Simple SummaryBladder cancer occurs mainly in older people and is expensive to manage. Swedish Herbal Rhodiola-5 (SHR-5), a standardizedRhodiola Roseaextract from the Swedish Herbal Institute (the SHI, Gothenburg, Sweden), has been in clinical studies for managing mild to moderate depression and physical and mental fatigue. Previous studies have shown that SHR-5 extended the life span of the fruit fly through a mechanism that was not associated with dietary restriction. In this study, we examined whether drinking SHR-5 can delay tumor development in a superficial bladder cancer mouse model. Drinking SHR-5 daily markedly improved the survival rate of the bladder tumor-bearing mice, by an absolute 61.7%, and reduced urinary tract obstruction and tumor burden. SHR-5 drinking reshaped the tumor metabolism via the inhibition of the mTOR leading to a decreased tumor cell proliferation.AbstractBackground:SHR-5 has been used as an “adaptogen” for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the underlying mechanisms of action.Methods:UPII-mutant Ha-ras bladder-cancer-transgenic mice, that developed low-grade and noninvasive papillary transitional urothelial cell carcinoma, were fed with 1.25 and 6.25 mg/mL SHR-5 in drinking water for 6 months. The survival of the mice, obstructive uropathy, tumor burden and morphology, and proliferation were evaluated by pathological, molecular, metabolic, and statistical analyses.Results:Approximately 95% or more of the male UPII-mutant Ha-ras mice that drank SHR-5 daily survived over 6 months of age, while only 33.3% of those mice that drank normal water survived over 6 months of age (p< 0.0001); SHR-5 drinking exposure also reduced tumor-bearing bladder weight and urinary tract obstruction and inhibited mTOR signaling in neoplastic tissues. Global metabolic analysis revealed that SHR-5 resulted in increased phenolic metabolites and decreased CoA, a critical metabolic cofactor for lipid metabolism.Conclusions:Our findings highlight the potential of SHR-5 as an anti-aging agent for bladder cancer prevention through reshaping tumor metabolism via the inhibition of the mTOR signaling. Global metabolomics profiling provides a unique and efficient tool for studying the mechanisms of complex herb extracts’ action.