Longevity Papers

Loss of proteostasis and the accumulation of insoluble protein aggregates are features of aging across model organisms and occur in all major age-related neurodegenerative diseases; yet how aggregation proceeds during normal human brain aging remains unknown. Here, using detergent-fractionation proteomics, we show that brain aging does not involve uniform aggregate accumulation; rather, the insoluble proteome undergoes asymmetric remodeling beginning in midlife, with maximum-stability aggregates declining sharply by old age and intermediate-stability aggregates accumulating progressively before accelerating after age 80. Intermediate-stability aggregates are prone to liquid-liquid phase separation and are enriched among Alzheimer's disease plaque and tangle constituents. Proteasome and cytosolic chaperone capacity predict individual differences in aggregate burden as strongly as chronological age, offering human-level evidence in support of therapies targeting these pathways. These findings establish aggregate remodeling as a feature of normal brain aging and position intermediate-stability aggregate accumulation as a molecular event on the path to neurodegenerative disease.

Background: Among cardiac measures, diastolic parameters demonstrate the earliest and most consistent age-related changes. This can be leveraged to develop a continuous left ventricular (LV) Diastolic Age from routine echocardiographic parameters. Analogous to how epigenetic clocks weight molecular markers against mortality risk, we calibrated Diastolic Age by weighting echocardiographic features against the validated PREVENT-Heart Failure (HF) risk score. Methods: We analyzed 1,952 participants from the Project Baseline Health Study (median age 50 [36-64] years, 54% female). The measure was derived using partial least-squares regression anchored on PREVENT-HF and calibrated within a healthy reference subgroup. External validation was performed in the WASE (n=1,708) and Stanford Cardiovascular Aging (n=313) cohorts. Associations with ASE-defined LV diastolic dysfunction (LVDD), epigenetic clocks, and major adverse cardiovascular events (MACE) were examined. Results: Diastolic Age correlated strongly with chronological age (r=0.78) with robust external validation (WASE r=0.76; Stanford r=0.82; calibration slopes {approx}1.0). It increased progressively across grades of diastolic dysfunction and discriminated LVDD with an AUC of 0.89 (95% CI 0.87-0.92), and was independently associated with hypertension, diabetes, and elevated C-reactive protein. While correlated with the Levine (r=0.76) and Horvath (r=0.41) epigenetic clocks, residual analyses indicated that Diastolic Age captures a distinct cardiac-specific dimension of biological aging. Over median follow-up of 4.2 years, it independently predicted MACE (HR 2.30, 95% CI 1.70-3.18), with accelerated diastolic aging across all age groups among those with events. Discrimination was comparable to ASE-defined LVDD (C-index 0.83 vs. 0.82). Conclusion: Diastolic Age provides a continuous, echocardiography-derived measure of cardiac biological aging that complements categorical diastolic grading and epigenetic aging clocks, and independently predicts cardiovascular outcomes.

Identifying robust, non-invasive biomarkers of biological age is key to preventive medicine. While gut aging clocks exist, the oral microbiome remains underexplored as a quantitative biomarker. Using oral microbiome data from two NHANES cohorts (N = 4,675), we identified 64 age-dependent bacterial genera and developed a machine learning model predicting chronological age, with generalizability in an independent external cohort (N = 1,293). We derived an Oral Microbiome Aging Acceleration (OMAA) Score as the residual of predicted age against chronological age. The OMAA Score independently predicted all-cause mortality (HR = 1.05, P = 0.024) and frailty (OR = 1.05, P = 0.008), correlated with impaired kidney function (lower eGFR: β = -0.066, P = 5.22×10

Ageing leads to diurnal misalignment with a global reduction in physiological fitness, yet the mechanisms underlying such age-related diurnal reprogramming and its role in ageing remain poorly understood. Here we generate diurnal transcriptomes across eight peripheral tissues and reveal that disrupted redox oscillations are common diurnal alterations in organismal ageing. Restoring redox rhythms through the time-restricted application of antioxidants and pro-oxidants markedly improved glucose metabolism, motor performance and ageing-related characteristics of liver and skeletal muscle in male aged mice. Through multi-omics analyses we further reveal that restoring redox rhythms partially rejuvenates the hepatic transcriptome and chromatin accessibility in ageing-associated functional pathways and involves redox modification of CLOCK protein. Perturbing redox-sensitive cysteine 195 of CLOCK causes premature ageing phenotypes and hepatic reprogramming. Overall, our study reveals that redox rhythms ameliorate functional decline by modulating ageing-relevant reprogramming in liver and skeletal muscle and indicates that redox rhythm-based interventions might promote healthy ageing.

The human brain varies across anatomical regions, cell types, development, ageing and disease states, yet existing single-cell transcriptomic resources remain fragmented and difficult to integrate into a unified biological model. Here we present DigitalBrain, a human brain-specific atlas and foundation-model framework for organizing diverse and fragmented human brain transcriptomic data across scales. We first built DigitalBrain-Atlas, a harmonized whole-brain single-cell resource comprising 16.35 million transcriptomes from 2,143 donors across 165 brain regions, spanning the human lifespan and multiple neurological and clinical conditions. We then developed DigitalBrain-M1, a Transformer-based model that jointly encodes gene identity and expression magnitude to learn a shared embedding space for cells and genes. Across held-out datasets, DigitalBrain supported robust single-cell integration, clustering and cell-type annotation while preserving major biological structure and reducing technical fragmentation. Beyond these benchmarks, the learned embeddings revealed emergent large-scale hierarchical organization of the human brain, linking anatomically distinct regions into higher-order patterns consistent with known functional systems. Applied to human hippocampal aging, DigitalBrain identified cell-type-specific aging sensitive gene sets, identified dentate gyrus granule cells as a particularly age-sensitive population, and discovered selective reorganization of gene programs related to synaptic transmission, postsynaptic structure, membrane excitability and axon guidance during aging. Cross-dataset convergence was strongest at the level of functional modules and recurrent aging sensitive genes. Together, these results demonstrate DigitalBrain as a brain-specific framework for mapping human brain organization across scales, and as an early step towards a complete virtual organ for the human brain.

Reduced insulin/IGF-1 signaling (IIS) can greatly extend lifespan in C. elegans. However, its effects on the duration of healthy life (healthspan) remain unclear, with several reports of either morbidity expansion or scaled effects, though none of morbidity compression. Moreover, life-extension by IIS reduction is particularly inter-individually variable within populations, confounding efforts to understand the intra-individual biology of such interventions. Here, we performed a longitudinal investigation at individual nematode resolution, of IIS reduction on aging-related health and lifespan, through temporally-controlled auxin-induced degradation (AID) of the DAF-2 insulin/IGF-1 receptor. Our results show how inter-individual variation in aging rate within control populations explains the complex demographic effects of age-specific DAF-2 AID on population lifespan. Strikingly, adult-limited IIS reduction causes an inter-individually homogeneous increase in lifespan (reducing Gompertz rather than {beta}) that is driven by healthspan expansion and compression of morbidity. Unexpectedly, cessation of DAF-2 AID in decrepit elderly individuals rejuvenates locomotory capacity and extends lifespan, showing that higher levels of IIS are optimal for health and survival towards the end of life. We also document a memory effect of transient IIS reduction during early adulthood, that is sufficient to fully extend lifespan (+189% median lifespan). Together, these findings demonstrate that both lifespan and healthspan can be maximized by appropriate temporal and directional modulation of IIS.

Aging is marked by a progressive breakdown of intestinal integrity and metabolic homeostasis, which together drive systemic decline in physiology and reduced lifespan. Here, we demonstrate that dietary lipids extracted from a genetically engineered long-lived yeast strain robustly extend lifespan in Drosophila by preserving gut function and modulating the gut brain axis. Using deuterium oxide probed stimulated Raman scattering microscopy, we show that these yeast-derived lipids restore age-related declines in gut lipid droplet abundance, enhance membrane lipid incorporation, and increase de novo lipid synthesis, thereby improving epithelial structure and barrier function. Single nucleus RNA sequencing reveals transcriptional remodeling in metabolically active enterocytes, including upregulation of autophagy and protein turnover genes, alongside reduction of unsaturated fatty acid biosynthesis. Complementary Raman spectroscopy and lipidomics demonstrate that the yeast lipids are enriched in shorter, more saturated fatty acids and phospholipids, contributing to increased membrane order and reduced lipid storage. Functionally, targeted dietary supplementation with these lipid components synergistically prolongs fly lifespan. In the brain, dietary lipids orchestrate a dual metabolic strategy, promoting energy conservation and enhanced signaling across most neuronal and glial populations, while selectively boosting mitochondrial function in memory-critical Kenyon cells. We also identify strengthened gut-to-glia communication, particularly through EGFR and FGFR pathways. Finally, a newly developed computational tool, FLY-MAP, reveals that yeast lipids restructure gut metabolic modules to coordinate energy production, redox balance, and nutrient flexibility. Our study uncovers a cross-kingdom mechanism of metabolic longevity regulation, paving the way for leveraging yeast-derived nutritional components to support tissue homeostasis and promote healthy aging.