The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 13 No. 2 • April 2010


Cardioprotection, Possible Life Extension

Inhibitors of mTOR Revisited: Resveratrol

In our Feb. 2010 issue of the Durk Pearson & Sandy Shaw Life Extension News, we discussed (“Life Extension by Inhibiting Growth”) the possible life extending effects of inhibiting the nutrient-sensitive growth-inducing gene mTOR (mammalian Target of Rapamycin). We discussed two potential nutrient inhibitors of mTOR: curcumin and resveratrol. The data we had at that time made it impossible to determine what the effective dose of resveratrol would be for the purpose of effectively and safely inhibiting mTOR. A new paper (thanks, Will) helps to close in on an appropriate dose.

Autophagy and Resveratrol

In the new paper,1 resveratrol was studied for its potential effects on autophagy, a self-digestion process by which a cells’ own components are degraded by lysosomes and the resulting chemicals reused. In a review on autophagy,2 the author wrote: “Autophagy, a highly conserved mechanism of quality control inside cells, is essential for the maintenance of cellular homeostasis and for the orchestration of an efficient cellular response to stress. The decrease in autophagic activity observed in almost all cells and tissues as organisms age was proposed to contribute in different aspects of the aging phenotype and to the aggravation of detrimental age-related diseases.” In another paper,3 the authors write: “... even on a day-to-day basis, autophagy is activated between meals in organs such as the liver to maintain its metabolic functions, supplying amino acids and energy through catabolism.” Increased autophagy is observed in caloric restriction models of lifespan increase in model animals. Other papers4 report that loss of autophagy in the central nervous system causes neurodegeneration in mice by preventing the degradation of inclusion bodies. Moreover, autophagy was reported to be required during cycling hypoxia to reduce ROS (reactive oxygen species) by removing ROS-producing species,5 which may be one reason why inhibiting autophagy increases cancer cell death.

Interestingly, increases in mTOR (as occurs after a meal) causes a decrease in autophagy. Inhibition of TOR by rapamycin induces autophagy. Inhibiting mTOR, then, is one way to increase autophagy.

Resveratrol, mTOR, and Autophagy

In the new paper,1 resveratrol at low doses (0.1 and 1 uM in H9c2 myoblast cells and 2.5 mg/kg/day in rats) induced cardiac autophagy. Autophagy was suppressed, however, by the higher dose of resveratrol (100 uM in the myoblast cells and 25 or 100 mg/kg/day in rats). Treatment with rapamycin, a known inducer of autophagy, did not further increase autophagy compared with resveratrol (low dose) alone.1 It was found that resveratrol attenuated the activation of mTOR complex 1, but significantly induced the expression of mTOR complex 2.

In summation, low dose resveratrol induced autophagy in cardiac myoblasts, as well as increasing cell survival. The effective dose in rats was 2.5 mg/kg/day, the equivalent of about 40 mg/day of resveratrol in humans.

Resveratrol and Polyamines Induce Autophagy

In another recent study,6 resveratrol (and, also, spermidine, a polyamine found in beans, especially soybeans7) were shown to induce pharmacological lifespan extension in model organisms (yeast, C. elegans) via increasing autophagy. Polyamines have also been found to increase lifespan in mice. For example, a recent paper7 reports that orally feeding polyamine-rich food (e.g., found in beans; soybeans were used in this study) for 88 weeks to mice resulted in a significantly lower incidence of senescent progression of glomerulosclerosis in the kidney, as well as increased concentrations of SMP-30, a liver protein that seems to protect organs from oxidative stress during aging.8 In addition, the mice fed the high polyamine containing chow lived longer and had less age-associated pathology and also had thick and healthy fur (as compared to the low polyamine containing chow fed mice) and appeared more active.

Another paper8 on polyamines (spermidine was used in this study) and autophagy reported enhanced autophagy and enhanced longevity in yeast, flies, worms, and human cells. It is important to note that, like other foods and food constituents, you can get different effects at very high concentrations as compared to moderate concentrations.9 It is probably best to get your polyamines from food. As reported in a paper9 on the effects of polyamine breakdown products on inflammation, while the “polyamine spermine has been shown to inhibit pro-inflammatory cytokine synthesis in human mononuclear cells,” “polyamine oxidation produces H2O2 [hydrogen peroxide] that, in the presence of transition metals, generates a highly toxic ROS [reactive oxygen species], the hydroxyl radical ... in normal non-cancerous cells, up-regulation of polyamine oxidation and H2O2 generation can have undesirable effects”9 such as DNA damage. Polyamines are also growth factors; hence decreasing intracellular polyamines below the optimal intracellular levels for growth is one way to reduce tumor growth and development.9

References

  1. Gurusamy et al. Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway. Cardiovasc Res 86:103-12 (2010).
  2. Cuervo. Autophagy and aging: keeping that old broom working. Trends Genet 24(12):604-12 (2008).
  3. Mizushima et al. Autophagy fights disease through cellular self-digestion. Nature 451:1069-1075 (2008).
  4. Komatsu et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880 (2006); Hara et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885 (2006); Klionsky. Good riddance to bad rubbish. Nature 441:819-20 (2006).
  5. Rouschop et al. Autophagy is required during cycling hypoxia to lower production of reactive oxygen species. Radiat Oncol 92:411-6 (2009).
  6. Morselli et al. Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging 1(12):961-70 (2009).
  7. Soda et al. Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp Gerontol 44:727-32 (2009).
  8. Eisenberg et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 11(11):1305-14 (2009).
  9. Babbar et al. Inflammation and polyamine catabolism: the good, the bad and the ugly. Biochem Soc Trans 35 part 2:300-4 (2007).

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