Research articles

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.

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.

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.

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.

Circulating factors have an important role in aging. Here the authors show that small extracellular vesicles derived from young plasma rejuvenate whole-body physiology in aged mice, at least in part, by stimulating PGC-1α expression and improving mitochondrial energy metabolism.

The Muscle Aging Cell Atlas presents approximately 200,000 single-cell and single-nuclei transcriptomes from 17 human donors across different ages, uncovering mechanisms of aging in muscle stem cells, myofibers and microenvironment cells, and demonstrates parallels in mouse muscle aging.

Lipid changes across the lifespan and their role in health and longevity are incompletely understood. Here, Tsugawa and colleagues conduct untargeted lipidomics across 13 sample types and four ages in mice, considering sex and microbiome dependencies. This study provides a comprehensive resource of lipid changes with aging and highlights regulatory metabolic components, such as the enzyme UGT8, as potentially responsible for male-specific glycolipid biosynthesis in the kidney.

Aging dynamics of complex lipids are incompletely understood. Here Janssens and colleagues describe lipids that change with age across ten tissues in mice. Notably, bis(monoacylglycerol)phosphate accumulated with age. This lipid also accumulated in muscle of older humans, and reduced upon a short bout of exercise.

Ovarian aging has an important role in health and fertility; however, the molecular mechanisms underlying it remain incompletely understood. Here the authors use single-cell and spatial transcriptomics in reproductively young, middle-aged and older human ovarian tissue to elucidate ovarian aging. They describe spatiotemporal changes in ovarian cells and highlight the important regulatory role of FOXP1.

Xu et al. use single-cell transcriptomics to reveal that targeted and systemic partial reprogramming restore the production of neuronal progenitors and new neurons in old mice and show a cell-autonomous effect of reprogramming in cultures of aged neural stem cells.

In a longitudinal population-based cohort, Liu et al. demonstrate that integrating polygenic risk scores and the gut microbiome improved prediction, over traditional risk factors, for heart disease, diabetes, Alzheimer disease and prostate cancer.

Todorov-Völgyi, González-Gallego et al. provide a proteomic profiling of brain endothelium during aging to unveil changes undetected in transcriptomic studies, identifying a dysregulation of proteins involved in vesicle-mediated transport pathways, most prominently Arf6.

Zhao, Deng and colleagues present a post hoc analysis of the STEP trial showing that intensive blood pressure control does not reduce the risk of cardiac conduction diseases in older adults with hypertension.

Salvadó et al. developed and validated a CSF-based staging model for sporadic Alzheimer’s disease, which accurately reflects biomarker and clinical changes, enhancing diagnostic and prognostic assessments of participants for clinical setting and trials.