Could Axolotls be the Key to Anti-Aging Therapies?

We’ve all seen countless pictures and videos of axolotls: a salamander species native to Mexico with larval, or developmental, features such as small legs, a tadpole-like tail, and frilly gills not typically seen in adult salamanders of other species. Although maintaining these youthful features into adulthood makes axolotls seem adorable, it seems a bit counterintuitive for axolotls’ appearances to never evolve from their larval stage. What benefits could larval features possibly have for axolotls?

Most species of salamanders go through a process called metamorphosis, during which they leave the water and adapt to life on land—similar to how a tadpole becomes a frog. The main evolutionary push for features that allowed salamanders to live on land was that most salamanders live in lakes that undergo seasonal wet and dry cycles, so they cannot live underwater during the dry cycle. During metamorphosis, salamanders develop lungs, lose their gills, and develop eyelids. However, axolotls do not typically go through a metamorphosis due to a phenomenon known as neoteny, which allows them to maintain their larval gills and tail and live in water throughout their lives.

The main reason axolotls retain their larval features is because of the evolutionary advantages of staying in water. First of all, axolotls face lower risks from predators when in water because of land animals and birds such as storks have a harder time reaching underwater prey. Additionally, the primary axolotl habitats, Lake Xochimilco and Lake Chalco, do not undergo a seasonal wet and dry cycle due to the climate of their location, unlike the habitats of other salamander species.

Axolotls not only retain their larval features as they grow, but they also retain regenerative abilities such as regrowing limbs. They show very few signs of age-related conditions, such as inflammation, certain cancers, and the buildup of senescent cells, which are non-dividing cells that remain in the body and can be harmful in large quantities. As such, understanding an axolotl’s ability to regrow body parts and avoid age-related ailments well into adulthood may present many possibilities for creating human anti-aging therapies.

Researchers have been working on understanding the mechanism for how neoteny occurs in axolotls. However, since aging does not occur uniformly between individuals and across species, researchers needed to use a methodology other than chronological age to measure aging. This is where epigenetic clocks come into play.

Epigenetic clocks are perfect for measuring aging. Epigenetic age is a measure of an organism’s biological age; it works by quantifying the level of methylation of the organism’s genome. As an organism ages, the level of DNA methylation—the process of adding methyl groups to regulate gene expression—increases. Since this is a phenomenon observed across many species, epigenetic age is a uniform method for generally studying biological aging. 

In a 2024 study, researchers measured epigenetic aging in axolotls. They collected samples of six different tissues—the limbs, tail, skin, liver, spleen, and blood—from 180 axolotls aged four weeks to 21 years and measured the level of DNA methylation. To decide which genes to study the methylation of, they referenced genes that have accurately determined the biological age of both mammals and amphibians; only genes specific to axolotls were studied.

Researchers noticed something strange in their measurements. From ages zero to four, the epigenetic clock of axolotls showed normal signs of aging. However, after the age of four, the epigenetic clocks of axolotls showed virtually no changes over time. The observed epigenetic age of a 15 year old axolotl was essentially the same as of a four year old axolotl—an especially surprising development given that there are usually some notable physical changes after the age of four, such as growth and bone formation. 

It’s not completely clear why axolotl genomes don’t undergo the same epigenetic aging as other species, but this process has important implications on axolotl development. Axolotl genes are effectively preserved in the larval stage, and scientists believe that this is the reason axolotls can retain their regenerative properties late into life. This also allows them to avoid scarring when regrowing limbs and to regenerate nerve cells later in life. 

Understanding the processes through which axolotls avoid epigenetic aging can help scientists develop treatments for age-related human conditions. For example, as cellular damage builds up over time and an organism epigenetically ages the incidence of cancer in humans increases. In axolotls, epigenetic stability is conserved, making their cells less likely to build up damage and form tumors. Another major way that humans differ from axolotls as they age is in the functioning of their immune system. In humans, age-related decline of the immune system, which includes chronic inflammation, correlates with many conditions such as autoimmune diseases. However, axolotls balance inhibitory immune signals with pro-growth signals in order to maintain their regenerative abilities, leading to a highly regulated immune system, even when they age. Although the mechanisms that axolotls use have not been directly tested on humans, this is an area of research with a lot of potential.

Axolotls’ unique ability to stop the processes of biological aging early in life provides them with health benefits that most other adult animal species lack. Further researching the biological mechanisms that allow these animals to pause their epigenetic clock may provide us with insights about how human aging occurs and potentially alter the negative effects associated with aging.