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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.
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.
Pan et al. demonstrate that hearing loss promotes cognitive decline in an APP/PS1 mouse model of Alzheimer disease via inhibition of the GDF1 signaling pathway, unveiling GDF1 as a therapeutic target for Alzheimer disease.
Aging is a risk factor of Parkinson’s disease (PD). Adams, Song et al. present a multiomics analysis of the human midbrain showing age-induced changes in genes associated with glial function, with further alterations of oligodendrocytes in PD.
Older age is associated with worse outcomes for patients with melanoma, and the underlying mechanisms are incompletely understood. Here the authors show that the loss of HAPLN1 in aged skin fibroblasts drives melanoma progression by increasing ICAM1 and angiogenesis. Blocking ICAM1 shrinks tumors, suggesting potential for age-specific melanoma therapy.
Zhang et al. demonstrate that S6K suppression in the Drosophila fat body mediates the longevity effects of rapamycin and identify Syntaxin 13 as a conserved downstream effector regulating lysosome morphology and inflammation in a sex-specific manner.
Plasma membrane damage (PMD) can induce cell death or be repaired, whereas other cell fates are not well explored. In this study, the authors found that PMD induces senescence in yeast and human fibroblasts in a manner that is distinct from DNA damage-dependent senescence. They present transcriptomic data suggesting that this PMD response may explain the origins of senescent cells near cutaneous wounds.
Large-scale proteomics data hold promise for individual disease risk prediction. Here the authors use data from more than 50,000 adults without dementia in the UK Biobank to predict the future risk of dementia and highlight GFAP as an important protein elevated in individuals more likely to develop dementia.
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.
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.
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.
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.
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.
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.