Senescent cells cease to replicate and start to secrete a potent mix of growth factors and inflammatory signals. In youth, senescent cells are removed fairly rapidly by the immune system or mechanisms of programmed cell death. They are created constantly as cells reach the Hayflick limit on replication, but also as a result of potentially cancerous DNA damage or in response to injury. The normal, useful purpose of a senescent cell present for only a limited period of time is to help attract the attention of the immune system, coordinating regeneration and clearance of damaged cells.
Unfortunately the immune system falters in its task of clearing senescent cells as people become older, and a population of lingering senescent cells accumulates. The inflammatory signaling that is helpful in the short term becomes disruptive and harmful when sustained. Senescent cells provide a meaningful contribution to degenerative aging, and their signaling actively maintains tissue dysfunction. Studies in mice in recent years have demonstrated meaningful degrees of rejuvenation to result from the targeted removal of senescent cells in old animals.
A senotherapeutic drug is one that in some way targets senescent cells. Most of the focus is on senolytics, treatments that exploit one or more of the distinctive biochemical features of senescent cells in order to destroy them while minimizing harms to other cells. But there are other strategies, such as inhibiting entry to the senescent state, suppressing senescent cell signaling, improving the ability of the immune system to clear senescent cells, reversing the senescent state, and so forth.
In today's open access paper, the authors sketch a big tent when it comes to deciding whether or not a given therapy is senotherapeutic. Just about anything that upregulates autophagy could be called senotherapeutic for its ability to reduce the pace at which cells becoming senescent. We when look to the future we would like to see a more profound, rapid rejuvenation result from targeting senescent cells. We would like to see the research community improve greatly on early senolytics and their impressive results in aged mice, rather than focus on the modest effects produced by exercise or mTOR inhibitors like rapamycin, both of which upregulate autophagy and reduce the creation of new senescent cells.
Senescent cells as a target for anti-aging interventions: From senolytics to immune therapies
The selective elimination of senescent cells with molecule chemicals represents an innovative approach to target the hallmarks of aging. Since the discovery of the dasatinib and quercetin combination as the first senolytic agent, numerous clinical drugs, synthetic products and natural compounds have been identified as candidate senolytics and senomorphics. The therapeutic benefit of senolytics is supported by evidence from preclinical studies in diseased and physiological aging models, which has fueled their progression into multiple clinical trials. Mechanistically, most senolytics inhibit survival pathways to induce apoptosis in senescent cells with relatively little harm to normal, proliferating cells. On the other hand, senomorphics inhibit the senescence-associated secretory phenotype (SASP) expression and reduce inflammation in the surrounding tissue without inducing cell death, offering an often equally effective but safer alternative to senolytic drugs.
Despite the efforts of ongoing clinical trials, the safety profile of chronically administering these small molecule senotherapeutics remains to be validated. A primary consideration is the tradeoff broad-spectrum senolytic effect and the negative effects on normal proliferating cells, due to the lack of clearly defined boundaries between senescent and cells undergoing milder, but non-senescence-inducing stresses, or even non-senescent cells that express markers of senescence. For example, some well-known side effects of continuous navitoclax treatment include thrombocytopenia, internal bleeding, and neutropenia, which might arise from the inhibition of anti-apoptotic Bcl-2 family proteins in platelets and neutrophils. The same is true for other chemotherapeutic-derived senolytics, whose inherent genotoxicity may pose unwanted risks for normal cells. In contrast to small molecules, senescent cell associated antigen directed immune therapies offer a more targeted approach to senescent cells with uniquely upregulated surface markers. Preliminary studies have demonstrated efficacy in reducing senescent cell burden and improving physical parameters. However, there remains the question whether established such antigens are sufficiently representative of the heterogeneous senescent cell population, and to what extent they are able to ameliorate senescent cell burden in vivo. To date the number of candidate antigens remains relatively few, yet emerging technologies such as single cell proteomic and multi-omic analyses may dramatically enhancing the efficiency of antigen discovery.
During the development of senescent cell targeted therapies, it is important to note that the elimination of senescent cells may not always be beneficial. Cellular senescence is known to play beneficial roles during embryogenesis, wound healing, tumor suppression and maintenance of tissue integrity. Transient initiation of senescence as a response to liver damage or cutaneous injury is known to promote tissue regeneration and prevent excessive fibrosis. Studies have shown that genetic depletion of p16 high cells may lead to disrupted physical barrier and fibrogenesis in the liver, as p16-enriched sinusoids are eliminated without eliciting replacement by new cells. Where the elimination of senescent cells is unfeasible or may lead to adverse effects, reversing the senescent cell age through epigenetic reprogramming could be an alternative solution. Proof-of-concept studies with partial reprogramming have been successfully carried out through transient activation of Yamanaka factors or administration of chemicals. Although the full mechanism behind this epigenetic-mediated rejuvenation effect remains to be elucidated, it is nevertheless an intriguing research avenue awaiting future exploration.
To date, a number of senotherapeutics have progressed into clinical phase and tested in those with age-related disorders. Studies with longer durations in larger patient cohorts utilizing composite markers for a comprehensive evaluation of senescence are needed to thoroughly assess the long-term systemic effect of senotherapeutics in combating diseases and aging, hence their overall translational potential.
Since the characterization of the first senolytics, the field of senotherapeutics has expanded rapidly to encompass nearly all aspects of translational medicine. By integrating principles of pharmacological treatment and immunotherapy to eliminate or rejuvenate senescent cells, it is possible to achieve therapeutic effects superior to symptomatically intervening on aging-related diseases. Although unresolved challenges exist, we maintain a positive outlook that the safety and applicability of senotherapeutics will be improved. Continued efforts in this area of study, particularly in rigorous studies in discovery science and collaboration to validate the effectiveness and safety of senotherapeutics in clinical trials, hold great importance in combating aging and improving human longevity.
View the full article at FightAging
