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Liu et al. identify downregulation of DDX5, an RNA helicase, in the cartilage of patients and mouse model of osteoarthritis. Targeted upregulation of DDX5 in mouse chondrocytes inhibits hyaline cartilage fibrosis and degradation via pre-mRNA splicing and G4 unwinding, a potential therapeutic strategy against osteoarthritis.

Aging-related DNA methylation changes are numerous. Their precise measurement has opened new avenues to explore aging-related disease pathology, including the construction of chronological and biological age predictors (termed DNA methylation ‘clocks’). Three studies investigate the substantial stochastic contribution to these epigenetic changes and further our understanding of aging biology, as well as of these predictors.

Moses, Atlan et al. profile the killifish (Nothobranchius furzeri) gonad using single-cell sequencing and reveal that genetic germline depletion induces sexually dimorphic phenotypes, enhancing lifespan in male fish and somatic repair in females.

Artificial intelligence (AI) chatbots offer the potential to enhance many aspects of social care for older adults, but also pose ethical risks. This Comment explores the responsible use of AI chatbots, which recognizes the distinct features of social care provision.

Zou and colleagues design and analyze a health education program that targeted college students (who were grandchildren) to encourage older persons who had already had their first COVID-19 vaccine dose to receive a booster. The program increased the uptake of booster doses, which highlights the fact that family ties can have positive roles in the context of a pandemic.

Tong et al. construct simulations using DNA methylation data to quantify what proportion of the predictive accuracy of epigenetic clocks could be explained by stochastic methylation changes, suggesting that stochasticity contributes more toward the accuracy of chronological rather than biological age predictions.

Cellular senescence is a hallmark of aging but also a potent tissue remodeling process. Here, Nehme et al. show that modulating poly (ADP-ribose) polymerase 1 can switch cell death into senescence, and that inducing senescence improves recovery from kidney ischemia–reperfusion injury.

Bian, Zhang, Guo, Li, Fu et al. present results of a parallel-group, cluster-randomized controlled trial demonstrating the efficacy of an educational intervention targeting college students in increasing COVID-19 booster vaccination uptake among grandparents in China.

At single-cell resolution, Tarkhov et al. delineate stochastic and co-regulated components of epigenetic aging, revealing a simultaneous loss of regulation at the epigenetic and transcriptional levels in aging.

Meyer and Schumacher use simulations to show that accumulation of stochastic variation is sufficient to build clocks that can measure both chronological and biological age, sensitive to changes induced by smoking, calorie restriction, parabiosis and reprogramming.

In this nationwide administrative register study, individuals diagnosed with infections were three times more likely to be diagnosed with dementia up to 30 years later. Preventing infections might reduce the burden of neurodegenerative conditions.

This study shows that normal microbial exposure increases inflammation and CD8⁺ T cell exhaustion and leads to mortality in old mice; it also shows that anti-PD1 antibody treatment restores survival and increases CD8⁺ cytotoxic capacity, without altering inflammation.

Zhou and colleagues explore reversing testicular aging and late-onset hypogonadism by targeting lysosomal function in Sertoli cells. The aging-related transformation of Sertoli cells into a lipid-hoarding subtype with dysregulated phagolysosomes and autolysosomes was reversed using the TRPML channel agonist ML-SA1, which demonstrates the potential of this targeted therapy in alleviating testosterone decline and systemic male-aging phenotypes.

In vivo human neuroimaging shows that locus coeruleus (LC) integrity changes precede medial temporal tau accumulation, and jointly predict future lower cognition in older people at risk for Alzheimer’s disease. A common transcriptomic profile underlies LC’s early vulnerability to tau.

Skeletal muscle is a highly heterogenous tissue that comprises multiple cell types. Leveraging single-cell and single-nucleus experiments, we systematically mapped the cellular and molecular changes across different skeletal muscle compartments with age. We identify neuromuscular-junction accessory nuclei that may be pivotal in mitigating denervation and uncovered differences between myofiber and myonucleus aging.

Late-onset hypogonadism (LOH) can occur with male reproductive aging and is characterized by declining testosterone levels as well as other clinical symptoms. Here the authors show that dysregulated phago-/auto-lysosomes in Sertoli cells are a key feature of LOH, linking metabolism and aging, and that pharmaceutical targeting of lysosome dysfunction can alleviate LOH in mice.

The advent of plaque-clearing antibodies to the amyloid-β as the first disease-modifying treatment for Alzheimer’s disease will change the course of this disease, the most common type of dementia. Related progress will gradually alter the trajectory of human aging.

He et al. characterizes a role of microcephalin (MCPH1), a known regulator of DNA damage response, in hematopoietic stem cell (HSC) aging demonstrating nuclear MCPH1 translocation that leads to activation of necroptosis and deterioration of HSC function with age.