The importance of chromatin remodeling proteins in defining the chromatin state of the cell, basal transcription and their ability to influence DNA repair 
suggests a common mechanism of action for CR and resveratrol. Based on the functional analysis of gene expression profiles in multiple tissues we postulate that both CR and resveratrol impact pathways that determine chromatin remodeling, perhaps in response to a metabolic stress signal. The ensuing alteration in chromosome architecture and transcription may facilitate pathways that maintain genomic stability, or prevent epigenetic alterations, and therefore retard some aspects of the aging process in the long-term. Understanding the pathways that influence the expression of genes involved in chromatin remodeling and transcription in response to both CR and resveratrol may therefore provide key insights into the molecular basis of aging in mammals.
Our studies suggest that dietary consumption of a low dose of resveratrol partially mimics CR and inhibits some aspects of the aging process. In long lived rodent strains and in humans, lifespan is often limited by spontaneous tumorigenesis. Studies have determined that the ability of CR to inhibit spontaneous tumorigenesis is linked to the CR-mediated reduction in circulating IGF-1 
, and in the case of mammary carcinogenesis can be reversed by the administration of IGF-1 to CR animals 
. Our study design involved the use of a long-lived F1 hybrid mouse strain, and sacrificing mice at 30-months of age, therefore we were unable to evaluate effects of resveratrol on average or maximum lifespan. We note that unlike CR, resveratrol did not reduce circulating IGF-1 levels (), and there was also no decrease in spontaneous tumors at the time of sacrifice (Supplemental Table S2
). In particular, spontaneous liver tumors were abundant in mice fed the control diet or resveratrol, but rare in CR mice. Thus, although a low dose of resveratrol can improve quality of life by retarding aging parameters such as cardiac dysfunction, a nutritional or pharmaceutical strategy to also increase lifespan in mice will likely require blockage of the IGF-1 axis or its targets.
Our study also raises questions regarding proposed mechanisms of action of both CR and resveratrol. Findings from previous studies performed with higher doses of resveratrol in mice suggested that an increase in SIRT1 activity and the resulting deacetylation of the transcriptional coactivator Pgc-1α is a central mechanism of action. Health benefits observed included reduced mortality associated with the high-fat diet, improved motor performance and improved insulin sensitivity 
. Surprisingly, the induction of Pgc-1α transcriptional targets was observed in skeletal muscle but not heart 
. Given that resveratrol is known to be cardioprotective in models of ischemia-reperfusion 
, and our own findings of strong activity in the retardation of cardiac aging, but no effects on Pgc-1α transcriptional targets, it seems unlikely that SIRT1/Pgc-1α play a role in resveratrol's cardiac effects. It is likely that the effects of resveratrol feeding at lower doses reported here are distinct than those observed with higher doses, with particular relevance to the induction of SIRT1 activity. We also did not find support for the hypothesis that induction of SIRT1 directly mediates the effects of CR in the tissues examined, since SIRT1 levels were not altered at the mRNA or protein levels. Previous studies in rats 
and humans 
suggest that CR induces SIRT1 in these species, but the only study in mice that addressed this issue used an “every other day” feeding protocol, and therefore does not represent CR 
. To our knowledge our study is the first to attempt to detect an induction of SIRT1 in CR mice, and we have not observed such induction in any of the tissues examined (heart, liver, skeletal muscle and brain). Given that overexpression of SIRT1 in mice does induce physiological alterations consistent with CR 
, it is possible that CR impacts the levels of SIRT1 and other sirtuins in other tissues that play a central role in regulating metabolism, such the pancreas 
. We also note that despite the absence of SIRT1 induction, our findings are consistent with a general alteration in the expression of genes involved in chromatin remodeling by CR and resveratrol, including other sirtuins (). Other proposed biochemical mechanisms of action of resveratrol that were not examined in this study may include stimulation of AMP kinase 
, and increased nitric oxide synthase activity 
. We also note that studies suggest that the nutrient sensor target of rapamycin (TOR) pathway, involved in the regulation of growth and autophagy mediates the life-extension effects of CR in Drosophila 
and C. elegans 
, and therefore may play a role in the resveratrol effects reported here. Because resveratrol mimics CR at the gene expression level, but did not mimic the effects of CR on the few proteins examined in this study (GLUT4, AKT, IGF-1 and SIRT1) it is possible that although similar at the transcriptional level, CR and resveratrol have different effects with regard to translational regulation. An examination of several proteins encoded by genes affected in expression by both CR and resveratrol should clarify this issue.
Our findings that a low dose of resveratrol partially mimics CR at the gene expression level and leads to prevention of some age-related parameters suggests that clinical trials with resveratrol should be conducted to test the relevance of these findings to humans. Because cardiac disease is a major contributor to age-related mortality, positive findings could lead to a novel and important approach to improve the quality of human life.