Discovery, development, and future application of senolytics: theories and predictions

Abstract

Senescent cells accumulate with aging and at etiological sites of multiple diseases, including those accounting for most morbidity, mortality, and health costs. Senescent cells do not replicate, can release factors that cause tissue dysfunction, and yet remain viable. The discovery of senolytic drugs, agents that selectively eliminate senescent cells, created a new route for alleviating age-related dysfunction and diseases. As anticipated for agents targeting fundamental aging mechanisms that are 'root cause' contributors to multiple disorders, potential applications of senolytics are protean. We review the discovery of senolytics, strategies for translation into clinical application, and promising early signals from clinical trials.

Keywords: Geroscience Hypothesis; MAD cells; SASP; SCAPs; dasatinib; fisetin; navitoclax; quercetin; senolytics.

Fig. 1

Timeline for the discovery of senolytics. The discovery of senolytics began with the finding of senescent cells in 1961 by Hayflick and Moorehead 19 and was prompted by the finding of the J. Krishnamurthy group that interventions that increase healthspan also delay senescent cell accumulation 38. Developing senolytics began before and independently from making or studying INK‐ATTAC mice.

Fig. 2

SCAPs targeted by D plus Q. D + Q has targets across the entire SCAP network. Targeting a single molecule is not generally sufficient to promote apoptosis of many types of senescent cells. Agents that target a single molecule (e.g., BCL‐2 inhibitors, such as navitoclax or A1331852) tend to have more off‐target and side effects, resulting in unacceptable side effects than agents that act across multiple nodes of the SCAP network such as D + Q, which tend to have a more restricted side effect profile, less effect on nonsenescent cells, and more specificity in targeting senescent cells. D + Q were developed based on first delineating the SCAP network and then using computer‐assisted approaches for selecting agents that act upon nodes across the SCAP network: Development of the first senolytics was entirely mechanism‐based and did not involve random approaches such as high‐throughput library screening 39, 41. [Copyright author].