期刊
AGING CELL
卷 18, 期 3, 页码 -出版社
WILEY
DOI: 10.1111/acel.12931
关键词
aging; cardiac regeneration; cardiac repair; myocardial infarction; p16INK4a; progenitor cells; senescence; senolytics; senescence-associated secretory phenotype
资金
- NIH [AG13925]
- British Heart Foundation [PG/14/11/30657]
- Noaber Foundation
- Glenn/American Federation for Aging Research (AFAR) BIG Award
- Italian Ministry of Health [GR-2010-2318945]
- Connor group
- MRC [MR/P026508/1] Funding Source: UKRI
Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32-86 years. In aged subjects (>70 years old), over half of CPCs are senescent (p16(INK4A), SA-beta-gal, DNA damage gamma H2AX, telomere length, senescence-associated secretory phenotype [SASP]), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wild-type mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67-, EdU-positive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart.
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