Yu Chen

Long interspersed nuclear element 1 (LINE‐1 or L1) retrotransposons pose a significant threat to somatic genomic integrity and are a source of sterile inflammation. Consequently, L1 activity is stringently controlled by multiple regulatory layers to ensure silencing, while its transcriptional derepression is linked to aging and age‐related diseases. Recent studies have revealed complex interrelationships between L1 and cGAS, but whether cGAS regulates L1 transcription and its biological significance remains unclear. Here, we demonstrate that human cGAS activates L1 transcription by upregulating the transcriptional regulators CTCF and RUNX3. This cGAS‐mediated promotion of L1 transcription is absent in mice due to functional divergence in CTCF and RUNX3. Furthermore, cGAS‐mediated elevation of L1 mRNA promotes cellular senescence via MAVS, a key RNA‐sensing pathway component. Together, our findings reveal a novel role of cGAS in activating L1 transcription and define a cGAS–L1–MAVS senescence pathway, thereby bridging the noncanonical function of cGAS and the RNA‐sensing signaling.

Impairments in DNA repair mechanisms undermine genomic integrity, accelerating the aging process and elevating the risk of age-related diseases in both murine models and humans. Despite the recognized link between DNA repair and aging, empirical evidence supporting the lifespan and healthspan extension through enhanced DNA repair is lacking. This knowledge gap is attributed to the complex interplay of numerous DNA repair genes involved in maintaining genomic stability, making it challenging to pinpoint specific pathways and factors that could be targeted for lifespan and healthspan improvements. In this study, we generated a knock-in mouse model overexpressing XRCC4 and DNA LIG4, key components of the non-homologous end joining (NHEJ) pathway, the predominant mechanism for repairing DNA double-strand breaks. Our findings reveal that augmenting NHEJ is a viable anti-aging strategy in mammals, as evidenced by extended lifespan and improved healthspan in both wild type mice and LmnaG609G/+ progeroid mice. Additionally, enhanced NHEJ activity improves cardiac, motor, and cognitive functions, as well as bone quality in aged mice. Transcriptomic and epigenetic analysis across different organs indicates significant downregulation in inflammatory responses and upregulation of pathways associated with maintaining organ homeostasis and function, further supporting the role of DNA repair in modulating aging and age-related diseases. Our data underscore the potential of targeting DNA repair pathways as a strategy to counteract aging and its associated health decline.

Efficient DNA repair might make possible the longevity of naked mole-rats. However, whether they have distinctive mechanisms to optimize functions of DNA repair suppressors is unclear. We find that naked mole-rat cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) lacks the suppressive function of human or mouse homologs in homologous recombination repair through the alteration of four amino acids during evolution. The changes enable cGAS to retain chromatin longer upon DNA damage by weakening TRIM41-mediated ubiquitination and interaction with the segregase P97. Prolonged chromatin binding of cGAS enhanced the interaction between repair factors FANCI and RAD50 to facilitate RAD50 recruitment to damage sites, thereby potentiating homologous recombination repair. Moreover, the four amino acids mediate the function of cGAS in antagonizing cellular and tissue aging and extending life span. Manipulating cGAS might therefore constitute a mechanism for life-span extension.

Evolution has shaped remarkably diverse species with distinct life histories, and comparative biology provides a novel lens for deciphering the mechanisms of aging and tumorigenesis across species [1, 2]. Recent discoveries using non-conventional animal models have revealed both cellautonomous and non-cell-autonomous strategies that counteract the elevated tumor risk associated with extended lifespans. Previous studies have established a positive correlation between lifespan and body size, which is that larger animals tend to live longer, even though having tumors is one of the major causes of death and its incidence significantly increases with age. Larger animals have a higher likelihood of developing tumors because their longer lifespans allow for more cell divisions, as well as a higher number of somatic cells, increasing the chances of accumulating mutations for tumorigenesis. Nevertheless, a recent study found that tumor mortality risk is independent of body mass [3], supporting what was proposed in Peto's paradox [4]. How large animals resist the onset of tumors remains an intriguing question. Accumulating evidence suggests that the evolution of replicative cellular senescence effectively suppress tumorigenesis, compensating for greater body size. Moreover, elephants have evolved an additional anti-tumor mechanism by increasing the copy number of Tp53 [5]. Notably, an interesting question arises: some small animals exhibit a extreme longevity compared to their relatives with similar body sizes. Replicative senescence is typically absent in these species. How might these animals have evolved alternative strategies to prevent tumor formation? Some bat species are exceptionally long-lived given their small body size. In a recent study, Athar et al. investigated the anti-tumor mechanisms in several long-lived bat species [6]. As expected, bats exhibit telomerase activity. However, the authors found that, unlike other long-lived mammals, bat fibroblasts can be easily transformed with just two oncogenic

A compelling body of evidence highlights DNA repair as a critical regulator of biological aging and longevity. In recent years, the growing recognition of the microbiome as an essential component of our bodies has made the intersection of aging and microbiome—especially gut microbiome—one of the most prominent areas of interest in aging biology. However, the role of oral microbiome in aging and its interaction with DNA repair remains a topic that warrants thorough investigation. In this article, we will review current insights into the tripartite relationship among oral microbiome, DNA repair, and aging. Additionally, we will discuss emerging novel directions within this complex interplay that require further exploration.

Yu Chen, Xiaoyu Xu, Zhixi Chen, Lingjiang Chen, Ying Jiang, Zhiyong Mao; Circadian factors CLOCK and BMAL1 promote nonhomologous end joining and antagonize cell