Fight Aging!

Naked mole-rats are an unusually long-lived mammalian species, of a similar size to mice but with a life span of decades rather than just a few years. This species also exhibits a near complete absence of cancer and very little age-related decline in function until very late in life. Investigations of their biochemistry have uncovered a range of interesting differences, such as senescent cells that are far more benign than their counterparts in other mammals, more efficient protein synthesis, more efficient DNA repair (such as an improved version of the cGAS protein), and more. That naked mole-rats live underground in oxygen poor environments, with a corresponding lack of predation, has prompted the evolution of greater longevity and the necessary co-evolution of the many features needed to support that longevity, such as improved cell resilience to common stresses.

In today's open access paper, researchers examine the gut microbiome in naked mole-rats. In mice and humans the composition of the gut microbiome changes with age, in ways that provoke greater inflammation and diminish the supply of beneficial metabolites. Animal studies have shown that restoring a youthful composition, such as via fecal microbiota transplantation from a young donor, improves health and extends life. Perhaps unsurprisingly, all things considered, the results in the paper here show that naked mole-rats exhibit very little change in the composition of the gut microbiome over a life span. Why this is the case is an interesting question, however. It perhaps argues for the hypothesis that changes in gut microbiome composition are downstream of the aging of the immune system, as it becomes ever less capable of suppressing populations of undesirable microbes.

The naked mole-rat microbiome is associated with healthy aging and social structure

The gut microbiome plays a pivotal role in health and disease, modulating digestion and xenobiotic processes, regulating metabolism, influencing epithelial development, and altering immune function. When the microbiome is dysregulated, as may occur during aging, it may contribute to myriad chronic diseases, such as cardiovascular disease, diabetes, and cognitive impairment. Similarly, therapeutic interventions that modify the microbiome with probiotics reportedly have been effective in the treatment of age-related cognitive impairment and sarcopenia and may even delay or abrogate the overall physiological declines that occur with advancing age.

Here, we investigate the naked mole-rat (NMR; Heterocephalus glaber) and its unique microbiome. These small (35-45 g) rodents are notable for both their unusual eusocial lifestyle and successful aging profile: breeding is monopolized by one female (the "queen") within a colony, with the result that although most NMRs remain in their natal colony, less than 1% of all individuals have the opportunity to reproduce over their exceptionally long lifespans (more than 40 years). In addition to their extraordinary longevity, NMRs show a lack of demographic aging, with no increased risk of dying in older animals, and well-maintained physiological, metabolomic, and biochemical function with advancing age. NMRs are also resistant to chronic age-associated diseases (e.g., cancer, neurodegeneration, and cardiovascular diseases). These atypical features suggest they are able to successfully retard, delay, or abrogate the functional declines that commonly accompany the aging process in other mammals.

Comparing fecal samples from NMR individuals over different social ranks and over a span of more than three decades. In contrast to a cohort of C57BL6/J mice, which showed extensive age-related changes, we found little difference in the microbiota of NMRs from different age cohorts. Only the archaea Methanomassiliicoccus intestinalis, which was present in the NMR gut but not the murine gut, showed an increased proportion with older age. Pregnant queens were found to have higher microbial diversity, potentially a consequence of their aggressive coprophagia. Overall, these findings provide a rich and dynamic picture of the NMR microbiome and starting points for future investigation.