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Disabling hearing impairment is a common human sensory deficit. OTOF is a major deafness gene. It codes for the synaptic protein otoferlin and is essential for transmitter release by inner hair cells (IHCs). Upon genetic loss of otoferlin, cochlear structure and function remain intact up to the IHC synapses, which fail to encode sound. Building on preclinical hearing restoration by AAV-mediated cochlear gene transfer in mice, clinical OTOF-gene-therapy trials are now targeting the pediatric...

Nur77 expression decreases with age in multiple organs, including the liver, brain, heart, and kidney, whereas Sirt2 increases with age in the mouse cerebral cortex and hippocampus. We identified the central role of the Sirt2-P300/Nur77/K310 acetylation axis in regulating muscle homeostasis and regeneration and its age-related alterations. Consistently, we observed reduced Nur77 and elevated Sirt2 expression in aging skeletal muscle, particularly the anterior tibialis, which is enriched in type...

This editorial delineates the conceptual distinctions among lifespan, longevity, and healthspan in biogerontology. Lifespan is defined as the chronological duration from birth to biological death. Longevity refers to the capacity for survival beyond the species-typical average and is best understood probabilistically rather than as a predetermined limit. Healthspan, by contrast, lacks a uniform definition but is most commonly described as the period of life free from major chronic disease and...

CONCLUSION: The between-couple findings support the similarity-attraction theory and highlight gender-specific role transitions that influence cognitive aging, while the absence of within-couple cognitive concordance may be due to the length of assessment intervals or individual differences. These findings emphasize the need for future research with more frequent assessments and better control of trait-like characteristics to clarify these dynamics and support targeted cognitive health...

Lipid metabolism plays a crucial role in maintaining brain homeostasis, affecting energy balance, membrane structure, and signaling pathways essential for neuronal and glial health. Disruption of lipid pathways is linked to neuroinflammation and the progression of neurodegenerative diseases like Alzheimer's and Parkinson's, as well as aging. Changes in cholesterol trafficking, sphingolipid and ceramide metabolism, and phospholipid remodeling can compromise synaptic membrane integrity and...

Global population aging intensifies "inflammaging," a bidirectional link between chronic inflammation and aging-related pathology. Among them, S100A8/A9 forms a positive feedback loop of "aging-inflammation". Here, we systematically review the structure and function of S100A8/A9, including extracellularly promoting leukocyte adhesion and myeloid-derived suppressor cell aggregation, and intracellularly regulating NOD-like receptor protein 3 inflammasome, arachidonic acid metabolism, autophagy,...

Telomere length is a biomarker of aging and disease risk. Most human studies have assessed average telomere length, limiting our understanding of variability across chromosome arms. Using long-read sequencing data from >2500 All of Us participants, we estimate chromosome-specific telomere lengths and characterize sources of biological and technical variation. Telomere length varies by chromosome arm, accounting for 9.1% of total variance. Substantial variance (8.9%) in chromosome-specific...

Diabetic retinopathy (DR) is a microvascular and retinal neurologic disorder that occurs in patients with long-term diabetes. Umbilical cord blood-derived mesenchymal stem cell (UCB-MSC) therapy has emerged as a promising treatment because of its regenerative potential; however, its effectiveness is limited under hyperglycemic conditions, which results in the overproduction of mitochondrial reactive oxygen species (mtROS), leading to cellular senescence. In this study, we examined the potential...

APOE4 is the leading genetic risk factor for Alzheimer's disease, and chronic stress is a leading environmental risk factor. Studies suggest that APOE4 confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimer's onset and progression. Whether and how APOE4-mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and...

As the largest subunit of RNA polymerase II, POLR2A plays an irreplaceable role in gene expression, with the regulation of its own expression and physiological function having attracted widespread attention. Here we report POLR2A as a critical guardian against cellular senescence. A significant decline in POLR2A expression was observed in senescent cells and certain tissues of aging mice. Whereas its depletion dramatically induced cellular senescence, conversely, activating endogenous POLR2A...

Aging accelerates central nervous system remyelination failure and neurodegeneration. Microglia promote remyelination by phagocytosing myelin debris, but this function is impaired by aging-related CD22 upregulation. However, the molecular mechanisms counteracting premature aging-related microglial dysfunction and remyelination impairment remain unclear. Here, we report that Aurka-Bhlhe41 axis prevents premature aging-like microglial dysfunction and promotes remyelination by restraining...

Although epigenetic changes during ageing are well documented, we lack an integrated framework to systematically explain their mechanistic relationships. In this Review, we present a systems-level framework that demonstrates how epigenetic regulation controls ageing. We discuss four interdependent processes through which epigenetic fidelity - the capacity of chromatin regulatory systems to maintain precise gene expression states - progressively fails: deterioration of nuclear architecture,...

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Scientists spot first example of vertebrate drinking with suction from the tongue alone

New way to analyze frozen tissue slices could reveal bodywide effects of drugs, diseases

The planet’s lightning storms can unleash the force of multiple nuclear weapons every minute

The G-protein-coupled receptor kinase 2 (GRK2) exerts essential functions in cell growth and survival. Searching for a connection between GRK2 and the neurodegenerative Alzheimer disease (AD), we find increased aggregated serine-670-phosphorylated GRK2 (phospho-S670-GRK2) in brains of AD mice and patients with dementia likely due to AD. Harmful phospho-S670-GRK2 aggregation is induced by two hallmark proteins of AD: beta-amyloid and the neurofibrillary-tangle-inducing, TAU-P301L. Aggregated...

Sex and apolipoprotein E ε4 (APOE4) interact to alter the risk for Alzheimer's disease and other neurodegenerative disorders. Herein, we show sex-specific differences in immune activation and lymphatic function in the meningeal dura of humanized female and male mice expressing two alleles of APOE4 (E4/E4), when compared with their respective sex-matched E3/E3 controls. We also describe distinct effects of APOE4 on brain lipid composition and inflammation in females and males that were partially...

Genetic variants affecting microglia can cause early-onset neurodegeneration or elevate Alzheimer's disease risk. To nominate regulators of relevant signaling pathways, we developed a genome-wide CRISPR screen in primary macrophages focused on survival. We identified Ptpn6, which encodes the inhibitory phosphatase SHP-1, as a crucial regulator for macrophage survival under reduced CSF1R signaling conditions in vitro. Deletion of Ptpn6 from adult microglia in vivo enhanced survival and decreased...