Cellular senescence and cardiovascular diseases: moving to the “heart” of the problem

Abstract

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 non-ischemic 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 is being increasingly explored, giving rise to the field of senotherapeutics. Therefore, we additionally attempt to clarifythe current state of this field with a focus on cardiac senescence, and discuss the potential of implementing senolytics as atreatment option in heart disease.

Role of Translationally Controlled Tumor Protein (TCTP) in the Development of Hypertension and Related Diseases in Mouse Models

“…Further studies regarding hitherto unknown potential mechanisms and roles of TCTP in terms of various cellular functions might delineate its pathophysiological network in the cardiovascular conditions. In this perspective, possible implications of TCTP in the cellular senescence and its contributory mechanism in the arterial hypertension and related disorders can be one of the future studies based on the causative roles of senescence in the majority of cardiovascular diseases [ 103 , 104 ].…”

Escape from senescence: molecular basis and therapeutic ramifications

“…From a molecular standpoint, senescence reversal represents a case of acute senescence, which is characterised by low p16 INK4A levels and a generally unaltered genotype, allowing backtracking to the presenescent state [27]. On the other hand, replicative senescence is associated with high p16 INK4A , which usually also reflects chronic senescence [18][19][20][21]24,28].…”

“…However, cell-cycle re-entry in the form of senescence escape and the emergence of malignant offspring may occur. These transitory cellular state dynamics are not completely understood and require further investigation [27].…”

A Unified Model of Age-Related Cardiovascular Disease

“…The inclusion of cell aging as a central process suggests a point of intervention that may prove more effective than current therapies [ 48 , 49 , 50 , 51 ]. Cell aging was first described more than sixty years ago [ 52 ], and taking it into consideration should have important medical and therapeutic implications [ 53 , 54 ].…”

“…Recently, senolytic therapies, aiming to remove senescent cells, have been touted [ 49 , 73 ], as have senomorphics [ 235 ] (small molecules mainly aimed at SASP), including their use as an intervention in cardiovascular disease [ 51 , 219 , 236 ]. The problem is that senolytics are expected to prompt additional division in the remaining cells in order to replace cells removed by senolytic therapy.…”