A Mutation Distinguishing Modern Humans from Other Primates Acts to Reduce Oxidative Stress and Inflammation

Humans are long-lived in comparison to other primates, despite exhibiting broad genetic similarity to our closest neighboring species. Our comparative longevity is thought to have evolved as a consequence of our intelligence and culture, allowing grandparents to contribute to the survival of descendants, and thus increasing the selection pressure operating in later life. Here researchers identify one genetic difference in modern humans that may contribute to greater longevity. Interestingly, it is absent from Neanderthals, an ancestral subspecies of human that one would also expect to exhibit a greater life span as a result of intelligence and culture changing the landscape of later life selection pressure.

Aerobic organisms face the challenge of oxidative damage caused by reactive oxygen species produced as metabolic by-products. Glutathione reductase (GR) is a critical enzyme for preventing oxidative stress and maintaining a reduced intracellular environment. Almost all present-day humans carry an amino acid substitution (S232G) in this enzyme relative to apes and Neanderthals.

Three Neanderthal genomes and one Denisovan genome have been sequenced to high quality. This makes it possible to identify genetic changes that characterize modern humans. Among the single-nucleotide substitutions on the lineage leading to modern humans, which alter protein sequences, approximately 100 are known to occur among all or almost all humans today but not in the archaic genomes available to date. One of these affects GR, which, in present-day humans, carries a glycine residue at position 232, whereas Neanderthals, Denisovans, and other primates carry a serine residue at this position.

We express the modern human and the ancestral enzymes and show that whereas the activity and stability are unaffected by the amino acid substitution, the ancestral enzyme produces more reactive oxygen species and increases cellular levels of transcripts encoding pro-inflammatory cytokines. We furthermore show that the ancestral enzyme has been reintroduced into the modern human gene pool by gene flow from Neanderthals and is associated with multiple traits in present-day people, including increased susceptibility for inflammatory-associated disorders and vascular disease.

Link: https://doi.org/10.1126/sciadv.abm1148


For the last 100K years humans never had a strong selection pressure favoring longevity, so all this is a bit incidental. Also I firmly believe that humans don't live much longer than the chimps, which are the closest genetically and sizewise to us.
As for the Neanderthal longevity genes. There are estimates that they had more or less the same lifespan and life expectancy as the hunter-gatherer modern humans . Nevertheless, if those genes can reliably show increased risk of number of diseases they might be useful. I , however, am quite skeptical that there will be clinical applications.

Posted by: Cuberat at January 12th, 2022 11:41 AM

there were studies linking level of SOD (superoxide dismutase) in humans, primates, and other species and their maximum lifespans. The more the longer life. It seems it's a good target for another lifespan study on whether supplementing it has any measurable effect on lifespan. Especially now when there are first successfull attempts to protect it from stomach acids (like GliSODin tm) and it's proved that it boosts catalase and glutathione peroxidase along with superoxide dismutase (SOD).

Posted by: SilverSeeker at January 13th, 2022 8:00 AM
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