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Researchers have developed a light-driven method for creating tiny, high-energy “housane” molecules that are valuable for drug development and materials science. These compact ring-shaped structures are difficult to produce because of the intense internal strain they contain. By using photocatalysis and carefully tuning the starting molecules, the team managed to guide the reaction into a clean and efficient pathway.

Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial...

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Among the earliest regions affected is the retrosplenial cortex (RSC), where parvalbumin-expressing (PV + ) interneurons are particularly susceptible to AD-related pathology. To understand the molecular alterations within these vulnerable neurons we employed a dual-platform spatial transcriptomics approach, integrating GeoMx Digital Spatial Profiler (DSP) and Xenium...

Once tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimer's disease being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting the neurotoxicity of tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in tau-related neurodegeneration (PS19 mouse model). Tau-expressing neurons undergo cell death through Z-DNA-binding...

Cellular senescence induced by internal and external stimuli features stable cell cycle arrest and SASP, closely linked to aging and various age-related diseases. It is accompanied by lipid metabolism disorders and epigenetic abnormalities, which interact closely to modulate senescence. This review summarizes their crosstalk in senescence and relevant diseases, aiming to offer new insights and therapeutic targets for alleviating cellular senescence and treating age-related diseases.

Intestinal stem cells (ISCs) continuously renew the gut epithelium by producing specialised cell types, yet the mechanisms that couple ISC renewal with lineage commitment remain poorly characterised. Here, we identify a self-limiting transcriptional program, mediated by the zinc-finger transcription factor Chronophage (Cph), that promotes both ISC maintenance and differentiation into enteroendocrine (EE) cells in the Drosophila midgut. Cph expression is transiently induced by the proneural...

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Telomere capping largely depends on telomere length. Abnormally short telomeres are prone to activate DNA damage checkpoint, undergo unscheduled chromosomal fusions through nonhomologous end-joining (NHEJ) and be resected. All these processes are mediated by the Mre11-Rad50-Xrs2^(NBS1) (MRX^(MRN)) complex. The response to telomere length is thought to correlate with the number of DNA-bound telomeric proteins but the mechanisms translating this number into functional protection remain unclear....

Recent work leveraging omics and imaging data now enables the estimation of aging at the level of individual organs. Emerging findings suggest that organs age at different rates, which may be linked to environmental exposures and genetic factors. However, premature aging in one organ may also drive aging in connected organs within multi-organ aging networks. Here, we outline methods for measuring organ-specific biological age and discuss insights derived from recent progress in multi-organ aging...

Biological age may provide a more informative metric of individual physiological function and life expectancy, compared to chronological age. Proteomic aging clocks are predictive models trained using high-dimensional proteomic data to quantify biological age. Owing to the central biological role of proteins and their established clinical utility as druggable targets and prognostic biomarkers, proteomics is particularly promising for the assessment of aging. In this Review, we provide an...

Aging impairs coordinated organelle dynamics essential for lipid metabolism, causing a decline in intracellular metabolic flexibility. However, the drivers of organelle collapse and their temporal order remain unclear. Here we identify peroxisomal function as a critical regulator of metabolic flexibility during youth and low-energy states. Using Caenorhabditis elegans, we show that fasting robustly induces peroxisomal function in youth, whereas this response is blunted during aging. Loss of...

Intrinsic capacity (IC) is a crucial determinant of healthy aging, operationalized through five essential functional domains -- locomotion, cognition, vitality, psychological, and sensory capacities. Integrating geroscience principles with IC assessment in preclinical models with accelerated aging profiles can support bidirectional translation. This narrative review aimed to summarize measurement approaches for each IC domain and to show how IC evolves longitudinally in mouse and fish models. A...

CONCLUSIONS: Observational analyses link diabetes and prediabetes to poorer balance performance, and genetic evidence supports an association between diabetes liability and increased fall risk.

Host-associated microbiomes are compositionally stable across most of the life span, yet undergo consistent and marked deterioration during aging, a phenomenon linked to metabolic dysfunction and disease. What drives this late-life collapse remains poorly understood, in part because the mechanisms by which hosts actively construct and maintain the microbial niche during adulthood remain incompletely characterized. This Unsolved Mystery integrates evidence from immunology and ecosystem ecology to...

The menstrual cycle is a rich yet underused source of physiological information. To address this, we developed an open-source tool called WAVES (women's health assessment through variability in endocrine-related signals) that leverages physiological signals to extract menstrual cycle metrics and facilitate biomarker discovery. We tested it on basal body temperature data from 5674 nonconceptive cycles from 753 participants aged 18 to 42 years. We identified multiple associations between aging and...

Age-related cataract (ARC) is a severe vision-impairing disorder primarily caused by oxidative stress-induced senescence and apoptosis of lens epithelial cells (LECs). In this study, a sodium selenite-induced oxidative stress cataract model in neonatal rats was established to simulate the pathological progression of ARC. We found that retinoic acid receptor-related orphan receptor α (RORA) exacerbates cellular senescence and oxidative damage by targeting prion protein (PRNP), and its...

Methionine restriction (MR) extends the lifespan and healthspan of numerous eukaryotic organisms, but the molecular mechanisms at play are unclear. Here we find that the ability of MR to extend the budding yeast chronological and replicative lifespans is the consequence of reduced methionine conversion to the methyl donor S-adenosylmethionine (SAM). Mechanistically, the key antiaging event downregulated by MR is the methylation of protein phosphatase 2A (PP2A). In chronological aging cells under...

Multimorbidity presents challenges for research and health care. We investigated how immune-proteins influence multiple diseases to identify shared mechanisms and therapeutic opportunities. Using eight large plasma proteome GWAS, we identified cis-acting variants for 151 immune-proteins and applied cis-Mendelian randomization to assess associations with 64 diseases and biomarkers. Protein-disease communities were derived using a knowledge graph integrating multiplicity-corrected associations,...

Transcranial ultrasound stimulation (TUS) is a promising noninvasive technique for modulating deep brain targets and circuits with high spatial precision. For its successful clinical translation, confirmation of target engagement, together with a deeper understanding of the effects of TUS, is essential. To advance these goals, we obtained direct measures of neural activity using electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) during TUS of deep and...

Non-neuronal brain cells and systemic immunity play a central role in Alzheimer's disease (AD) and other brain disorders. The immune system, initially protective, becomes dysfunctional as the disease progresses. Here, we discuss next-generation therapeutic approaches aimed at treating the immune system rather than the brain to combat AD and other neurodegenerative diseases.