Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Abstract

Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16^INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.

Keywords: SASP; adult stem cells; aging; epigenetics; metabolism; senescence; tissue homeostasis.

Figure 1

The Hallmarks of the Senescence Phenotype: Senescent cells exhibit the following four interdependent hallmarks: (1) cell-cycle withdrawal, (2) macromolecular damage, (3) the secretory phenotype (SASP), and (4) a deregulated metabolism (see also text). Figure reproduced with permission from Gorgoulis, V. et al. [1].

Figure 2

Molecular and Cellular Mechanisms of Senescence: A variety of stressors induce replicative senescence by the induction of the p16^INK4a/ARF and p53/p21^CIP1 pathways converging on the Rb family members to block cell growth. Telomere shortening and epigenetic modifications contribute to the senescent status. These molecular modifications progress to the development of the SASP that amplify senescence through cell-to-cell connections that modify tissue homeostasis, repair, and function.

Figure 3

Molecular and Cellular Mechanisms of Senescence: Replicative senescence and SASP characterize the senescent phenotype of aged and dysfunctional CSCs. Senolityc drugs and SASP inhibitors are able to eliminate senescent cells and senescent dysfunctional CSCs, thus favoring the expansion of healthy and functional CSCs.

Figure 4

Phenotypic Characteristics of Senescent Cells: Diagram depicting some of the phenotypic alterations associated with senescence initiation, early senescence, and late phases of senescence, which suggest that senescence is a dynamic rather terminal phenomenon. Figure reproduced with permission from Herranz N. and Gil J. [243].