Abstract
Reduced dietary protein intake and intermittent fasting (IF) are both linked to healthy longevity in rodents, and are effective in inhibiting cancer growth. The molecular mechanisms underlying the beneficial effects of chronic protein restriction (PR) and IF are unclear, but may be mediated in part by a down-regulation of the IGF/mTOR pathway. In this study we compared the effects of PR and IF on tumor growth in a xenograft mouse model of breast cancer. We also investigated the effects of PR and IF on the mechanistic Target Of Rapamycin (mTOR) pathway, inhibition of which extends lifespan in model organisms including mice. The mTOR protein kinase is found in two distinct complexes, of which mTOR complex 1 (mTORC1) is responsive to acute treatment with amino acids in cell culture and in vivo. We found that both PR and IF inhibit tumor growth and mTORC1 phosphorylation in tumor xenografts. In somatic tissues, we found that PR, but not IF, selectively inhibits the activity of the amino acid sensitive mTORC1, while the activity of the second mTOR complex, mTORC2, was relatively unaffected by PR. In contrast, IF resulted in increased S6 phosphorylation in multiple metabolic tissues. Our work represents the first finding that PR may reduce mTORC1 activity in tumors and multiple somatic tissues, and suggest that PR may represent a highly translatable option for the treatment not only of cancer, but also other age-related diseases.
Highlights
Chronic restriction of dietary protein intake and intermittent fasting are both strongly associated with health and longevity in rodents [1,2,3,4]
We compare the effect of dietary composition and intermittent fasting on cancer growth and mechanistic Target Of Rapamycin (mTOR) pathway signaling
We have found that both a reduction in dietary protein and intermittent fasting slow tumor growth rate, but have distinguishable effects on mTOR signaling both in the tumor and the somatic tissues of a tumor-bearing mouse
Summary
Chronic restriction of dietary protein intake and intermittent fasting are both strongly associated with health and longevity in rodents [1,2,3,4]. Protein restriction (PR) and intermittent fasting (IF) regimens show beneficial effects on rodent models of age-related diseases, including cancer and Alzheimer’s disease [6,7,8]. Inhibition of the insulin/IGF-1/PI3K/mTOR signaling pathway either genetically or by treatment with the FDA-approved pharmaceutical rapamycin promotes longevity and inhibits tumor growth in model organisms [7, 11,12,13,14]. Disruption of mTORC2 contributes to the negative metabolic and immunological side-effects of rapamycin, and we have proposed that inhibiting mTORC1 would promote longevity and prevent age-associated diseases (e.g. cancer) with many fewer side effects than rapamycin, which inhibits both complexes [16]
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