The effects of the dietary polyphenol resveratrol on ...

Epigenetics

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The effects of the dietary polyphenol resveratrol on human healthy aging and lifespan Agustín F. Fernández & Mario F. Fraga To cite this article: Agustín F. Fernández & Mario F. Fraga (2011) The effects of the dietary polyphenol resveratrol on human healthy aging and lifespan, Epigenetics, 6:7, 870-874, DOI: 10.4161/epi.6.7.16499 To link to this article: http://dx.doi.org/10.4161/epi.6.7.16499

Published online: 01 Jul 2011.

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Epigenetics 6:7, 870-874; July 2011; © 2011 Landes Bioscience

The effects of the dietary polyphenol resveratrol on human healthy aging and lifespan Agustín F. Fernández1 and Mario F. Fraga1,2,* Cancer Epigenetics Laboratory; Instituto Universitario de Oncología del Principado de Asturias (IUOPA); HUCA; Universidad de Oviedo; Oviedo, Spain; Department of Immunology and Oncology; National Center for Biotechnology; CNB-CSIC; Cantoblanco, Madrid, Spain

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he physiological effects of the dietary polyphenol resveratrol are being extensively studied. Resveratrol has been proposed to promote healthy aging and to increase lifespan, primarily through the activation of the class III histone deacetylases (sirtuins). Although its positive effects are evident in yeast and mice, they still have to be confirmed in humans. The molecular mechanisms involved in the processes are not fully understood because resveratrol may have other targets than sirtuins and the direct activation of sirtuins by resveratrol is under debate.

receiving considerable attention in recent years.2 The study of diseases associated with premature aging7,8 and experiments in different model organisms9 have demonstrated the relevance of genetic alterations in these processes. However, the role of epigenetics has not been clearly established yet.2,10 Many studies have highlighted the importance the environment may have on the epigenome.1,11 It has been proposed that specific environmental exposures during early ontogenic development may have long-term effects in adulthood.1,11 These studies support the idea that maternal influences (dietary and feeding habits) may trigger permanent changes in the epigenome of the offspring.11-13 Such changes increase the risk of developing a variety of diseases during adulthood; conversely, modifying our habits, including food components, may reduce the risk of developing those very same diseases.14-18 Polyphenol resveratrol is one of the most studied dietary supplements,19 and its physiological effects mediated at the epigenetic level have been well reported.20-24 Polyphenols are natural chemicals found in many plants known for their healthenhancing effects.16 They are known as “antioxidant compounds” for their ability to react with reactive oxygen species (ROS) produced during metabolic processes that are thought to contribute to the aging process.25 Furthermore, polyphenols have gained much attention from the scientific community because of their ability to prevent the cytotoxic effects of heavy metal accumulation over time, their

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Key words: resveratrol, lifespan, aging, SIRT1, cancer Submitted: 05/13/11 Accepted: 05/16/11 DOI: 10.4161/epi.6.7.16499 *Correspondence to: Mario F. Fraga; Email: [email protected]

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Aging is a complex biological process encompassing all the morphological and physiological changes that occur as a consequence of the action of time and which leads to loss of cellular and bodily functions. Aging is characterized by the gradual deterioration of the organs and their associated functions, and by a decreased responsiveness to stress. Although the biological basis of aging is unknown as of yet, this process seems to be determined by genetic and epigenetic factors, and depends on hereditary, environmental and stochastic factors.1,2 Certain diseases, such as dementia, cardiovascular diseases and some types of cancer have been associated with the aging process.3-6 The interaction of genetic and environmental factors is the cause of these complex aging-related diseases. It is for this reason that research of the aging process at the molecular level has been

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Figure 1. Schematic representation of the associations between resveratrol, SIRT1, lifespan and cancer, as found in different organisms. +, positive effects; ?, unknown or mixed results.

type information regulation-2 homologue (SIRT1) in different organisms.32,40 Sirtuins are involved in many cellular functions, including chromatin remodeling and stability, cellular stress response, apoptosis and cell differentiation. They also feature a remarkable ability to respond to environmental changes.41-43 SIRT1 was the first sirtuin gene identified in mammals and it is a gene sequence homologous to Sir2 (silent information regulator 2), which had been previously identified in the yeast Saccharomyces cerevisiae. Of the seven mammalian sirtuins SIRT1–7, SIRT1 is the closest homologue to Sir2, based on amino acid identity.28 Although sirtuins were defined originally as class III histone deacetylases, it was later discovered that they contributed to the deacetylation of non-histone proteins. Some of these target proteins can become active or inactive when they are deacetylated by sirtuins, and regulate many metabolic pathways.44 Several studies suggest that CR is a regulated process in which sirtuins may play a crucial role by mediating its beneficial effects.45 Sir2 homologues extend lifespan when overexpressed in yeast, worms, flies,45,46 and mammals.47,48 However, even though resveratrol was identified as a potential activator of SIRT1 in vitro,31 the mechanism by which it may activate SIRT1 is being questioned (Fig. 1).32 SIRT1 has been found to be related to telomere maintenance in a mouse model.49 This constitutes another link between sirtuins and aging, since the shortening of telomeres (an effect dependent on telomerase activity) seems to contribute to agerelated changes resulting in senescence or apoptosis.50 In a recently published study, a positive effect of resveratrol on telomerase activity in vitro has been found,37 reinforcing the possibility that sirtuins may mediate resveratrol’s effects on aging. The progressive decline in function of stem cells, to which telomere dysfunction also seems to contribute, has been described to be associated with aging as well.2,51,52 The positive role for SIRT1 in stemness by aiding in the silencing of differentiation genes hints at the potential of this system to extend lifespan and to avoid cell senescence.53-55 Based on this idea, several studies have reported the effects of resveratrol on the differentiation

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anticancer properties, and their inhibitory effects against chronic vascular inflammation associated with atherosclerosis.16,26 Resveratrol (3,5,4'-trihydroxy-transstilbene) is one of these polyphenolic compounds, present in many plants and fruits and, in recent years, it has become notably relevant due to its beneficial health effects, since it features antioxidant, antitumor and anti-inflammatory properties. In addition, it also helps to reduce the risk of cardiovascular disease, increasing the lifespan in several animal models.19,27 All these properties make resveratrol a promising therapeutic agent for humans.28 This article reviews the recent literature on the effects of resveratrol on health and aging and discusses the possible mechanisms of action of this compound at the molecular level. Resveratrol, Lifespan and Aging The physiological effects of resveratrol on the lifespan studied in many animal models remain controversial and seem to mimic several of the effects of caloric restriction (CR), i.e., a dietary regimen that restricts caloric intake closely linked to lifespan extension.29,30

A seminal study by Howitz et al. identified resveratrol as an enhancer of yeast lifespan.31 Many studies have been performed in different species, such as worms and flies, supporting or questioning the general conclusions about the role of resveratrol in lifespan extending effects.32 In mammals, controversial results have also been found (Fig. 1), and they seem to depend on the composition of the diet supplied with the resveratrol supplementation. In this line, several studies in mice have shown that resveratrol does not increase lifespan in healthy mice, but does prevent mortality due to obesity and it partially mimics CR effects.32 In any case, a number of studies have reported the beneficial and overlapping effects of resveratrol and CR on health and aging processes.33-39 The molecular mechanisms mediating these effects of resveratrol are under debate. The complexity of determining its mechanisms of action has to do with the number of targets with which it is associated, including kinases, lipo- and cyclooxygenases, sirtuins and other proteins.19,27 Although the mechanism of action of resveratrol involved in lifespan extension has not been clearly elucidated, it has been shown to activate the silent mating

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and pluripotency mechanisms; in some of these studies, SIRT1 has been shown to be implicated.55,56 AMP-activated protein kinase (AMPK) appears to be another potential substrate activated by resveratrol. AMPK is a key enzyme that regulates cellular energy and controls energy homeostasis.27 However, although resveratrol might induce the beneficial effects on lifespan and aging mediated by AMPK, the exact mechanism still has to be elucidated.57 The effects and mechanisms of action of resveratrol are not fully understood yet, and although it is currently being sold as a nutritional supplement for humans, caution should be advised and more studies performed in order to assess its benefits on lifespan and aging. Resveratrol and Cancer Other beneficial effects of resveratrol and derivatives on health include its potential effects against cancer cells.58,59 Several studies with human cancer cells support the antitumorigenic properties of resveratrol in vitro.28 The first evidence of the anticarcinogenic effects of resveratrol was found by Jang et al. in 1997 while working with a skin cancer animal model.60 The results of several subsequent experiments with rodent cancer models supported the potential of resveratrol to inhibit the tumorigenic process;28 however, no final data from human clinical trials have been reported yet (Fig. 1). Nevertheless, preclinical and phase I clinical human data have exposed the potential of resveratrol against cancer.61,62 This preliminary results revealed that resveratrol might be tolerated by the organism and is rapidly metabolized in humans.61,62 Thus, dosage and administration requirements must be properly adjusted depending on the particular cancer therapies used. Resveratrol seems to affect many cellular signaling pathways involved in antitumorigenic processes, including Wnt, nuclear factor κB (NFκB), CD95, apoptotic and phosphoinositol-3-kinase (PI3Ks)/Akt.27,28,63,64 Resveratrol targets members of these important pathways and exerts its anticarcinogenic effects. It may, for instance, suppress the cyclooxygenase (COX) which encodes for enzymes related

to pro-inflammatory properties19,27,28,63-65 or induce p53-dependent apoptosis in cancer cells through integrin αvβ3.63 Furthermore, resveratrol’s properties as an antioxidant and as a potential angiogenesis inhibitor allow it to counter the effects of ROS and COX in the initiation and progression of cancer.28 The role resveratrol plays in the activation of SIRT1 in cancer is particularly interesting, but the consequences of its involvement are not fully elucidated yet.66 SIRT1 may increase the risk of cancer by inhibiting p53 and it is usually associated with tumor suppressor gene silencing. On the other hand, there are strong evidences that support its relation with tumor suppression by inhibiting apoptosisrelated oncogenes such as β-catenin, or by repairing the DNA-double strand breaks favoring DNA damage response and promoting lifespan extension and tumor suppression (Fig. 1).40,53,66 Furthermore, several studies have found that resveratrol activates SIRT1 in vivo and mediates the antitumorigenic response.67 Consequently, resveratrol or similar compounds could be considered good candidates to activate the SIRT1 response against cancer. The protective properties of SIRT1 should be taken into account whenever resveratrol is used clinically together with traditional cancer therapies such as radiotherapy and chemotherapy, since SIRT1 might promote the repair of DNA lesions caused by the effects of radiation or genotoxic agents such as cisplatin, thus counteracting their activity against human cancer cells.40 Taking into account the aforementioned facts, it may follow that SIRT1 regulation might play a dual role in aging and cancer. Should this be the case, increasing SIRT1 activity through molecules such as resveratrol would be akin to “killing two birds with one stone,” both extending lifespan and reducing cancer development. These dual effect of SIRT1 has already been observed in animal models68,69 but further research with human subjects is still necessary.

other disorders, have been found in different animal models.19,65,70 Although the mechanism of action of resveratrol in cardiovascular diseases is not clearly understood, its beneficial effects on atherosclerosis, thrombosis, hypertension, ischemic injury, diabetes and obesity have been reported in several rodent models.19,70,71 A schematic model recently described by Csiszar shows the mechanisms by which resveratrol is implicated in the inhibition of inflammatory processes and the reduction of ROS production, promoting cardiovascular system protection. Although the mechanisms have not been fully elucidated as of yet, it seems that SIRT1 and NF-E2-related factor 2 (Nrf2) mediate the effects of resveratrol in these processes.65 The potential of resveratrol as an antidiabetic agent has been reported in a number of in vitro and in vivo studies in animal models as well. It has been proven that this polyphenol contributes to the protection of β cells and that it features anti-hyperglycemic activity, probably via AMPK activation.72-75 In addition to the positive effects reported in vascular-related diseases, it has also been found that resveratrol plays a beneficial role in other types of diseases, such as age-related skin disorders, fatty acid β-oxidation (FAO) disorders, obesity, osteoporosis and arthritis.76-79 Furthermore, resveratrol possesses neuroprotective and antiviral effects,80-82 supporting again the potential role of this polyphenol as a therapeutic agent.

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Resveratrol and Other Aging-Associated Pathologies Positive effects of resveratrol on autoimmune and cardiovascular diseases, among

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Conclusions and Perspectives The effects of resveratrol on lifespan, aging and aging-related diseases have been tested over the past years. Studies suggest that it might exert beneficial effects against cancer or cardiovascular diseases, and that it may increase lifespan in different organisms. Also, resveratrol seems to be effective against initiation and progression of the tumorigenic process through those pathways in which SIRT1 plays a key role. Thus, it is possible that SIRT1 activation by resveratrol may extend lifespan and also reduce cancer risk.

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However, the functions of resveratrol and SIRT1 in cancer are not entirely clear. As an example, it has been reported that resveratrol stimulates the growth of human breast cancer cells in vitro.83 Consequently, any potential adverse effects associated with administration of resveratrol should be taken into account when administering it to humans, and the data obtained so far must be carefully interpreted. In fact, some phase I clinical trials have conveyed that resveratrol intake is associated with a decrease in insulinlike growth factor-1 (IGF-1),84 a protein potentially associated with the development of several human cancers, including colorectal cancer.85 Thus, further research is necessary to assess and minimize any potential secondary effects on health. More animal studies should be carried out, for example, to investigate the dose of administration of resveratrol taking into account the fast rate at which the organism metabolizes it, to test the effects on long-term administration (a type of trial which has not been performed so far), or to clarify the importance of SIRT1 as a mediator of resveratrol’s effects. It is worth mentioning that, although the study of model organisms may expose the potential of resveratrol for lifespan extension and its beneficial effects on aging-related diseases, research with human subjects would be required before any definitive inferences can be made. Several clinical trials focused on resveratrol’s pharmacokinetics and metabolism have been published; 86 conversely, no studies on its therapeutic effects have been completed yet.86 Obviously, more clinical trials are needed and, although a number of studies are already in phases II and III, we must wait for the final results in order to properly clarify the role of resveratrol on human health. Until then, dietary supplementation in humans with resveratrol should be used with caution.

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Acknowledgments

O.I.B. provided editorial assistance. A.F.F. is funded by the Instituto Universitario de Oncología de Asturias, supported by Obra Social Cajastur. This work was supported by the MICINN (PI061267; PS09/02454; Ref. 200820I172) and the Community of Asturias (FICYT IB09-106).

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Epigenetics

Volume 6 Issue 7