Researchers hope to ‘steal’ protein modifications evolved by long-lived animals to extend human lifespan.
Scientists at the Sagol Center for Healthy Human Longevity at Bar-Ilan University have made progress in the quest to learn why some mammals have evolved to live much longer, and comparatively healthier, lives than others. A group led by renowned aging researcher Professor Haim Cohen, recently published a paper in Nature Communications, investigating how a certain type of protein modification influences longevity, comparing short-lived animals with those which have longer lifespans.
The researchers are now seeking to explore whether some of the protein modifications evolved by other long-lived species hold the potential to extend the lifespan of humans, and affect how our bodies respond to aging and disease.
Longevity.Technology: Analyzing more than 100 different types of mammals, the Bar-Ilan study focused on acetylation – a process where a tiny “tag” is attached to a protein and controls how it behaves, akin to flipping a switch. The study explored acetylation’s role in balancing cellular processes like metabolism and DNA repair to enhance lifespan, and suggests therapeutic strategies mimicking these evolutionary changes could be used to target age-related diseases.
The findings also challenge the traditional view of acetylation as a binary on/off switch, instead positioning it as a nuanced system of regulatory “dials” shaped by natural selection to optimize longevity. We sat down with Professor Cohen to learn more about the study – and where it goes next.
While acetylation has previously been linked to lifespan extension, it remains largely unknown how the process directly regulates aging. Cohen, who is perhaps best known for his research into the longevity-linked SIRT6 protein, describes acetylation as a “hidden biological language” that cells use to communicate and adapt to changing environments. His team, led by computer scientist-turned biologist Sarit Feldman-Trabelsi, sought to decode that language from a longevity perspective.
“First we had to map the acetylome of the mammals in our study – but that was essentially a technical exercise that created a long list some 30,000 sites,” says Cohen. “What’s really unique about our work is that we then analyzed this huge number of sites to find which ones changed during evolution to allow certain species to live longer in comparison to others.”
Linking acetylation to long life
By analyzing acetylome and proteome data across 107 mammalian species with diverse lifespans, the study employed a computational tool called PHARAOH to systematically identify acetylation sites correlated with extended lifespan. The approach revealed a few hundred longevity-associated sites in each mammal species.
“We started with 30,000 sites and finished with around 300 specifically related to long life,” says Cohen. “Then we looked at the pathways that these sites are related to, and found many connected with pathways that we know are linked to longevity – DNA repair, metabolism and inflammation, for example. Our findings suggest that some of these acetylation sites fine-tune enzyme activity and protein interactions in ways that mitigate age-related damage.”
The study further uncovered acetylation’s role in metabolic regulation. Some longevity-associated sites correlated with enhanced metabolic flexibility, while others aligned with stress resistance. The work also proposes a “acetylation plasticity” model, where long-lived species balance fixed acetylation at certain sites with reversible acetylation at others, creating a regulatory hierarchy that prioritizes stability in critical pathways while maintaining adaptability in others.
Cohen says the team’s work also helps explain “Peto’s paradox”, which essentially states that the incidence of cancer in smaller mammals means it should be relatively impossible for mammals to evolve large sizes and long lifespans.
“If I compare myself to a mouse, I live 50 times longer, and I have at least 10 billion more cells that can become tumors, so how come we don’t all die of cancer early in life?” he says. “The answer is because large mammals have somehow evolved to address the challenge of cancer. In our studies, we found a single acetylation site that had evolved in humans but not in mice, and resulted in a three-fold reduction in tumorigenesis in humans, which perhaps provides some answers to the paradox.”
‘Stealing’ from evolution to boost human longevity
Ultimately, Cohen suggests the research provides a potential roadmap for exploring acetylation as a tunable mechanism of lifespan extension, offering the potential for pharmacological interventions to emulate evolutionary strategies for healthy aging and lifespan extension. The next stage for the researchers is to see if the sites found in long-lived mammals can be targeted to extend lifespan and healthspan in shorter-lived species.
“We’ve already started – we’ve generated mice where we switched a longevity-implicated acetylation site to a human one, so now we’re going to see what happens with these mice, in terms of their lifespan and healthspan,” says Cohen, who adds that there are several other avenues that the team is now exploring.
“We aren’t stopping at acetylation – there is another protein modification called phosphorylation, with hundreds of thousands of sites in mammals. So it’s a more complex area, but we are almost finished this analysis, and soon we’ll be able to say which phosphorylation sites are related to longevity.”
Most interesting of all, Cohen also reveals that his team is already looking at potential human applications of its findings in mammals.
“If you think about the evolutionary tree, there are several animals that are long-lived like humans – whales or elephants, for example,” he says. “What we are searching for now are acetylation sites that changed in other long-lived animals, but that didn’t happen in humans during our evolution. We want to see if we can ‘steal’ what’s happened during evolution and find out whether or not we can use it to extend the lifespan of humans.”
Main photograph: fokkebok/Envato. Article photographs courtesy of Bar-Ilan University.
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