Aged-senescent cells contribute to impaired heart regeneration

Article


Lewis-McDougall, F. C., Ruchaya, P. J., Domenjo-Vila, E., Teoh, T. S., Prata, L., Cottle, B. J., Clark, J. E., Punjabi, P. P., Awad, W., Torella, D., Tchkonia, T., Kirkland, J. L. and Ellison-Hughes, G. M. 2019. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell. 18 (3), p. Art. e12931. https://doi.org/10.1111/acel.12931
AuthorsLewis-McDougall, F. C., Ruchaya, P. J., Domenjo-Vila, E., Teoh, T. S., Prata, L., Cottle, B. J., Clark, J. E., Punjabi, P. P., Awad, W., Torella, D., Tchkonia, T., Kirkland, J. L. and Ellison-Hughes, G. M.
Abstract

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 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.

KeywordsAging; Cardiac regeneration; Cardiac repair; Myocardial infarction; p16INK4a; Progenitor cells; Senescence; Senescence-associated secretory phenotype; Senolytics
JournalAging Cell
Journal citation18 (3), p. Art. e12931
ISSN1474-9726
Year2019
PublisherWiley
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Supplemental file
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Digital Object Identifier (DOI)https://doi.org/10.1111/acel.12931
Web address (URL)https://onlinelibrary.wiley.com/doi/10.1111/acel.12931
Publication dates
Print10 Mar 2019
Online14 May 2019
Publication process dates
Accepted31 Jan 2019
Deposited13 Jun 2023
FunderBritish Heart Foundation (BHF)
National Institute for Health Research (NIHR)
Robert and Arlene Kogod
Robert J. and Theresa W. Ryan
The Connor Group
Noaber Foundation
Glenn/American Federation for Aging Research (AFAR) BIG Awards
Italian Ministry of Health
Copyright holder© 2019, The Author(s)
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