March 11th, 2005
Friday Science: How Does Resveratrol Activate Sirtuins?
A little science from PubMed for your entertainment today; signs that the investigation of calorie restriction mimetics and metabolism is proceeding apace.
[Sir2 or sirtuins are] important for many cellular processes including gene silencing, regulation of p53, fatty acid metabolism, cell cycle regulation, and lifespan extension. Resveratrol, a polyphenol found in wines and thought to harbor major health benefits, was reported to be an activator of Sir2 enzymes in vivo and in vitro. In addition, resveratrol was shown to increase lifespan in three model organisms through a Sir2-dependent pathway. Here, we investigated the molecular basis for Sir2 activation by resveratrol.
At this rate - coupled with venture investment in this field of research - we should expect to see interesting results in few years. A treatment to replicate the beneficial effects of calorie restriction on health and life span does not seem far fetched at the moment.
All:
Importantly, what this study (2) shows -- confirming & expanding the results of a previous study by an apparently independent group (1) -- is that the activation of sirtuins by resveratrol is a laboratory artifact, resulting from the fact that the molecular "tag" ("Fluor de Lys") that Sinclair's group has been using to detect the activation (deacetylation) of various enzymatic targets by sirtuins actually decreases the binding affinity of sirtuins to their target protein; resveratrol makes it easier for sirtuins to overcome the resistance posed by the "tag"-bound protein.
But take away the "tag," and there is no enhancement of the activity of the sirtuin.
To use an analogy: imagine if you bought a contaminated supply of gasoline, containing some evil chemical that gunks up your carburetor, making your car run inefficiently. Now imagine that someone, looking to design an efficiency-boosting fuel additive, just starts randomly throwing chemicals into your gas line to see what might work. S/he hits upon a substance that breaks down the noxious gak that's causing the problem in your carburetor, causing your car to run normally again.
This normalization is made to look as if it were an actual /improvement/ in the normal functioning of your car, and is hailed as a boon to engine longevity.
But as soon as you revert to pure fuel, you find that the miracle additive is of no benefit, because the hindrance that it removed isn't there in the first place.
The previous study, finding the same basic thing (1), also found that resveratrol did not extend lifespan in normal strains of yeast. This study is discussed here:
http://www.imminst.org/forum/index.php?s=&act=ST&f=6&t=4526&st=0&#entry51799
Bottom line: whatever the place of sirtuins in the CR effect in mammals (still an open question, tho' there remain promising hints), resveratrol is not a shortcut to their activation in real-world conditions.
-Michael
1. Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell S, Napper A, Curtis R, Distefano PS, Fields S, Bedalov A, Kennedy BK. Substrate specific activation fo sirtuins by resveratrol. J Biol Chem. 2005 Jan 31; [Epub ahead of print] PMID: 15684413 [PubMed - as supplied by publisher]
2: Borra MT, Smith BC, Denu JM.
Mechanism of human SIRT1 activation by resveratrol.
J Biol Chem. 2005 Mar 4; [Epub ahead of print]
PMID: 15749705 [PubMed - as supplied by publisher]