, most studies have sought human longevity genes by comparing genomes within our species. However, the mutations observed can only explain the moderate variability – of tens of years – in the life expectancy of modern humans, far less than the variation observed between other mammals.
Now, an international research team led by researchers at the Institute of Evolutionary Biology (IBE), a centre of the Spanish National Research Council (CSIC), and Pompeu Fabra University in Barcelona, Spain, has identified more than 2,000 new genes linked to longevity in humans from an evolutionary comparative genomic study that included 57 species of mammals.
The genes identified are involved in biological mechanisms linked to the prolongation of life in mammals, such as DNA repair, coagulation and inflammatory response, and codify more stable proteins in longer-living species. Altogether, the mutations observed largely reflect the variance in longevity of today’s human populations.
“When you only compare human genomes, you see differences between the genes that codify small differences in longevity between people. But the genetic structure behind the character may be based on mutations that occurred millions of years ago in our lineage, and we all have incorporated now”, explains Arcadi Navarro, principal investigator at the Evolutionary Genomics Laboratory at the IBE and co-director of the study.
“Using the variation that exists between other species of mammals you can get much closer to identifying other changes that are in the nature of longevity that may not differentiate us significantly at the genetic level between humans”, comments co-director of the study Gerard Muntané, a researcher with Arcadi Navarro’s group and also a researcher at the Pere Virgili Institute for Health Research.
Protein stability, at the heart of longevity
One of the effects observed in all mammals after a certain age is that the proteome – all of the proteins expressed by the genome – is destabilized, for reasons not yet well understood. Over time, proteins become unstable and this contributes to general physiological decline. The proteins that destabilize in each species, however, do so at very different ages.
As a result of this study, the research team has discovered that the proteins that contain amino acid changes in longer-living organisms, are significantly more stable than the proteins of shorter-living organisms.
“We believe that a protein is more stable when it continues to perform its function longer within the cell without degradation. With our approach, we have seen that this generic stabilization of the proteome is fundamentally found in genes we have identified as being related to age and longevity”, says Muntané.
The application of evolutionary biology to medicine
The research, published in Molecular Biology and Evolution, opens the door to developing new therapeutic targets to treat diseases associated with ageing in humans. The results of this study demonstrate the potential of the approach to medicine from the evolutionary standpoint. “The perspective of evolutionary biology can make significant contributions and be directly applied to human health, although it is often ignored as a research paradigm”, says Navarro.
The methodology developed by the research team could be used to answer other questions related to human health in the future. “We could study any character of human health or disease, such as blood pressure, cholesterol or cancer, following the same approach”, Muntané concludes.
Funding: The study has received funding from the European Regional Development Fund, the State Research Agency and the Government of Catalonia, among others.
Comparative Analysis of Mammal Genomes Unveils Key Genomic Variability for Human Life Span
The enormous mammal’s lifespan variation is the result of each species’ adaptations to their own biological trade-offs and ecological conditions. Comparative genomics have demonstrated that genomic factors underlying both, species lifespans and longevity of individuals, are in part shared across the tree of life.
Here, we compared protein-coding regions across the mammalian phylogeny to detect individual amino acid (AA) changes shared by the most long-lived mammals and genes whose rates of protein evolution correlate with longevity.
We discovered a total of 2,737 AA in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (P = 0.003). 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.