Aging is accompanied by chronic inflammation, which is also the main cause of several age-related pathophysiologic diseases such as cancer, diabetes, and atherosclerosis. Recent studies have shown that cellular senescence, an aging related stress response, dramatically induces secretion of proinflammatory cytokines (senescence associated secretion phenotype, SASP) and thus might be an important additional source to chronic inflammation. SASP can also alter tissue environments, attract innate immune cells, and promote malignant phenotypes in nearby premalignant cells. Genetic or pharmacological inhibition of mTOR (mammalian target of rapamycin) extends life span in yeast, nematodes and mice and mTOR inhibitors are a widely used immunosuppressant in clinic and as promising anti-cancer therapies. Our recent data suggest that mTOR inhibitors might reduce inflammation caused by senescent cells in mammals, raising the possibility that some - or many - beneficial effects of mTOR inhibition on longevity and anti-cancer therapies might due to diminished inflammation. I thus propose to explore the molecular basis for our novel findings, and will examine the hypothesis that mTOR inhibitors reduce age-related pathologies like cancer in part by reducing the pro-inflammatory microenvironment. We plan to: (1) characterize the mTOR pathway in senescence response by determining the effect of mTOR inhibition on different stimuli induced SASPs and on multiple senescence phenotypes. (2) Identify critical mTOR pathway components, target cytokines, and translational targets in SASP. The proposal brings together the biological phenomena of senescence, inflammation, and mTOR in new ways which adds in its novelty. (3) Explore the consequences of mTOR inhibition on SASP-induced malignant phenotypes. The proposed experiments have the potential to provide a fresh perspective on how rapamycin extends mammalian life span (by suppressing low level inflammation caused by senescent cells). Further, it can provide a rationale for developing new strategies for using mTOR inhibitors in cancer therapy (suppressing the inflammatory tumor microenvironment fueled by senescent or damaged cells).
This proposal explores the novel hypothesis that mTOR drives the inflammatory secretory phenotype of senescent cells, and that mTOR inhibitors suppress this phenotype. The proposed experiments have the potential to provide a fresh perspective on how rapamycin extends mammalian life span (suppressing low level inflammation caused by senescent cells). Further, it can provide a rationale for developing new strategies for using mTOR inhibitors in cancer therapy (suppressing the inflammatory tumor microenvironment fueled by senescent or damaged cells).
| Liu, Su; Uppal, Harpreet; Demaria, Marco et al. (2015) Simvastatin suppresses breast cancer cell proliferation induced by senescent cells. Sci Rep 5:17895 |
