Why do common shrews live for only two years, while bowhead whales survive for two centuries? And could the answer give us hints as to how to extend our own, human life spans?
The maximum life span of each species is estimated using the age of its longest-living member, and these vary by orders of magnitude among mammals. Now, scientists propose that "epigenetics" could at least partly explain these differences. They initially posted their findings in November 2023 to the preprint database bioRxiv, and on Friday (June 7), the study was published in the journal Science Advances.
While "genetics" is the study of genes, "epigenetics" is the study of chemical modifications to genes that boost or limit their expression, controlling which genes are switched on or off. These modifications have long been linked to aging, but the new study suggests they also play a role in determining maximum age.
One such modification is DNA methylation, the addition of molecules called methyl groups to cytosine (C), one of the four "letters" within DNA's code. Methylation often occurs when C sits next to guanine (G) bases at so-called CpG sites in DNA.
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Methyl groups that latch onto CpG sites control gene expression by influencing which regulatory proteins can attach to DNA. These proteins can promote or block gene expression, but methylation alters the shape of the DNA molecule, making it more or less likely that the proteins will attach.
Using epigenetic data from 348 mammal species, the researchers trained a machine learning algorithm to predict the maximum life span of each species based on CpG methylation patterns. The algorithm predicted the maximum life span of each species as a whole but not the longevity of any one individual. It was even possible to predict a species' maximum life span without knowing which species a sample came from, New Scientist reported.
The study reveals that CpG methylation is correlated with maximum life span, but a causal link has not been identified yet.
"I think it was a fascinating first step to understand the inherent differences in species life span — something that the field has been discussing for a long time now," James White, who researches aging at Duke University and was not involved with the work but collaborates with the authors on other projects, told Live Science.
The algorithm produced ballpark predictions for each species, meaning it wasn't perfectly accurate for each mammal. It predicted a 4.8-year maximum for the desert hamster, exactly matching the oldest age on record, but it predicted humans can live 98 years at most, even though humans have been known to reach 119. Another limitation of the analysis is that CpG methylation differs across tissues, such as blood and skin, so different samples yield different predictions.
Other epigenetic factors not explored in this study may also contribute to maximum life span — for example, histones. These act as "spools" that wind up DNA like thread to conceal it from enzymes that could activate genes, and they interact with methylated DNA to regulate genes. CpG methylation determines which stretches of DNA are preferentially wound up by histones, for example.
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However, study co-author Vera Gorbunova, an epigeneticist at the University of Rochester, said it would be difficult to map out histone proteins across mammalian genomes to the same level of detail as CpG methylation patterns with current technology.
Until scientists discover the underpinning biochemistry of how epigenetics influences aging, it's unclear whether therapeutically targeting these epigenetic features could boost longevity.
Looking forward, "it would be fascinating to learn if these DNA methylation patterns are linked to processes relevant to established aging hallmarks, such as DNA repair," Adiv Johnson, a biogerontologist at the Tally Health aging research company who was not involved with the work, told Live Science in an email.
"In my opinion, we are far away from being able to extend maximum life span in humans," Johnson said. "I think that we need a much deeper, more comprehensive understanding of the biology of aging for this to be a near-future reality."
White agreed, suggesting that the factors that promote life span evolved alongside other genes in long-lived species and may not elicit the same beneficial effect if introduced into short-lived species with different genomes. However, Gorbunova has hope for finding therapeutic applications of the research. She said it might one day be possible to target epigenetic enzymes that install or remove methyl groups on CpGs.
"Those enzymes can be quite selective — we just need to understand how to tweak them properly," she said. Doing so could possibly boost longevity or slow aging, but for the moment this remains speculative.
Editor's note: This story was first published on Dec. 11, 2023, and was updated on June 7, 2024, following the publication of the related study in a peer-reviewed journal.
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