期刊
AGING CELL
卷 20, 期 2, 页码 -出版社
WILEY
DOI: 10.1111/acel.13296
关键词
aging; brain; cognition; memory; neurodegeneration; SASP; senescence; senolytic; telomeres
资金
- National Institutes of Health [AG050886, AG056053]
- Biotechnology and Biological Sciences Research Council [BB/H022384/1, BB/K017314/1]
- Center for Computational Biology of Human Disease [P20GM109035]
- National Institute of General Medical Sciences [AG050582-01A1]
- Ted Nash Long Life Foundation
- National Center for Advancing Translational Sciences [UL1 TR0002377]
- National Institute on Aging [AG050582-01A1, AG062413, AG013925, AG062413-02S1, AG068182-01, R01 AG069048]
- Academy of Medical Sciences [SBF003_1179]
- BBSRC [BB/K017314/1, BB/H022384/1] Funding Source: UKRI
- MRC [MR/P020941/1] Funding Source: UKRI
Clearing senescent cells, either through drug treatment or senolytic cocktail, has been shown to improve cognitive function, providing proof-of-concept for senolytic interventions as a potential therapeutic avenue for alleviating age-associated cognitive impairment.
Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16(Ink4a) senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16(Ink4a)-positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16(Ink4a) exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions' being a potential therapeutic avenue for alleviating age-associated cognitive impairment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据