How Axolotls Resist Aging: Insights from DNA Methylation

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For years, scientists have been fascinated by the ability of certain animals to regenerate lost limbs and resist aging, and axolotls (Ambystoma mexicanum) stand out as one of the most intriguing models. Renowned for their incredible regenerative capabilities, these amphibians exhibit not only the power to regrow body parts but also possess remarkable longevity, showing minimal signs of aging, a phenomenon known as negligible senescence. A recent study has taken a closer look at the molecular mechanisms behind this extraordinary resilience, with a particular focus on the axolotl’s epigenome—especially the DNA methylation patterns that influence biological aging.

What Are Epigenetic Clocks?

Epigenetic clocks are biological tools used to estimate an organism's age by analyzing changes in DNA methylation, particularly at CpG sites—specific areas in the genome where a cytosine nucleotide is followed by a guanine nucleotide. These methylation changes occur as organisms age and can serve as molecular "signatures" of aging.

In mammals, for instance, these clocks have been highly accurate in predicting chronological age and revealing insights into biological age (the rate at which an organism ages based on biological markers). But for creatures like the axolotl, which seem to age more slowly, epigenetic clocks can help uncover why they exhibit such prolonged longevity and limited aging signs.

The Unique Epigenome of Axolotls

In this groundbreaking study, researchers developed the first axolotl epigenetic clocks, which turned out to be biphasic—capable of predicting age during early life but not in later stages. This means that while the axolotl’s epigenome shows age-related changes early in life, these changes stabilize, or “stop ticking,” for the rest of their lifespan.

This finding is crucial because it suggests that axolotls may follow a different biological aging pathway than other organisms. Unlike mammals, where age-related methylation changes are consistent throughout life, axolotls show a remarkable epigenetic stability after reaching maturity, which may be tied to their negligible senescence traits​(2024.09.09.611397v1.full).

Epigenetic Stability and Regeneration

One of the most intriguing aspects of the study was the relationship between regeneration and epigenetic age. When axolotls regenerate lost limbs, particularly in younger individuals, their epigenetic clocks showed signs of rejuvenation. Specifically, repetitive limb regeneration led to a reduction in the epigenetic age of the tissues, suggesting that regeneration may actively reverse certain age-related epigenetic changes.

This rejuvenation effect was seen more strongly in limb regeneration, where dedifferentiation of mature cells occurs—a process where mature cells revert to a more primitive, stem-like state. In contrast, tail regeneration, which relies more on pre-existing stem cells, did not show as pronounced an effect on reducing epigenetic age. These findings suggest that the mode of regeneration—whether it involves dedifferentiation or stem cells—could impact how much rejuvenation occurs​(2024.09.09.611397v1.full).

Implications for Negligible Senescence

The discovery that axolotls exhibit negligible shifts in DNA methylation after early life provides molecular backing for their negligible senescence. Unlike other species, including amphibians like frogs, axolotls' methylation patterns at critical sites—such as those targeted by the Polycomb Repressive Complex 2 (PRC2)—remain largely stable throughout life. This stability, especially in PRC2-regulated genes, which are typically associated with aging in mammals, could explain their resistance to the typical hallmarks of aging​(2024.09.09.611397v1.full).

In mammals, for instance, PRC2 target sites tend to gain methylation as animals age, a process that contributes to cellular dysfunction and aging. In axolotls, however, this gain is minimal, suggesting that their cells avoid some of the key molecular traps that lead to aging in other organisms.

A Model for Human Aging?

The ability to develop dual-species epigenetic clocks—with shared signatures between axolotls, frogs, and even humans—opens the door to further comparative studies that may unravel universal aging mechanisms. These clocks not only provide a tool for understanding axolotl biology but also offer a potential avenue for aging research in humans.

By studying how axolotls manage to stave off aging, scientists hope to uncover new strategies for combating age-related diseases and extending healthy lifespans in humans. While there are still many unanswered questions about the exact mechanisms driving this epigenetic stability, this research is a critical step toward decoding the secrets of negligible senescence.