Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging DOI Creative Commons
Matthew P. Baier,

Rojina Ranjit,

Daniel B. Owen

et al.

Aging Cell, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

ABSTRACT Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient retain cognitive throughout their lifespan. The molecular mechanisms that underlie these divergent trajectories, however, largely unresolved. Here, we utilized a high‐resolution home‐cage‐based testing paradigm to delineate contribute age‐related heterogeneity. We cognitively stratified aged C57Bl/6N male mice by performance into intact (resilient) or impaired subgroups based on young benchmarks. Cognitively males exhibited marked reactive gliosis the hippocampus, characterized microglial activation, increased astrocyte arborization, elevated transcriptional expression of reactivity markers. These changes were accompanied markers cellular senescence associated senescence‐associated secretory phenotype (SASP) animals, including p16 INK4a , SASP factors (e.g., Il‐6 Il‐1b Mmp3 ), SA‐β‐gal staining hippocampus. Notably, clearance senescent cells using senolytic agents dasatinib quercetin ameliorated heterogeneity observed with age attenuated impairment‐associated gliosis, markers, mitochondrial dysfunction. Aged female could not be yet showed neuroinflammation was resolved senolytics. Collectively, our findings implicate as central driver sex‐specific drives trajectories aging. Thus, demonstrate treatment an effective therapeutic strategy mitigate impairment reducing metabolic disturbances.

Language: Английский

Cellular Senescence Is a Central Driver of Cognitive Disparities in Aging DOI Creative Commons
Matthew P. Baier,

Rojina Ranjit,

Daniel B. Owen

et al.

Aging Cell, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

ABSTRACT Cognitive function in aging is heterogeneous: while some older individuals develop significant impairments and dementia, others remain resilient retain cognitive throughout their lifespan. The molecular mechanisms that underlie these divergent trajectories, however, largely unresolved. Here, we utilized a high‐resolution home‐cage‐based testing paradigm to delineate contribute age‐related heterogeneity. We cognitively stratified aged C57Bl/6N male mice by performance into intact (resilient) or impaired subgroups based on young benchmarks. Cognitively males exhibited marked reactive gliosis the hippocampus, characterized microglial activation, increased astrocyte arborization, elevated transcriptional expression of reactivity markers. These changes were accompanied markers cellular senescence associated senescence‐associated secretory phenotype (SASP) animals, including p16 INK4a , SASP factors (e.g., Il‐6 Il‐1b Mmp3 ), SA‐β‐gal staining hippocampus. Notably, clearance senescent cells using senolytic agents dasatinib quercetin ameliorated heterogeneity observed with age attenuated impairment‐associated gliosis, markers, mitochondrial dysfunction. Aged female could not be yet showed neuroinflammation was resolved senolytics. Collectively, our findings implicate as central driver sex‐specific drives trajectories aging. Thus, demonstrate treatment an effective therapeutic strategy mitigate impairment reducing metabolic disturbances.

Language: Английский

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