The abstract I quoted above (PMID: 15749705) indicates that resveratrol molecule binds to Sirt1 without activating it, but increases the activation by other substances. NAD+ is an endogenous activator of Sirt1. (see below). It is known that an increased NAD+/NADh ratio correlates with increased life-span, at least in lower organisms.
This is something of a leap, but it suggests that increasing NAD+ will enhance the effect of resveratrol at increasing expression of Sirt1 (and probably other sirtuins.) I have found references to two substances increasing the NAD+/NADH ratio: methylene blue in microgram doses, and a combination of caffeine anl l-serine.
"While SIRT1 may play a role in maintaining cell viability under conditions of sufficient energy availability, we found that the SIRT1-activating agent resveratrol could not rescue neurons under excitotoxic conditions, and even exacerbated excitotoxic neuronal death at higher concentrations (data not shown). Similar death-promoting effects of resveratrol and SIRT1 have been observed in models of zinc-induced cytotoxicity (
Cai et al. 2006). The latter finding is of interest because zinc is released from excitatory synapses and may contribute to excitotoxicity and neuronal death following ischemia (
Choi and Koh 1998). Other studies show that resveratrol can promote apoptosis of tumor cells and some types of normal mitotic cells (
Clement et al. 1998;
Gao et al. 2002). Consistent with our findings, a recent study showed that heart-specific overexpression of SIRT1 increases the vulnerability of cardiac myocytes to age-dependent apoptosis, whereas lower levels of SIRT1 overexpression were protective, possibly by activating an adaptive stress response pathway (
Alcendor et al. 2007). We found that the SIRT1 inhibitors nicotinamide and sirtinol protected neurons against excitotoxicity, a finding consistent with previous data demonstrating neuroprotective effects of sirtuin inhibitors in models of Alzheimer's and Huntington's diseases (
Green et al. 2008;
Butler and Bates 2006). Pretreatment with resveratrol has been reported to protect neurons against ischemic cell death, apparently by inducing an adaptive stress response (
Raval et al. 2006). Our findings suggest that SIRT1 may promote cell survival and be involved in adaptive stress responses under conditions where cells have sufficient NAD
+; however, when NAD
+ levels are limited, stimulating SIRT1 activity may render cells vulnerable to death."
Our findings indicate that cellular NAD
+ bioenergetic state is a critical factor in determining the fate of neuronal survival in excitotoxic and ischemic conditions. Previous studies have supported the neuroprotective potential of treatments that increase cellular energy levels, with creatine being one prominent example (
Matthews et al. 1998,
1999;
Sullivan et al. 2000;
Tarnopolsky and Beal 2001). Here we found that nicotinamide partially preserved cellular NAD
+ levels and was effective in protecting neurons against ischemic injury in a mouse stroke model at a dose of 200 mg/kg administered 1 h after the onset of permanent MCAO ischemia. The latter findings are consistent with previous reports of neuroprotective effects of nicotinamide in other models of hypoxic/ischemic brain damage (
Sadanaga-Akiyoshi et al. 2003;
Yang et al. 2002;
Feng et al. 2006). The neuroprotective effects of nicotinamide appear to result from both elevation of NAD
+ levels and sirtuin inhibition. Preventing NAD
+ depletion, either by increasing its biosynthesis or reducing its consumption, could be an important therapeutic strategy for protecting neurons against ischemia, excitotoxic insults involving DNA damage and age-related metabolic impairment."
http://www.ncbi.nlm....les/PMC2677622/This suggests that you may not want to be on resveratrol if you suffer any form of large-scale tissue damage (infarct, trauma, infection). Similar to the observed fragility in CR animals. There may also be problem under milder NAD+ deficieny like mild ischemia. On the other hand this cytotoxic effect may be part of the anti-cancer effect of resveratrol. So if you increase NAD+ then you may possible decrease the anti-cancer effect.
Edited by Blue, 15 November 2009 - 04:20 PM.
