Exploring the fuzzy border between senolytics and senomorphics with chemoinformatics and systems pharmacology

Senescent cells accumulate within tissues during aging and secrete an array of pro-inflammatory molecules known as senescent-associated secretory phenotype (SASP), which contribute to the appearance and progression of various chronic degenerative diseases. Novel pharmacological approaches aimed at modulating or eliminating senescent cells´ harmful effects have recently emerged: Senolytics are molecules that selectively eliminate senescent cells, while senomorphics modulate or decrease the inflammatory response to specific SASP. So far, the physicochemical, structural, and pharmacological properties that define these two kinds of pharmacological approaches remain unclear. Therefore, the identification and correct choice of molecules, based on their physicochemical, structural, and pharmacological properties, likely to exhibit the desired senotherapeutic activity is crucial for developing effective, selective, and safe senotherapies. Here we compared the physicochemical, structural, and pharmacological properties of 84 senolytics and 79 senomorphics using a chemoinformatic and systems pharmacology approach. We found great physicochemical, structural, and pharmacological similarities between them, also reflected in their cellular responses measured through transcriptome perturbations. The identified similarities between senolytics and senomorphics might explain the dual activity of some of those molecules. These findings will help design and discover new, more effective, and highly selective senotherapeutic agents.