Aged-senescent cells contribute to impaired heart regeneration

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

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Article numbere12931
JournalAging Cell
Volume18
Issue number3
DOIs
StatePublished - Jun 2019

Keywords

  • aging
  • cardiac regeneration
  • cardiac repair
  • myocardial infarction
  • p16INK4a
  • progenitor cells
  • senescence
  • senescence-associated secretory phenotype
  • senolytics

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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