Senescent Cells and Declining Heart Health in the Context of Oxidative Stress
There is every reason to believe that selective destruction of senescent cells in older individuals should improve heart health, lowering the risk of cardiovascular disease and dysfunction. Researchers who demonstrated 25% median life extension in mice engineered to lack senescent cells found improvements in a number of measures of cardiac health. There is a good deal of evidence for senescent cells to reduce stem cell activity and tissue regenerative capacity, perhaps through chronic inflammation and other consequences of changes in immune cell behavior. Senescent cells spur fibrosis, which disrupts small scale tissue structure with the formation of scar-like tissue, and the growth of fibrosis is important in heart tissue aging. And so on, through much of the list of problems in cell and tissue function known to be caused by the presence of senescent cells. In the paper I’ll point out here, researchers focus specifically on oxidative signaling and rising levels of oxidative stress in the heart, and how senescent cells might be involved in this facet of heart aging.
Oxidative theories of aging were among the first such views of the causes of aging to be established in the modern era of cellular biochemistry. The original, simple theories that postulated aging as directly driven by oxidative damage to important molecules have since been put to one side in favor of more nuanced views. The failure of antioxidants, when applied generally, to slow aging is considered to disprove the simple view of aging as cellular damage that scales as the presence of oxidative molecules increases with age. It is certainly true that the oxidative molecules and signatures of harmful oxidative modification of vital proteins do increase with age, however. Equally it is also true that oxidative molecules and oxidative damage are used as signals in beneficial processes, such as the response to exercise — antioxidants can actually cause harm by interfering there. In short, oxidative metabolism is a complex, balanced process; that it is disrupted and runs awry with aging doesn’t necessarily make it a cause rather than a consequence.
Over the years, attention has focused upon mitochondria, the power plants of the cell, as the prime source of oxidative molecules and possibly the prime source of disruption in oxidative metabolism in old tissues. Modestly increasing or reducing the flux of oxidative molecules generated by these organelles can improve health in short-lived species — in one direction by causing less damage and in the other by spurring greater repair and maintenance activities. Severe disruption of correct mitochondrial function, something that is known to occur in aged tissues, can drive cells into a failure state that results in large quantities of oxidative molecules pumped out into the surrounding tissues. To close the circle, mitochondrial dysfunction goes hand in hand with cellular senescence, though the bigger picture of cause and consequence here is complicated and still incomplete.
Among age-related diseases, cardiovascular disease has an impressive prevalence, considering that the remaining lifetime risk for cardiovascular disease is about 50% at the age of 40. Consistently, the pathophysiologic modifications that are observed in aging hearts and arteries interact with alterations that characterize atherosclerosis progression, concurring to the development of age-associated heart failure. This latter is due to a combined diastolic and systolic dysfunction, caused by cardiac hypertrophy, replacement fibrosis, and myocardial ischemia, even in the absence of atherosclerotic coronary disease.
Morphometric data acquired in the early 1990s suggested that the number of left ventricle cardiomyocytes declines progressively with aging. Consistently, investigators have documented that although cardiomyocyte turnover occurs postnatally, the rate of cardiomyocyte renewal declines as age advances. Intriguingly, while the same investigators have recently suggested that the total number of cardiomyocytes residing in the left ventricle does not change with aging, evidence of myocyte death has been shown to occur both in male primates and in humans. In these latter, cardiac troponin T levels increase with aging and can predict cardiovascular events and death in the general population. This finding is thought to be the consequence of the age-related reduction of expression or activity of proteins that are involved in cardioprotection, a condition that eventually leads to an increased susceptibility of cardiac myocytes to injury.
To understand the mechanisms leading to heart failure, we and other authors hypothesized that the reduced cardiomyocyte turnover observed in aging was a consequence of the reduced cardiac growth reserve. Several independent groups have shown that undifferentiated, primitive cells reside in mammalian hearts and are involved in cardioprotection against heart failure, possibly generating new myocytes. Conversely, different lines of evidence obtained in animal models of heart failure and in humans indicate that senescent and dysfunctional cardiac resident stem/progenitor cells (CS/PC) accumulate as a consequence of cardiac pathology. Furthermore, with organism aging, senescent primitive and differentiated cells accumulate in mammalian hearts.
Although the concept of cellular senescence was introduced more than 50 years ago, the debate around this programmed cellular behavior is still ongoing. Specifically, in relatively recent years, it has been shown that cell senescence may exert positive effects, by promoting tissue healing after injury and protecting young organisms from cancer. However, in line with the antagonistic pleiotropy theory of aging, these beneficial effects exerted by cell senescence in young animals may be also responsible for the occurrence of functional impairment and age-related pathologies. Consistently, “rejuvenation” strategies aimed at reducing the frequency of senescent cells in the organism or designed to modulate those pathways whose activation status is altered in cell senescence can restore cardiac function in aged and failing hearts. Finally, we should emphasize that, while it has been postulated that reactive oxygen species (ROS) play a primary role in the development of cell senescence, the molecular mechanisms responsible for the development and evolution of cellular senescence are still a matter of intense research.
For many years it was believed that ROS were produced in an unregulated manner as a byproduct of cellular metabolism. Moreover, their ability to cause damage to macromolecules was thought to be responsible for organism aging (also known as the mitochondrial free radical theory of aging, MFRTA). Consistently, several pieces of evidence have shown an age-dependent decrease in mitochondrial integrity, and a parallel increase in the level of oxidized DNA (including mitochondrial DNA). These alterations have led to the formulation of “the vicious cycle hypothesis of mitochondrial ROS generation,” according to which the mitochondrial production of ROS would damage mitochondrial DNA (mtDNA) and lead to mitochondrial dysfunction, thus increasing ROS generation. However, discordant results have been obtained in more recent years, which have either supported or refuted the increased production of mitochondrial ROS with aging.
These seemingly contradictory results can be reconciled if we consider that ROS have a dual nature. In fact, on top of their ability to damage in non-specific fashion biological molecules, ROS can exert useful and beneficial effects, by regulating signaling pathways. According to current models, ROS generation is highly regulated, and therefore oxidative stress would arise from the loss of this architecture. Importantly, redox signaling is a crucial regulator of stem cell quiescence, self-renewal, and differentiation. Conversely, loss of controlled redox signaling (oxidative stress) can obliterate stem cell function and promote cell senescence of stem and differentiated cells, two conditions that have been associated with the progressive loss of tissue renewal and reparative reserve that characterize aging.
Cardiac stem cells are not immune from these pathological processes, becoming dysfunctional and unable to effectively repair cardiac damage with organism aging and pathology. mTOR signaling, which associates with cardiac stem cell senescence, may affect redox signaling at multiple levels, overloading the endoplasmic reticulum, and inhibiting both lysosomal function and autophagy. Therefore, innovative interventions aimed at restoring proper redox signaling in primitive cells have the potential to reverse or attenuate age-associated stem cell dysfunction.