Senescent cells grow in number in tissues throughout the body with advancing age. Cells become senescent throughout life, largely as a result of reaching the Hayflick limit on replication, but it can also happen in response to injury, or various forms of cytotoxic stress. These cells are removed by the immune system or programmed cell death and do not accumulate. Only later in life when there are greater levels of damage and cell stress on the one hand, and a failing immune system on the other hand, does creation outpace clearance to allow senescent cells to linger and grow in number.
The research and development communities are pursuing the development of senolytic therapies to selectively destroy senescent cells. To a lesser degree, there are also programs aimed at senostatic approaches to slow the creation of senescent cells or senomorphic approaches to alter the behavior of senescent cells to make them less harmful.
The expansion of these latter two approaches is in part driven by reservations in portions of the research community to the use of senolytics. Today's open access paper touches on most of those concerns, some more hypothetical than others. A few are the usual concerns for new classes of therapy: is the target well enough understood, is there enough knowledge to apply therapies effectively. Some are specific to senescent cells, however, in particular the question of whether senescent cells in any specific circumstance or tissue are actually needed despite the problems they cause, and thus could only be replaced slowly rather than cleared outright.
Is Senolytic Therapy in Cardiovascular Diseases Ready for Translation to Clinics?
Aging is a predominant risk factor for cardiovascular diseases. There is evidence demonstrating that senescent cells not only play a significant role in organism aging but also contribute to the pathogenesis of cardiovascular diseases in younger ages. Encouraged by recent findings that the elimination of senescent cells by pharmacogenetic tools could slow down and even reverse organism aging in animal models, senolytic drugs have been developed, and the translation of results from basic research to clinical settings has been initiated. Because numerous studies in the literature show beneficial therapeutic effects of targeting senescent cells in cardiomyopathies associated with aging and ischemia/reperfusion and in atherosclerotic vascular disease, senolytic drugs are considered the next generation of therapies for cardiovascular disorders.
According to the current research in the literature, we could conclude that senescent cells exhibit two faces in cardiovascular disease and aging, i.e., they have either detrimental effects or beneficial effects. Although the reasons for these contradictory results are not clear, the following considerations may provide hints for explanation and point towards further research directions.
First, it has been demonstrated that not all senescent cells have the same functions. For example, with the development of mouse models for genetic tracing and the manipulation of p16ink4+ cells, specific depletion of senescent cell types, such as endothelial cells and macrophages, and other cell types becomes possible. Moreover, senescent cells derived from the same cell type are not homogenous even in the same disease microenvironment. At least two groups of senescent cells might exist, i.e., pro-inflammatory tissue destructive and anti-inflammatory tissue reparative senescent cells, depending on the profile of the senescence-associated secretory phenotype (SASP).
Second, it therefore seems that the effects of senolytic therapy, whether beneficial or detrimental, are context-dependent in specific diseases. In cardiac diseases, e.g., myocardial infarction, heart failure, or age-related cardiac dysfunction, removal of senescent cardiomyocytes could be detrimental if survived or available cardiomyocytes under the condition are not adequate or not sufficient to support the pumping function of the heart. On the other hand, the elimination of senescent cardiomyocytes will be beneficial if the remaining cardiomyocytes are adequate to compensate for the heart pumping function and the detrimental paracrine effects of cardiomyocytes on other non-myocyte cells, such as fibroblasts, endothelial cells, and immune cells, could be removed.
Moreover, the SASP factor profiles from senescent cells might be different depending on the stimuli that induce cell senescence. Replicative senescent vascular endothelial cells or the endothelium from aged mouse exhibit a pro-inflammatory phenotype, while the SENEX gene induced premature endothelial senescence, revealing an anti-inflammatory phenotype. These observations implicate that senescent cells in different pathological conditions, such as atherosclerosis, insulin resistance, diabetes, hypertension, etc., and natural aging may have different profiles of SASP factors, which may also influence the effects of senolytic and/or senomorphic therapies.
Anti-senescence therapies or senolytic and senomorphic drug therapies are attractive and promising future therapeutic modalities for the treatment of cardiovascular diseases, and they represent a novel research direction for cardiovascular aging and age-associated cardiovascular diseases. However, we shall be cautious not to endorse clinical use of senolytics for the prevention or treatment of cardiovascular diseases or other age-associated chronic diseases until the roles of cell senescence in specific disease development are well-studied and the safety and efficacy of the drugs in well-designed clinical trials are investigated.
View the full article at FightAging
