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Transcriptome-wide association studies (TWAS) have successfully identified genes associated with complex traits and diseases, but most have been performed using bulk gene expression data, which aggregate signals across heterogeneous cell types. Population-scale single-cell RNA sequencing data now make it possible to perform TWAS at the cell-type resolution, but present unique challenges due to strong noises, technical variations, and high sparsity. Here, we propose scTWAS, a statistical method...

The redox theory of aging proposes that an oxidative imbalance, possibly amplified by infection, drives senescence. We experimentally evolved mosquitoes under early or late reproduction with or without parasite exposure, and quantified longevity, fecundity, and redox markers. Although selection generated the expected life-history divergence, there was only a poor, non-linear association between a redox gradient and longevity. Thus, oxidative stress contributed to, but did not determine, the...

Vascular dysfunction, including endothelial cell (EC) senescence and hypertension, is a hallmark of metabolic syndrome, yet its underlying mechanisms remain unclear. Here, we show that metabolic stress upregulates regulated in development and DNA damage response 1 (REDD1), driving vascular dysfunction. Overexpression of REDD1, but not the REDD1^(KK219/220AA) mutant, which cannot activate atypical NF-κB, promotes EC senescence and hypertension through NF-κB-dependent induction of miR-155-5p and...

Senescent cells (SnCs) are increasingly recognized as key contributors to osteoarthritis, with conventional strategies centered on their elimination. However, senolytic approaches face mounting limitations, driving the need for refined interventions. Here, we exploit SnCs' lipid metabolic signature to develop a senotherapeutic strategy. Given the universal lipid accumulation in SnCs and the dual role of lipids as both metabolic liabilities and essential lubricants, we engineer an injectable...

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Normal aging leads to regional vascular and neural alterations. Age-related impairments in neurovascular coupling (NVC) affect the blood-oxygen-level-dependent (BOLD) hemodynamic response function (HRF) measured with functional magnetic resonance imaging, causing changes in both amplitude and temporal dynamics. Previously, global, systematic age-related changes in HRF characteristics were demonstrated, consistent with known microvascular aging effects. In this follow-up study, a standard space...

Traditional Alzheimer's disease (AD) research has predominantly focused on neuronal pathology within the amyloid-tau-neurodegeneration (ATN) framework, emphasizing β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTS), and neuroinflammation as primary drivers of disease progression. Recently, converging evidence suggests that oligodendrocytes (OLs) and myelin abnormalities are not merely downstream consequences of neuronal injury. Instead, OL dysfunction may emerge early and actively shape...

In this meet-the-author Q&A, Scientific Editor Sara Rohban and Editor-in-Chief Laura Zahn speak with Junyue Cao about his Cell Genomics paper. He discusses his ambitions to study aging and how his newly developed method, EnrichSci, was used to look at changes over time in oligodendrocytes in the brain.

Aging is associated with oxidative stress, but specific druggable pathways remain elusive. Here, we define a conserved iron-lipid axis driving primate aging, termed "ferro-aging." Multi-tissue profiling in humans and non-human primates reveals age-progressive iron accumulation, fueling chronic lipid peroxidation orchestrated by acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4). Distinct from acute ferroptosis, this ACSL4-mediated process promotes cellular senescence and...

Aging is a major risk factor for neurodegenerative diseases, yet the underlying epigenetic mechanisms remain unclear. Here, we generated a comprehensive single-nucleus cell atlas of brain aging across multiple brain regions, comprising 132,551 single-cell methylomes and 72,666 joint chromatin conformation-methylome nuclei. Integration with companion transcriptomic and chromatin accessibility data yielded a cross-modality taxonomy of 36 major cell types. We observed that transposable element (TE)...

Mitochondrial disease encompasses inherited disorders affecting mitochondrial function. A severe and untreatable form of mitochondrial disease is Leigh syndrome (LS), causing psychomotor regression and metabolic crises. To accelerate drug discovery for LS, we screen a library of 5,632 repurposable compounds in neural cells from LS-patient-derived induced pluripotent stem cells (iPSCs). We identify phosphodiesterase type 5 (PDE5) inhibitors as leads and prioritize sildenafil for its clinical...

CONCLUSIONS: The effects of PM(2.5) exposure on the skeletal muscle system are age-specific, with distinct damaging effects during growth and aging, whereas skeletal muscles in middle-aged mice are resistant to PM(2.5)-induced damage.

The ageing global population faces a rising prevalence of chronic kidney disease (CKD), now recognized as a state of accelerated ageing driven by chronic low-grade inflammation-inflammaging. This review synthesizes current evidence positioning the kidney not merely as a passive target but as an active participant in systemic inflammaging, a process fueled by immunosenescence, metabolic reprogramming, and cellular senescence. We explore how resident renal cells, including tubular epithelial...

Aging alters prefrontal recruitment, often showing posterior-anterior shifts that may reflect compensatory mechanisms. Working memory capacity (WMC) is a key individual difference shaping attention and control but its role in age-related functional reorganization remains unclear. We examined 72 adults (36 younger, 36 older) who completed standardized span tasks and an fMRI visual discrimination paradigm with three manipulations: perceptual load, fine discrimination, and mapping-switch....

Recent advances suggest a correlation between gut dysbiosis and neurological diseases, however, relatively little is known about how gut bacteria impact the brain. Here, we reveal that bacteria can translocate directly from the gut to the brain in small numbers when mice are fed an atherogenic, high-fat diet (Paigen diet) that causes alterations in gut microbiome composition and gut barrier permeability. The bacteria were not found in other systemic sites or the blood, but were detected in the...

Acute stress triggers the release of cortisol, which broadly affects cognitive processes. Path integration, a specific navigational process, relies heavily on grid cells in the entorhinal cortex. The entorhinal cortex contains glucocorticoid receptors and is therefore likely to be influenced by cortisol, though little is known about this relationship. Given the role of the entorhinal cortex in neurological diseases such as Alzheimer's Disease, investigating the effects of cortisol on this brain...

Balance training in geriatric rehabilitation reduces fall risk by eliciting multifaceted cortical reorganization through repeated sensorimotor challenges, supporting more efficient postural control in aging. This study combined minimum spanning tree (MST) and k-iteration second-best MST analyses to characterize training-induced changes in cortical network efficiency and resilience. Twenty-four older adults (70.4 ± 3.3 years) completed 12 sessions of stabilometer training with real-time visual...

The dynamic changes in immune cell composition throughout the human lifespan remain poorly understood. Here, we performed single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing on peripheral blood mononuclear cells from healthy donors, spanning mid-fetal to late adulthood. Our findings revealed age-associated reprogramming across lymphoid and myeloid lineages, with T cells undergoing the most significant transcriptional remodeling. Notably,...