Longevity Papers

Nucleotide availability is crucial for DNA replication and repair; however, the coordinating mechanisms in vivo remain unclear. Here, we show that the circadian clock in the liver controls the activity of the pentose phosphate pathway (PPP) to support de novo nucleotide biosynthesis for DNA synthesis demands. We demonstrate that disrupting the hepatic clock by genetic manipulation or mistimed feeding impairs PPP activity in male mice, leading to nucleotide imbalance. Such defects not only elicit DNA replication stress to limit liver regeneration after resection but also allow genotoxin-induced hepatocyte senescence and STING signalling-dependent inflammation. Mechanistically, the molecular clock activator BMAL1 synergizes with hypoxia-inducible factor-1α (HIF-1α) to regulate the transcription of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD), which is enhanced during liver regeneration. Overexpressing G6PD restores the compromised regenerative capacity of the BMAL1- or HIF-1α-deficient liver. Moreover, boosting G6PD expression genetically or through preoperative intermittent fasting potently facilitates liver repair in normal mice. Hence, our findings highlight the physiological importance of the hepatic clock and suggest a promising pro-regenerative strategy.

The mammalian dentate gyrus (DG) is involved in certain forms of learning and memory, and DG dysfunction has been implicated in age-related diseases. Although neurogenic potential is maintained throughout life in the DG as neural stem cells (NSCs) continue to generate new neurons, neurogenesis decreases with advancing age, with implications for age-related cognitive decline and disease. In this study, we used single-cell RNA sequencing to characterize transcriptomic signatures of neurogenic cells and their surrounding DG niche, identifying molecular changes associated with neurogenic aging from the activation of quiescent NSCs to the maturation of fate-committed progeny. By integrating spatial transcriptomics data, we identified the regional invasion of inflammatory cells into the hippocampus with age and show here that early-onset neuroinflammation decreases neurogenic activity. Our data reveal the lifelong molecular dynamics of NSCs and their surrounding neurogenic DG niche with age and provide a powerful resource to understand age-related molecular alterations in the aging hippocampus.

As the global population continues to age, understanding the complex role of cellular senescence and its implications in healthy lifespans has gained increasing prominence. Cellular senescence is defined as the irreversible cessation of cell proliferation, accompanied by the secretion of a range of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP), in response to various cellular stresses. While the accumulation of senescent cells has been strongly implicated in the aging process and the pathogenesis of age-related diseases owing to their pro-inflammatory properties, recent research has also highlighted their essential roles in processes such as tumour suppression, tissue development, and repair. This review provides a comprehensive examination of the dual nature of senescent cells, evaluating their deleterious contributions to chronic inflammation, tissue dysfunction, and disease, as well as their beneficial roles in maintaining physiological homeostasis. Additionally, we explored the therapeutic potential of senolytic agents designed to selectively eliminate detrimental senescent cells while considering the delicate balance between transient and beneficial senescence and the persistence of pathological senescence. A deeper understanding of these dynamics is critical to develop novel interventions aimed at mitigating age-related dysfunctions and enhancing healthy life expectancies.