Aged‐senescent cells contribute to impaired heart regeneration

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.

Transient DNMT3L Expression Reinforces Chromatin Surveillance to Halt Senescence Progression in Mouse Embryonic Fibroblast

“…The secretions from senescent cells lead to a senescence-associated secretory phenotype (SASP), which might contribute to aging-associated tissue dysfunction or the development of a cancerous niche in old tissue (Coppe et al, 2010;Castro-Vega et al, 2015;Buhl et al, 2019;Lopes-Paciencia et al, 2019). A recent study showed that the transplantation of senescent cells into mice leads to the early onset of aging-related phenotypes (Xu et al, 2017(Xu et al, , 2018, which supports the current hypothesis that senescence can be a driver of aging (Krtolica et al, 2001;Sturmlechner et al, 2017;Lewis-McDougall et al, 2019).…”

Regulatory Mechanisms of Mitochondrial Function and Cardiac Aging

“…In subsequent studies, D+Q has been shown to elicit beneficial effects on cardiac regenerative capacity, frailty, osteoporosis, muscle weakness and endurance, and to extend lifespan [36][37][38]. In studies in human, D+Q alleviated physical dysfunction in patients with idiopathic pulmonary fibrosis and in subjects with diabetic kidney disease, D+Q reduced senescence cell burden in the adipose tissue [39,40].…”

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

“…Thus, the leaking mtDNA activates caspase-1 and promotes the secretion of IL-1β and IL-18 in macrophages. In the aged heart, the increased senescent cells modulate inflammation through secreting chemokine and cytokines, such as IL-1β, IL-6, and IL-8, termed the senescence-associated secretory phenotype (SASP) [19,20]. The cyclic GMP-AMP synthase (cGAS) is a stimulator of the interferon genes (STING).…”