Research articles

Young, cognitively normal APOE4 mice display hippocampal network hyperactivity that predicts later memory decline. This phenotype is driven by neuronal APOE4 expression, which causes hyperexcitability of hippocampal neurons and can be reversed by targeting Nell2.

The dynamics of breast tissue aging are characterized by imaging mass cytometry of over 500 reduction mammoplasties, revealing nonlinear loss of cellularity and a compositional shift favoring inflammation.

To dissect lncRNA functions in aging, here the authors perform a CRISPRi-based single-nucleus multiomics screen systematically perturbing 32 aging- and senescence-associated lncRNAs and measuring matched changes in gene expression and chromatin accessibility. They pinpoint a role for HOTAIRM1 linked to DNA repair-related gene control and show that replenishing HOTAIRM1 in mouse lungs reduces fibrosis.

Turquoise killifish are naturally short-lived vertebrates that serve as a model system for aging. The authors show that killifish exhibit age-related transformation in the immune system, which rapidly develops inflammation, genome instability and functional decline.

Epigenetic clocks are promising biomarkers of biological aging but require longitudinal evaluation. In this longitudinal study, the authors evaluated whether temporal acceleration of multiple epigenetic clocks was associated with mortality, and report that faster increases in several clocks were linked to higher risk of death, independent of baseline epigenetic age and other confounders.

By integrating microglial transcriptomics with CSF proteomics, this study reveals protein markers that distinguish early and late Alzheimer’s disease and that have the potential to improve disease tracking and prediction.

Subcellular mRNA localization shapes microglial morphology and function. Using multiplexed error-robust fluorescence in situ hybridization, Henze et al. identify distinct transcript patterns associated with microglial states across young and aged mouse brains.

The glycolytic metabolite phosphoenolpyruvate (PEP) is identified as a protective factor during aging. Acting as an endogenous inhibitor of cGAS−STING, PEP reduces inflammation and improves cognition in Alzheimer’s disease mice. PEP levels correlate with healthy traits in humans.

The mechanisms underlying impaired myelination during aging remain incompletely understood. Here, Gao et al. report that ACSS2-mediated acetate utilization is essential for maintaining the oligodendrocyte progenitor cell pool and facilitating myelination throughout life.

Characterizing molecular aging features is crucial for understanding systemic and local factors contributing to the aging process. Here Costa, Chen et al. performed RNA sequencing on 13 tissues across six ages in male and female African turquoise killifish. This sex-balanced killifish aging atlas provides a comprehensive resource for studying aging dynamics across tissues in the killifish—a powerful, short-lived vertebrate model of aging.

To investigate the link between the gut microbiome and ovarian health, here the authors transplant gut microbiota from estropausal female mice to young adult female mice. Microbial transplantation improves ovarian hormone profiles, follicle metrics and fertility-related outcomes, highlighting a causal role for the aging gut microbiome in regulating ovarian function.

Lin et al. identify a mechanism by which swimming exercise attenuates cognitive decline in Alzheimer’s disease mice, via induction of skeletal muscle-derived vesicles containing miR-378a-3p, taken up by microglia to regulate metabolism and enhance plaque clearance.

Son et al. profile plasma protein structural changes to identify potential conformational biomarkers of Alzheimer’s disease. They report that disease progression, genotype and sex influence structure, and develop a diagnostic panel that tracks disease status.

Using large-scale UK health records and machine learning, Lian and colleagues identify subtypes of Alzheimer’s and Parkinson’s disease, revealing shared clinical patterns and genetic differences that could support earlier diagnosis and more targeted care.

Chen et al. present EMRAge, a biological age measure built using electronic medical records, and OMICmAge, a multi-omic signal superimposed on DNA methylation. Both measures show strong associations with disease and mortality in validation cohorts.

High-throughput proteomics reveals shared and distinct protein signatures of cerebral small-vessel disease, linking vascular, immune and neuronal pathways to its pathophysiology, and identifying plasma proteins predicting cerebrovascular events.

Dai and colleagues implicate defective dendritic cell migration in impaired vaccine responses in aged mice. Oral delivery of yeast-derived nanoparticles promotes migration of dendritic cells from the gut to lymph nodes and restores vaccine efficacy in aged mice.

Werner et al. present the results of the 201 Trial, a 12-week randomized, double-blind placebo-controlled phase 2a study of risvodetinib, in patients with early untreated Parkinson’s disease. Risvodetinib was found to be safe and well tolerated.

Chiche, Djoual, Charifou and colleagues identify a dual role for cell senescence in postpartum tissue remodeling: senescent cells drive mammary gland involution, yet create a permissive niche for tumor initiation, revealing how a conserved repair program can be redirected toward cancer progression.

The authors show that plasma AT(N) biomarkers can distinguish Alzheimer’s disease and frontotemporal lobar degeneration in diverse Latin American populations. Using machine learning and integrating neuroimaging, significant diagnostic accuracy was achieved, enhancing clinical assessments of these conditions in Latin America.