The Light and Shadow of Senescence and Inflammation in Cardiovascular Pathology and Regenerative Medicine (original) (raw)
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Current Pharmaceutical Design, 2013
The aging process is associated with a loss of complexity in the dynamics of physiological systems that reduce the ability to adapt to stress, causing frailty and/or age-related diseases. At the cellular level, proliferative and/or oxidative-stress induced cell senescence associated with a pro-inflammatory state may greatly contribute to age-associated impaired tissue and organ functions. Senescence of endothelial and cardiac cells observed over normal aging, appear to be accelerated in age-related diseases and in particular, in cardiovascular disease (CVD). Although the molecular mechanisms of cellular senescence have been extensively studied, a complete understanding of their role in CVD is still limited. Cardiac, endothelial (EC), vascular smooth muscle (VSMC), leukocytic and stem cells (endothelial progenitor cells (EPC), embryonic stem cells (ESC) and haematopoietic stem cells (HSC)) may play a pivotal role on the maintenance and regeneration of cardiovascular tissue. Age-associated changes of such cells may enhance the risk of developing CVD. The purpose of this review is to illustrate how cellular senescence may affect tissue repair and maintenance toward CVD, focusing on the role played by telomere length and microRNA expression. Finally, interventions aimed at improving the age-related decline in vascular cells during aging and disease, as well as strategies to harness the regenerative capacity of stem cells in CVD will be discussed.
Aged‐senescent cells contribute to impaired heart regeneration
Aging Cell, 2019
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...
Cellular senescence and cardiovascular diseases: moving to the “heart” of the problem
Physiological Reviews
Cardiovascular diseases (CVDs) constitute the prime cause of global mortality, with an immense impact on patient quality of life and disability. Clinical evidence has revealed a strong connection between cellular senescence and worse cardiac outcomes in the majority of CVDs concerning both ischemic and nonischemic cardiomyopathies. Cellular senescence is characterized by cell cycle arrest accompanied by alterations in several metabolic pathways, resulting in morphological and functional changes. Metabolic rewiring of senescent cells results in marked paracrine activity, through a unique secretome, often exerting deleterious effects on neighboring cells. Here, we recapitulate the hallmarks and key molecular pathways involved in cellular senescence in the cardiac context and summarize the different roles of senescence in the majority of CVDs. In the last few years, the possibility of eliminating senescent cells in various pathological conditions has been increasingly explored, giving ...
The Journal of Cardiovascular Aging, 2022
Ischemic heart disease and heart failure (HF) remain the leading causes of death worldwide. The inability of the adult heart to regenerate itself following ischemic injury and subsequent scar formation may explain the poor prognosis in these patients, especially when necrosis is extensive and leads to severe left ventricular dysfunction. Under physiological conditions, the crosstalk between cardiomyocytes and cardiac interstitial/vascular cells plays a pivotal role in cardiac processes by limiting ischemic damage or promoting repair processes, such as angiogenesis, regulation of cardiac metabolism, and the release of soluble paracrine or endocrine factors. Cardiovascular risk factors are the main cause of accelerated senescence of cardiomyocytes and cardiac stromal cells (CSCs), causing the loss of their cardioprotective and repairing functions. CSCs are supportive cells found in the heart. Among these, the pericytes/mural cells have the propensity to differentiate, under appropriate stimuli in vitro, into adipocytes, smooth muscle cells, osteoblasts, and chondroblasts, as well as other cell types. They contribute to normal cardiac function and have an antifibrotic effect after ischemia. Diabetes represents a condition of accelerated senescence. Among the new pharmacological armamentarium with hypoglycemic effect, gliflozins have been shown to reduce the incidence of HF and re-hospitalization, probably through the anti-remodeling and anti-senescent effect on the heart, regardless of diabetes. Therefore, either reducing the senescence of CSC or removing senescent cells from the infarcted heart could represent future antisenescence strategies capable of preventing the deterioration of heart function leading to HF.
Frontiers in Cardiovascular Medicine
Global aging is a hallmark of our century. The natural multifactorial process resulting in aging involves structural and functional changes, affecting molecules, cells, and tissues. As the western population is getting older, we are witnessing an increase in the burden of cardiovascular events, some of which are known to be directly linked to cellular senescence and dysfunction. In this review, we will focus on the description of a few circulating molecules, which have been correlated to life span, aging, and cardiovascular homeostasis. We will review the current literature concerning the circulating levels and related signaling pathways of selected proteins (insulin-like growth factor 1, growth and differentiation factor-11, and PAI-1) and microRNAs of interest (miR-34a, miR-146a, miR-21), whose bloodstream levels have been associated to aging in different organisms. In particular, we will also discuss their potential role in the biology and senescence of cardiovascular regenerative cell types, such as endothelial progenitor cells, mesenchymal stromal cells, and cardiac progenitor cells.
Pharmacologic Attenuation of Cardiac Stem Cell Senescence
Background: We demonstrated that both age and pathology exert detrimental effects on human cardiac stem cells (CSC) and are associated with reduced telomerase activity and telomere length, telomere erosion, telomere induced dysfunction foci and CSC dysfunction in vitro. Our aims were to investigate whether CSC senescence is associated with their reduced reparative ability in vivo, to identify the molecular determinants possibly responsible for CSC senescence, to screen drugs (i.e. rapamycin, resveratrol, and DETA/NO) able to interfere with CSC senescence, and to verify if CSC drug treatment in vitro is effective in restoring the reparative potential of senescent CSC in vivo. Methods: CSCs were isolated both from normal (D) and failing (F) human hearts. The reparative capacity of CSC was evaluated in a SCID/beige mouse model of acute myocardial infarction (AMI). Echocardiography and cardiac catheterization were performed 2 weeks post-AMI. Fibrosis, angiogenesis, myocyte growth, myocy...
Circulation Research, 2003
Chronological myocardial aging is viewed as the inevitable effect of time on the functional reserve of the heart. Cardiac failure in elderly patients is commonly interpreted as an idiopathic or secondary myopathy superimposed on the old heart independently from the aging process. Thus, aged diseased hearts were studied to determine whether cell regeneration was disproportionate to the accumulation of old dying cells, leading to cardiac decompensation. Endomyocardial biopsies from 19 old patients with a dilated myopathy were compared with specimens from 7 individuals of similar age and normal ventricular function. Ten patients with idiopathic dilated cardiomyopathy were also analyzed to detect differences with aged diseased hearts. Senescent cells were identified by the expression of the cell cycle inhibitor p16 INK4a and cell death by hairpin 1 and 2. Replication of primitive cells and myocytes was assessed by MCM5 labeling, myocyte mitotic index, and telomerase function. Aged diseased hearts had moderate hypertrophy and dilation, accumulation of p16 INK4a positive primitive cells and myocytes, and no structural damage. Cell death markedly increased and occurred only in cells expressing p16 INK4a that had significant telomeric shortening. Cell multiplication, mitotic index and telomerase increased but did not compensate for cell death or prevented telomeric shortening. Idiopathic dilated cardiomyopathy had severe hypertrophy and dilation, tissue injury, and minimal level of p16 INK4a labeling. In conclusion, telomere erosion, cellular senescence, and death characterize aged diseased hearts and the development of cardiac failure in humans. (Circ Res. 2003;93:604-613.)
Effects of Age and Heart Failure on Human Cardiac Stem Cell Function
American Journal of Pathology, 2011
Currently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21 Cip1 and p16 INK4a expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the decompensated myopathy. A correlation was found previously between telomere length in circulating bone marrow cells and cardiovascular dis-eases, but that analysis was restricted to average telomere length in a cell population, neglecting the fact that telomere attrition does not occur uniformly in all cells. The present study provides the first demonstration that dysfunctional telomeres in hCSCs are biomarkers of aging and heart failure. The biomarkers of cellular senescence identified here can be used to define the birth date of hCSCs and to sort young cells with potential therapeutic efficacy.