Fight Aging!

An impressive regenerative capacity often goes hand in hand with longevity. Salamanders are capable of regrowth of lost limbs and injured internal organs, and are unusually long-lived for their size. Like other smaller species that exhibit an exceptional life span, salamanders are the subject of research initiatives that aim to find the relevant biochemical differences that produce greater species longevity. Additionally, scientists are very interested in understanding the specific mechanistic differences between mammals, largely incapable of regeneration without scarring, and species such as salamanders that are capable of scarless regeneration.

More inroads have been made into the question of regeneration than the question of longevity, and it remains far too early to say whether or not there is anything in salamander biochemistry that can be adapted into therapies and safely applied to a mammal in order to lengthen life span. The genetics and cellular metabolism that underlies differences in species life span is a complex swamp of detail piled upon detail, poorly understood and poorly mapped. Progress is slow, as there are only so many researchers in this part of the field, and only so much funding.

Salamander Insights Into Ageing and Rejuvenation

A salient feature of salamander regeneration is its resilience. Urodele regenerative capacity does not decline with time, and most studies suggest it is not impaired by repetitive regeneration events. A landmark study tracked the process of lens regeneration over 16 years in Japanese newts, removing the lens from the same animals 18 times and allowing them to undergo regeneration. Remarkably, the resulting lenses were structurally identical to the original ones and expressed similar levels of lens-specific genes. Subsequent analysis revealed that the transcriptomes of young and old (19-times regenerated) lenses are nearly indistinguishable, showcasing the robustness of newt lens regeneration. Of note, by the end of the study the specimens were at least 30 years old, representing a geriatric population in this species. This provides an interesting contrast to the declines in regenerative capacities observed in most vertebrate contexts.

Additional studies indicate that repetitive amputations do not affect tail regenerative potential in the newt Triturus carnifex, as examined over a 10 year period with up to nine tail regeneration cycles, nor that of the axolotl limb, challenged by five regeneration rounds during 3 years. Taken together, the evidence to date suggests that the ability of urodeles to regenerate complex structures does not decline with time or serial regeneration cycles. In mammals, loss of regenerative potential with ageing has been largely attributed to the ageing of stem cell populations and/or their niche. Whether the prevalence of dedifferentiation as a regenerative mechanism in salamanders is linked to the indefinite nature of their regenerative potential remains an outstanding question.

Beyond their remarkable regenerative abilities, salamanders exhibit extraordinary longevity, constituting lifespan outliers with respect to organismal size. Among animal species, there is a notable correlation between body mass and lifespan, with larger animals living longer. Yet, salamanders break this rule by several orders of magnitude. For example, axolotls - average mass: 60-110g - live over 20 years, and cave olms - Proteus anguinus; average mass: 17g - can surpass 100 years. Indeed, they match and in some cases exceed the lifespan/body mass ratios found in other well-known outliers such as the naked mole rat and Brandt's bat. This is even more remarkable given that most salamander longevity data derive from specimens in the wild, where animals are exposed to environmental challenges, predation, pathogens, and food source fluctuations. Thus, salamanders are not only lifespan outliers, but also in many cases their longevity may be underestimated.