Does Efficient DNA Damage Repair Mediate the Long-Life Span of Naked Mole-Rats?

The extraordinarily long lifespan of the naked mole-rat (nearly 40 years; Lee et al.) results from the accumulation of numerous adaptations to diverse biological processes that have occurred during evolution. Importantly, we still lack a complete understanding of the DNA damage repair mechanisms that protect this burrowing rodent from genomic instability (a primary hallmark of aging) caused by endogenous or exogenous DNA damage. Interestingly, naked mole-rats represent a crucial model that we can employ to understand the aging process, as their transcriptomes and protein-coding sequences resemble those of humans more than those of mice (Lewis et al.). Can the anti-aging-related knowledge garnered from studies in this remarkable animal lead to breakthroughs in human aging research?

Researchers from the laboratories of Ying Jiang and Zhiyong Mao (Tongji University) recently sought to determine whether naked mole-rats possess distinctive, highly efficient DNA damage repair mechanisms to reduce genomic instability, with a focus on cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS). This DNA sensor localizes to the nucleus and regulates DNA double-strand break repair by suppressing the homologous recombination pathway in humans (Liu et al.) and mice, thereby promoting genomic instability and tumorigenesis and potentially reducing lifespans (Liu et al. and Jiang et al.). Of note, DNA double-strand breaks - the most deleterious type of DNA damage – can undergo homologous recombination-mediated DNA damage repair via a complex multi-stage process (Heyer et al.), although the levels of these insults increase during normal aging (White & Vijg). Could the attenuation of negative regulators of DNA repair, such as cGAS, play a driving role in the evolution of longevity in the naked mole-rat? Chen and Chen et al. set out to better understand DNA damage repair mechanisms in naked mole-rats and now report their exciting findings in a new study in the journal Science.

Paired-Tag technology from Epigenome Technologies enables simultaneous profiling of transcriptomics and epigenetics in single cells; could integrating this approach into this fascinating new study have yielded additional insights into the chromatin landscape and transcriptomic profiles in single cells of important tissues in the naked mole-rat, which could inform anti-aging therapeutics in humans? Paired-Tag technology from Epigenome Technologies generates joint epigenetic and transcriptomic profiles at single-cell resolution and detects histone modifications and RNA transcripts in individual nuclei with comparable efficiency to single-nucleus RNA-seq/ChIP-seq assays while avoiding the need for cell sorting.

How a Four-Amino-Acid Switch Creates a Pro-Longevity Form of the cGAS Protein

The authors discovered that the naked mole-rat cGAS exhibits enhanced homologous recombination-based DNA damage repair efficiency compared to the human and mouse versions (which suppress homologous recombination repair) due to a four-amino-acid substitution in the C-terminal domain of the cGAS protein. These four alternate amino acid residues allowed naked mole-rat cGAS to stay associated with chromatin for prolonged periods of time following induction by DNA damage by weakening E3 ubiquitin-protein ligase TRIM41-mediated ubiquitination, which alters interactions with the human ubiquitin-selective protein segregase p97 (also known as VCP; valosin-containing protein). The prolonged maintenance of naked mole-rat cGAS bound to chromatin facilitated the formation of a complex between the canonical homologous recombination factor RAD50 (Hopfner et al.) and the Fanconi anemia pathway factor FANCI, where FANCI (Sirbu et al. and Chen et al.) promotes the recruitment of RAD50 to chromatin to potentiate homologous recombination-based DNA repair.

In the final part of this fascinating paper, the authors revealed that introducing the naked mole-rat cGAS into fruit flies prompted a reduction in stress-induced cellular senescence and organ degeneration and the extension of life span; furthermore, the adeno-associated virus–mediated delivery of naked mole-rat cGAS into aged mice reduced levels of frailty, hair graying, and plasma immunoglobulin G and interleukin-6 levels (which display a known increase during normal aging; Yu et al. and Jergović et al.) and decreased the presence of cellular senescence markers in multiple tissues. However, reverting the four amino acid residues that differ between naked mole-rats and flies and mice abolished any protective effects.

Can We Manipulate Human cGAS to Extend Healthy Lifespans through Efficient DNA Damage Repair?

Overall, this fascinating new study reveals how the evolution of the naked mole-rat has endowed this burrowing rodent with an extended lifespan thanks to the evolution of a cGAS protein with elevated homologous recombination-based DNA double-strand break repair capacity, which differs significantly from that in humans, mice, and fruit flies. This added activity allows naked mole-rats to maintain a higher level of genome stability, which supports reduced cell senescence and organ dysfunction over time and an extended lifespan. Overall, these findings highlight how inducing efficient DNA damage repair can decelerate the aging process; now, the next question is whether manipulating cGAS (or the FANCI-RAD50 interaction) in humans to enhance DNA damage repair represents a therapeutic mechanism that could extend healthy lifespan.

The additional integration of simultaneous profiling of transcriptomics and epigenetics in single cells, afforded by applying Paired-Tag technology from Epigenome Technologies, could provide additional insights into how the dysregulation of the chromatin landscape and transcriptome – both critical components of the aging process – may become reversed in in single cells of important tissues upon the expression of naked mole-rat cGAS, which could then inform on the development of anti-aging therapeutics in humans.