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CONCLUSION: This study demonstrates that estrogen deficiency impairs mitophagy originated from Rab9-dependent alternative autophagy, leading to mitochondrial dysfunction and sarcopenia, while enhancement of Rab9 restores mitochondrial quality control and muscle function. These results identify Rab9-dependent mitophagy as a potential therapeutic target for postmenopausal sarcopenia.

C-reactive protein (CRP) and growth differentiation factor 15 (GDF15) are important markers of inflammation associated with brain health. Compared to plasma, DNA methylation (DNAm) measures of CRP and GDF15 may provide stable epigenetic measures of chronic exposure to inflammation and could therefore be robustly predictive of inflammation-related brain aging and neurodegeneration. We leveraged a subsample of Baltimore Longitudinal Study of Aging (BLSA) participants with DNAm/plasma data and...

The BCL-2 protein family governs critical cell-fate decisions between survival, senescence, and apoptosis, yet the dynamical principles underlying these choices remain poorly understood. Here, we integrate mathematical modeling, bifurcation analysis, and stochastic simulations to dissect how BCL-2 network architecture encodes multistability and fate plasticity. Our coarse-grained model reveals tristable regimes requiring cooperative BH3-only and anti-apoptotic BCL-2 interactions, with stochastic...

Glucagon-like peptide-1 (GLP-1) is a hormone known for its critical functions in managing blood sugar and offering cardiovascular benefits. Our study focuses on Glucagon Like Peptide 1 Receptor (GLP1R) agonists that act beyond glycemic control in cardiovascular and metabolic health. A comprehensive bioinformatic analysis was conducted, incorporating GLP1R, Gastric Inhibitory Polypeptide Receptor (GIPR), Gastric Inhibitory Polypeptide (GIP) and glucagon receptor (GCGR) to assess the effects of...

The objectives of this study are to examine colorectal cancer (CRC) screening, incidence, and mortality among veterans 45 to 75 years who are enrolled in the U.S. Department of Veterans Affairs (VA) healthcare system by housing instability or homelessness (HUH) and determine whether receiving primary care via Homeless Patient Aligned Care Teams (HPACTs) affects CRC screening, incidence, and mortality among veterans experiencing HUH. A retrospective cohort study was conducted among > 3,000,000...

CONCLUSION: Our findings reveal that elderly individuals showed larger MNCSA, whether or not they have diabetes, compared to young group. These findings suggest that aging is a dominant factor in the increase in MNCSA and that T2D may exacerbate it We propose that changes in MNCSA associated with diabetes could be part of the normal aging process, rather than representing an independent pathology.

CONCLUSION: Loneliness significantly explains the sarcopenia-mental health relationship, with men exhibiting stronger indirect pathways via loneliness. This highlights the need for integrated interventions targeting sarcopenia (e.g., resistance training) and loneliness (e.g., group-based social activities), tailored to sex-specific mechanisms. Scaling such approaches is urgent for the aging society, with highly prevalent sarcopenia and mental health problems among older adults.

CONCLUSION: The model generated for this study showed that adults with older age, diabetes, greater dependency in activities of daily living, and decreased functional status were more frail and that genetic markers conferred a greater risk of presenting frailty.

Cell type-specific analysis is crucial for uncovering biological insights hidden in bulk tissue data, yet single-cell or single-nuclei approaches are often cost-prohibitive for large samples. We introduce EPIC-unmix, a novel two-step empirical Bayesian method combining reference single-cell/single-nuclei and bulk RNA-seq data to improve cell type-specific inference, accounting for the difference between reference and target datasets. Under comprehensive simulations, we demonstrate that...

Expressed in the entorhinal cortex (EC), the cholecystokinin (CCK) B receptor (CCKBR) plays an important role in memory and learning. Here, we identify that CCKBR-Gs and -Gq signaling, rather than CCKBR-Gi signaling, are beneficial for Alzheimer's disease (AD) treatment. Clinically, patients with more severe AD associated with lower CCKBR-Gq activity. The cryo-electron microscopy (cryo-EM) structures of CCKBR in complex with the endogenous agonist sulfated CCK8 (CCK8s) and 3 different G protein...

Alzheimer's disease (AD), a leading neurodegenerative disorder, involves blood-brain barrier (BBB) dysfunction as a critical contributor to its pathogenesis. This review synthesizes current advancements in in vivo magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques for imaging BBB breakdown in AD. The BBB, a dynamic neurovascular interface, regulates amyloid-beta (Aβ) and tau clearance through specialized transporters and cellular interactions. BBB dysfunction,...

Alzheimer's disease (AD) is a complex neurodegenerative disorder driven by multilayered molecular and cellular mechanisms that cannot be fully elucidated through single-omics approaches. Consequently, large-scale multi-omics integration-encompassing transcriptomics, epigenomics (e.g., methylation), and genetic association studies (GWAS/eQTL/mQTL)-has uncovered critical genetic and epigenetic networks underlying disease risk and progression.Based on these integrative insights, this review...

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, remains a global health crisis due to the lack of early diagnostic tools, dynamic monitoring strategies, and effective therapies. Current diagnostic methods such as cerebrospinal fluid (CSF) analysis and neuroimaging, while accurate, are invasive, expensive, and unsuitable for routine screening, highlighting the pressing need for alternative approaches. This review comprehensively examines the transformative role of...

Cognitive and behavioral deficits in Alzheimer's disease (AD) and frontotemporal dementia (FTD) arise alongside gray matter atrophy and altered functional connectivity, yet the structure-function relationship across the dementia spectrum remains unclear. Here we combine structural and functional MRI from 221 patients-AD (n = 82), behavioral variant FTD (n = 41), corticobasal syndrome (n = 27), and nonfluent (n = 34) or semantic (n = 37) variant primary progressive aphasia-and 100 cognitively...

Spermine, a pivotal player in biomolecular condensation and diverse cellular processes, has emerged as a focus of investigation in aging, neurodegeneration, and other diseases. Despite its significance, the mechanistic details of spermine remain incompletely understood. Here, we describe the distinct modulation by spermine on Alzheimer's Tau and Parkinson's α-synuclein, elucidating their condensation behaviors in vitro and in vivo. Using biophysical techniques including time-resolved SAXS and...

Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leverages 13 longitudinal datasets, including 3737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimer's Disease. Both factors are associated with accelerated brain decline, yet it remains unclear...

Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta, which is strongly associated with disease progression and cognitive decline. Despite the approval of monoclonal antibodies targeting Aβ, optimizing treatment strategies while minimizing side effects remains a challenge. This study develops a mathematical framework to model Aβ aggregation dynamics, capturing the transition from monomers to higher-order aggregates, including protofibrils, toxic oligomers, and fibrils,...

Impairment of axonal transport has been emphasized as a common feature in a series of neurodegenerative diseases (NDs). Variations in DCTN1 have been reported in NDs such as Parkinson's disease (PD), Perry syndrome (PS) and Amyotrophic lateral sclerosis (ALS). The overall objective of this study was to investigate the contribution of DCTN1 variants in different NDs and to explore the correlation between DCTN1 variants and disease phenotypes. We identified a previously published mutation p.G71E...

To further understand whether childhood maltreatment (CM) is associated with indicators of accelerated cognitive aging, this study investigated whether CM moderated the relationship of age with gray matter volume (GMV) and executive functions among community adults aged 21-55. Participants (N = 225) underwent MRI scanning, and a composite measure of executive functions was computed across measures of inhibitory control, switching, and working memory. To interpret interactions, we created high...

Accumulation of senescent cells is a key contributor to multiple diseases across the lifespan, including metabolic dysfunction. We previously demonstrated that elimination of senescent cells using senolytic drugs alleviates obesity-induced metabolic dysfunction. However, the contribution of senescent endothelial cells to metabolic disorders remains elusive. Hence, we crossed mice that allow selective elimination of senescent cells (p16^(Ink4a)-LOX-ATTAC mice) with Tie2-Cre mice...