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The accumulation of senescent cells drives age-related diseases. In this study, the authors show that senolytic CAR T cells can rejuvenate metabolic function and fitness in old mice and that a single dose is sufficient to lead to long-term preventive effects.
An inflammatory profile is associated with aging and senescence. Here, Hao et al. show that TXNRD1 drives the senescence-associated secretory phenotype through the cGAS–STING pathway, independently of its enzymatic activity, during senescence and that the TXNRD1–cGAS interaction may be a target for selectively suppressing inflammaging.
The authors identify causality-enriched CpGs linked to aging using Mendelian randomization. They develop new epigenetic clocks, DamAge and AdaptAge, that more reliably track age-related changes, offering insights into aging mechanisms and interventions.
Cikes et al. report dysregulation of glycerophosphocholine (GPC) metabolism in aged mouse muscle, which they functionally link to severe glucose intolerance. Correspondingly, muscle GPC levels are altered in both older adults and patients with type 2 diabetes.
He et al. demonstrate a noncanonical role for the TRMT6–TRMT61A methyltransferase complex in hematopoietic stem cell (HSC) aging, where its enrichment activates necroptosis signaling. Blocking necroptosis counters features of HSC aging, suggesting a therapeutic strategy.
This study reveals that many previously reported changes in gene expression in aging hematopoietic stem cells (HSCs) may be linked to extraction stress rather than aging itself and has implications for future HSC aging research.
Isola, Ocañas et al. report age-related changes in the mouse ovarian transcriptome at single-cell resolution, demonstrating an increase in lymphocytes that corresponds to declines in collagen degradation and accumulation of multinucleated giant cells.
Griffin et al. present a versatile method for scalable and low-cost sequencing for the construction of epigenetic clocks. They assay 2,892 human or mouse samples, benchmark their method and assess diverse interventions.
Tijms et al. identify five molecular Alzheimer’s disease subtypes typified by hyperplasticity, impaired immune activation, RNA metabolism, and choroid plexus or blood–brain barrier function. Subtypes may need tailored cures.
Li and Guo et al. demonstrate that epigenetic dysregulation of the MLL complex at promoters of particular age-dependent genes results in their transcriptional downregulation and subsequent age-related dysfunction of neural stem and progenitor cells.
Yang et al. demonstrate that inhibition of early-acting autophagy genes in neurons extend C. elegans lifespan, improve neuronal proteostasis and increase exopher formation mediated by the autonomous WD40 domain-related function of ATG-16.2.
Multiple lines of research show that NAD+ has an important role in ovarian aging; however, the role of NAD+ consumption during ovarian aging is incompletely understood. Here the authors study the role of the NADase CD38 to show that CD38 expression increases and NAD+ levels decrease with age in mice, and that CD38 deletion ameliorates ovarian aging.
To analyze neuronal aging in Huntington’s disease, Lee et al. perform direct neuronal reprogramming of longitudinally aged human fibroblasts, uncovering RCAN1 as a therapeutic target to promote neuronal resilience through chromatin reconfiguration.
Stitching together electronic health records with partial longitudinal coverage, Mendelson Cohen et al. use machine learning to untangle healthy aging from chronic disease, identifying markers of healthy aging and analyzing the heritability of longevity.
Using C. elegans, Oleson et al. demonstrate that developmental exposure to reactive oxygen species protects against amyloid toxicity later in life, mediated by disruption of the H3K4me3 epigenetic machinery through HSF-1-dependent shifts in lipid metabolism.
DNA methylation rates correlate with maximum lifespan in mammals, but a precise relationship had not been defined. Here Crofts et al. develop a statistical framework to compare methylation rates at conserved age-related sites and find that methylation rates negatively scale with maximum lifespan in 42 mammalian species.
The authors present the results of a phase 2 study of gosuranemab, a monoclonal antibody targeting N-terminal tau, in patients with early Alzheimer’s disease. Gosuranemab was safe and well tolerated, but the clinical efficacy endpoint was not met.
Partial reprogramming to enhance regeneration and mitigate age-related phenotypes is limited by toxicity. Parras et al. report a transgenic reprogrammable mouse strain with attenuated toxicity, by avoiding OSKM expression in the liver and intestine.
Aging is associated with increased atherosclerosis risk and a changing immune landscape. In this study, the authors examined T cell changes in atherosclerotic plaques in mice with age and report an accumulation of clonally expanded effector and memory CD8+ T cells, including Gzmk+CD8+ T cells, which have cytotoxic transcriptomic signatures.
Aguado et al. show that SARS-CoV-2 induces senescence in human brain organoids and in the brains of COVID-19-infected mice and humans. They demonstrate the therapeutic potential of senolytic therapy in protection against COVID-19-induced brain aging.