Natural mTOR-inhibitors for longevity
Posted: Thu Sep 19, 2019 9:58 am
This is the section on diet-derived mTOR-inhibitors from a paper concentrating on the synthetic rapalogs like everolimus and rapamycin. Note that these natural derived molecules require fairly high concentration to inhibit mTOR but on the other hand, green tea and turmeric are easy to integrate into your diet. I use 1 tsp of turmeric + a dash of black pepper (the piperine increases curcumin bioavailability) and enjoy several cups of green tea a day.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2980558/3.4. Diet-derived natural products
Increasing studies have demonstrated that some diet-derived natural products, including curcumin, resveratrol, epigallocatechin gallate (EGCG), genistein, 3, 3-diindolylmethane (DIM) and caffeine, may inhibit mTOR signaling directly or indirectly (Table 1) [140-147].
EGCG, the most studied polyphenol component in green tea, is a potent antioxidant that may have therapeutic potential for many disorders including cancer. In the co-cultured keloid fibroblasts and HMC-1 cells, EGCG treatment dose-dependently reduced the increased phosphorylation of Akt, S6K and 4E-BP1 . In both p53 positive and negative human hepatoma cells, EGCG activated AMPK, resulting in the suppression of downstream substrates, including mTOR and 4E-BP1, and a general decrease of mRNA translation .
Resveratrol is a polyphenolic flavonoid from grapes and red wine with potential anti-inflammatory, antioxidant, neuroprotective and anticancer properties . In human U251 glioma cells, resveratrol downregulated PI3K/Akt/mTOR-mediated signaling pathway, and combination with rapamycin enhanced resveratrol-induced cell death . In smooth muscle cells (SMC), resveratrol inhibited the proatherogenic oxidized LDL-induced activation of the PI3K/Akt/mTOR/S6K pathway and remarkably suppressed DNA synthesis and proliferation of SMC . Recently it has been described that resveratrol activated AMPK in both ER-positive and ER-negative breast cancer cells, and consequently inhibited mTOR and its downstream 4E-BP1 signaling and mRNA translation. It was also found that the activation of AMPK by resveratrol was due to the induction of Sirtuin type 1 (SIRT1) expression in ER-positive breast cancer cells .
Increasing evidence suggested that curcumin may exert its antiproliferative effects by inhibiting mTOR signaling and thus may represent a new class of mTOR inhibitor. Curcumin is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa and is undergoing early clinical trials as a novel anticancer agent . Numerous studies have shown that curcumin inhibited the growth of a variety of cancer cells and showed effectiveness as a chemopreventive agent in animal models of carcinogenesis [152,153]. In our studies, we showed that curcumin inhibited cell growth, induced apoptosis and inhibited the basal or IGF-I-induced motility of rhabdomyosarcoma cells . In numerous cancer cell lines, curcumin inhibited phosphorylation of mTOR and its downstream targets, S6K1 and 4E-BP1, suggesting that curcumin may execute its anticancer effect primarily through blocking mTOR mediated signaling pathways [153,154]. Most recently, we further found that curcumin was able to dissociate raptor from mTOR, leading to inhibition of mTORC1 activity .