A large portion of research into senescent cells in the context of degenerative aging is focused on how these cells fail to destroy themselves. Senescent cells are primed to enter the programmed cell death process of apoptosis, but various mechanisms hold this off. Sabotaging some of those mechanisms is an effective way to clear a sizable fraction of senescent cells in many old tissues, as demonstrated by the initial small molecule senolytic treatments, such as the dasatinib and quercetin combination.
As the authors of today's open access paper note, the fact that these apoptosis-inducing senolytics are only partially effective raises questions about the diversity of anti-apoptosis mechanisms and varieties of senescent cell. It is a fertile area of research, in which scientists are uncovering new ways to provoke senescent cells into apoptosis, with different degrees of effectiveness on senescent cells of different origins. There are many more areas of cellular biochemistry yet to explore, and likely many more effective senolytic small molecules yet to be identified.
Cellular senescence is a process that leads to a state of irreversible growth arrest in response to a variety of intrinsic and extrinsic stresses. Initially, the phenomenon was found when cultured cells were shown to undergo a limited number of cell divisions in vitro. Cellular senescence is different from cell quiescence which represents a transient and reversible cell cycle arrest. Cellular senescence can be a physiologically or pathologically relevant program depending on the specific situation. It normally functions as a vital tumor suppressive mechanism and also plays an important role in tissue damage repair. However, senescent cells (SnCs) have been implicated in various age-related diseases.
Accordingly, selective elimination of SnCs has been exploited as a novel strategy to treat the diseases. In addition, SnCs have also been implicated in infectious diseases. For example, virus infection can induce cellular senescence, which was found to be a pathogenic trigger of cytokine escalation and organ damage, and recently found to be associated with the COVID-19 severity in the elderly. Clearance of virus-induced SnCs was considered as a novel treatment option against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and perhaps other viral infections.
One of the characteristics of SnCs is their ability to resist apoptosis. Until now, small molecules that can selectively kill SnCs, termed senolytics, were developed to target the proteins in the SnC anti-apoptotic pathways (SCAPs). However, due to the high heterogeneity in gene expression and their diverse origins, SnCs may use different SCAPs to maintain their survival, making it difficult to use a single senolytic to kill all types of SnCs. Although significant progresses on the development of senolytics have been made, some proteins involved in the SCAPs have been overlooked, their potential of being senolytic targets have not been investigated. Therefore, gaining more insights into the apoptosis-resistant mechanism of SnCs may greatly help to design or screen more effective senolytics that can be used to treat SnC-associated disorders.
In this review, we discussed the latest research progresses and challenge in senolytic development, described the significance of regulation of senescence and apoptosis in aging, and systematically summarized the SCAPs involved in the apoptotic resistance in SnCs.