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Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and...

Neuroinflammation plays a key role in Alzheimer's disease (AD) and many other neurodegenerative disorders. Chronic activation of astrocytes and microglia fuels neuronal damage via cytokine secretion, oxidative stress, and proteolysis, yet glial inflammatory regulation remains poorly understood. Using chemoproteomics, we identified CK2, particularly the brain-enriched catalytic subunit CK2α2, as a key driver of astrocytic inflammation. CK2 enhances NF-κB activity by phosphorylating NF-κB S529 and...

Diagnostic models using primary care routine clinical variables have been limited in their ability to identify Alzheimer's disease (AD) patients. In this study, we sought to better understand the effect of mild cognitive impairment (MCI) on the predictive performance of AD diagnostic models. We sourced data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. CatBoost was used to assess the utility of routine clinical variables that are accessible to primary care physicians, such...

The subthalamic nucleus (STN) is a critical hub for inhibitory control, implicated in decision making under conflict and impulsivity. Delta frequency oscillations have also been associated with inhibitory control processes, yet the relationship between human STN neuronal activity and local delta frequencies during response inhibition remains unresolved. Here we recorded STN neurons and local field potentials in patients with Parkinson's disease performing a stop-signal reaction time task during...

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons. Insufficiency of neurotrophic factors is suspected to underlie the disease, but direct evidence remains scarce. In this study, we discover that brain-derived neurotrophic factor (BDNF) val/met mutation, which results in a decrease in BDNF secretion, reduces survival time of ALS patients in two separate cohorts. Using a knockin mouse model of the ALS causal gene FUS^(R521C), we demonstrate...

Triple-negative breast cancer (TNBC) lacks effective targeted therapies and carries a poor prognosis. TNBC cells escape oncogene-induced senescence and adapt to elevated replication stress. Here, we show that cells escaping senescence depend on overexpression of RNase H2, which removes misincorporated ribonucleotides from genomic DNA. RNASEH2A, the catalytic subunit of RNase H2, is overexpressed in TNBC tumors and correlates with poor survival. Genetic silencing or pharmacological inhibition of...

Semaglutide, a GLP-1 receptor agonist, improves metabolic health and reduces liver fat in people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease (MASLD). This post hoc analysis of the 24-week SLIM LIVER single-arm trial (ACTG A5371, No. NCT04216589, registered 02nd Jan 2020) in 41 PWH with MASLD receiving semaglutide (1.0 mg weekly) aimed to evaluate its effect on epigenetic aging and determine whether changes in epigenetic clocks associate with clinical...

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Aging is associated with progressive deterioration of vascular function and cardiovascular risk. Cardiorespiratory fitness (CRF) is closely associated with cardiovascular health, yet longitudinal data in healthy older adults remain limited. This study examined 3-year changes in vascular and echocardiographic parameters in older adults and their associations with CRF and muscle strength. Forty-nine participants (mean age 63.8 ± 3.8 years) underwent vascular assessments (brachial/central blood...

Aging is a complex process influenced by various factors, including gut microbiota and food likings. Focusing on gut and dietary health is a crucial strategy for promoting long-term health and active aging. This study investigates the reciprocal causal relationships between gut microbiota, food likings and aging using Mendelian Randomization (MR) approaches. We leveraged the summary statistics of gut microbiota (n = 5,959), food likings (n = 161,625), and three aging phenotypes including...

The ubiquitin-proteasome system is essential for neuronal proteostasis, yet its function declines with age. How aging affects deubiquitylating enzymes (DUBs) in the vertebrate brain remains unclear. Here we used activity-based proteomics to profile cysteine protease DUBs in aging mouse and killifish brains. We identified a subset of DUBs that progressively lose catalytic activity with age despite stable protein abundance. Mechanistically, oxidative stress impaired DUB function through thiol...

Alternative lengthening of telomeres (ALT) is a recombination-based pathway enabling cancer cells to maintain telomeres. ALT establishment remains poorly understood due to difficulties identifying its molecular steps. Here, using Oxford Nanopore sequencing and computational modeling, we track the evolution of individual chromosome end structures during ALT establishment in yeast and delineate three molecular milestones. First, homologous recombination via break-induced replication (BIR) at...

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The naked mole-rat (NMR), Heterocephalus glaber, is an unusual mammal that lives underground in eusocial colonies. NMRs show remarkable longevity and are resistant to cancer, neurodegeneration, and cardiovascular disease. The gut microbiome is known to modulate human health and disease; here, we investigate the microbiome of NMRs, comparing fecal samples from individuals over different social ranks and over a span of more than three decades. In contrast to a cohort of C57BL6/J mice, which showed...

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The liver is a major metabolic organ, responsible for synthesizing and breaking down diverse metabolites. Recently, the liver's immunological functions have gradually been unveiled: combating pathogens and maintaining tissue homeostasis. Age-related functional alterations in these immune cells emerge as potential drivers of hepatic dysfunction and age-associated pathologies. However, systematic investigations into spatiotemporal immune cell dynamics during liver aging remain limited. To address...

As the global population ages, cellular senescence contributes increasingly to the burden of age-related diseases. Hallmarks of this process include telomere shortening and loss of proteostasis, frequently linked to DNA damage-associated transcriptional stress. Although telomere dysfunction-induced foci (TIF) have been well documented in lungs from patients with idiopathic pulmonary fibrosis (IPF), their occurrence and role during physiological lung aging remain unclear. Analysis of senescence...

Skeletal muscle mass and force decline with age, and the loss of muscle force precedes muscle atrophy. However, the underlying mechanisms remain unclear. Here, we investigated the role of the myosin co-chaperone, uncoordinated mutant number-45 myosin chaperone B (UNC45B), in regulating muscle mass and force. UNC45B expression decreased in mouse gastrocnemius muscle with age, particularly at 24 months old, and adeno-associated virus vector-mediated knockdown of Unc45b in 3-month-old mouse triceps...