PLoS ONE 2008 (Jun 4); 3 (6): e2264 ~ FULL TEXT
Jamie L. Barger, Tsuyoshi Kayo, James M. Vann, Edward B. Arias,
Jelai Wang, Timothy A. Hacker, Ying Wang, Daniel Raederstorff,
Jason D. Morrow, Christiaan Leeuwenburgh, David B. Allison,
Kurt W. Saupe, Gregory D. Cartee, Richard Weindruch, Tomas A. Prolla
LifeGen Technologies, LLC,
Madison, Wisconsin, United States of America
Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg(-1) day(-1)), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.
From the FULL TEXT Article:
Caloric restriction (CR) retards several aspects of the aging process in mammals, including age-related mortality, tumorigenesis, physiological decline  and the establishment of age-related transcriptional profiles . The wide scope of these actions, and the profound metabolic and hormonal shifts induced by CR has led to efforts at identifying natural or synthetic compounds that mimic the effects of CR in the absence of overt metabolic and endocrine disturbances or reduced caloric intake. Because most age-related diseases are likely to be secondary to the aging process itself, the discovery of such compounds could have a profound public health impact by reducing disease incidence and possibly extending the quality and length of the human lifespan.
Resveratrol, a natural compound found in grapes and red wine has previously been shown to extend lifespan in S. cerevisiae, C. elegans and Drosophila through a SIRT1 dependent mechanism , . However, recent studies have failed to reproduce these life extension results , , and other studies have demonstrated that the ability of resveratrol to activate yeast Sir2 or human SIRT1 is substrate-specific in vitro  and resveratrol has no effect on Sir2 activity in vivo . Thus, the effects and mechanisms of resveratrol in life extension in invertebrates are currently unclear. Recently, mice fed a high fat diet supplemented with high levels of resveratrol (22 or 186 mg kg?1 day?1) were shown to have extended lifespan as compared to controls, and several metabolic alterations similar to what is observed with CR, including markers of increased mitochondrial biogenesis , . Because control animals in this study had early mortality due to toxicity of the high fat diet, the role of resveratrol in the aging process in mammals is also unclear and a detailed examination of the physiological impact of resveratrol on aging and health parameters is indicated.
Global gene expression profiling can be used to evaluate the biological age of a tissue, because as shown for animals subjected to CR, such profiles correlate with biological as opposed to chronological age . Given that compounds that retard aging may do so in a tissue-specific manner, we and others have used gene expression profiling as a method to search for compounds that can mimic the effects of CR , . This study aimed to examine the role of resveratrol in gene expression profiles associated with mammalian aging and the specific effects of both resveratrol and CR on gene expression patterns in multiple tissues. We also compared the effects of resveratrol and CR in insulin signaling, oxidative damage, age-related cardiac function, and spontaneous tumorigenesis.
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 (Figure 2B), 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-1? 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-1? 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-1? transcriptional targets, it seems unlikely that SIRT1/Pgc-1? 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 (Figure 5). 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 [36–38]. 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.