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Map of brain 'microproteins' could offer new clues to Alzheimer's disease
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Publisher Correction: Three-dimensional mapping of intact ovaries reveals the aging dynamics of the ovarian reserve
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Sex-specific biological aging clocks across organs and omics
Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and...
The TyrRS cascade: circadian gating of neuronal DNA repair and its collapse in aging
Age-related neurodegenerative diseases are characterized by progressive DNA damage in post-mitotic neurons against a backdrop of deteriorating circadian rhythms, yet the molecular link between these conjoined features of brain aging remains unclear. We propose the TyrRS cascade as that link: a signaling architecture in which the noncanonical nuclear functions of tyrosyl-tRNA synthetase (TyrRS/YARS1) schedule neuronal genome maintenance across the day through three coregulated streams,...
Age-dependent changes in lipid droplet distribution and vascularization in naked mole rat vs. mouse hippocampus
The accumulation of lipid droplets in microglia has been reported to increase in response to ageing and age-related diseases like Alzheimer's disease. The present study investigates changes in lipid droplet dynamics with increasing age in the mouse and the similarly sized long-lived rodent, the naked mole rat (Heterocephalus glaber). We show that the naked mole rat contains large amounts of microglial lipid droplets in the CA1 and CA3 region of the hippocampus with an age-dependent increase in...
Adaptive hypergraph learning reveals high-order functional network alterations in mild cognitive impairment
Mild cognitive impairment (MCI) is an important prodromal stage of Alzheimer's disease, and its early identification is critical for risk assessment and timely intervention. Resting-state functional magnetic resonance imaging (rs-fMRI) can noninvasively characterize brain functional activity and connectivity. However, most existing methods rely on static second-order functional connectivity, limiting their ability to capture dynamic coordination and high-order interactions among multiple brain...
Inflection points and transitions in Alzheimer's disease
Alzheimer's disease is widely depicted as a linear cascade from amyloid-β accumulation to Tau pathology and neurodegeneration. We propose instead that the disease unfolds through discrete molecular, cellular and network phases organized around biological inflection points. At these thresholds, stress-driven loss of homeostasis produces qualitative shifts in cellular behavior that alters disease progression. These altered states spread across local tissue-domains, accumulate as a mosaic across...
Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement
Apolipoprotein E (APOE) genotype is the strongest genetic determinant of late-onset Alzheimer's disease (AD) risk. Of its three common isoforms, E4 increases AD risk and promotes inflammatory and metabolic dysregulation, whereas E2 is protective and is associated with altered lipid handling and immune function. Microglia express APOE in response to stress or injury and exhibit isoform-dependent transcriptional profiles, but the specific contribution of microglial APOE to these phenotypes remains...
NAA10 and NAA15 mutations in cardiovascular disorders: Recent advances and mechanistic insights
N-terminal acetylation (NTA) is a ubiquitous eukaryotic post-translational modification catalyzed by Nα-acetyltransferases (NATs). Among the eight NAT families, the NatA complex-composed of the catalytic subunit NAA10 and auxiliary subunit NAA15-mediates N-terminal acetylation of ~40% of mammalian proteins. Pathogenic mutations in NAA10 or NAA15 disrupt NatA complex integrity or enzymatic activity, resulting in NAA10- or NAA15-related syndromes. Both disorders share overlapping clinical...
Catechol-<em>O</em>-methyltransferase connects dopamine homeostasis to redox signaling, metal homeostasis, and protein folding in schizophrenia
Dysregulated dopamine (DA) signaling and redox homeostasis contributes to multiple neuropsychiatric and neurodegenerative disorders. Polymorphisms that influence the activity of catechol-O-methyltransferase (COMT), an enzyme critical for degrading DA in the dorsolateral prefrontal cortex, have been implicated in behavioral and neuropsychiatric alterations associated with schizophrenia (SCZ). Adverse neuropsychiatric effects have also been reported in Parkinson's disease (PD) patients...
Discovery of a small peptide that increases yeast lifespan by enhancing the function of APCCdh1 in nondividing quiescent cells
Aging is accompanied by molecular hallmarks conserved from yeast to humans. One such hallmark, senescence, is an irreversible nondividing state that promotes aging. We previously reported that mutants of the yeast Anaphase Promoting Complex (APC) shorten the lifespan of both dividing and nondividing cells. Here, we propose that activation of the APC will promote the maintenance of quiescent yeast cells, thereby delaying senescence and aging. We observed that APC activity in aging quiescent cells...
A rapid CRISPR-based nanodroplet assay enables direct clinical identification of mycobacteria species
The global incidence and mortality of nontuberculous mycobacterial infections have risen sharply with population aging. In some regions, they are now surpassing Mycobacterium tuberculosis complex infections, imposing a substantial clinical and economic burden. Because nontuberous mycobacteria exhibit species-level heterogeneity and require prolonged culture for identification, their diagnosis remains slow and is frequently inaccurate. Here, we describe a multiplexed clustered regularly...
Pseudotime uncovers restructuring dynamics and mitigators of metal catalyst deactivation
Structural reconstruction is a major cause of heterogeneous catalyst deactivation, yet elucidating the restructuring mechanism remains difficult due to underresolved dynamics. Here, by introducing pseudotime, we recover dynamics and identify the key determinant of nanoparticle sintering from ex situ electron microscopy alone, beyond the general view that postmortem observations provide only end-state structures. Pseudotemporal ordering of SiN(x)-supported gold across asynchronous aging states...
Endothelial C/EBPbeta/AEP pathway drives vascular deterioration and systemic aging
Age-related microvascular dysfunction disrupts nutrient homeostasis and waste clearance, leading to organ failure. However, a critical gap remains in our understanding of the specific molecular drivers of vascular deterioration and how they orchestrate organism-wide aging. Here, we identify progressive activation of the CCAAT/enhancer-binding protein β (C/EBPβ)/asparagine endopeptidase (AEP) pathway in aging vascular endothelial cells contributes to vascular degeneration and lifespan reduction....
Structural and functional alterations of posterior cingulate cortex subregions in successful cognitive aging
Successful cognitive aging (SCA) describes the preservation of cognitive abilities into advanced age, but its neural basis remains incompletely understood. Metabolic and pathological evidence implicates the posterior cingulate cortex (PCC) as a key region supporting cognitive resilience. However, functionally distinct PCC subregions have rarely been examined using complementary structural, microstructural, and functional imaging measures. In this cross-sectional secondary analysis of publicly...
Advances in the treatment of age-related hearing loss: from molecular mechanisms to targeted interventions
Age-related hearing loss (ARHL) is the most common sensory disorder in older adults. Current hearing interventions, including hearing aids and cochlear implants, face limitations in accessibility and adherence. Therefore, efforts have been devoted to elucidating the molecular mechanisms underlying cochlear aging and identifying effective therapeutic targets for ARHL. This review summarizes several molecular mechanisms implicated in cochlear aging and ARHL, including autophagy dysregulation,...
Common and distinct plasma proteomic signature of aerobic and motor physical activity interventions and their link to episodic memory
Aging is accompanied by chronic low-grade inflammation which has been associated with cognitive decline. Physical activity might regulate plasma levels of inflammatory-related proteins and may contribute to cognitive benefits, although the underlying mechanisms remain poorly understood. This exploratory secondary analysis aimed to evaluate whether different physical activity modalities were associated with distinct inflammatory-related plasma proteomic signatures in healthy older adults and to...
Energetic pathway to lower urinary tract symptoms in older adults: associations with cardiorespiratory fitness and walking energetics in the study of muscle, mobility and aging
Lower urinary tract symptoms (LUTS) are associated with older age and mobility limitations. We evaluated whether energetic determinants of mobility-maximum oxygen consumption (VO(2)peak), energetic cost of walking (EC(w)), and cost-capacity ratio (CCR) were associated with LUTS in community-dwelling older adults. We used baseline data from 629 participants aged ≥ 70 years in the Study of Muscle, Mobility and Aging. The 10-item LURN Symptom Index (LURN SI-10; range: 0-38, higher = worse) assessed...
The degenerating intervertebral disc leading to structural failure of the aging spine: from cellular pathways, risk factors, radiological diagnosis, to surgical management
Low back pain is a leading cause of disability worldwide. While non-specific low back pain accounts for the majority of cases, older adults are at increased risk of pathological and structural causes related to age-associated spinal degeneration, including intervertebral disc degeneration. Despite widespread use, conventional diagnostic imaging often fails to reliably identify pain-generating sources. Treatment decisions remain challenging, with many current interventions providing limited...
Dietary composition and metabolic stress differentially affect the ovarian microenvironment in mice
The ovarian microenvironment is a dynamic target of aging and highly responsive to metabolic and dietary stressors. Western diets (WD) and high-fat diets (HFD) promote obesity and systemic metabolic dysfunction. However, whether these diets induce remodeling of the ovarian microenvironment remains unclear. In this study, we investigated how distinct dietary patterns influence metabolic homeostasis, estrous cyclicity, ovarian reserve, and stromal remodeling in female mice. Three-month-old C57BL/6...