Naked mole-rats live as much as nine times longer than similarly sized rodent species, suffer little age-related decline of function until very late life, and there are next to no examples of individuals in captivity suffering from cancer. Researchers have spent more than twenty years investigating the biochemistry of this species, in search of the reasons for their longevity and resistance to cancer. As for other areas of the study of the comparative biology of aging, the hope is that some of these findings could form the basis for therapies to treat cancer and slow aging in humans. Whether this is the case remains to be seen; researchers have only comparatively recently reached the point of identifying specific differences that might be relevant, and then introducing those differences into mice and other laboratory species to observe the results.
One of the noteworthy differences in naked mole rat cellular biology is that the species exhibits far more efficient DNA repair than is the case in most other mammals. This may contribute to both slowed aging and resistance to cancer, and so has attracted the attention of researchers. Today's paper is an example of progress on this front, in which the authors report that cGAS in naked mole rats has different sequence that encourages more efficient DNA repair. cGAS is more commonly discussed in the context of inflammation, as it is a sensor for mislocalized DNA in the cell cytosol, a part of the innate immune system intended to detect infectious pathogens and raise the alarm. Evolution tends to produce proteins with multiple distinct functions, however, and so in the cell nucleus cGAS has a different role, participating in the regulation of DNA repair. The researchers show that naked mole rat cGAS alterations can extend life in flies when introduced into that species, and reduce aspects of aging when delivered to mice via gene therapy, an interesting result.
A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging
DNA repair constitutes a crucial mechanism for stabilizing the genome. Earlier studies have demonstrated that the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) participates in regulating DNA double-strand break repair by suppressing the homologous recombination (HR) pathway, thereby promoting genomic instability. Although enhanced function of DNA repair proteins contributes to the evolution of longevity, it remains unexplored whether evolution has selected for the attenuation of negative regulators such as cGAS.
In a panel of assays, we found that naked mole-rat cGAS, in contrast to human and mouse cGAS, enhanced HR repair efficiency. This functional reversal is mediated by the substitution of four specific amino acid residues within the C-terminal domain of the cGAS protein. Mechanistically, this amino acid alteration enabled naked mole-rat cGAS to prolong its retention on chromatin in the wake of DNA damage by modulating its ubiquitination status, thereby altering its interaction with the segregase P97. The prolonged presence of naked mole-rat cGAS on chromatin facilitated the formation of a complex between the canonical HR factor RAD50 and FANCI, a factor primarily associated with the Fanconi anemia pathway. We further demonstrated that FANCI promoted the chromatin recruitment of RAD50, thereby potentiating HR repair.
Consequently, naked mole-rat cGAS attenuated stress-induced cellular senescence, mitigated organ degeneration, and extended life span in fruit flies. Critically, reverting these four amino acid residues abolished these protective effects. Furthermore, adeno-associated virus-mediated delivery of naked mole-rat cGAS to aged mice reduced frailty, attenuated hair graying, lowered circulating levels of immunoglobulin G and interleukin-6, and decreased cellular senescence markers in multiple tissues. Once again, these beneficial effects were dependent on the four specific amino acids.
View the full article at FightAging