The longevity code in four letters (amino acids)

Aging poses a fundamental challenge for humanity. Understanding the underlying mechanisms will provide crucial insights into how to address the challenges faced by an aging population. While studies have implicated diminished DNA repair activity and declining genomic stability as key drivers of aging,[1,2] it is unclear whether therapeutic activation of DNA repair pathways and genome stabilization can effectively counteract aging. Recently, we addressed this question by investigating the exceptionally long-lived rodent, the naked mole-rat, providing novel insights into the mechanisms underlying longevity.[3] Our previous studies have indicated that the innate immune sensor, cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS), translocates into the nucleus following DNA damage and it inhibits homologous recombination (HR) repair.[4,5] However, we observed a dramatic functional reversal of cGAS in this long-lived species: It significantly promotes HR repair to stabilize the genome. Remarkably, this functional switch hinges solely on changes in four specific amino acids within the C-terminal domain of the naked mole-rat cGAS protein. Previous studies have reported that a superior DNA repair system has evolved in the naked mole-rat.[6,7] To investigate how cGAS in the naked mole-rat changes the HR regulatory function, we performed molecular analyses to demonstrate that these four amino acid substitutions reduce the K48-linked ubiquitination of cGAS. This prolongs retention of cGAS in chromatin, facilitating the recruitment of downstream repair factors. Intriguingly, our study also suggests that there is a novel role for FA complementation group I (FANCI), a core factor in crosslink repair, which appears to collaborate with the classical HR factor, RADiation sensitive 50 (RAD50), in regulating HR repair. Furthermore, the absence of a detectable poly(ADP-ribose) polymerase 1 (PARP1)-Timeless interaction in the naked mole-rat indicates that there are unique features within the DNA repair regulatory network. Elucidation of the distinct regulatory mechanism represents a critical future research direction [Figure 1].Figure 1: Naked mole-rat cGAS promotes HR repair to attenuate senescence and delay aging. aa: Amino acids; cGAS: Cyclic guanosine monophosphate-adenosine monophosphate synthase; HR: Homologous recombination. Figure 1: was created with BioRender.com.Do these changes confer resistance against cellular senescence and aging? We demonstrated that naked mole-rat cGAS, via four key amino acid variants, has potent anti-aging effects at multiple levels. First, overexpression of naked mole-rat cGAS significantly reduces radiation-induced senescence. Moreover, in an invertebrate Drosophila melanogaster model, naked mole-rat cGAS antagonizes aging in multiple tissues. These include reducing hyperproliferation of intestinal stem cells, maintaining the integrity of the gut barrier, enhancing motor ability, and delaying reproductive aging. Notably, the expression of naked mole-rat cGAS in Drosophila extends its lifespan. Furthermore, in a mammalian murine model, adeno-associated, virus-mediated delivery of naked mole-rat cGAS, reduces systemic inflammation and immunoglobulin G (IgG),[8,9] decreases senescence markers in multiple organs, and lowers the frailty index. Future studies should investigate whether naked mole-rat cGAS extends the lifespan in murine models. Subsequently, the use of large animal models, such as non-human primates, will be essential to rigorously assess the efficacy and safety of naked mole-rat cGAS-based interventions. Ultimately, the development of small-molecule compounds that mimic the beneficial effects of naked mole-rat cGAS is a critical translational goal. In conclusion, our study has established a framework for leveraging comparative biology to harness mechanisms of longevity from long-lived species,[10] thereby delaying aging and improving health span across species. Furthermore, this study lays the groundwork for the development of systemic antiaging interventions that target genomic stability. Fundings This work was funded by grants from the National Natural Science Foundation of China (NSFC) (Nos. 82522035, 32470796, and 32200595), Fundamental Research Funds for the Central Universities (Nos.22120250374 and 22120240273) and Peak Disciplines (Type IV) of Institutions of Higher Learning in Shanghai. Conflicts of interest None.