Macedo et al. report the longitudinal spatiotemporal dynamics of tau from positron emission tomography. They find distinct dynamics in tau extent and load across Alzheimer’s disease stages, highlighting spatial extent metrics as sensitive indicators for early pathology, while load metrics correlate with advanced disease severity.

Carver and colleagues profile the aged mouse brain using spatial transcriptomic and imaging analysis and identify a senescence- and disease-associated microglial-linked state enriched in white matter and reduced by senotherapeutic interventions.

Gao et al. identify a toxicity-driving region within TDP-43 and show that a brain-penetrant small molecule targeting this region improves mitochondrial function, reduces neurodegeneration and extends survival in ALS mouse models.

Exercise has an important role in healthy aging, yet the underlying molecular mechanisms are incompletely understood. Here the authors consider age, physical function and acute exercise in the context of the multiomics of human skeletal muscle, linking fitness to distinct aging profiles. Physically trained older individuals show ~50% fewer age-related differences and stronger exercise responses, and maintain expression of key energy metabolism and cellular respiration genes.

Physical activity has geroprotective properties, yet its role in ovarian aging is incompletely understood. Here, a cross-sectional analysis of human cohorts links lower physical activity with menopause, while in mice, exercise delays ovarian aging at least in part by boosting adiponectin levels; an adiponectin receptor agonist reproduces these protective effects.

The spatiotemporal dynamics of the depletion of the ovarian reserve remain incompletely understood. Combining whole-ovary imaging, AI and modeling, the authors mapped over 85,000 mouse oocytes and found that ovaries maintain a stable fraction of newly activated oocytes throughout aging, suggesting organ-wide control of oocyte activation.

Wang et al. identify TNFR1 signaling as a key link between inflammation and intestinal stem cell aging. This aging phenotype is transferable from old to young mice via shared circulation, suggesting systemic inflammation as a target to improve intestinal health.

Using plasma proteomics, Yu, Chen, Feng, Li et. al report a panel of five blood proteins that can predict future risk of metabolic dysfunction-associated steatotic liver disease (MASLD) up to 16 years before clinical onset, offering a potential tool for early risk stratification.

Cole and colleagues identify fructose as a component of the secretome in therapy-induced senescent ovarian cancer cells that drives metastasis. Fructose metabolically reprograms neighboring cancer cells, enhancing their ability to detach by reducing plasma membrane cholesterol through modulation of complex I and NAD.

Using an aged rat model, patient tissue samples and patient-derived organoids, Carleton et al. profiled age-associated differences in estrogen receptor-positive breast cancer, identifying inflammation and altered estrogen metabolism as possible contributors to age-related tumor permissiveness.

Mapping senescent cells across tissues, species and lifespan.

Blood biomarkers enable early detection of Alzheimer’s disease pathology, but clinical pathways wait to detect late-stage cognitive impairment. Digital cognitive assessments that target Alzheimer’s-disease-vulnerable systems can detect earlier functional change and strengthen plasma-biomarker prognosis. Modernizing cognition is essential for true early detection in Alzheimer’s disease.

Epigenetic drift leads to gradual alterations of the epigenome that have been harnessed (particularly at the DNA-methylation level) to build epigenetic clocks. However, the functional significance of the signals these clocks capture remains unclear. We discuss the evolution of the concept of epigenetic drift and examine how epigenetic clocks have emerged as quantitative readouts of this phenomenon.