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Errors during cell division lead to aneuploidy, which is associated with genomic instability and cell transformation. In response to aneuploidy, cells activate the tumour suppressor p53 to elicit a surveillance mechanism that halts proliferation and promotes senescence. The molecular sensors that trigger this checkpoint are unclear. Here, using a tunable system of chromosome mis-segregation, we show that mitotic errors trigger nuclear deformation, nuclear softening, and lamin and heterochromatin...

CONCLUSIONS: Community programs that incorporate structure, accountability, and opportunities for social interaction, can help improve motivation to increase outdoor walking activity and a sense of belonging for older adults with difficulty walking outdoors. Park-based OWG programs appear to convey additional important benefits related to improved physical function and well-being.

Loss of dopaminergic neurons in Parkinson's disease (PD) is preceded by loss of synaptic dopamine (DA) and accumulation of proteinaceous aggregates. Linking these deficits is critical to restoring DA signaling in PD. Using murine and human pluripotent stem cell (hPSC) models of PD coupled with human postmortem tissue, we show that accumulation of α-syn micro-aggregates impairs metabolic flux through the pentose phosphate pathway (PPP). This leads to decreased nicotinamide adenine dinucleotide...

Infection with herpes simplex virus type 1 (HSV-1) in the brains of APOE4 carriers increases the risk of Alzheimer's disease (AD). We previously found that latent HSV-1 in a three-dimensional in vitro model of APOE4-heterozygous human brain tissue was reactivated in response to neuroinflammation caused by exposure to other pathogens. Because traumatic brain injury also causes neuroinflammation, we surmised that brain injury might similarly reactivate latent HSV-1. Here, we examined the effects...

The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology of Parkinson disease (PD). PLK2 (polo like kinase 2) is an evolutionarily conserved serine/threonine kinase that is more abundant in the brains of all family members, is highly expressed in PD, and is linked to SNCA deposition. However, in addition to its role in phosphorylating SNCA, the role of PLK2 in PD and the mechanisms involved in triggering neurodegeneration remain unclear. Here, we found that...

Continuous compensation for cerebral dopamine deficiency represents an ideal treatment for Parkinson's disease. Dopamine does not cross the digestive and blood-brain barriers and is rapidly oxidized. The new concept is the intracerebroventricular administration of anaerobic dopamine (A-dopamine) using an abdominal pump connected to a subcutaneous catheter implanted in the third ventricle, near the striatum. An open-label phase 1 study showed no serious adverse reactions induced by A-dopamine in...

Men, despite having a lower likelihood of longevity compared to women, generally exhibit better health status when they achieve longevity. The role of DNA methylation in this paradox remains unclear. We performed whole-genome bisulfite sequencing on long-lived men (LLMs), long-lived women (LLWs), younger men (YMs) and younger women (YWs) to explore specific methylation characteristics in LLMs. Despite an accelerated methylation aging rate in LLMs compared to LLWs, we identify thousands of...

Sleep spindles are cortical electrical oscillations considered critical for memory consolidation and sleep stability. The timing and pattern of sleep spindles are likely to be important in driving synaptic plasticity during sleep as well as preventing disruption of sleep by sensory and internal stimuli. However, the relative importance of factors such as sleep depth, cortical up/down-state, and temporal clustering in governing sleep spindle dynamics remains poorly understood. Here, we analyze...

Ataxia-telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of the homeostatic protein kinase ATM. The complex phenotype of A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts from A-T patients exhibit premature senescence, highlighting the association...

Functional compensation is a common notion in the neuroscience of healthy ageing, whereby older adults are proposed to recruit additional brain activity to compensate for reduced cognitive function. However, whether this additional brain activity in older participants actually helps their cognitive performance remains debated. We examined brain activity and cognitive performance in a human lifespan sample (N = 223) while they performed a problem-solving task (based on Cattell's test of fluid...

CONCLUSIONS: Leisure activities are linked to depression, with diet and cognition acting as chain-mediating factors. Public health experts recommend that older adults engage in leisure activities, ensure a broad spectrum of dietary intake, and prioritize the augmentation of plant-based diets as preventative strategies against depression.

Although the impact of gender-affirming hormone therapy (GAHT) on spermatogenesis in trans women has already been studied, data on its precise effects on the testicular environment is poor. Therefore, this study aimed to characterize, through histological and transcriptomic analysis, the spermatogonial stem cell niche of 106 trans women who underwent standardized GAHT, comprising estrogens and cyproterone acetate. A partial dedifferentiation of Sertoli cells was observed, marked by the...

The emergence of insecticide resistance has increased the need for alternative pest management tools. Numerous genetic biocontrol approaches, which involve the release of genetically modified organisms to control pest populations, are in various stages of development to provide highly targeted pest control. However, all current mating-based genetic biocontrol technologies function by releasing engineered males which skew sex-ratios or reduce offspring viability in subsequent generations which...

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling pathway, which recognizes both pathogen DNA and host-derived DNA, has emerged as a crucial component of the innate immune system, having important roles in antimicrobial defence, inflammatory disease, ageing, autoimmunity and cancer. Recent work suggests that the regulation of cGAS-STING signalling is complex and sophisticated. In this Review, we describe recent insights from structural studies that have helped...

Over the years, the study of adult sex ratio is a topic that has gained attention for its impact on reproductive outcomes and aging across various insect species. However, there is still limited research focused on insects reared for food and feed production. To address this gap, this study aimed to evaluate the impact of different adult sex ratios on the reproductive dynamics and longevity of the superworm, Zophobas morio (F.) (Coleoptera: Tenebrionidae), a species with interesting potential as...

Biomarkers of ageing (BA) can predict health risks beyond chronological age, but little is known about how marital/living status affects longitudinal changes in BA. We examined the association between marital/living status and BA over time using the-Swedish-Adoption/Twin-Study-of-Aging (SATSA) cohort. Four BAs were analyzed: telomere length (TL) (638 individuals; 1603 measurements), DNAmAge (535 individuals; 1392 measurements), cognition (823 individuals; 3218 measurements), and frailty index...

Human populations are experiencing unprecedented growth and longevity with lingering knowledge gaps of the characteristics, mechanisms, and pathologies of senescence. Invasive measurements and long-term control conditions for longitudinal studies are infeasible, necessitating the need for surrogate animal models. Rats have short lifespans (2-3 years) with translatable cardiovascular systems, and Sprague Dawley microcirculatory preparations are key to studying the oxygen transport mechanisms...

Extracellular vesicles (EVs) are implicated in inter-organ communication, which becomes particularly relevant during aging and exercise. DNA methylation-based aging clocks reflect lifestyle and environmental factors, while regular exercise is known to induce adaptive responses, including epigenetic adaptations. Twenty individuals with High-fitness (aged 57.7 ± 9.8 years) and twenty Medium-Low-fitness (aged 57.5 ± 9.7 years) subjects provided blood samples. EVs were isolated from the samples...

Nucleotide availability is crucial for DNA replication and repair; however, the coordinating mechanisms in vivo remain unclear. Here, we show that the circadian clock in the liver controls the activity of the pentose phosphate pathway (PPP) to support de novo nucleotide biosynthesis for DNA synthesis demands. We demonstrate that disrupting the hepatic clock by genetic manipulation or mistimed feeding impairs PPP activity in male mice, leading to nucleotide imbalance. Such defects not only elicit...

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