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1.  Evolution of Human Longevity Uncoupled from Caloric Restriction Mechanisms 
PLoS ONE  2014;9(1):e84117.
Caloric restriction (CR) and chemical agents, such as resveratrol and rapamycin that partially mimic the CR effect, can delay morbidity and mortality across a broad range of species. In humans, however, the effects of CR or other life-extending agents have not yet been investigated systematically. Human maximal lifespan is already substantially greater compared to that of closely related primate species. It is therefore possible that humans have acquired genetic mutations that mimic the CR effect. Here, we tested this notion by comparing transcriptome differences between humans and other primates, with the transcriptome changes observed in mice subjected to CR. We show that the human transcriptome state, relative to other primate transcriptomes, does not match that of the CR mice or mice treated with resveratrol, but resembles the transcriptome state of ad libitum fed mice. At the same time, the transcriptome changes induced by CR in mice are enriched among genes showing age-related changes in primates, concentrated in specific expression patterns, and can be linked with specific functional pathways, including insulin signalling, cancer, and the immune response. These findings indicate that the evolution of human longevity was likely independent of CR-induced lifespan extension mechanisms. Consequently, application of CR or CR-mimicking agents may yet offer a promising direction for the extension of healthy human lifespan.
doi:10.1371/journal.pone.0084117
PMCID: PMC3882206  PMID: 24400080
2.  The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster 
Age  2011;35(1):69-81.
Resveratrol, a polyphenolic compound, has been shown to extend lifespan in different organisms. Emerging evidence suggests that the prolongevity effect of resveratrol depends on dietary composition. However, the mechanisms underlying the interaction of resveratrol and dietary nutrients in modulating lifespan remain elusive. Here, we investigated the effect of resveratrol on lifespan of Drosophila melanogaster fed diets differing in the concentrations of sugar, yeast extract, and palmitic acid representing carbohydrate, protein, and fat, respectively. Resveratrol at up to 200 μM in diets did not affect lifespan of wild-type female flies fed a standard, restricted or high sugar–low protein diet, but extended lifespan of females fed a low sugar–high protein diet. Resveratrol at 400 μM extended lifespan of females fed a high-fat diet. Lifespan extension by resveratrol was associated with downregulation of genes in aging-related pathways, including antioxidant peroxiredoxins, insulin-like peptides involved in insulin-like signaling and several downstream genes in Jun-kinase signaling involved in oxidative stress response. Furthermore, resveratrol increased lifespan of superoxide dismutase 1 (sod1) knockdown mutant females fed a standard or high-fat diet. No lifespan extension by resveratrol was observed in wild-type and sod1 knockdown males under the culture conditions in this study. Our results suggest that the gender-specific prolongevity effect of resveratrol is influenced by dietary composition and resveratrol promotes the survival of flies by modulating genetic pathways that can reduce cellular damage. This study reveals the context-dependent effect of resveratrol on lifespan and suggests the importance of dietary nutrients in implementation of effective aging interventions using dietary supplements.
doi:10.1007/s11357-011-9332-3
PMCID: PMC3543742  PMID: 22083438
Resveratrol; Lifespan; Dietary composition; Aging intervention; Superoxide dismutase 1; Oxidative stress
3.  The Prolongevity Effect of Resveratrol Depends on Dietary Composition and Calorie Intake in a Tephritid Fruit Fly 
Experimental gerontology  2009;44(6-7):472-476.
Several studies have shown that resveratrol can extend lifespan in yeast, worm, fruit fly and short-lived fish, as well as mice under a high-fat diet, probably acting through molecular pathways similar to dietary restriction. However, the putative prolongevity effect of resveratrol has not been observed in other studies. To evaluate the robustness of the prolongevity effects of resveratrol, we designed a nutritional study to address the question, Under what nutritional conditions does resveratrol affect lifespan and reproduction? We fed 2592 individual tephritid fruit fly of the species, Anastrepha ludens, 24 diets of different sugar:yeast ratios supplemented with or without 100 μM resveratrol. Sex-specific survival and daily egg laying in females were recorded. Resveratrol was found to have no or little effect on lifespan of males in all the treatments, as well as on lifespan and reproduction of females. Only under one diet combination, resveratrol appears to increase mean lifespan of females but not at a statistically significant level after multiple comparison adjustment. These findings suggest that the prolongevity effect of resveratrol is at most limited to a narrow range of dietary composition and calorie content in this fruit fly. Coupled with a recent study indicating that resveratrol does not extend lifespan of mice fed the standard diet, our findings further question the ability of resveratrol to increase lifespan in organisms under normal conditions.
doi:10.1016/j.exger.2009.02.011
PMCID: PMC3044489  PMID: 19264118
Dietary restriction; Calorie Restriction; Lifespan; Anastrepha ludens; aging intervention
4.  A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice 
PLoS ONE  2008;3(6):e2264.
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.
doi:10.1371/journal.pone.0002264
PMCID: PMC2386967  PMID: 18523577
5.  Consuming a Diet Supplemented with Resveratrol Reduced Infection-Related Neuroinflammation and Deficits in Working Memory in Aged Mice 
Rejuvenation Research  2009;12(6):445-453.
Abstract
Aged mice treated peripherally with lipopolysaccharide (LPS) show an exaggerated neuroinflammatory response and cognitive deficits compared to adults. Considerable evidence suggests resveratrol, a polyphenol found in red grapes, has potent antiinflammatory effects in the periphery, but its effects on the central inflammatory response and cognitive behavior are unknown. Therefore, the current study investigated if resveratrol dietary supplementation would inhibit neuroinflammation as well as behavioral and cognitive deficits in aged mice given LPS to mimic a peripheral infection. In initial studies, adult (3–6 months) and aged (22–24 months) mice were provided control or resveratrol-supplemented diet for 4 weeks and then injected intraperitoneally (i.p.) with saline or LPS, and locomotor activity and spatial working memory were assessed. As anticipated, deficits in locomotor activity and spatial working memory indicated aged mice are more sensitive to LPS compared to adults. More importantly, the LPS-induced deficits in aged animals were mitigated by dietary supplementation of resveratrol. In addition, resveratrol consumption reduced LPS-induced interleukin-1β (IL-1β) in plasma and the IL-1β mRNA in the hippocampus of aged mice. Finally, pretreatment of BV-2 microglial cells with resveratrol potently inhibited LPS-induced IL-1β production. These data show that aged mice are more sensitive than adult mice to both the inflammatory and cognitive effects of peripheral immune stimulation and suggest that resveratrol may be useful for attenuating acute cognitive disorders in elderly individuals with an infection.
doi:10.1089/rej.2009.0888
PMCID: PMC2903454  PMID: 20041738
6.  The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction 
Aging (Albany NY)  2012;4(7):499-508.
Our interest in healthy aging and in evolutionarily conserved mechanisms of lifespan extension prompted us to investigate whether features of age-related decline in the honey bee could be attenuated with resveratrol. Resveratrol is regarded as a caloric restriction mimetic known to extend lifespan in some but not all model species. The current, prevailing view is that resveratrol works largely by activating signaling pathways. It has also been suggested that resveratrol may act as an antioxidant and confer protection against nervous system impairment and oxidative stress. To test whether honey bee lifespan, learning performance, and food perception could be altered by resveratrol, we supplemented the diets of honey bees and measured lifespan, olfactory learning, and gustatory responsiveness to sucrose. Furthermore, to test the effects of resveratrol under metabolic challenge, we used hyperoxic environments to generate oxidative stress. Under normal oxygen conditions, two resveratrol treatments—30 and 130 μM—lengthened average lifespan in wild-type honey bees by 38% and 33%, respectively. Both resveratrol treatments also lengthened maximum and median lifespan. In contrast, hyperoxic stress abolished the resveratrol life-extension response. Furthermore, resveratrol did not affect learning performance, but did alter gustation. Honey bees that were not fed resveratrol exhibited greater responsiveness to sugar, while those supplemented with resveratrol were less responsive to sugar. We also discovered that individuals fed a high dose of resveratrol—compared to controls—ingested fewer quantities of food under ad libitum feeding conditions.
PMCID: PMC3433935  PMID: 22868943
hyperoxia; learning performance; aging; lifespan; Apis mellifera; resveratrol
7.  Dietary resveratrol prevents Alzheimer’s markers and increases life span in SAMP8 
Age  2012;35(5):1851-1865.
Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer’s disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.
doi:10.1007/s11357-012-9489-4
PMCID: PMC3776096  PMID: 23129026
Senescence; Resveratrol; Sirtuin 1; AMPK; Alzheimer’s disease; β-Amyloid; Tau; Memory impairment
8.  Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations 
The dietary polyphenolic compound resveratrol, by activating the protein deacetylase enzyme silent information regulator 2/sirtuin 1 (SIRT1), prolongs life span in evolutionarily distant organisms and may mimic the cytoprotective effects of dietary restriction. The present study was designed to elucidate the effects of resveratrol on cigarette smoke-induced vascular oxidative stress and inflammation, which is a clinically highly relevant model of accelerated vascular aging. Cigarette smoke exposure of rats impaired the acetylcholine-induced relaxation of carotid arteries, which could be prevented by resveratrol treatment. Smoking and in vitro treatment with cigarette smoke extract (CSE) increased reactive oxygen species production in rat arteries and cultured coronary arterial endothelial cells (CAECs), respectively, which was attenuated by resveratrol treatment. The smoking-induced upregulation of inflammatory markers (ICAM-1, inducible nitric oxide synthase, IL-6, and TNF-α) in rat arteries was also abrogated by resveratrol treatment. Resveratrol also inhibited CSE-induced NF-κB activation and inflammatory gene expression in CAECs. In CAECs, the aforementioned protective effects of resveratrol were abolished by knockdown of SIRT1, whereas the overexpression of SIRT1 mimicked the effects of resveratrol. Resveratrol treatment of rats protected aortic endothelial cells against cigarette smoking-induced apoptotic cell death. Resveratrol also exerted antiapoptotic effects in CSE-treated CAECs, which could be abrogated by knockdown of SIRT1. Resveratrol treatment also attenuated CSE-induced DNA damage in CAECs (comet assay). Thus resveratrol and SIRT1 exert antioxidant, anti-inflammatory, and antiapoptotic effects, which protect the endothelial cells against the adverse effects of cigarette smoking-induced oxidative stress. The vasoprotective effects of resveratrol will likely contribute to its anti-aging action in mammals and may be especially beneficial in patho-physiological conditions associated with accelerated vascular aging.
doi:10.1152/ajpheart.00235.2008
PMCID: PMC2551743  PMID: 18424637
tobacco; polyphenol; stroke; inflammation; apoptosis; vascular aging; sirtuin 1
9.  Dietary Resveratrol Prevents the Development of Food Allergy in Mice 
PLoS ONE  2012;7(9):e44338.
Background
Resveratrol is a bioactive polyphenol enriched in red wine that exhibits many beneficial health effects via multiple mechanisms. However, it is unclear whether resveratrol is beneficial for the prevention of food allergy. This study investigated whether resveratrol inhibited the development of food allergy by using a mouse model of the disease.
Methodology/Principal Findings
Mice fed standard diet or standard diet plus resveratrol were sensitized by intragastric administration of ovalbumin (OVA) and mucosal adjuvant cholera toxin (CT). Several manifestations of food allergy were then compared between the mice. The effects of resveratrol on T cells or dendritic cells were also examined by using splenocytes from OVA-specific T cell-receptor (TCR) transgenic DO11.10 mice or mouse bone marrow-derived dendritic cells (BMDCs) in vitro. We found that mice fed resveratrol showed reduced OVA-specific serum IgE production, anaphylactic reaction, and OVA-induced IL-13 and IFN-ã production from the mesenteric lymph nodes (MLNs) and spleens in comparison to the control mice, following oral sensitization with OVA plus CT. In addition, resveratrol inhibited OVA plus CT-induced IL-4, IL-13, and IFN-ã production in splenocytes from DO11.10 mice associated with inhibition of GATA-3 and T-bet expression. Furthermore, resveratrol suppressed the OVA plus CT-induced CD25 expression and IL-2 production in DO11.10 mice-splenocytes in association with decreases in CD80 and CD86 expression levels. Finally, resveratrol suppressed CT-induced cAMP elevation in association with decreases in CD80 and CD86 expression levels in BMDCs.
Conclusions/Significance
Ingestion of resveratrol prevented the development of a food allergy model in mice. Given the in vitro findings, resveratrol might do so by inhibiting DC maturation and subsequent early T cell activation and differentiation via downregulation of CT-induced cAMP activation in mice. These results suggest that resveratrol may have potential for prophylaxis against food allergy.
doi:10.1371/journal.pone.0044338
PMCID: PMC3433457  PMID: 22962611
10.  Resveratrol and Food Effects on Lifespan and Reproduction in the Model Crustacean Daphnia 
Longevity is a highly variable life history trait and its variation is attributable to both genetic and environmental factors. Exploring well-known environmental factors in a new model system is a useful approach to explore taxonomic variation in plasticity of longevity. We examined responsiveness of the Daphnia pulex clone TCO to potentially related interventions that have been reported to extend lifespan: resveratrol and dietary restriction. First, we examined effects of resveratrol on lifespan and fecundity in TCO which were grown at moderate (12K cells Ankistrodesmus falcatus mL−1) and high (20K cells A. falcatus mL−1) food levels. We found no evidence for lifespan extension by resveratrol, but found a reduction of lifetime fecundity. The effect of resveratrol on fecundity was more pronounced early in life. We then conducted an additional life table to test the effect of dietary restriction on TCO. Surprisingly, reduced food level did not extend the lifespan of TCO, which contrasts with previous studies in D. pulex. Our results suggest that variation in the response to dietary restriction might be more common than previously thought. If resveratrol activates genes involved in the response to dietary restriction, genetic polymorphisms in dietary restriction will influence responses to resveratrol. Thus, this experiment suggests that careful re-examination of resveratrol effects using diverse genotypes is required.
doi:10.1002/jez.1836
PMCID: PMC4103430  PMID: 24133070
11.  Resveratrol Worsens Survival in SCID Mice With Prostate Cancer Xenografts in a Cell-Line Specific Manner, Through Paradoxical Effects on Oncogenic Pathways 
The Prostate  2012;73(7):754-762.
BACKGROUND
Resveratrol increases lifespan and decreases the risk of many cancers. We hypothesized resveratrol will slow the growth of human prostate cancer xenografts.
METHODS
SCID mice were fed Western diet (40% fat, 44% carbohydrate, 16% protein by kcal). One week later, human prostate cancer cells, either LAPC-4 (151 mice) or LNCaP (94 mice) were injected subcutaneously. Three weeks after injection, LAPC-4 mice were randomized to Western diet (control group), Western diet plus resveratrol 50 mg/kg/day, or Western diet plus resveratrol 100 mg/kg/day. The LNCaP mice were randomized to Western diet or Western diet plus resveratrol 50 mg/kg/day. Mice were sacrificed when tumors reached 1,000 mm3. Survival differences among groups were assessed using Cox proportional hazards. Serum insulin and IGF axis were assessed using ELISAs. Gene expression was analyzed using Affymetrix gene arrays.
RESULTS
Compared to control in the LAPC-4 study, resveratrol was associated with decreased survival (50 mg/kg/day—HR 1.53, P = 0.04; 100 mg/kg/day—HR 1.22, P = 0.32). In the LNCaP study, resveratrol did not change survival (HR 0.77, P = 0.22). In combined analysis of both resveratrol 50 mg/kg/day groups, IGF-1 was decreased (P = 0.05) and IGFBP-2 was increased (P = 0.01). Resveratrol induced different patterns of gene expression changes in each xenograft model, with upregulation of oncogenic pathways E2F3 and beta-catenin in LAPC-4 tumors.
CONCLUSION
Resveratrol was associated with significantly worse survival with LAPC-4 tumors, but unchanged survival with LNCaP. Based on these preliminary data that resveratrol may be harmful, caution should be advised in using resveratrol for patients until further studies can be conducted.
doi:10.1002/pros.22619
PMCID: PMC3628095  PMID: 23192356
resveratrol; prostate cancer; xenograft; IGF-1; E2F3; beta-catenin
12.  Pleiotropic mechanisms facilitated by resveratrol and its metabolites 
Biochemical Journal  2010;429(2):273-282.
Resveratrol has demonstrated cancer chemopreventive activity in animal models and some clinical trials are underway. In addition, resveratrol was shown to promote cell survival, increase lifespan and mimic caloric restriction, thereby improving health and survival of mice on high-calorie diet. All of these effects are potentially mediated by the pleiotropic interactions of resveratrol with different enzyme targets including COX-1 (cyclo-oxygenase-1) and COX-2, NAD+-dependent histone deacetylase SIRT1 (sirtuin 1) and QR2 (quinone reductase 2). Nonetheless, the health benefits elicited by resveratrol as a direct result of these interactions with molecular targets have been questioned, since it is rapidly and extensively metabolized to sulfate and glucuronide conjugates, resulting in low plasma concentrations. To help resolve these issues, we tested the ability of resveratrol and its metabolites to modulate the function of some known targets in vitro. In the present study, we have shown that COX-1, COX-2 and QR2 are potently inhibited by resveratrol, and that COX-1 and COX-2 are also inhibited by the resveratrol 4′-O-sulfate metabolite. We determined the X-ray structure of resveratrol bound to COX-1 and demonstrate that it occupies the COX active site similar to other NSAIDs (non-steroidal anti-inflammatory drugs). Finally, we have observed that resveratrol 3- and 4′-O-sulfate metabolites activate SIRT1 equipotently to resveratrol, but that activation is probably a substrate-dependent phenomenon with little in vivo relevance. Overall, the results of this study suggest that in vivo an interplay between resveratrol and its metabolites with different molecular targets may be responsible for the overall beneficial health effects previously attributed only to resveratrol itself.
doi:10.1042/BJ20091857
PMCID: PMC3265359  PMID: 20450491
cancer chemoprevention; cyclo-oxygenase (COX); molecular docking; quinone reductase 2; resveratrol metabolite; SIRT1
13.  Resveratrol, Sirtuins, and the Promise of a DR Mimetic 
Dietary restriction (DR) delays or prevents age-related diseases and extends lifespan in species ranging from yeast to primates. Although the applicability of this regimen to humans remains uncertain, a proportional response would add more healthy years to the average life than even a cure for cancer or heart disease. Because it is unlikely that many would be willing or able to maintain a DR lifestyle, there has been intense interest in mimicking its beneficial effects on health, and potentially longevity, with drugs. To date, such efforts have been hindered primarily by our lack of mechanistic understanding of how DR works. Sirtuins, NAD+-dependent deacetylases and ADP-ribosyltransferases that influence lifespan in lower organisms, have been proposed to be key mediators of DR, and based on this model, the sirtuin activator resveratrol has been proposed as a candidate DRmimetic. Indeed, resveratrol extends lifespan in yeast, worms, flies, and a short-lived species of fish. In rodents, resveratrol improves health, and prevents the early mortality associated with obesity, but its precise mechanism of action remains a subject of debate, and extension of normal lifespan has not been observed. This review summarizes recent work on resveratrol, sirtuins, and their potential to mimic beneficial effects of DR.
doi:10.1016/j.mad.2010.02.007
PMCID: PMC2862768  PMID: 20219519
Resveratrol; Sirtuins; Dietary Restriction; Longevity; Mimetic
14.  Effects of Resveratrol and SIRT1 on PGC-1α Activity and Mitochondrial Biogenesis: A Reevaluation 
PLoS Biology  2013;11(7):e1001603.
Feeding resveratrol to rodents has no effect on mitochondrial biogenesis, and deacetylation of PGC-1α results in a decrease, not an increase, in its coactivator activity.
It has been reported that feeding mice resveratrol activates AMPK and SIRT1 in skeletal muscle leading to deacetylation and activation of PGC-1α, increased mitochondrial biogenesis, and improved running endurance. This study was done to further evaluate the effects of resveratrol, SIRT1, and PGC-1α deacetylation on mitochondrial biogenesis in muscle. Feeding rats or mice a diet containing 4 g resveratrol/kg diet had no effect on mitochondrial protein levels in muscle. High concentrations of resveratrol lowered ATP concentration and activated AMPK in C2C12 myotubes, resulting in an increase in mitochondrial proteins. Knockdown of SIRT1, or suppression of SIRT1 activity with a dominant-negative (DN) SIRT1 construct, increased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C2C12 cells. Expression of a DN SIRT1 in rat triceps muscle also induced an increase in mitochondrial proteins. Overexpression of SIRT1 decreased PGC-1α acetylation, PGC-1α coactivator activity, and mitochondrial proteins in C2C12 myotubes. Overexpression of SIRT1 also resulted in a decrease in mitochondrial proteins in rat triceps muscle. We conclude that, contrary to some previous reports, the mechanism by which SIRT1 regulates mitochondrial biogenesis is by inhibiting PGC-1α coactivator activity, resulting in a decrease in mitochondria. We also conclude that feeding rodents resveratrol has no effect on mitochondrial biogenesis in muscle.
Author Summary
Studies on cultured muscle cells have shown that treatment with resveratrol, a chemical famously found in the skin of red grapes, stimulates the manufacture of new mitochondria. This has been attributed to the activation of the deacetylase SIRT1 either directly by resveratrol or indirectly via the activation of AMP-activated protein kinase (AMPK). SIRT1 is then thought to deacetylate and activate the transcriptional coactivator PGC-1α, which in turn stimulates mitochondrial biogenesis. It has also been reported that feeding resveratrol to mice increases muscle mitochondria and results in improved running endurance. Here we further analyze the adaptive response of muscle mitochondria to resveratrol treatment to see if it mimics the response to endurance exercise. We find that feeding rats or mice large amounts of resveratrol did not increase muscle mitochondria. In these rodents, the bioavailability of oral resveratrol is low, and the resulting plasma level of resveratrol is far below the concentration required to activate AMPK. Contrary to previous reports we find that deacetylation by SIRT1 decreases PGC-1α activity and results in a decrease in mitochondria; moreover we show that the increase in mitochondria induced in cultured muscle cells by a high resveratrol concentration is due to the toxic activation of AMPK and, in turn, PGC-1α. However, this effect requires resveratrol concentrations that are very much higher than those attained by oral administration, and we conclude that oral resveratrol has no effect on mitochondrial biogenesis in skeletal muscle.
doi:10.1371/journal.pbio.1001603
PMCID: PMC3706311  PMID: 23874150
15.  Role of PGC-1α in exercise training- and resveratrol-induced prevention of age-associated inflammation 
Experimental gerontology  2013;48(11):1274-1284.
Background/aim
Age-related metabolic diseases are often associated with low-grade inflammation. The aim of the present study was to investigate the role of the transcriptional co-activator PGC-1α in the potential beneficial effects of exercise training and/or resveratrol in the prevention of age-associated low-grade inflammation. To address this, a long-term voluntary exercise training and resveratrol supplementation study was conducted.
Experimental setup
Three month old whole body PGC-1α KO and WT mice were randomly assigned to four groups: untrained chow-fed, untrained chow-fed supplemented with resveratrol, chow-fed voluntarily exercise trained and chow-fed supplemented with resveratrol and voluntarily exercise trained. The intervention lasted 12 months and three month old untrained chow-fed mice served as young controls.
Results
Voluntary exercise training prevented an age-associated increase (p<0.05) in systemic IL-6 and adiposity in WT mice. PGC-1α expression was required for a training-induced prevention of an age-associated increase (p<0.05) in skeletal muscle TNFα protein. Independently of PGC-1α, both exercise training and resveratrol prevented an age-associated increase (p<0.05) in skeletal muscle protein carbonylation.
Conclusion
The present findings highlight that exercise training is a more effective intervention than resveratrol supplementation in reducing age-associated inflammation and that PGC-1α in part is required for the exercise training-induced anti-inflammatory effects.
doi:10.1016/j.exger.2013.07.015
PMCID: PMC4045249  PMID: 23916840
Aging; low-grade inflammation; exercise training; resveratrol; PGC-1α
16.  Metabolic benefits of inhibiting cAMP-PDEs with resveratrol 
Adipocyte  2012;1(4):256-258.
Calorie restriction (CR) extends lifespan in species ranging from yeast to mammals. There is evidence that CR also protects against aging-related diseases in non-human primates. This has led to an intense interest in the development of CR-mimetics to harness the beneficial effects of CR to treat aging-related diseases. One CR-mimetic that has received a great deal of attention is resveratrol. Resveratrol extends the lifespan of obese mice and protects against obesity-related diseases such as type 2 diabetes. The specific mechanism of resveratrol action has been difficult to elucidate because resveratrol has a promiscuous target profile. A recent finding indicates that the metabolic effects of resveratrol may result from competitive inhibition of cAMP-degrading phosphodiesterases (PDEs), which increases cAMP levels. The cAMP-dependent pathways activate AMP-activated protein kinase (AMPK), which is essential for the metabolic effects of resveratrol. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including protection against diet-induced obesity and an increase in mitochondrial function, physical stamina and glucose tolerance in mice. This discovery suggests that PDE inhibitors may be useful for treating metabolic diseases associated with aging.
doi:10.4161/adip.21158
PMCID: PMC3609109  PMID: 23700542
AMP-activated protein kinase; Epac1; Sirt1; aging; cAMP; calorie-restriction; metabolic; phosphodiesterases; resveratrol
17.  AMP-Activated Protein Kinase–Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol 
Diabetes  2009;59(3):554-563.
OBJECTIVE
Resveratrol, a natural polyphenolic compound that is found in grapes and red wine, increases metabolic rate, insulin sensitivity, mitochondrial biogenesis, and physical endurance and reduces fat accumulation in mice. Although it is thought that resveratrol targets Sirt1, this is controversial because resveratrol also activates 5′ AMP-activated protein kinase (AMPK), which also regulates insulin sensitivity and mitochondrial biogenesis. Here, we use mice deficient in AMPKα1 or -α2 to determine whether the metabolic effects of resveratrol are mediated by AMPK.
RESEARCH DESIGN AND METHODS
Mice deficient in the catalytic subunit of AMPK (α1 or α2) and wild-type mice were fed a high-fat diet or high-fat diet supplemented with resveratrol for 13 weeks. Body weight was recorded biweekly and metabolic parameters were measured. We also used mouse embryonic fibroblasts deficient in AMPK to study the role of AMPK in resveratrol-mediated effects in vitro.
RESULTS
Resveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPKα1−/− mice. In the absence of either AMPKα1 or -α2, resveratrol failed to increase insulin sensitivity, glucose tolerance, mitochondrial biogenesis, and physical endurance. Consistent with this, the expression of genes important for mitochondrial biogenesis was not induced by resveratrol in AMPK-deficient mice. In addition, resveratrol increased the NAD-to-NADH ratio in an AMPK-dependent manner, which may explain how resveratrol may activate Sirt1 indirectly.
CONCLUSIONS
We conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol.
doi:10.2337/db09-0482
PMCID: PMC2828647  PMID: 19934007
18.  Anticancer activity of resveratrol on implanted human primary gastric carcinoma cells in nude mice 
AIM: To investigate the apoptosis of implanted primary gastric cancer cells in nude mice induced by resveratrol and the relation between this apoptosis and expression of bcl-2 and bax.
METHODS: A transplanted tumor model was established by injecting human primary gastric cancer cells into subcutaneous tissue of nude mice. Resveratrol (500 mg/kg, 1000 mg/kg and 1500 mg/kg) was directly injected beside tumor body 6 times at an interval of 2 d. Then changes of tumor volume were measured continuously and tumor inhibition rate of each group was calculated. We observed the morphologic alterations by electron microscope, measured the apoptotic rate by TUNEL staining method, detected the expression of apoptosis-regulated genes bcl-2 and bax by immunohistoch-emical staining and PT-PCR.
RESULTS: Resveratrol could significantly inhibit carcinoma growth when it was injected near the carcinoma. An inhibitory effect was observed in all therapeutic groups and the inhibition rate of resveratrol at the dose of 500 mg/kg, 1000 mg/kg and 1500 mg/kg was 10.58%, 29.68% and 39.14%, respectively. Resveratrol induced implanted tumor cells to undergo apoptosis with apoptotic characteristics, including morphological changes of chromatin condensation, chromatin crescent formation, nucleus fragmentation. The inhibition rate of 0.2 mL of normal saline solution, 1 500 mg/kg DMSO, 500 mg/kg resveratrol, 1000 mg/kg resveratrol, and 1500 mg/kg resveratrol was 13.68±0.37%, 13.8±0.43%, 48.7±1.07%, 56.44±1.39% and 67±0.96%, respectively. The positive rate of bcl-2 protein of each group was 29.48±0.51%, 27.56±1.40%, 11.86±0.97%, 5.7±0.84% and 3.92±0.85%, respectively by immunohistochemical staining. The positive rate of bax protein of each group was 19.34±0.35%, 20.88±0.91%, 40.02±1.20%, 45.72±0.88% and 52.3±1.54%, respectively by immunohistochemical staining. The density of bcl-2 mRNA in 0.2 mL normal saline solution, 1500 mg/kg DMSO, 500 mg/kg resveratrol, 1000 mg/kg resveratrol, and 1500 mg/kg resveratrol decreased progressively and the density of bax mRNA in 0.2 mL normal saline solution, 1500 mg/kg DMSO, 500 mg/kg resveratrol, 1000 mg/kg resveratrol, and 1500 mg/kg increased progressively with elongation of time by RT-PCR.
CONCLUSION: Resveratrol is able to induce apoptosis of transplanted tumor cells. This apoptosis may be mediated by down-regulating apoptosis-regulated gene bcl-2 and up-regulating the expression of apoptosis-regulated gene bax.
doi:10.3748/wjg.v11.i2.280
PMCID: PMC4205418  PMID: 15633232
Gastric carcinoma; Resveratrol; Neoplasm Transplantation; Apoptosis
19.  Resveratrol Is Rapidly Metabolized in Athymic (Nu/Nu) Mice and Does Not Inhibit Human Melanoma Xenograft Tumor Growth1 
The Journal of nutrition  2006;136(10):2542-2546.
Resveratrol has been shown to have anticarcinogenic activity. We previously found that resveratrol inhibited growth and induced apoptosis in 2 human melanoma cell lines. In this study we determined whether resveratrol would inhibit human melanoma xenograft growth. Athymic mice received control diets or diets containing 110 μmol/L or 263 μmol/L resveratrol, 2 wk prior to subcutaneous injection of the tumor cells. Tumor growth was measured during a 3-wk period. Metabolism of resveratrol was assayed by bolus gavage of 75 mg/kg resveratrol in tumor-bearing and nontumor-bearing mice. Pellets containing 10–100 mg resveratrol were implanted into the mice, next to newly palpated tumors, and tumor growth determined. We also determined the effect of a major resveratrol metabolite, piceatannol, on experimental lung metastasis. Resveratrol, at any concentration tested, did not have a statistically significant effect on tumor growth. The higher levels of resveratrol tested (0.006% in food or 100 mg in slow-release pellets) tended to stimulate tumor growth (P = 0.08–0.09). Resveratrol and its major metabolites, resveratrol glucuronide and piceatannol, were found in serum, liver, skin, and tumor tissue. Piceatannol did not affect the in vitro growth of a murine melanoma cell line, but significantly stimulated the number of lung metastases when these melanoma cells were directly injected into the tail vein of the mouse. These results suggest that resveratrol is not likely to be useful in the treatment of melanoma and that the effects of phytochemicals on cell cultures may not translate to the whole animal system.
PMCID: PMC1612582  PMID: 16988123
20.  SIRT1 IS INVOLVED IN ENERGY METABOLISM: THE ROLE OF CHRONIC ETHANOL FEEDING AND RESVERATROL 
Sirt1, a deacetylase involved in regulating energy metabolism in response to calorie restriction, is up regulated after chronic ethanol feeding using the intragastric feeding model of alcohol liver disease. PGC1α is also up regulated in response to ethanol. These changes are consistent with activation of the Sirt1/PGC1α pathway of metabolism and aging, involved in alcohol liver disease including steatosis, necrosis and fibrosis of the liver. To test this hypothesis, male rats fed ethanol intragastrically for 1 month were compared with rats fed ethanol plus resveratrol or naringin. Liver histology showed macrovesicular steatosis caused by ethanol and this change was unchanged by resveratrol or naringin treatment. Necrosis occurred with ethanol alone but was accentuated by resveratrol treatment, as was fibrosis. The expression of Sirt1 and PGC1α was increased by ethanol but not when naringin or resveratrol was fed with ethanol. Sirt3 was also up regulated by ethanol but not when resveratrol was fed with ethanol. These results support the concept that ethanol induces the Sirt1/PGC1α pathway of gene regulation and both naringin and resveratrol prevent the activation of this pathway by ethanol. However, resveratrol did not reduce the liver pathology caused by chronic ethanol feeding.
doi:10.1016/j.yexmp.2008.08.002
PMCID: PMC2874466  PMID: 18793633
21.  Resveratrol prevents inflammation-dependent hepatic melanoma metastasis by inhibiting the secretion and effects of interleukin-18 
Background
Implantation and growth of metastatic cancer cells at distant organs is promoted by inflammation-dependent mechanisms. A hepatic melanoma metastasis model where a majority of metastases are generated via interleukin-18-dependent mechanisms was used to test whether anti-inflammatory properties of resveratrol can interfere with mechanisms of metastasis.
Methods
Two experimental treatment schedules were used: 1) Mice received one daily oral dose of 1 mg/kg resveratrol after cancer cell injection and the metastasis number and volume were determined on day 12. 2) Mice received one daily oral dose of 1 mg/kg resveratrol along the 5 days prior to the injection of cancer cells and both interleukin-18 (IL-18) concentration in the hepatic blood and microvascular retention of luciferase-transfected B16M cells were determined on the 18th hour. In vitro, primary cultured hepatic sinusoidal endothelial cells were treated with B16M-conditioned medium to mimic their in vivo activation by tumor-derived factors and the effect of resveratrol on IL-18 secretion, on vascular cell adhesion molecule-1 (VCAM-1) expression and on tumor cell adhesion were studied. The effect of resveratrol on melanoma cell activation by IL-18 was also studied.
Results
Resveratrol remarkably inhibited hepatic retention and metastatic growth of melanoma cells by 50% and 75%, respectively. The mechanism involved IL-18 blockade at three levels: First, resveratrol prevented IL-18 augmentation in the blood of melanoma cell-infiltrated livers. Second, resveratrol inhibited IL-18-dependent expression of VCAM-1 by tumor-activated hepatic sinusoidal endothelium, preventing melanoma cell adhesion to the microvasculature. Third, resveratrol inhibited adhesion- and proliferation-stimulating effects of IL-18 on metastatic melanoma cells through hydrogen peroxide-dependent nuclear factor-kappaB translocation blockade on these cells.
Conclusions
These results demonstrate multiple sites for therapeutic intervention using resveratrol within the prometastatic microenvironment generated by tumor-induced hepatic IL-18, and suggest a remarkable effect of resveratrol in the prevention of inflammation-dependent melanoma metastasis in the liver.
doi:10.1186/1479-5876-9-59
PMCID: PMC3112440  PMID: 21569399
22.  Caloric restriction or resveratrol supplementation and ageing in a non-human primate: first-year outcome of the RESTRIKAL study in Microcebus murinus 
Age  2010;33(1):15-31.
A life-long follow-up of physiological and behavioural functions was initiated in 38-month-old mouse lemurs (Microcebus murinus) to test whether caloric restriction (CR) or a potential mimetic compound, resveratrol (RSV), can delay the ageing process and the onset of age-related diseases. Based on their potential survival of 12 years, mouse lemurs were assigned to three different groups: a control (CTL) group fed ad libitum, a CR group fed 70% of the CTL caloric intake and a RSV group (200 mg/kg.day–1) fed ad libitum. Since this prosimian primate exhibits a marked annual rhythm in body mass gain during winter, animals were tested throughout the year to assess body composition, daily energy expenditure (DEE), resting metabolic rate (RMR), physical activity and hormonal levels. After 1 year, all mouse lemurs seemed in good health. CR animals showed a significantly decreased body mass compared with the other groups during long day period only. CR or RSV treatments did not affect body composition. CR induced a decrease in DEE without changes in RMR, whereas RSV induced a concomitant increase in DEE and RMR without any obvious modification of locomotor activity in both groups. Hormonal levels remained similar in each group. In summary, after 1 year of treatment CR and RSV induced differential metabolic responses but animals successfully acclimated to their imposed diets. The RESTRIKAL study can now be safely undertaken on a long-term basis to determine whether age-associated alterations in mouse lemurs are delayed with CR and if RSV can mimic these effects.
doi:10.1007/s11357-010-9156-6
PMCID: PMC3063642  PMID: 20532988
Ageing; Food restriction; Resveratrol; Energy balance; Biomarkers; Doubly labelled water method
23.  Resveratrol Enhances Antitumor Activity of TRAIL in Prostate Cancer Xenografts through Activation of FOXO Transcription Factor 
PLoS ONE  2010;5(12):e15627.
Background
Resveratrol (3, 4′, 5 tri-hydroxystilbene), a naturally occurring polyphenol, exhibits anti-inflammatory, antioxidant, cardioprotective and antitumor activities. We have recently shown that resveratrol can enhance the apoptosis-inducing potential of TRAIL in prostate cancer cells through multiple mechanisms in vitro. Therefore, the present study was designed to validate whether resveratrol can enhance the apoptosis-inducing potential of TRAIL in a xenograft model of prostate cancer.
Methodology/Principal Findings
Resveratrol and TRAIL alone inhibited growth of PC-3 xenografts in nude mice by inhibiting tumor cell proliferation (PCNA and Ki67 staining) and inducing apoptosis (TUNEL staining). The combination of resveratrol and TRAIL was more effective in inhibiting tumor growth than single agent alone. In xenografted tumors, resveratrol upregulated the expressions of TRAIL-R1/DR4, TRAIL-R2/DR5, Bax and p27/K IP1, and inhibited the expression of Bcl-2 and cyclin D1. Treatment of mice with resveratrol and TRAIL alone inhibited angiogenesis (as demonstrated by reduced number of blood vessels, and VEGF and VEGFR2 positive cells) and markers of metastasis (MMP-2 and MMP-9). The combination of resveratrol with TRAIL further inhibited number of blood vessels in tumors, and circulating endothelial growth factor receptor 2-positive endothelial cells than single agent alone. Furthermore, resveratrol inhibited the cytoplasmic phosphorylation of FKHRL1 resulting in its enhanced activation as demonstrated by increased DNA binding activity.
Conclusions/Significance
These data suggest that resveratrol can enhance the apoptosis-inducing potential of TRAIL by activating FKHRL1 and its target genes. The ability of resveratrol to inhibit tumor growth, metastasis and angiogenesis, and enhance the therapeutic potential of TRAIL suggests that resveratrol alone or in combination with TRAIL can be used for the management of prostate cancer.
doi:10.1371/journal.pone.0015627
PMCID: PMC3011015  PMID: 21209944
24.  Resveratrol Ameliorates Motor Neuron Degeneration and Improves Survival in SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis 
BioMed Research International  2014;2014:483501.
Resveratrol has recently been used as a supplemental treatment for several neurological and nonneurological diseases. It is not known whether resveratrol has neuroprotective effect on amyotrophic lateral sclerosis (ALS). To assess the effect of resveratrol on the disease, we tested this agent on an ALS model of SOD1G93A transgenic mouse. Rotarod measurement was performed to measure the motor function of the ALS mice. Nissl staining and SMI-32 immunofluorescent staining were used to determine motor neurons survival in the spinal cord of the ALS mice. Hematoxylin-eosin (H&E), succinic dehydrogenase (SDH), and cytochrome oxidase (COX) staining were applied to pathologically analyze the skeletal muscles of the ALS mice. We found that resveratrol treatment significantly delayed the disease onset and prolonged the lifespan of the ALS mice. Furthermore, resveratrol treatment attenuated motor neuron loss, relieved muscle atrophy, and improved mitochondrial function of muscle fibers in the ALS mice. In addition, we demonstrated that resveratrol exerted these neuroprotective effects mainly through increasing the expression of Sirt1, consequently suppressing oxidative stress and downregulating p53 and its related apoptotic pathway. Collectively, our findings suggest that resveratrol might provide a promising therapeutic intervention for ALS.
doi:10.1155/2014/483501
PMCID: PMC4095711  PMID: 25057490
25.  Renal Protective Effects of Resveratrol 
Resveratrol (3,5,4′-trihydroxystilbene), a natural polyphenolic compound found in grapes and red wine, is reported to have beneficial effects on cardiovascular diseases, including renal diseases. These beneficial effects are thought to be due to this compound's antioxidative properties: resveratrol is known to be a robust scavenger of reactive oxygen species (ROS). In addition to scavenging ROS, resveratrol may have numerous protective effects against age-related disorders, including renal diseases, through the activation of SIRT1. SIRT1, an NAD+-dependent deacetylase, was identified as one of the molecules through which calorie restriction extends the lifespan or delays age-related diseases, and this protein may regulate multiple cellular functions, including apoptosis, mitochondrial biogenesis, inflammation, glucose/lipid metabolism, autophagy, and adaptations to cellular stress, through the deacetylation of target proteins. Previous reports have shown that resveratrol can ameliorate several types of renal injury, such as diabetic nephropathy, drug-induced injury, aldosterone-induced injury, ischemia-reperfusion injury, sepsis-related injury, and unilateral ureteral obstruction, in animal models through its antioxidant effect or SIRT1 activation. Therefore, resveratrol may be a useful supplemental treatment for preventing renal injury.
doi:10.1155/2013/568093
PMCID: PMC3863562  PMID: 24379901

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