A Cautious View of the Benefits of Senolytic Therapies
Senolytic therapies to selectively destroy senescent cells in old tissues have produced rapid rejuvenation in mice, turning back many different age-related diseases in many different studies. Senescent cells actively maintain a disrupted, inflammatory state of tissue when not cleared effectively by the immune system. Initial human trials of the dasatinib and quercetin combination (readily available to self-experimenters as well, prescribed off-label) have produced promising results. But as the authors of this paper note, there is still far too little human data to satisfy the cautions of regulators. Many more trials should be underway, particularly for dasatinib and quercetin, to definitively establish that this is a path worth pursuing, and allow the physician community to prescribe senolytics widely in the aged population.
Over the past decade, it has become clear that tissue ageing is caused by the accumulation of senescent cells, which alters the physiological responses in the surrounding microenvironment in an autocrine and paracrine fashion through the senescence-associated secretory phenotype (SASP). The body of evidence showing that elimination of senescent cells seemed to be largely beneficial led to huge research efforts to identify novel agents that eliminate senescent cells in humans. However, the repurposing of existing drugs and the use of new senotherapeutics are associated with various side-effects; incomplete functional characterisation of peripheral tissues at systemic administration; an absence of standardised guidelines for timing, dose, and route of administration; and a paucity of efficacy and safety data from clinical trials. Therefore, the full potential of senotherapeutics has been hampered in clinical applications.
It is likely that the best senotherapeutic against age-associated diseases and malignancies is yet to be discovered. Dasatinib, quercetin, and other senolytics were discovered using a mechanism-based approach. High throughput screening technology, which allows for automated testing of thousands of molecules present in chemical compound libraries in in-vitro senescence models, could assist with the discovery of new effective senolytics. To date, high throughput screening of commercial chemical compound libraries has led to the discovery of new families of senolytics: HSP90 inhibitors,the BET family protein degraders, and cardiac glycosides.
Furthermore, the safety and potency of existing senolytics can be improved by molecular engineering and drug delivery approaches. For example, the use of ABT263 is limited due to dose-limiting platelet toxicity. Researchers devised a proteolysis-targeting chimera technology to reduce the platelet toxicity of ABT263 by converting it into PZ15227. Compared with ABT263, PZ15227 was shown to be less toxic to platelets, but was a more potent senolytic in vitro and in vivo. Similar strategies might be useful to improve the efficacy and the safety profile of other toxic or repurposed senolytic agents.
In conclusion, senolytic drugs have shown promising results in the elimination of senescent cells and in alleviating various diseases in animal models. However, in patients, there is a paucity in data on the efficacy and safety of senotherapeutics from clinical trials, including systemic effects and side-effects. In this regard it is important to assess the specificity of senolytics in killing targeted senescent cells and their cytotoxic effects, to identify reliable markers for intervention responses, to elucidate interactions with comorbidities and other drugs, and to standardise administration protocols.