Digging Deeper into the Epigenetics of Supercentenarians

Supercentenarians, much as one might expect, exhibit signs of being biologically younger than their years. It is a lower burden of age-related damage and dysfunction that allows them the chance to survive. That said, it is worth noting that many characteristics so far observed in studies of supercentenarians are also present in large numbers of people who die well before reaching a century of life. The fortunately biochemistry of supercentarians adjusts small odds of survival to be slightly more favorable, but still small odds of survival. It is far from an assurance, and it certainly doesn't prevent one from becoming frail and dependent. Supercentenarians are greatly impacted by aging, exhibiting a roughly 50% yearly mortality rate.

For these reasons, efforts to better understand the survival of supercentenarians seem to me to be a matter of scientific interest, but not a matter of practical interest. It is not the path that will lead to ways of ensuring meaningfully greater health and longevity for all. Today's open access paper is an example of this sort of research, a deeper dive into differences in epigenetic patterns exhibited in supercentenarians. Epigenetic decorations to DNA determine the expression of genes and thus behavior of cells. Given the advent of epigenetic clocks, measures of biological age based on characteristic age-related changes in specific sets of epigenetic marks on the genome, it is now possible to look at areas of the age-related portion of epigenetics, and declare that an individual's biochemistry appears either older or younger than the norm. Perhaps unexpectedly, supercentenarians are a mix of both.

Epigenetic profile of Japanese supercentenarians: a cross-sectional study

Centenarians and supercentenarians with exceptional longevity are excellent models for research towards improvements of healthy life expectancy. Extensive research regarding the maintenance and reduction of epigenetic age has provided insights into increasing healthy longevity. To this end, we explored the epigenetic signatures reflecting hallmarks of exceptional healthy longevity, including avoidance of age-related diseases and cognitive functional decline.

Our findings show that the epigenetic ages of Japanese centenarians and supercentenarians were remarkably lower than their chronological ages, consistently with previous findings for Italian semi-supercentenarians, suggesting that their healthy longevity has an epigenetic basis. However, whether these epigenetic ages also reflect biological age has not yet been validated. Whether healthy longevity depends on slowing epigenetic ageing or on having a younger baseline DNA methylation state would be the next subject of interest. For our multiple-sampled centenarians and supercentenarians, the longitudinal changes in epigenetic age showed that their epigenetic ageing was slower than that indirectly inferred from the cross-sectional non-centenarian cohort. Further research comparing the longitudinal epigenetic change of centenarians and supercentenarians with non-centenarians will help to answer this question.

Our study further suggests a link between the specific epigenetic states and exceptional healthy longevity in centenarians and supercentenarians. Some epigenetic signatures in centenarians and supercentenarians were maintained at young states, whereas others were maintained at advanced (or old) states. Young-state DNA-methylation signatures were overrepresented around cancer-related and neuropsychiatric disease-related genes. Conversely, CpG sites with accelerated (advanced) demethylation were also detected in centenarians and supercentenarians. Knowledge-based analyses indicated that some of these demethylated CpG sites can affect the activity of TGF-β, a major anti-inflammatory cytokine. Given that many age-related diseases can develop as a consequence of excessive pro-inflammatory responses, anti-inflammatory responses, such as those mediated by TGF-β and other cytokines, are crucial for healthy ageing and longevity. For instance, immunoassays have identified greater TGF-β activity in centenarians than in younger controls.

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