Senescent cells are a cause of aging. They accumulate with the passage of years and decades, a process that is in part just a matter of numbers and averages over time, in which a minuscule fraction of the vast number of newly senescent cells arising every day manage to evade destruction. Importantly, it is also due to the progressive failure of the immune system in its surveillance of errant cells. Senescent cells, like cancer cells, are attacked and destroyed by immune cells, and thus their numbers rise as immune cells become less competent. The harm done by senescent cells is mediated by the wide range of inflammatory, harmful factors that they secrete. The presence of even a small number of senescent cells disrupts tissue function, structure, and regenerative capacity.
As noted in today's open access paper, the presence of senescence cells is important in the aging of the heart and the rest of the cardiovascular system. Cellular senescence contributes to ventricular hypertrophy, the process by which heart muscle becomes larger and weaker. Senescent cells are also implicated in the fibrosis found to disrupt structure and function of heart tissue; removing senescent cells via senolytic treatment reserves this fibrosis. Further, the chronic inflammation produced by senescent cells is generally harmful to the cardiovascular system, contributing to the progression of arterial stiffening via smooth muscle cell dysfunction, and atherosclerosis via macrophage dysfunction.
Senescent cells actively enforce their contribution to the state of aging via their secretions. Remove the cells, and that contribution vanishes, leaving behind downstream damage that can be repaired by cell populations to a sizable degree. Senolytic therapies to clear senescent cells have been demonstrated to extend life in mice, and turn back the progression of many aspects of aging and age-related diseases. Targeted destruction of senescent cells is a rejuvenation therapy, albeit a narrowly focused form of rejuvenation, targeting only one of many forms of damage that cause aging. The work here is one of many papers to demonstrate this point.
Cellular senescence is classically defined as the irreversible cell cycle arrest of somatic cells. While senescence can act as a potent antitumour mechanism, recent studies have shown that senescent cells accumulate in several tissues with age where they contribute to age-dependent tissue dysfunction and several age-related diseases. Senescent cells are thought to contribute to aging via a pro-oxidant phenotype and the secretion of a senescence-associated secretory phenotype (SASP), which is pro-inflammatory, profibrotic, and can also promote senescence in surrounding cells.
Senescence has been shown to occur in the heart during aging and contributes to the pathophysiology of a number of cardiovascular diseases, as clearance of senescent cells in aged and atherosclerotic mice using both genetic and pharmacological approaches improves vascular and myocardial function and attenuates age-dependent remodelling. However, the impact of senescent cells in myocardial infarction (MI) has not been investigated thus far. In this study, we hypothesise that senescent cells contribute to the poor prognosis and survival of aged individuals following MI. Previously we found that in addition to clearing senescent cells, navitoclax treatment reduced fibrosis and cardiomyocyte (CM) hypertrophy in aged mice and considered that these beneficial effects may help to improve outcomes in aged mice following MI. We therefore performed a more detailed longitudinal study to examine this possibility and to explore potential mechanisms.
Histological analysis was performed on a cohort of noninfarcted mice, to assess the baseline effects of navitoclax treatment. In addition to decreasing CM hypertrophy, treatment reduced markers of CM senescence, indicating clearance of senescent cells from the hearts of treated aged mice. Furthermore, we found a significant reduction in expression of profibrotic TGFβ2, which we previously identified as a key component of CM SASP. Functionally, navitoclax treatment significantly reduced the age-dependent increase in left ventricular (LV) mass but did not impact on ejection fraction (EF). Aged mice also exhibited a decrease in the percentage change in diastole versus end systole LV wall thickness, indicating an increased LV rigidity compared with young animals, which was also partly rescued by navitoclax treatment. Clinically, increased ventricle stiffness is related to fibrosis and hypertrophy during aging, is symptomatic of diastolic dysfunction and is observed in heart failure with preserved ejection fraction patients.
We observed that aged mice had significantly higher mortality rates following MI (60% over 5 weeks) compared with young mice and that this outcome was rescued by prior navitoclax treatment. In contrast to young mice, old mice show a significant reduction in EF between 1 and 4 weeks post-MI. Importantly, navitoclax was able to rescue this functional decline which may help to explain the improved survival of this group. Furthermore, expression of senescence markers p16 and p21 at 4 weeks following MI was reduced in the hearts of navitoclax-treated mice, consistent with reduction of the senescence burden.
Collectively, this study shows that pharmacological clearance of senescent cells in aging mice alleviates age-dependent myocardial remodelling and attenuates expression of profibrotic mediators. Navitoclax improved the maintenance of cardiac function following MI, ultimately increasing survival. An important limitation of this study is that our experimental strategy was not able to distinguish which senescent cell types are responsible for this effect, and it is possible that clearance of senescent cells in noncardiac organs impact on survival following MI. We have focussed our attention on CMs in this study as our earlier findings showed that, in the heart, markers of senescence accumulate primarily in CMs during aging. However, further studies using animal models where senescent cells can be cleared in a cell-type specific manner are required to formally show the contribution of senescent CMs to cardiac recovery post-MI.