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Aged-senescent cells contribute to impaired heart regeneration

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Fiona C Lewis-McDougall, Prashant J Ruchaya, Eva Domenjo-Vila, Tze Shin Teoh, Larissa Prata, Beverley J Cottle, James E Clark, Prakash P Punjabi, Wael Awad, Daniele Torella, Tamara Tchkonia, James L Kirkland, Georgina M Ellison-Hughes

Original languageEnglish
Article numbere12931
Issue number3
Early online date10 Mar 2019
Accepted/In press31 Jan 2019
E-pub ahead of print10 Mar 2019
PublishedJun 2019

Bibliographical note

© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.


King's Authors


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 (p16INK4A, SA-β-gal, DNA damage γH2AX, 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 wildtype 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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