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Plasma phosphorylated tau 217 (pTau217) is an excellent biomarker of Alzheimer's disease (AD) pathology, but it remains uncertain whether pTau217 can predict amyloid-β (Aβ) and tau accumulation prior to Aβ positron emission tomography (PET) positivity. Here, we leverage data from a well-characterized prospective cohort of cognitively unimpaired older adults to examine mass spectrometry-based plasma %pTau217 (pTau217/non-phosphorylated-Tau217×100) relative to changes in Aβ/tau PET and cognition....

Astrocytes are key partners for neurons and can impact diseases such as Alzheimer's disease (AD), as they exhibit multiple reactive changes. Recent single cell/nucleus genomics analyses evidence astrocyte subpopulations coexisting in normal and AD brains. However, the signaling cascades controlling them, their functional characteristics and roles in AD are still unknown. Here, thanks to astrocyte-specific reporters for STAT3 and NF-kB signaling pathways, two regulators of astrocyte reactivity,...

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Cognitive flexibility is an executive function that enables adapting behaviour to a changing environment and is thus critical for daily life. The degree of its preservation upon healthy aging and the neural mechanisms underlying it are still a matter of debate. To investigate the electrophysiological correlates of cognitive flexibility in older age, we measured cognitive flexibility in 99 young (24.75 ± 4.45 years) and 83 older adults (69.19 ± 6.25) using electroencephalography (EEG). Compared...

Mutations in DNA damage repair (DDR) genes lead to genomic instability, driving a range of degenerative syndromes. In addition to promoting mutation accumulation, unrepaired DNA damage can leak into the cytosol and activate innate immune-sensing pathways, particularly the cGAS-STING axis. However, the extent to which cGAS causally contributes to organismal pathology in DDR syndromes in vivo remains unresolved. Here, we genetically model ataxia telangiectasia (A-T) and Bloom syndrome in the...

Transmembrane protein 65 (TMEM65) depletion in a patient caused severe mitochondrial encephalomyopathy, highlighting its clinical importance. Recent studies show TMEM65 acts as a mitochondrial Na^(+)/Ca^(2+) exchanger in vitro. Here, we generated conditional Tmem65 knockout mice to define its role in neuromuscular tissues in vivo. Both whole-body and nervous system-specific Tmem65 knockouts exhibited severe growth retardation and seizure-associated sudden death at ~3 weeks, establishing TMEM65...

Although seawater electrolysis holds great promise for green hydrogen production, the persistent challenges of chloride ions (Cl^(-))-induced chemical corrosion and localized acid etching under high potential severely hinder the lifespan of the anode. Herein, we propose that Os nanoparticles anchored on CoP nanowires supported by Ni foam (Os-CoP/NF) acts as a dual-protection anode with proton-buffering and Cl^(-)-repelling capabilities to simultaneously inhibit corrosion during seawater...

Aging is an important risk factor for Parkinson's disease (PD). Characterizing age-related alterations in the nigrostriatal system may help identify early vulnerability prior to overt neurodegeneration. We aimed to delineate aging trajectories of structure and hemodynamics of the nigrostriatal system and examine their associations with motor and cognitive functions. We analyzed 486 healthy adults from Human Connectome Project-Aging dataset, stratified into younger (≤ 60 years) and older (> 60...

Accelerated biological aging has been associated with mortality, but it remains unclear whether longitudinal changes in age acceleration predict long-term mortality risk. In the population-based Dutch Lifelines cohort, we estimated biological age using the Klemera-Doubal method (KDM-BA) and derived KDM-BA acceleration at baseline and follow-up. We examined baseline acceleration (continuous and categorical: < - 1, - 1 to 1 [reference], > 1 year), annual change in acceleration and four aging...

Stroke survivors often face long-term cognitive and motor deficits. Brain age gap (BAG), the difference between chronological age and age estimated based on MRI data, has emerged as a biomarker for neurodegeneration. While prior work links BAG to stroke outcomes, the relationship between BAG and cerebral microbleeds (CMBs), particularly infratentorial CMBs common in hypertensive arteriopathy, remains unclear. The sensorimotor network (SMN) is highly susceptible to both direct and remote injury...

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CONCLUSION: These findings underscore the importance of incorporating physical performance measures and social factors in MCR screening protocols and may inform screening and risk stratification in aging populations.

Cellular senescence, a state of permanent cell cycle arrest, contributes to tissue dysfunction and aging through the accumulation of apoptosis-resistant senescent cells. Although the transcription factor FOXO4 is known to enhance senescent cell survival, the mechanisms regulating its stability have remained unclear. Here, we identify a DNA damage response (DDR)-driven CHK2-USP37-FOXO4 axis essential for maintaining the apoptotic resistance of senescent cells. We demonstrate that FOXO4 protein...

Cellular senescence, a state of irreversible cell cycle arrest, plays a key role in neurodegenerative diseases, including Alzheimer's disease (AD). While senescent cells are emerging as potential therapeutic targets, the dynamics of their occurrence over time and the specific cell types most affected by AD are still not well understood. This study investigates age- and pathology-dependent changes in senescence markers, specifically p16, p21, and p53, using the amyloidogenic App^(NL-G-F) knock-in...

Frailty denotes a state of high vulnerability and, as proposed by Fried and colleagues, arises from "energetic collapse" across multiple physiological systems, in which altered energy metabolism undermines resilience. We suggest that dysregulation of acid-base balance represents a critical yet underappreciated mechanism driving this collapse. With aging, cumulative stress burden diminishes the capacity for intracellular and extracellular acid buffering, renal acid excretion and ventilatory...

Cellular senescence, a state of irreversible cell cycle arrest, plays a key role in neurodegenerative diseases, including Alzheimer's disease (AD). While senescent cells are emerging as potential therapeutic targets, the dynamics of their occurrence over time and the specific cell types most affected by AD are still not well understood. This study investigates age- and pathology-dependent changes in senescence markers, specifically p16, p21, and p53, using the amyloidogenic App^(NL-G-F) knock-in...

Aging impairs skeletal muscle mass and function, but the cell-type-resolved transcriptional states and intercellular signaling changes in human muscle aging remain incompletely mapped. Here, we constructed a single-nucleus RNA sequencing (snRNA-seq) atlas of human vastus lateralis muscle from adult (22-60 years) and elderly (99-101 years) male donors. We identified a comprehensive cellular census and discovered a profound reorganization of the myofiber transcriptional landscape. Aging was...

Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study...