In a new study, researchers show that the presence of senescent cells is an important contributor to aging of the cardiovascular system, particularly the heart [1].
Senescent cells and senolytics
As your body ages, increasing amounts of your cells enter into a state of senescence. Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful inflammatory chemical signals, which are known as the senescence associated secretory phenotype (SASP). The SASP can also encourage other nearby healthy cells to also enter the same senescent state.
Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer. Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of these senescent cells escape this process and accumulate.
One possible solution to this problem is to remove senescent cells in order to improve tissue regeneration and health. A class of drugs called senolytics focuses on the destruction of these stubborn, “death-resistant” cells, thus reducing inflammation and improving tissue function.
Aiding recovery from heart attacks
Senescent cells are known to contribute to hypertrophy, in which the heart becomes enlarged and less able to pump blood. The presence of senescent cells is also linked to fibrosis in the heart tissue, which causes structural and functional failure.
The SASP increases systemic inflammation and creates a background of inflammaging, the chronic inflammation that is typically seen in older people. This chronic inflammation is harmful to all cells and tissues, and it impairs regeneration while contributing to vascular aging. Arterial stiffening via dysfunction of the smooth muscle cells and the development of atherosclerosis via macrophage dysfunction are two ways in which senescent cells promote vascular aging.
These researchers investigated if the senolytic clearance of senescent cells following a heart attack would improve survival odds in mice. They used the repurposed cancer drug navitoclax, a drug that targets the Bcl-2 family of proteins, a pro-survival pathway that has consistently turned up in the literature as one that many senescent cells use to avoid destruction. Various studies have shown that targeting this particular family of proteins allows the selective destruction of senescent cells.
This study showed that removal of senescent heart cells from mice reduced the development of fibrotic tissue and myocardial remodeling, improved diastolic function, and increased survival odds following a heart attack.
Abstract
Cardiovascular disease is the leading cause of death in individuals over 60 years old. Aging is associated with an increased prevalence of coronary artery disease and a poorer prognosis following acute myocardial infarction (MI). With age, senescent cells accumulate in tissues, including the heart, and contribute to age‐related pathologies. However, the role of senescence in recovery following MI has not been investigated. In this study, we demonstrate that treatment of aged mice with the senolytic drug, navitoclax, eliminates senescent cardiomyocytes and attenuates profibrotic protein expression in aged mice. Importantly, clearance of senescent cells improved myocardial remodelling and diastolic function as well as overall survival following MI. These data provide proof‐of‐concept evidence that senescent cells are major contributors to impaired function and increased mortality following MI and that senolytics are a potential new therapeutic avenue for MI.
Conclusion
Once again, the role of senescent cells in aging has been confirmed, as has the plausibility of clearing these problem cells from the body to improve tissue health and regeneration and to prevent disease progression. Senolytics are currently in human trials, and studies like this only serve to add to the ever-growing pool of data in support of senescent cell removal as a way to combat age-related diseases by targeting this underlying aging process itself.
Literature
[1] Walaszczyk, A., Dookun, E., Redgrave, R., Tual‐Chalot, S., Victorelli, S., Spyridopoulos, I., … & Richardson, G. D. (2019). Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction. Aging cell, e12945.
