Provocative Data from Shared Epigenetic Clocks for Naked Mole Rats and Humans

Epigenetic clocks appear to perform quite well as a measure of chronological age in species that exhibit negligible senescence, meaning that they show little evidence of degenerative aging across much of their life span. Researchers recently published their work on epigenetic aging in lobsters, a species in which a first method of determining chronological age was only discovered comparatively recently. Today's open access paper covers epigenetic aging in naked mole rats, a eusocial species that can live up to nine times longer than similarly sized mammals, and maintains robust health across much of that life span.

Since epigenetic clocks are produced via machine learning techniques applied to data on epigenetic modifications to the genome, as the pattern of modifications appears at different ages, it remains an interesting question as to what exactly is being measured. What processes drive chronological epigenetic change in a negligibly senescent species? It is particularly curious that the researchers here managed to produce clocks that work in both naked mole rats and humans. What does this say about the mechanisms by which naked mole rats achieve robust and healthy longevity? Even in mice and humans, it is largely unclear as to how epigenetic change is produced by the damage and dysfunction of aging. Thus these questions remain to be answered.

DNA methylation clocks tick in naked mole rats but queens age more slowly than nonbreeders

This study describes seven epigenetic clocks for naked mole rats (NMRs), of which five are specific to NMRs (for different tissue types) and two are dual-species human-NMR clocks that are applicable to humans as well. The human-NMR clocks for chronological and relative age demonstrate the feasibility of building epigenetic clocks for different species based on a single mathematical formula. This further consolidates emerging evidence that epigenetic aging mechanisms are conserved, at least between members of the mammalian class.

On a phenotypic level, the NMRs appear to evade aging. Hence, we did not know whether they display epigenetic changes with increasing age. Our study clearly detected significant age-related changes in DNA methylation levels across the entire lifespan of the animal, even in relatively young animals. This contradiction between phenotypic and epigenetic aging could imply that age-related DNA methylation changes do not matter since they do not appear to correlate with any adverse functional consequences in NMRs. However, accelerated epigenetic aging has been correlated to a very wide range of pathologies and health conditions.

Alternatively, it could mean that while the NMR ages at a molecular level, as do all other mammals, it has developed compensatory mechanisms that counteract the consequences of these epigenetic changes. The NMR age-related CpGs that we identified, and the availability of epigenetic clocks, are valuable resources to resolve this question.

Further clues to NMR aging were also revealed from the three-way comparison of age-related CpGs between NMRs, primates, and mice. Although primates and NMRs are phylogenetically more distantly related than NMRs and the mouse, these relationships are not similarly manifested when it comes to longevity. Indeed, NMRs and humans are more akin to each other as they are both outliers with regards to lifespan expected from their adult size. Here, the three-way comparison revealed that the reason for the unusually long lifespans of NMRs and primates may lie in the coregulation of developmental and metabolic processes. Conversely, similarly regulated developmental genes between NMR and human may reflect neotenic features characteristic of these two species. Neoteny is defined as retention of juvenile features into adulthood. A shift towards longer development and retention of youthful tissue repair can lead to longevity.

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