Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging.

IF 8 1区 医学 Q1 CELL BIOLOGY
Aging Cell Pub Date : 2025-03-12 DOI:10.1111/acel.70041
Matthew P Baier, Rojina Ranjit, Daniel B Owen, Jenna L Wilson, Megan A Stiles, Anthony M Masingale, Zachary Thomas, Anne Bredegaard, David M Sherry, Sreemathi Logan
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引用次数: 0

Abstract

Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient and retain cognitive function throughout their lifespan. The molecular mechanisms that underlie these divergent cognitive trajectories, however, remain largely unresolved. Here, we utilized a high-resolution home-cage-based cognitive testing paradigm to delineate mechanisms that contribute to age-related cognitive heterogeneity. We cognitively stratified aged C57Bl/6N male mice by cognitive performance into intact (resilient) or impaired subgroups based on young performance benchmarks. Cognitively impaired males exhibited marked reactive gliosis in the hippocampus, characterized by microglial activation, increased astrocyte arborization, and elevated transcriptional expression of reactivity markers. These changes were accompanied by increased markers of cellular senescence and the associated senescence-associated secretory phenotype (SASP) in impaired animals, including p16INK4a, SASP factors (e.g., Il-6, Il-1b, Mmp3), and SA-β-gal staining in the hippocampus. Notably, clearance of senescent cells using senolytic agents dasatinib and quercetin ameliorated the heterogeneity in cognitive performance observed with age and attenuated impairment-associated gliosis, senescence markers, and mitochondrial dysfunction. Aged female mice could not be stratified into subgroups yet showed increased neuroinflammation with age that was not resolved with senolytics. Collectively, our findings implicate cellular senescence as a central driver of sex-specific neuroinflammation that drives divergent cognitive trajectories in aging. Thus, we demonstrate that senolytic treatment is an effective therapeutic strategy to mitigate cognitive impairment by reducing neuroinflammation and associated metabolic disturbances.

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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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