Aging is a major risk factor for most chronic disorders, for which cellular senescence is one of the central hallmarks. Senescent cells develop the pro-inflammatory senescence-associated secretory phenotype (SASP), which significantly contributes to organismal aging and age-related disorders. Development of
senotherapeutics, an emerging class of therapeutic agents to target senescent cells, allows to effectively delay aging and alleviate chronic pathologies. Here we report preliminary outputs from screening of a natural medicinal agent (NMA) library for senotherapeutic candidates and validated several agents with prominent potential as
senomorphics.
Rutin, a
phytochemical constituent found in a number of plants, showed remarkable capacity in targeting senescent cells by dampening expression of the full spectrum SASP. Further analysis indicated that
rutin restrains the acute stress-associated phenotype (ASAP) by specifically interfering with the interactions of ATM with HIF1α, a master regulator of cellular and systemic homeostasis activated during senescence, and of ATM with
TRAF6, part of a key signaling axis supporting the ASAP development toward the SASP.
Conditioned media produced by senescent stromal cells enhanced the malignant phenotypes of
prostate cancer cells, including in vitro proliferation, migration, invasion, and more importantly, chemoresistance, while
rutin remarkably downregulated these gain-of-functions. Although classic
chemotherapy reduced
tumor progression, the treatment outcome was substantially improved upon combination of a chemotherapeutic agent with
rutin. Our study provides a proof of concept for
rutin as an emerging natural senomorphic agent, and presents an effective therapeutic avenue for alleviating age-related pathologies including
cancer.