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Spatial disorientation represents a clinically meaningful vulnerability during aging and is an early manifestation along the Alzheimer's disease continuum. Understanding how aging-related central nervous system (CNS) changes affect the neural computations required for spatial perspective taking (SPT) is essential for characterizing early neurodegenerative processes. In this study, older adults with mild cognitive impairment (MCI) and subjective cognitive decline (SCD) completed a simplified...

Mitochondrial dysfunction is a prominent hallmark of aging contributing to the decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here we use proteomics, lipidomics, genetics and functional tests in wild type Caenorhabditis elegans and long-lived clk-1(qm30) and isp-1(qm150) mitochondrial mutants to identify molecular pathways that support longevity...

Children who had cerebral malaria or severe malaria anemia have lower scores on tests measuring general cognition and math achievement

The nicotinamide adenine dinucleotide (NAD^(+)) hydrolase sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is the central executioner of pathological axon degeneration and is allosterically activated by an increased nicotinamide mononucleotide (NMN)/NAD^(+) ratio. DNA damage induces NAD^(+) loss and an increased NMN/NAD^(+) ratio by hyperactivating poly(ADP-ribose) polymerase 1 (PARP1), which triggers the parthanatos cell death pathway. Multiple mechanistically distinct...

PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration...

The spatiotemporal dynamics of hydrogen peroxide (H(2)O(2)) signaling and its effects on gene expression and cell fitness remain unclear. Using fission yeast, we applied genetic tools to control and monitor intracellular H(2)O(2) levels. We expressed the H(2)O(2) biosensor HyPer7 in four subcellular compartments, overexpressed D-amino acid oxidase (Dao1) in specific locations to induce localized H(2)O(2) production, and modulated H(2)O(2) detoxification or sensing. H(2)O(2) concentrations showed...

Cerebral ischemic small vessel disease (SVD) is a leading cause of vascular dementia and stroke. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common monogenic SVD, is caused by dominant missense mutations in Notch3 expressed in smooth muscle cells (SMCs) and pericytes. However, cell-type-specific contributions driving CADASIL remain unknown. Here, we generate two conditional knockin mouse models carrying the CADASIL-causing...

The pro-inflammatory, senescence-associated secretory phenotype (SASP) is a hallmark of senescent cells (SnCs) that exacerbates age-related pathophysiology and chronic diseases. Although unique gene regulation is essential for fulfilling the pro-inflammatory SASP, the epigenomic basis in SnCs remains largely unknown. Here, we show that FOXF1/2 define the senescence-specific enhancer landscape by shaping chromatin accessibility. FOXF1/2 interact with p300/CREB-binding protein (CBP) and stimulate...

The global aging population presents a pressing challenge, highlighting the urgent need for interventions that target the fundamental mechanisms of aging. Gene therapy, leveraging its success in treating monogenic and aging-related diseases such as progeria and neurodegenerative disorders, has emerged as a promising strategy. It holds the potential not only to mitigate specific age-related pathologies but also to robustly extend healthspan. Although preclinical studies have shown encouraging...

The liver performs a wide range of physiological functions, including lipid/glucose metabolism, energy storage, immune regulation, molecular biosynthesis, and the clearance of xenobiotics, all of which are essential for maintaining systemic homeostasis. Liver ageing increases its susceptibility to acute stress and injury, which in turn enhances the body's sensitivity to ageing-related responses. These processes interact with other organs, accelerating systemic ageing and the pathogenesis of...

Aging is a complex biological process characterized by the loss of metabolic homeostasis, epigenetic drift, and systemic functional decline. Although exercise is widely recognized as a potent non-pharmacological intervention for aging, the mechanisms by which it translates transient metabolic fluctuations into long-term systemic adaptations remain incompletely understood. During physical activity, skeletal muscle exhibits significantly enhanced glycolytic flux, leading to the accumulation of...

Alterations in the epigenetic transcriptome are crucial in the aging process and the occurrence of age-related diseases. This study aims to define global RNA methylation patterns in nursing home residents, an aged population with a high burden of age-related health deficits and sharing a common environment. The study was conducted on RNA samples extracted from blood samples of 56 older adults in a nursing home and of 36 young subjects living independently in their own homes. The RNA samples were...

CONCLUSIONS: Bed rest was associated with increases in frailty that were not fully reversed by four months. Exercise during bed rest could support earlier recovery. These findings highlight the harmful effects of bed rest and the potential role of exercise for hospitalised adults.

CONCLUSIONS: This study adds large-scale, population-based evidence on the associations between different PA intensities and NHHR. Regular moderate-to-vigorous PA is associated with more favorable lipid profiles and lower mortality risk. These findings highlight NHHR as a valuable biomarker linking physical activity to cardiometabolic health and longevity in middle-aged and older adults.

Immune-stromal crosstalk governs tissue fibrosis, which is marked by dysregulated extracellular matrix (ECM) production and aberrant vasculature. Here, we investigate how γδ T cell interactions with stromal cells shape fibrosis in the foreign body response in a murine biomaterial implant model. During the acute reaction, type-1 (γδIFNγ) and type-17 (γδ17) γδ T cell subsets accumulate at the implant site. While γδIFNγ cells decrease as fibrosis progresses, activated γδ17 cells persist as dominant...

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)...

BACKGROUND: The ageing population faces numerous physiological changes, among which immunosenescence plays a central role. Understanding the mechanisms underlying immunosenescence remains a priority. Within this framework, the contribution of comorbidities to immune dysfunction is still poorly characterized, despite growing evidence suggesting that it may represent a critical determinant in the evaluation of immunosenescence. The main objective of this report was to disentangle the respective...

Alzheimer's disease (AD) is a major cause of dementia and cognitive decline. Here, we assessed how episodic memory (EM) network dysfunction, a hallmark of AD, is related to the longitudinal progression of AD biomarkers, neurodegeneration and cognition using data from the DZNE DELCODE study. This data set includes over 1000 longitudinal functional magnetic resonance imaging measurements of EM network function. We related activation and deactivation of EM to individual disease progression scores...

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...