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Evaluating Senescence-Targeted Approaches in Alzheimer's Disease: What We Know and What Lies Ahead

2 weeks 1 day ago
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, which represents the most prevalent dementia worldwide. Although amyloid-β (Aβ) and tau pathology have been the classic focus of treatment, accumulating evidence indicates that ageing-associated cellular senescence plays a central role in AD pathogenesis. Senescent neurons, astrocytes, microglia and endothelial cells accumulate in the ageing and Alzheimer's brain and adopt a senescence-associated secretory...
Pratik Prashant Doshi

Cell type-specific gene regulatory atlas prioritizes drug targets and repurposable medicines in Alzheimer's disease

2 weeks 1 day ago
Alzheimer's disease (AD) is a complex and poorly understood neurodegenerative disorder that lacks sufficiently effective treatments. Computational and integrative analyses that leverage multiomics data provide a promising strategy to uncover disease mechanisms and identify therapeutic opportunities. Here, we develop a cell type-specific regulatory atlas of the human middle temporal gyrus via leveraging single-nucleus RNA-seq (1,197,032 nuclei) and ATAC-seq (740,875 nuclei) datasets from 84...
Yunxiao Ren

DNA nanodevices detect an acidic nanolayer on the lysosomal surface

2 weeks 1 day ago
Lysosomes maintain a highly acidic lumen to regulate H^(+)-dependent hydrolase-mediated degradation, but how protons are 'leaked' out to regulate organellar functions through cytosolic effectors remains unknown. Here we developed DNA nanodevices on the cytosolic leaflet of lysosomal membranes to monitor juxta-organellar pH in cells. Unexpectedly, we revealed a radiating acidic layer (up to 21 nm in thickness) on the outer surface of all lysosomes, typically 0.2-0.7 pH units more acidic than the...
Yutong Zhang

Concurrent associations between visit-to-visit changes in actigraphy-based physical activity and cognitive aging in older adults

2 weeks 1 day ago
Physical activity (PA) is associated with lower dementia risk, yet few studies examine objectively measured PA with concurrently measured brain and cognitive aging outcomes longitudinally, leaving a gap in knowledge regarding temporality of these brain-behavior associations. We examined how longitudinal within-person changes in average daily step count track with changes in memory, executive function, hippocampal volumes, white matter hyperintensities (WMH), and depressive symptoms over time....
Ranjani P Shankar

Longitudinal body mass index exposure-based threshold to prevent mortality for populations with type 2 diabetes mellitus

2 weeks 1 day ago
The long-term body mass index (BMI) threshold to prevent mortality among aging individuals with type 2 diabetes mellitus (T2DM) remains unclear. We quantify BMI exposure using two metrics: the percentage of time BMI above target range (TAR) and the percentage of time BMI within target range (TTR). In a cohort of 3,708 adults aged ≥40 years with T2DM and at least 5 BMI measurements across 4 years, 1,020 deaths occurred during a median 5-year follow-up. Sustained BMI ≥27 kg/m² (TAR) is positively...
Tingting Hu

Evaluating Senescence-Targeted Approaches in Alzheimer's Disease: What We Know and What Lies Ahead

2 weeks 1 day ago
Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, which represents the most prevalent dementia worldwide. Although amyloid-β (Aβ) and tau pathology have been the classic focus of treatment, accumulating evidence indicates that ageing-associated cellular senescence plays a central role in AD pathogenesis. Senescent neurons, astrocytes, microglia and endothelial cells accumulate in the ageing and Alzheimer's brain and adopt a senescence-associated secretory...
Pratik Prashant Doshi

Divergent aging of nulliparous and parous mammary glands reveals IL33+ hybrid epithelial cells

2 weeks 1 day ago
Aging increases breast cancer risk while an early first pregnancy reduces a woman's life-long risk. Several studies have explored the effect of either aging or pregnancy on mammary stem/progenitor cells, however, the combined effect of both remains unclear. Here, we interrogate the functional and transcriptomic changes at single-cell resolution in the mammary gland of aged nulliparous and parous mice to discover that pregnancy normalizes age-related imbalances in lineage composition, while also...
Andrew Olander

PURE-seq integrates FACS and PIP-seq for single-cell genomics of ultra-rare cells

2 weeks 1 day ago
Single-cell transcriptomics is valuable for uncovering individual cell properties, particularly in heterogeneous systems. However, this technique often results in the reanalysis of many well-characterized cells, increasing costs and diluting rare cell populations. To address this, we develop PIP-seq for Rare-cell Enrichment and Sequencing (PURE-seq). PURE-seq allows direct FACS sorting of cells into PIP-seq reactions, minimizing handling and reducing cell loss. PURE-seq reliably sequences...
Sixuan Pan

Common variation in meiosis genes shapes human recombination and aneuploidy

2 weeks 1 day ago
The leading cause of human pregnancy loss is aneuploidy, often tracing to errors in chromosome segregation during female meiosis^(1,2). Although abnormal crossover recombination is known to confer risk for aneuploidy^(3,4), limited data have hindered understanding of the potential shared genetic basis of these key molecular phenotypes. To address this gap, we performed retrospective analysis of pre-implantation genetic testing data from 139,416 in vitro fertilized embryos from 22,850 sets of...
Sara A Carioscia

Ageing promotes microglial accumulation of slow-degrading synaptic proteins

2 weeks 1 day ago
Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing^(1,2). Here we engineered bioorthogonal tools³ that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old...
Ian H Guldner

Blood Cell Mitochondrial Respiration Increases With Age and Varies by Sex in Healthy Adults

2 weeks 1 day ago
Mitochondrial dysfunction is recognized as a biological hallmark of aging; however, bioenergetic capacity across the healthy human life course remains insufficiently characterized. While aging is generally associated with a systemic decline in mitochondrial function ("age-related bioenergetic decline"), recent research suggests that age-related bioenergetic differences are context dependent. Blood cells are extensively utilized as accessible samples for human bioenergetic profiling; therefore,...
Howard J Phang