Aging & Longevity

To determine the genes and pathways that are up- or down-regulated in a consistent manner throughout the rodent lifespan, we generated a high N age-related gene expression atlas in mice and rats, by profiling 28 tissues in male and female C57BL/6J mice and 32 tissues in male Sprague Dawley rats (>5000 samples) over multiple time points. We identified age-related genes and pathways that change either early in life, at mid-age, late in life, or linearly throughout the animals' lifespan. Linear...

Depletion of TRF2 from chromosome ends causes telomeric fusions and genome instability in mammals, but in mouse neural stem cells (mNSCs), Trf2's role is non-telomeric. Although essential for mNSC proliferation and survival, Trf2 does not protect telomeres, aligning with findings that Trf2 is dispensable for telomere protection in pluripotent stem cells. In Trf2-deficient adult mNSCs (Trf2fl/fl; Nestin-Cre), proliferation decreased and neuronal differentiation was impaired, yet no telomere...

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Understanding how aging reshapes balance is essential for targeted assessment and rehabilitation. Because wobble boards impose continuous instability, their kinematics may provide a noninvasive readout of long-latency (transcortical) reflex function in ecologically valid conditions. We analyzed wobble-board dynamics in healthy younger adults ( 19 -- 35 y, n = 29 ) and community-dwelling older adults ( 56 -- 70 y, n = 29 ) performing with and without a concurrent cognitive load (Trail...

Cortical thinning and atrophy are hallmarks of brain aging that have been characterized using magnetic resonance imaging (MRI). Brain aging involves many neuroanatomic features whose effects on brain structure remain unexplored. To address this challenge, we trained interpretable deep neural networks (DNNs) to estimate brain age (BA) from T(1)-weighted (T(1)w) MRI. By identifying MRI features unapparent to humans, DNNs can find aging-related structural alterations above and beyond cortical...

CONCLUSION: Integrating assessments for multisensory impairment, vision, and hearing loss may add to elder mistreatment prevention and detection efforts.

Alzheimer's disease (AD) is an aging-associated neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation and progressive cognitive decline. Increasing evidence implicates the glymphatic system, a brain-wide perivascular pathway involved in cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, in the removal of Aβ, tau, and other solutes relevant to AD pathogenesis. Aging-related alterations in aquaporin-4 polarization, arterial pulsatility, sleep...

CONCLUSION: The selection of QSM reconstruction pipelines impacts results obtained from multi-site studies, indicating the importance of harmonizing QSM pipelines when interpreting susceptibility measures across studies.

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...

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...