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Resveratrol Mechanisms

By Liji Thomas, MD

Resveratrol has been much studied over the last 20 years, because of its promise as an elixir of youth and health. Research proves that it does have anti-aging, anti-inflammatory, antioxidant, anti-platelet and anti-cancer effects. But how exactly does it work?

Anti-cancer effects:

  • Resveratrol may prevent the transformation of some cancer-producing chemicals to their active forms by inhibiting the cytochrome P450 enzymes required for their activation.
  • Resveratrol also promotes the excretion of these toxins by increasing the activity of the enzymes involved in this phase of metabolism
  • Resveratrol induces the cell cycle arrest of cancer cells in culture. This is the normal response to cell DNA damage, which is lost in the evolution of a cancerous cell.
  • Resveratrol inhibits the proliferation of cancer cells, and restores the ability of cancer cells to enter into the programmed cell death response, or apoptosis, which is a normal cellular response to irreparable DNA damage.
  • Resveratrol also inhibits the class of enzymes called matrix metalloproteinases, which aid in cancerous invasion into deeper tissues. It also inhibits angiogenesis, or the growth of new blood vessels, which is required for cancer growth.

How does resveratrol act?

Resveratrol acts via multiple mechanisms. One route of bioactivity for resveratrol involves one of the genetic molecules called transfer RNA. These normally bind amino acids and bring them to the protein-synthesizing site to be incorporated into the new protein that is being synthesized. Resveratrol affects a specific tRNA called TyRS, which transports tyrosine to the protein-synthesis site. Resveratrol is very similar to tyrosine structurally.

When resveratrol is produced in higher quantities, as happens in stressful conditions, it binds to TyRS, instead of tyrosine. This binding moves the resveratrol-TyRS complex to the nucleus, where it activates a protein called PARP-1. This protein is known to be important in the stress response, and for DNA repair. PARP-1 activation turns on a network of genes which protects the cell from stress-induced damage. These genes include the tumor-suppressor gene p53, which suppresses inflammatory chemicals like interleukin-6, and the longevity genes FOXO3A and SIRT6.  

Resveratrol also activates the sirtuin family of enzymes, most notably the SIRT1 enzyme. This protein is activated by resveratrol and other sirtuin-activating compounds (STACs, for short),  only if a specific amino acid is present at a specific location on the protein. When this amino acid is replaced by another, STACs fail to activate the enzyme. Similarly, when the substrate, or the chemical on which the enzyme acts, lacks a particular amino acid at a specific location, STACs cannot activate the reaction.

SIRT1 is known to promote longevity in several lower animal species in the laboratory. The effect of activating this enzyme is to increase mitochondrial activity, improve mitochondrial aerobic capacity, and promote oxidative dephosphorylation. The SIRT1 effect is important because these genes are key to producing homeostasis and energy regulation.

Resveratrol activation of mitochondrial activity via SIRT1 activation occurs, however, only at concentrations in mice and other lower life forms which far exceed the dosage achievable by human dietary means.  To attain such concentrations in blood, a man would have to drink between 600-1000 bottles of red wine a day. The adverse effects of this high intake of alcohol would more than neutralize any benefit of resveratrol!

The TyRS-resveratrol complex, on the other hand, exerts its protective effects at far lower concentrations. This thus seems to provide a more plausible explanation as to how a glass or two of red wine could protect the body from aging, inflammation and cancer, as well as confer heart health. This mechanism is called hormesis, which is the process of activating a natural stress response in a mild, health-promoting manner.

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Further Reading

Last Updated: May 25, 2015

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