Rutin Suppresses the SASP of Senescent Cells

Senescent cells accumulate with age and cause harm via a sustained, energetic production of signal molecules, the senescence-associated secretory phenotype (SASP), that disrupts tissue structure and function. In addition to the search for senolytic drugs that can selectively destroy senescent cells by pushing them into programmed cell death, researchers are also looking for senomorphic drugs that can suppress some or most of the SASP by interfering in its regulatory mechanisms. This seems to me a poor alternative to clearance of senescent cells, as a senomorphic drug must be taken continually, but nonetheless a great many such research programs are underway.

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 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.


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