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Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging

2 months 2 weeks ago
Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or...
Rabia R Khawaja

The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer

2 months 2 weeks ago
Propionate metabolism dysregulation has emerged as a source of metabolic health alterations linked to aging, cardiovascular and renal diseases, obesity and diabetes, and cancer. This is supported by several large cohort population studies and recent work revealing its role in cancer progression. Mutations in several enzymes of this metabolic pathway are associated with devastating inborn errors of metabolism, resulting in severe methylmalonic and propionic acidemias. Beyond these rare diseases,...
Moniquetta Shafer

Metformin delays the decline in thermogenic function of brown adipose tissue in a mouse model of Hutchinson-Gilford progeria syndrome

2 months 2 weeks ago
Brown adipose tissue (BAT) is the primary site for non-shivering thermogenesis in the body and plays a crucial role in maintaining core body temperature. However, its function gradually declines with age. To mitigate the age-related decline in BAT thermogenic capacity, we treated progeroid mice with metformin to investigate the potential mechanisms by which metformin can slow the reduction in BAT thermogenic function. We found that progeroid mice, after receiving metformin treatment, showed...
Xin Xiang

Rhythms and shifts of chemokines and cytokines interplay in a decade lifespan: The longitudinal community-based Bambui health and aging study

2 months 2 weeks ago
Aging is associated with several physiological changes, including a remarkable remodeling of the immune system. Herein, the rhythms and shifts in serum immune mediators were characterized in a decade lifespan as a longitudinal community-based prospective investigation from Bambuí Health and Aging Study. The study population included paired samples from 713 subjects survivors from the original BHAS cohort and at 10-years Follow-up, categorized into 5-years age range intervals (60-64^(Yrs) towards...
Joaquim Pedro Brito-de-Sousa

Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging

2 months 2 weeks ago
Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or...
Rabia R Khawaja

Stability of locus coeruleus cell counts despite volume loss in cognitively impaired aged rhesus macaques

2 months 2 weeks ago
The locus coeruleus (LC) is a brainstem nucleus that provides the primary source of noradrenaline (NA) in the nervous system and optimizes behavioral performance in mammals. In humans, the LC shows Alzheimer's disease (AD)-like pathology at its earliest stages, but little is known about LC integrity in normative, non-pathological aging. The present research addresses these gaps by investigating neuron numbers, densities of glia and vasculature, and volume of the LC itself in cognitively assessed...
Kelsey E McDermott

HCNetlas: A reference database of human cell type-specific gene networks to aid disease genetic analyses

2 months 2 weeks ago
Cell type-specific actions of disease genes add a significant layer of complexity to the genetic architecture underlying diseases, obscuring our understanding of disease mechanisms. Single-cell omics have revealed the functional roles of genes at the cellular level, identifying cell types critical for disease progression. Often, a gene impact on disease through its altered network within specific cell types, rather than mere changes in expression levels. To explore the cell type-specific roles...
Jiwon Yu

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes

2 months 2 weeks ago
We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72, 38 GRN, and 25 MAPT) and 55 symptomatic (27 C9orf72, 17 GRN, and 11 MAPT) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct...
Aitana Sogorb-Esteve

Reducing microglial lipid load enhances beta amyloid phagocytosis in an Alzheimer's disease mouse model

2 months 2 weeks ago
Macrophages accumulate lipid droplets (LDs) under stress and inflammatory conditions. Despite the presence of LD-loaded macrophages in many tissues, including the brain, their contribution to neurodegenerative disorders remains elusive. This study investigated the role of lipid metabolism in Alzheimer's disease (AD) by assessing the contribution of LD-loaded brain macrophages, including microglia and border-associated macrophages (BAMs), in an AD mouse model. Particularly, BAMs and activated...
Xiaoting Wu

Rev-erb-α antagonism in alveolar macrophages protects against pneumococcal infection in elderly mice

2 months 2 weeks ago
Circadian rhythms control the diurnal nature of many physiological, metabolic, and immune processes. We hypothesized that age-related impairments in circadian rhythms are associated with high susceptibility to bacterial respiratory tract infections. Our data show that the time-of-day difference in the control of Streptococcus pneumoniae infection is altered in elderly mice. A lung circadian transcriptome analysis revealed that aging alters the daily oscillations in the expression of a specific...
Fabiola Silva Angulo

Elderly vulnerability to temperature-related mortality risks in China

2 months 2 weeks ago
The elderly face elevated mortality risk due to rising temperature. Previous assessments of temperature-related mortality, however, lack a comprehensive analysis of distinct impacts of temperature change across different timescales and characteristics. Using a longitudinal survey of 27,233 elderly Chinese citizens from 2005 to 2018, we establish connections between rising temperatures, temperature variability, and extreme heat with increased mortality risk, assessed through four annual metrics...
Xin Yao

Chromatin remodeler CHD4 establishes chromatin states required for ovarian reserve formation, maintenance and male germ cell survival

2 months 2 weeks ago
The ovarian reserve defines female reproductive lifespan, which in humans spans decades due to the maintenance of meiotic arrest in non-growing oocytes (NGOs) residing in primordial follicles. Unknown is how the chromatin state of NGOs is established to enable long-term maintenance of the ovarian reserve. Here, we show that a chromatin remodeler, CHD4, a member of the Nucleosome Remodeling and Deacetylase (NuRD) complex, establishes chromatin states required for formation and maintenance of the...
Yasuhisa Munakata