Fight Aging!

Species capable of exceptional regeneration also tend to have longer life spans and slowed aging relative to similar species with less proficient regenerative capabilities. Various closely related species of spiny mouse have been studied in the context of mammalian regeneration because of their ability to shed a large amount of skin and supporting tissues as a defensive mechanism, and later regrow that tissue without scarring. This exceptional regenerative capacity extends to at least some internal organs as well. Spiny mice have been used in past studies that pointed to differences in the activity of macrophage cells as one of the important determinants of complete regeneration versus scar formation.

Macrophages are innate immune cells that are deeply involved in ongoing tissue maintenance and regeneration from injury. Finding out exactly how differences in macrophage behavior are regulated in species capable of proficient regeneration, and whether those changes can be introduced into humans as a basis for therapy, remains an ongoing project. Today's open access paper extends this line of research to further link altered macrophage and broader immune behavior in spiny mice to a slowed pace of age-related decline. There is clearly a bigger picture here regarding aging, tissue maintenance, regeneration, and the innate immune system that researchers are in the early stages of assembling, step by step. At the end of the day it seems likely that there will be close ties between how the innate immune system regulates inflammation, its efficiency in certain activities, such as clearance of senescent cells, and both aging and regeneration.

Immunometabolic resistors of aging in long-lived golden spiny mice

One of the key manifestations of aging is a loss of biological resilience, including a slowdown in cell and tissue repair processes due to chronic sterile inflammation and metabolic stress. Long-lived wild rodents closely related to laboratory mice on the evolutionary scale may allow identification of dormant pathways that resist aging. Spiny mice (Acomys) are known for their exceptional regenerative capacity, but their resilience to aging is unknown.

Here, we report that aged golden spiny mice (Acomys russatus), reared in a non-pathogen-free environment, resist functional decline, have a greater repair capacity with reduced senescence in immune-metabolic organs compared to their sister species, eastern spiny mice (Acomys dimidiatus). Compared to A. dimidiatus, A. russatus retained high tissue repair capacity, reduced frailty with lower inflammaging, fibrosis, cellular senescence, and youthful transcriptome even beyond 4 years. Given that our A. russatus cohort was outbred and reared under non-SPF conditions, this model could be especially relevant for the identification of biomedically relevant mechanisms of health and longevity that are typically obscured in standard genetically identical laboratory mice.

Aged A. russatus maintains transcriptional integrity akin to young mice, highlighting experimental checkpoints for inflammation and mortality. A finding of immune system adaptation of A. russatus was the maintenance of functional thymic architecture till 4 years of age. Notably, the thymi of A. russatus were protected from lipoatrophy and involution, similar to naked mole-rat and long-lived fibroblast growth factor 21 (FGF21) transgenic mice that maintain naïve T cell repertoire till advanced age. We further identified that elevated levels of clusterin in A. russatus macrophages restrain inflammaging and enhance health span in aged mice. Thus, A. russatus biology reveals therapeutically actionable targets that may enhance or maintain function during aging.