The Strange Epigenetic Clock of the Negligibly Senescent Axolotl
Some species, including a number of highly regenerative species, exhibit little to no age-related decline over much of their life span. Much of the effort put into exploring the comparative biology of aging has focused on these species, in search of specific differences in their cellular biochemistry that might explain why they age so differently from most animals. Negligibly senescent species tend to be long-lived in comparison to normally aging neighboring species in the tree of life, consider naked mole rats versus mice for example, but the question of how they exhibits little degenerative aging in later life may be distinct from the question of why they exhibit a specific life span.
The development of epigenetic clocks and other aging clocks derived from omics data continues apace, gathering increased interest and funding. To be able to measure biological age from a tissue sample is a strong incentive, as this capability would greatly speed up the development of effective therapies to treat aging. There is some way to go yet before aging clocks can be trusted to reflect the results of a given potential therapy, however. It is unclear as to how the measured omics markers connect to aging and specific aspects of aging. But why not apply these technologies to negligibly senescent species and see what the results look like? Hence researchers here attempt to build an epigenetic clock for the axolotl, a highly regenerative and negligibly senescent species of salamander. The results are interesting, to say the least.
Axolotl epigenetic clocks offer insights into the nature of negligible senescence
Salamanders such as the axolotl (Ambystoma mexicanum) are the evolutionarily closest organisms to humans capable of regenerating extensive sections of their body plan, including parts of their eyes, lungs, heart, brain, spinal cord, tail, and limbs throughout their lives, constituting valuable models for regeneration studies. Yet, urodele amphibians are also characterised by an apparent lack of physiological declines through lifespan, indefinite regenerative capacity, extraordinary longevity, and defiance of the Gompertz law of mortality, key features of negligible senescence. Their long lifespans and lack of experimental tractability have historically restricted their use in ageing studies. However, recent technological advances have enabled the axolotl as a tractable model system.
Throughout life, axolotls exhibit several age-defying traits, including dermal thickening, progressive skeletal ossification, and cancer resistance. Further, their tissues do not accumulate senescent cells with age, thereby circumventing a major hallmark of ageing and driver of age-related disorders, in keeping with their proposed negligible senescence status. Yet, whether axolotls exhibit signs of molecular ageing remains unknown.
Changes in the methylation level of cytosines within CpG dinucleotides constitute a primary hallmark of molecular ageing. Indeed, age-related changes in DNA methylation (DNAm) occur across animal species, including mammals, birds, fishes and amphibians. More recently, the Mammalian Methylation Consortium has confirmed that age-related gains in methylation can be observed at target sites of the Polycomb Repressive Complex 2 (PRC2), which catalyses the tri-methylation of lysine 27 on histone H3 (H3K27me3) in all mammalian species. DNA methylation at PRC2 target sites may constitute a universal biomarker of aging and rejuvenation in mammalian systems.
Multivariate regression models based on the methylation status of multiple CpG sites provide accurate age estimators, commonly known as 'epigenetic clocks,' in mammalian species. Initially restricted to humans and mice, the identification of highly conserved CpGs facilitated the construction of multispecies clocks. Here, we conduct DNA methylation profiling of axolotl tissues at CpGs associated with ageing across mammalian and amphibian species. We develop axolotl epigenetic clocks at both pan-tissue and single tissue levels and uncover that axolotls exhibit conserved epigenetic ageing traits during early life but not thereafter, deviating from the established notion of organismal ageing. We reveal that, in contrast to mammals, the axolotl methylome is remarkably stable and does not exhibit substantial shifts at either global or PRC2-associated gene levels late in life.