In a preprint published in bioRxiv, researchers explored the use of epigenetic clocks on the axolotl (Ambystoma mexicanum), a salamander species that demonstrates exceptional regenerative capabilities and does not age in the same way humans do. This research highlights the potential for new insights into aging and regeneration in non-mammalian species.
Axolotl: Beyond Regeneration
Axolotls, like other salamanders, are famous for their ability to regrow lost limbs, continuing to regenerate throughout their lives. Unlike humans and other mammals, they do not experience a decline in physical function or show traditional signs of aging. Axolotls also exhibit a remarkable resistance to cancer, even when injected with carcinogens[1][2][3].
Despite their 10-13 year lifespan, which is relatively short for salamanders, axolotls’ longevity and resilience make them an attractive model for research. Modern genetic and transfection techniques, often used in mouse studies, have now been applied to axolotls[4].
| Key Traits of Axolotls | Description |
|---|---|
| Regeneration | Ability to regrow limbs and maintain physical function throughout life |
| Cancer Resistance | Resistance to cancer, even when exposed to carcinogens |
| Lifespan | Average lifespan of 10-13 years |
| Research Interest | Potential insights into aging, regeneration, and cancer resistance |
What Are Epigenetic Clocks?
An epigenetic clock measures DNA methylation levels to estimate an organism’s biological age. These clocks are considered gold-standard aging biomarkers and are currently used to study aging mechanisms, predict morbidity and mortality, and assess the effectiveness of anti-aging interventions. While pan-mammalian clocks exist for humans, mice, and naked mole rats, amphibians like axolotls present new challenges in applying these clocks[5][6].
| Epigenetic Clocks | Description |
|---|---|
| Definition | Biomarkers that measure DNA methylation to determine biological age |
| Applications | Aging studies, anti-aging interventions, and predicting health risks |
| Challenges in Amphibians | Amphibians differ from mammals in epigenetic aging, requiring new approaches |
No Correlation Between Epigenetic and Chronological Age
The researchers identified 5,386 common CpG sites shared between axolotls, clawed frogs, and mammals. However, attempts to create an epigenetic clock for axolotls across their lifespan showed no correlation between epigenetic age and chronological age. This failure was consistent across different tissues and sample sizes, suggesting that axolotls do not age in the same way as mammals.
| Research Findings | Description |
|---|---|
| Common CpG Sites | 5,386 sites shared between axolotls, clawed frogs, and mammals |
| Clock Development | No correlation between epigenetic and chronological age in axolotls |
| Significance | Axolotls appear to stop aging epigenetically after a certain point |
Early-Life Aging and Biphasic Epigenetic Aging
The study revealed that axolotls exhibit early-life epigenetic aging, up to around 4 years of age, after which the process seems to stop. Researchers developed a clock trained only on axolotls younger than 4 years, which successfully predicted their ages. The results suggest that axolotls undergo biphasic aging: they age early in life but cease to epigenetically age beyond that point.
| Early-Life Aging | Description |
|---|---|
| Epigenetic Aging | Axolotls age epigenetically until approximately 4 years of age |
| Biphasic Aging | Epigenetic aging halts after early life |
| Predictive Accuracy | Age prediction was accurate for axolotls under 4 years old |
Regeneration and Epigenetic Rejuvenation
Interestingly, limb regeneration in axolotls was shown to rejuvenate epigenetic markers. When an axolotl’s tail was cut off six times, there were no significant changes in epigenetic age. However, repeated limb amputations resulted in the younger epigenetic age of the regrown limb. The researchers hypothesize that dynamic regulation during regeneration may play a central role in this epigenetic rejuvenation.
| Regeneration Effects | Description |
|---|---|
| Tail Regeneration | No significant change in epigenetic age after six tail amputations |
| Limb Regeneration | Repeated limb regrowth made the limb epigenetically younger |
| Implication | Dynamic regulation during regeneration could contribute to rejuvenation |
Implications for Anti-Aging and Regenerative Medicine
The axolotl’s ability to regenerate without aging presents exciting possibilities for anti-aging research and regenerative medicine. Understanding how axolotls halt epigenetic aging and rejuvenate tissues may offer potential pathways for applying these mechanisms to mammalian systems, though significant research is still required.
| Anti-Aging Potential | Description |
|---|---|
| Epigenetic Rejuvenation | Regeneration may rejuvenate tissues epigenetically |
| Cancer Resistance | Lack of CpG markers associated with cancer in axolotl epigenome |
| Future Research | Applying these mechanisms to mammals will require further study |
More Information:
- Title: Epigenetic Aging in Axolotls: Insights into Regeneration and Anti-Aging
- Published By: Researchers from bioRxiv
- Journal: bioRxiv (2024)
References:
- Brockes, J. P., & Kumar, A. (2008). Comparative aspects of animal regeneration. Annual Review of Cell and Developmental Biology, 24(1), 525-549. ↩︎
- Yun, M. H. (2021). Salamander insights into ageing and rejuvenation. Frontiers in Cell and Developmental Biology, 9, 689062. ↩︎
- Ingram, A. J. (1971). The reactions to carcinogens in the axolotl (Ambystoma mexicanum) in relation to the ‘regeneration field control’ hypothesis. Development, 26(3), 425-441. ↩︎
- Murawala, P., Oliveira, C. R., Okulski, H., Yun, M. H., & Tanaka, E. M. (2022). Baculovirus Production and Infection in Axolotls. In Salamanders: Methods and Protocols (pp. 369-387). New York, NY: Springer US. ↩︎
- Lu, A. T., Fei, Z., Haghani, A., Robeck, T. R., Zoller, J. A., Li, C. Z., … & Singh, K. (2023). Universal DNA methylation age across mammalian tissues. Nature Aging, 3(9), 1144-1166. ↩︎
- Zoller, J. A., Parasyraki, E., Lu, A. T., Haghani, A., Niehrs, C., & Horvath, S. (2024). DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic aging. GeroScience, 46(1), 945-960. ↩︎
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