Life extension and
disease treatment through
periodic fasting and
caloric restriction -
the most powerful
scientifically proven
natural anti-aging method

Calculate your BMI
(Body Mass Index)

BMI Categories:
Underweight = <18.5
Normal weight = 18.5-24.9
Overweight = 25-29.9
Obesity = BMI of 30 or greater

Your Height: cm
Your Weight: kg
Your BMI:

Recent advances on pharmacological properties of resveratrol and its analogues and new anti-aging and regenerative therapies


Physiological aging is a complex process that results in a progressive loss of phenotypic and functional integrity of tissues and organs in the body with advancing age and that ultimately culminates in their degeneration and death of individuals (1-4). At the present time, the molecular mechanisms and altered signaling networks associated with aging are not yet well defined. Accumulating lines of experimental evidence have indicated that specific age-related pathophysiological changes in tissue-resident adult stem/progenitor cells, and their differentiated progenies can contribute of a major fashion to the chronological aging (1, 2, 5, 6). Among the important factors that are involved in aging process and degenerative disorders, there are chronic inflammation and fibrosis and cumulative oxidative and metabolic stress leading to the generation of reactive oxygen species (ROS) and altered metabolic pathways (1-4). A decreased antioxidant defense system and increased telomere shortening and impaired DNA repair mechanisms also can result in genomic instability and cellular dysfunctions during chronological aging (1, 2, 7).

Importantly, the occurrence of these age-related molecular events in adult stem/progenitor cells with stem cell-like properties, including a high self-renewal capacity and their differentiated progenies combined with the changes in their local microenvironment may lead to their loss of functional properties (fig. 1) (1, 5, 7, 8). In particular, the telomere shortening and enhanced expression and activation of different tumor suppressor genes typically occur during the aging process of adult stem/progenitor cells and their progenies (Fig. 1) (1, 5, 7, 8). These tumor suppressor gene products, including p53, p16INK4A, p19ARF and cycling-dependent kinase inhibitors, p21CIP1/WAP1 and p27KIP1, in turn, may cooperate to induce the replicative senescence or programmed cell death by apoptosis of adult stem/progenitor cells and their differentiated progenies (Fig. 1) (1, 5). Hence, the occurrence of these cellular dysfunctions results in a decrease of tissue regenerative capacity and decline or loss of the number of adult stem/progenitor cells and their differentiated progenies, irreversible tissue degeneration and disease development with advancing age (1, 5, 8). In contrast, the activation of distinct oncogenic products in adult stem/progenitor cells during chronological aging may lead to their malignant transformation into cancer stem/progenitor cells that can give rise to the bulk mass of differentiated cancer cells (Fig. 1) (1, 5, 9). Of therapeutic interest, a growing body of experimental evidence has also indicated that some pharmacological agents, such as resveratrol, sirtuins, metformin and antifungal antibiotic rapamycin, endowed with the anti-oxidant and anti-inflammatory properties able to modulate the oxidant and metabolic pathways (4, 5, 10-14). In this manner, these pharmacological agents can prevent or reduce the cellular changes associated with aging process and extend the lifespan (4, 5, 10-14). More specifically, the bioactive natural product, resveratrol (3, 5, 4'-trihydroxy-trans-stilbene), a stilbenoid, polyphenol phytochemical present in red wine, berries, grape and peanuts has been observed to induce the pleiotropic effects to depend on the cell-type and drug concentration. In fact, resveratrol induced not only tissue-protective effects through its potent antioxidant, anti-inflammatory and anti-aging properties, but also showed strong antiviral and antitumor activities and prevented tumor invasion and metastasis by inhibiting proliferation and inducing apoptosis of cancer cells (Fig.1 and Table 1) (15-19). Particularly, resveratrol has been reported to mediate potent therapeutic effects and counteract the development of numerous age-related diseases and some types of degenerative disorders and cancers in vitro and in vivo (7, 11, 14, 16, 20). The results from recent studies have also revealed that resveratrol, alone or in combination therapy, can induce the recovery of functional properties of adult stem/progenitor cells and prevent their loss during chronological as well as their malignant transformation in cancer stem/progenitor cells (Fig. 1) (3, 5, 7, 13, 21-27).

In this matter, we review recent investigations on the pharmacological properties of resveratrol and molecular mechanisms at the basis of its preventive and therapeutic effects on the development of age-related diseases. The emphasis is on the anti-aging and regenerative effects mediated by resveratrol in adult stem/progenitor cells and their differentiated progenies through the induction of antioxidant, anti-inflammatory and recovery of metabolic responses during chronological aging as well as its beneficial effects as a caloric restriction mimic and expansion of lifespan. Recent data obtained from clinical trials on the bioavailability, effective dose, toxicity and chemopreventive and therapeutic benefits of resveratrol in humans are also discussed. The provided information should help to develop novel anti-aging and regenerative strategies to treat diverse age-related tissue dysfunctions and diseases such as bone loss, heart failure, metabolic and degenerative disorders and aggressive and recurrent cancers.
Characterization of pharmacological and therapeutic effects of resveratrol
The alterations in several signaling elements leading in excessive oxidative and metabolic stress and intense inflammatory responses in cells and their local microenvironment have been shown to cause oxidative damages and death of various cells, and organ dysfunctions associated with aging (3, 4, 28). Consequently, some investigations have been undertaken to evaluate the anti-aging and regenerative potentials of natural antioxidant products as polyphenol resveratrol to prevent and treat diverse age-related disorders. Resveratrol, a grape-derived antioxidant has been shown to induce beneficial effects on the rescue of organ failures, bone loss, heart attack, hematopoietic, cardiovascular, neurodegenerative, diabetic and retinal disorders and obesity, and promote longevity in vitro and in vivo (Table 1) (3, 7, 10, 11, 14, 16, 20, 28-31). It has also been shown that resveratrol can induce its anti-aging effects, at least in part, through the stimulation of telomerase activity and increase of expression levels and activities of other anti-aging gene products (7, 10, 16). These antiaging signaling elements induced by resveratrol comprise sirtuins 1 and 3 (Sirt1 and Sirt3), a member of the Forkhead box subgroup O (Foxo) transcription factor (Foxo3a), phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) and parkin E3 ubiquitin ligase (7, 10, 16). These signaling elements can protect against mitochondrial and metabolic dysfunctions during cellular oxidative stress (7, 10, 16). Moreover, resveratrol can also act as a potent inhibitor of nuclear factor-kappaB (NF-κB) activation through its ability to inhibit IkappaB kinase activity and Akt as well as by activating cyclooxygenases (COXs) (32-35). More particularly, Sirt1 and Sirt3 are nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that are located in the cytoplasm and nucleus and mitochondria, respectively (36-38). These Sirts control the functions of many target proteins, including anti-aging gene products involved in cell protection and repair mechanisms against oxidative and metabolic stress and maintaining of tissue homeostasis (10, 16, 29, 36-38). Sirt1 and Sirt3 can cooperate to the strict regulation of oxidative stress and aging process, and the prevention of metabolic diseases through induction of Foxo family of transcription factors and heat-shock protein 70 (HSP70), and thereby improve the lifespan (10). Moreover, it has also been observed that resveratrol was effective at inducing Sirt1 mRNA expression and increasing renal anti-aging Klotho gene expression via the activation of transcription factor 3 (ATF3)/c-Jun complex-mediated signaling pathway both in vivo and in vitro (29). In this matter, we are reporting here in a more detailed manner, the pharmacological properties of resveratrol and its therapeutic effects to prevent and treat age-related disorders and aggressive cancers.

In vitro and in vivo characterization of antioxidant and anti-inflammatory effects of resveratrol
The activation of oxidative stress and inflammatory pathways may contribute to re-establish the cellular and tissue homeostasis. Nevertheless, excessive production of ROS such as superoxide, hydrogen peroxide and hydroxyl radical, and severe inflammation lesion may result in severe pain, chronic inflammatory disorders such as arthritis, atherosclerosis, and even cancers (3, 4). The persistent oxidative stress and inflammation are typically associated with tissue microenvironment remodeling, cellular damages, including DNA genomic instability, apoptotic and necrotic cell death and tissue dysfunctions (Fig. 1) (3, 4). These molecular events may ultimately lead to the development of age-related disorders and cancers. Notably, grape-derived antioxidant resveratrol has been observed to display antioxidant and anti-inflammatory activities, at least in part, through the protection or rescue of functional properties of adult stem/progenitor cells in experimental research in vitro and in vivo (Fig. 1 and Table 1) (3, 23-27, 30). The antioxidant activity of resveratrol may be mediated directly by decreasing ROS production and scavenging free radicals and indirectly by increasing the production of antioxidant enzymes such as mitochondrial superoxide dismutase, Sirt1 activation and tumor necrosis factor-α inhibition (23, 27, 30). For instance, it has been reported that resveratrol prevented the oxidation of low-density lipoprotein particles by chelating copper and by directly scavenging free radicals (27). Moreover, resveratrol was also effective at inducing the rescue of retinal pigment epithelium from oxidative stress-induced senescence through Sirt1 activation and anti-oxidant activity (30). In addition, some lines of experimental evidence have also indicated that resveratrol displayed a more potent anti-inflammatory effect than non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (4, 31-33, 35, 39-42). For instance, it has been observed that the injections of resveratrol decreased inflammation and reduced cartilage destruction in animal models (41). The anti-inflammatory activity of resveratrol was mediated, at least in part, through the inhibition of two enzymes, COX-1 and COX-2, which are involved in the production of prostaglandins (32, 33, 35, 40-42). Thereby, the inhibition of COX enzymes may prevent inflammation, pain, and fever as well as the production of other inflammatory substances, including hydroperoxidases, 5-lipoxygenase and cytokines (32, 33, 35, 40-42).
Preventive and therapeutic effects of resveratrol on cardiovascular disorders
The cardiac disorders such as ischemia/reperfusion (I/R) injuries, which can cause oxidative and inflammatory responses in multiples organs including lungs, liver, gut, pancreas, kidney and gut, may result in severe organ dysfunctions and failures (10, 26, 43). In this regard, it has been reported that the treatment of hearts isolated from I/R rats with resveratrol facilitated the remodeling of damaged mitochondria as compared to the untreated I/R rat group (Table 1) (10, 26). The cardioprotective effect of resveratrol was accompanied by the stimulation of Sirt1/Sirt3 that, in turn, activated Foxo3a-PINK1-parkin signaling pathway that protected against mitochondrial dysfunctions during cellular oxidative stress (10). Hence, it appears that resveratrol may mediate its cardioprotective effects by inducing the changes in the intracellular environment from an oxidizing milieu into a reducing milieu, up-regulating intracellular accumulation of glutathione as well as by stimulating Sirt1/Sirt3-induced parkin activation that in turn causes mitochondrial fission-induced mitophagy (10). These data support previous studies suggesting a crucial role of mitochondrial dysfunctions caused by morphological alterations and mitochondrial DNA mutations in aging process (44). Importantly, recent studies have also indicated that resveratrol, alone or in combination with other drugs, could restore the functional properties of aged cardiac stem/progenitor cells and prevent their senescence (Table 1) (26, 45). For instance, a combination of resveratrol plus a specific inhibitor of molecular target of rapamycin (mTOR), rapamycin has been observed to prevent the senescence of human c-Kit+-cardiac stem cells (CSCs) in vitro and ischemia/reperfusion injury in severe combined immunodeficient (SCID) Beige mice in vivo (26). Moreover, trans-resveratrol treatment also reduced atrial loss of cardiac stem/progenitor cells (CSPCs) and preserved the functional abilities of CSPCs and mature cardiac cells (26). In addition, resveratrol has also been reported to induce protective effects on the cardiovascular system in vitro and in vivo (26, 46-49). For example, resveratrol was able to inhibit platelet aggregation which if excessive can result in the formation of blood clots, and blockages of blood vessels leading to insufficient blood flow, heart attack or stroke (46). A treatment of human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 cells with resveratrol for 24 to 72 also up-regulated endothelial nitric oxide synthase (eNOS) mRNA expression in a time- and concentration-dependent manner (up to 2.8-fold), and eNOS-derived NO production after long-term incubation with resveratrol (47). On the other hand, it has been observed that resveratrol induced a marked recovery of ventricular function in adult Wistar rats (n = 64) with streptozotocin-induced type-1 diabetes compared to untreated animals (n=54) (26). These beneficial effects of resveratrol improved cardiac environment by reducing inflammatory state and decreased unfavorable ventricular remodeling of the diabetic heart (26). Moreover, some animal studies have indicated that high oral doses of resveratrol could decrease the risk of thrombosis and atherosclerosis (48, 49). Hence, these findings suggest that resveratrol can constitute an adjuvant therapeutic option for diabetic cardiomyopathy prevention and to treat cardiovascular disorders.

Preventive and therapeutic effects of resveratrol on neurodegenerative disorders
Age is among the leading cause of risk factors for the development of acute and chronic neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and Huntington's diseases and stroke (46, 50-54). Of therapeutic interest, accumulating lines of experimental evidence have revealed that resveratrol can protect against numerous neurodegenerative disorders (46, 50-54). For instance, it has been shown that resveratrol enhanced the production of neurotropic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) that in turn induced neurotrophic effects on dopaminergic neurons in primary midbrain neuron-glia cultures (51). In fact, BDNF and GDNF have been reported to be responsible for the development, maintenance, and survival of neurons, microglia, astroglia, and oligodendrocytes (52). Moreover, BDNF and GDNF have also been observed to improve the cognition, learning, and memory formation and to protect against the development of some of central nervous system disorders such as Alzheimer’s and Parkinson's diseases, depression, epilepsy and chronic pain in animal models (46, 52, 53). Importantly, the results from recent in vitro studies using in animal models of neurodegenerative diseases, have also indicated that resveratrol displayed anti-neuroinflammatory and neuroprotective effects (Table 1) (4, 14, 16, 20, 55-57). These neuroprotective effects of resveratrol were mediated through Sirt1 activation and reduction of the expression of inducible enzymes related to inflammation, such as inducible isoform of nitric oxide synthase (iNOS) and COX-2 in neural cells (4, 14, 16, 20, 55-57). Furthermore, resveratrol also decreased intracellular ROS production, most likely by mechanisms involving N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainite (KA), intracellular Ca2+ and the heme oxygenase 1 (HO1) pathway (55). These effects of resveratrol prevented mitochondrial dysfunctions and impairments in Na+K+-adenosine triphosphatase (ATPase) and glutamine synthase activity after glutamate activation in acute hippocampal slices cells (55). On the other hand, it has also been shown that resveratrol treatment of primary fibroblast cultures from two patients with early-onset Parkinson’s disease linked to different parkin RBR E3 ubiquitin protein ligase (Park2) gene mutations resulted in energy homeostasis (20). This effect of resveratrol was mediated through activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and Sirt1 and up-regulation of mRNA expression of a number of the transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-γ  coactivator 1 α (PGC-1α)'s target genes (20). The stimulation of these signaling elements by resveratrol, in turn, resulted in a decrease of oxidative stress and increase of mitochondrial biogenesis and recovery of mitochondrial oxidative functions (20). The resveratrol also increased complex I and citrate synthase activities, basal oxygen consumption, and mitochondrial adenosine triphosphate (ATP) production and decreased lactate content, indicating that resveratrol can induce a switch from glycolytic to oxidative metabolism (20). Moreover, it has been reported that the resveratrol treatment caused an enhanced macro-autophagic flux through activation of microtubule-associated protein 1 light chain 3 (LC3)-independent pathway (20). These results suggest that resveratrol may display important neuroprotective effects against neuropsychiatric and neurodegenerative disorders by modulating mitochondrial bioenergetics and oxidative stress and inducing inhibitory effects on ionic channels.

Characterization of calorie restriction mimicking and anti-aging effects of resveratrol
The extension of lifespan and reduction of food/energy intake, also known as calorie restriction (CR), has been associated with the prevention, retardation or suppression of aging-related function decline and age-related diseases (Table ) (58-62). For instance, it has also reported that CR delayed the onset of numerous age-associated pathologies, including diabetes, cancer, cardiovascular disease and brain atrophy, and decreased mortality in rhesus monkeys (63). Similarly, some studies have been carried out with CR mimic, resveratrol by using animal models (Table 1). It has been shown that resveratrol can counteract the development of cardiovascular and neurodegenerative diseases, obesity, diabetes and cancers in organisms and species of diverse phylogenic groups (58-62). For instance, it has been reported that resveratrol extended the lifespan of diverse species, including yeast Saccharomyces cerevisiae, worm Caenorhabditis elegans and fruit fly Drosophila melanogaster (54, 64, 65). In these lower organisms, lifespan extension was dependent on Sir2, which is a conserved Sirt deacetylase that has been proposed to mediate the beneficial effects of CR and prolong the lifespans of lower organisms (12). Moreover, resveratrol has also been shown to promote swimming and cognitive performance, and induce life extension effects on short-lived fish, Nothobranchius furzeri (66). The investigation of anti-aging effects of CR and resveratrol on male grey mouse lemurs (Microcebus murinus), which have a median survival time of 5.7 years in captivity, has also indicated that CR and resveratrol prevented oxidative DNA and RNA damages with advancing age compared to standard-fed control animals (61). In the same way, resveratrol was also able to shift the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increase their survival (66). The calorie restriction mimicking effects of resveratrol can produce changes associated with the longer lifespan. For instance, resveratrol can promote insulin sensitivity, reduce insulin-like growth factor-1 (IGF-I) levels, increase AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) activity, increase mitochondrial number, and improved motor function (66). The parametric analysis of gene set enrichment has also revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways (66). The results from another study have revealed that resveratrol improved the health and survival of mice that were on a high-calorie diet (66). In addition, exercise training may improve health wellness and quality of life, and induce protective and beneficial effects against the development of chronic diseases such as cardiovascular diseases, obesity, and diabetes. In this regard, it has also been noted that the decline in physical performance of SAMP1-Ex mice was associated with a significant increase in oxygen consumption and skeletal muscle mRNA levels of mitochondrial function-related enzymes (67). Interestingly, it has been observed that a combination of 0.2% (w/w) resveratrol with habitual exercise was effective at increasing the endurance capacity of senescence-accelerated prone mice (SAMP1) as compared to the endurance capacity of SAMP1 mice undergoing an exercise regimen (SAMP1-Ex) without treatment with resveratrol (67). These effects of resveratrol on physical endurance may be attributable, at least in part, to Sirt1 activation and improvement of mitochondrial function in skeletal muscle. Moreover, a synergistic cooperation of regular exercise and 40 mg/kg resveratrol given daily during 6 weeks also resulted in an inhibitory effect on kainate-induced seizure activity and oxidative stress in mice (68). These studies suggest that the intake of resveratrol combined with habitual exercise is effective for suppressing the aging-related decline in physical performance and the development of age-related diseases. In this regard, we are reporting here the anti-aging effects mediated by resveratrol via the telomere uncapping as well as its therapeutic benefits for treating age-related complications associated with obesity and diabetes.
Preventive effects of resveratrol against telomere shortening and age-related decline in adult stem cells
Among the other hallmarks of aging process, the shortening of telomeres in adult stem/progenitor cells and their progenies has been recognized as an important factor of age-related cellular dysfunctions (Fig. 1) (1, 7, 69). In this regard, it has been reported that resveratrol significantly induced telomerase activity by increasing the expression of the catalytic subunit, human telomerase reverse transcriptase (hTERT) via Akt activation in endothelial progenitor cells (EPCs) in a dose-dependent manner and inhibited the onset of EPC senescence in culture (7). In the same way, Srt1 activator, resveratrol, also inhibited the differentiation of murine bone marrow-resident c-Kithigh/Sca-1+/Lineage- (KSL) hematopoietic cells during the culture system ex vivo (69). In support with the results from the experiments using resveratrol, KSL cells isolated from Sirt1 knockout (KO) mice were more differentiated and lost the KSL phenotype than those from wild-type mice (69). Furthermore, the data from colony assay, replating assay, or serial transplantation assay have also indicated that Sirt1 KO KSL cells lost earlier the characteristics of stem cells than wild-type KSL cells (69). It has also been reported that resveratrol-induced Sirt1 also maintained prematurity of hematopoietic cells through ROS elimination, Foxo activation, and p53 inhibition (69). Hence, these results suggest that resveratrol-induced Sirt1 activation may induce the anti-aging effects in tissue-resident adult stem/progenitor cells and thereby prevent their functional decline.

Protective effects of resveratrol against obesity-associated complications
The obesity is biologically characterized at the cellular level by an increase in the number and size of adipocytes, also designated as fat cells in adipose tissue and may result in diverse oxidative and metabolic disorders (59, 60, 62, 70-74). Of particular interest, resveratrol via the Sirt1 activation has been shown to protect fat cells and mice against diabetic complications, including excessive oxidative and metabolic stress, inflammation and diet-induced obesity in vitro and in vivo (Table 1) (60, 62, 70, 73). For example, resveratrol has been observed to inhibit pre-adipocytes, and thereby reduce the production of new fat cells and improve glucose balance by stimulating Sirt1 in mice (71, 74).Moreover, the SIR2 gene in the body of animals and humans also induced the Sirt1 activation that in turn promoted fat mobilization in adipose tissue (72). In addition, resveratrol and resveratrol dimer have also been observed to improve fatigue resistance under hypoxia conditions in vitro and in vivo in part via the up-regulation of estrogen-receptor-β (75). These results suggest the potent use of resveratrol for treating upper airway dilator muscle deviancy associated with obstructive sleep apnea-hypopnea syndrome.

In vitro and in vivo characterization of antidiabetic effects of resveratrol
The diabetes mellitus is often associated with cellular oxidative stress and some organ dysfunctions, such as diabetic retinopathy and cardiac, renal and liver disorders (60, 63, 76-78). In general, aging is implicated in metabolic diseases, including diabetes, and is recognized as an important risk factor for the initiation and the development of type 2 diabetes mellitus. Importantly, it has been observed that resveratrol delayed the development of diabetic complications in animal models (Table 1) (60, 63, 76-79). More specifically, it has been observed that the diabetic retinopathy may be mediated via Sirt1 inhibition leading to the NF-κB activation and production of MMP-9 (76). MMP-9 in turn induced damages to retinal mitochondria that resulted in the activation of the apoptotic cascade in retinal H2O2 stimulated-retinal endothelial cells and retina of wild-type diabetic mice (76). A treatment with resveratrol, however, was effective at preventing the activation of NF-κB and MMP-9, mitochondria damages and cell apoptosis (76). Of clinical interest, it has also been noted that retinal microvasculture from human donors with established diabetic retinopathy shown decreased Sirt1 suggesting that resveratrol could also be effective to inhibit the development of diabetic retinopathy in humans (76). Although specific mechanisms by which resveratrol affects fatigue resistance, obesity, diabetes and longevity remain not well understood, it appears based on these studies that resveratrol can decrease body temperature, rate of metabolism, and oxidant production and retard the age-related pro-oxidizing shift in the redox state. In vitro and in vivo characterization of cancer preventive and anticancer effects of resveratrol Numerous studies have revealed that resveratrol can display chemopreventive effects and inhibit the proliferation and tumor growth of various human cancer cell lines in vitro and in vivo (Table 1) (15, 22, 38, 42, 62, 70, 80-88). These cancer cells include those from leukemia, lymphomas, brain tumors, melanomas and breast, prostate, esophagus, stomach, colon, pancreatic, nasopharyngeal, thyroid and head and neck cancers (15, 22, 38, 42, 62, 70, 80-88). In this regard, accumulating line of evidence have revealed that chemoradioresistant cancer stem cells (CSCs), also designated as cancer- or tumor-initiating cells, are a major cause of cancer treatment failure, relapse, and drug resistance and are known to be responsible for cancer cell invasion and metastasis (1, 89-91). Of great therapeutic interest, resveratrol, alone or in combination therapies, has also been shown to inhibit the proliferation and/or induce apoptotic/necrotic death of cancer stem/progenitor cells without major secondary effect on their normal counterparts (Fig. 1) (22, 38, 82, 83, 83, 85, 86, 88, 92). These cancer stem/progenitor cells comprise those invoved in the development of leukemia, melanoma, glioma and breast, pancreatic and head and neck cancers (22, 38, 82, 83, 83, 85, 86, 88, 92). For instance, the treatment of CD133+-glioblastoma multiform (GBM)- tumor-initiating cells (TICs) with 100 µM resveratrol induced apoptosis and enhanced their radiosensitivity by suppressing signal transducer and activator of transcription-3 (STAT3) signaling cascade (83). Microarray results have also revealed that resveratrol inhibited the stemness gene signatures of CD133+-GBM-TICs and promoted their differentiation into CD133--GBM cells or astrocytoma cells (83). Additionally, xenotransplant experiments have revealed that resveratrol significantly improved the survival rate and synergistically enhanced the radiosensitivity of radiation-treated CD133+-GBM-TICs (83). Hence, resveratrol can reduce in vivo tumorigenicity and enhance the sensitivity of CD133+-GBM-TIC to radiotherapies through the STAT3 pathway. In addition, other mechanisms by which resveratrol exerts its preventive and therapeutic effects on the development of cancer also include the inhibition of the enzymatic activity of COX-1 and COX-2 and tumor angiogenic process (Fig. 1) (1, 46, 86, 90, 91). Moreover, resveratrol can inhibit MMPs, which are responsible for the extracellular matrix degradation observed during cancer progression, via the p38 kinase and c-Jun N-terminal kinase (JNK) pathways in HTB94 chondrosarcoma cells (93). Hence, all these studies underline the potential to use resveratrol, alone or in combination with other anticancer agents, to eradicate the total cancer cells, including cancer-initiating cells, and thereby prevent or treat diverse aggressive and recurrent cancers. Of particular interest, ionizing radiation (IR) which is often used as a treatment for some cancers cause long-term residual hematopoietic injury via the generation of ROS in hematopoietic cells (21). The results of cell viability assays, clonogenic assays, and competitive repopulation assays have also revealed that a treatment with two analogues of resveratrol, isorhapontigenin and heyneanol-A could protect mice bone marrow mononuclear cells (BMMNC) and hematopoietic stem/progenitor cells from IR-induced bone marrow suppression (21). The treatment with these resveratrol analogues also decreased the expression and activity of superoxide dismutase 2 and gluthatione peroxidase1 in irradiated BMMNC, and ameliorated IR-induced bone marrow suppression suggesting that these compounds can induce their protective effects through their antioxidant properties (21).

Clinical trials on the therapeutic applications of resveratrol in humans
Some randomized and large studies have been made to estimate the bioavailability, safety and therapeutic effects of resveratrol in humans. In fact, promotional marketing of resveratrol as a dietary supplement in last few years was based on the observation of low rate of death from cardiovascular disease in the Mediterranean population that had consumed resveratrol and other bioactive compounds from red wine, despite a diet that was relatively high in saturated fat. To completed (Table 2)

Conclusions and future directions

Taken together, these investigations have shown that natural bioactive compound resveratrol can improve the general health in mammals supporting its potential use to prevent and treat diverse age-related diseases. These age-related disorders include organ failures, cardiovascular and neurodegenerative disorders, arthritis, atherosclerosis, obesity- and diabete-related disorders and aggressive cancers. The anti-aging effects of resveratrol on adult stem/progenitor cells and their differentiated progenies appear to be principally mediated via the activation of Sirts 1 and 3, and inhibition of oxidant and metabolic pathways. In contrast, the anticancer properties of resveratrol on cancer stem/progenitor cells seem rather to implicate the activation of apoptotic and necrotic pathways of cell death and inhibition of the angiogenic process. Additional investigations are, however, necessary to further establish the molecular mechanisms of the CR mimicking and anti-aging effects of resveratrol on diverse types of tissue-resident adult stem/progenitor cells and their local microenvironment designated as niches versus their differentiated progenies. More particularly, it will be important to determine the common signaling elements modulated by resveratrol and CR involved in the expansion of lifespan. The molecular signaling components responsible for the pleiotropic effects of resveratrol on adult stem/progenitor cells versus their malignant counterparts, cancer stem/progenitor cells, is also  of critical significance to optimize the potential therapeutic use of resveratrol for treating diverse age-related diseases and aggressive and recurrent cancers. Of therapeutic interest, the development of novel analogs or nanotechnology-derived delivery systems of resveratrol is also of major importance to improve its water solubility and bioavailability. The large and randomized clinical trials performed with resveratrol, alone and in combination therapies, in health individuals and patients are also required to confirm its potential use to prevent and treat numerous age-related disorders in humans. Hence, nutraceutical compound, resveratrol should offer great promises to develop new combination therapies for preventing and treating diverse devastating age-related disorders and aggressive cancers in safe conditions in humans.
(1) Mimeault M, Batra SK. Recent insights into the molecular mechanisms involved in aging and the malignant transformation of adult stem/progenitor cells and their therapeutic implications. Ageing Res Rev 2009;8:94-112.

(2) Leonov A, Titorenko VI. A network of interorganellar communications underlies cellular aging. IUBMB Life 2013 Aug ;65 (8 ):665 -74 doi : 10 1002 /iub 1183 Epub 2013 Jul 2 2013;65:665-74.

(3) Paschalaki KE, Starke RD, Hu Y, Mercado N, Margariti A, Gorgoulis VG, et al. Dysfunction of endothelial progenitor cells from smokers and chronic obstructive pulmonary disease patients due to increased DNA damage and senescence. Stem Cells 2013 Dec ;31 (12 ):2813 -26 doi : 10 1002 /stem 1488 2013;31:2813-26.

(4) Renaud J, Martinoli MG. Resveratrol as a protective molecule for neuroinflammation: a review of mechanisms. Curr Pharm Biotechnol 2014 Jun 16 2014.

(5) Menendez JA, Joven J. Energy metabolism and metabolic sensors in stem cells: the metabostem crossroads of aging and cancer. Adv Exp Med Biol 2014 ;824 :117 -40 doi : 10 1007 /978 -3-319 -07320 -0 _10 2014;824:117-40.

(6) Orozco-Solis R, Sassone-Corsi P. Circadian clock: linking epigenetics to aging. Curr Opin Genet Dev 2014 Jul 14;26C :66 -72 doi : 10 1016 /j gde 2014 06 003 2014;26C:66-72.

(7) Wang XB, Zhu L, Huang J, Yin YG, Kong XQ, Rong QF, et al. Resveratrol-induced augmentation of telomerase activity delays senescence of endothelial progenitor cells. Chin Med J (Engl ) 2011 Dec ;124
:4310 -5 2011;124:4310-5.

(8) Geiger H, Denkinger M, Schirmbeck R. Hematopoietic stem cell aging. Curr Opin Immunol 2014 Jun 3;29C :86 -92 doi : 10 1016 /j coi 2014 05 002 2014;29C:86-92.

(9) Mimeault M, Batra SK. Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies. Mol Aspects Med 2013 Aug 29 pii : S0098 -2997 (13)00059 -9 doi : 10 1016 /j mam 2013 08 001 2013.

(10) Das S, Mitrovsky G, Vasanthi HR, Das DK. Antiaging properties of a grape-derived antioxidant are regulated by mitochondrial balance of fusion and fission leading to mitophagy triggered by a signaling network of Sirt1-Sirt3-Foxo3-PINK1-PARKIN. Oxid Med Cell Longev 2014 ;2014 :345105 doi : 10 1155 /2014 /345105 Epub 2014 Jan 12 2014;2014:345105-8.

(11) Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006 Jun ;5(6 ):493 -506 Epub 2006 May 26 2006;5:493-506.

(12) Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006 Nov 16 ;444 (7117 ):337 -42 Epub 2006 Nov 1 2006;444:337-42.

(13) Avolio E, Gianfranceschi G, Caragnano A, Athanasakis E, Katare R, Meloni M, et al. 289Pharmacologic rejuvenation of senescent human cardiac stem cells enhances myocardial repair. Cardiovasc Res 2014 Jul 15 ;103 Suppl 1:S52 doi : 10 1093 /cvr /cvu087 3 Epub 2014 Jun 27 2014;103 Suppl 1:S52.

(14) Scuderi C, Stecca C, Bronzuoli MR, Rotili D, Valente S, Mai A, et al. Sirtuin modulators control reactive gliosis in an in vitro model of Alzheimer's disease. Front Pharmacol 2014 May 13;5:89 doi : 10 3389 /fphar 2014 00089 eCollection 2014 2014;5:89.

(15) Tsai JH, Hsu LS, Lin CL, Hong HM, Pan MH, Way TD, et al. 3,5,4'-Trimethoxystilbene, a natural methoxylated analog of resveratrol, inhibits breast cancer cell invasiveness by downregulation of PI3K/Akt and Wnt/beta-catenin signaling cascades and reversal of epithelial-mesenchymal transition. Toxicol Appl Pharmacol 2013 Nov 1;272 (3):746 -56 doi : 10 1016 /j taap 2013 07 019 Epub 2013 Aug 3 2013;272:746-56.

(16) Zhang J, Feng X, Wu J, Xu H, Li G, Zhu D, et al. Neuroprotective effects of resveratrol on damages of mouse cortical neurons induced by beta-amyloid through activation of SIRT1/Akt1 pathway. Biofactors 2014 Mar -Apr;40 (2):258 -67 doi : 10 1002 /biof 1149 Epub 2013 Oct 17 2014;40:258-67.

(17) Campagna M, Rivas C. Antiviral activity of resveratrol. Biochem Soc Trans 2010 Feb ;38 (Pt 1):50 -3 doi : 10 1042 /BST0380050 2010;38:50-3.

(18) Faith SA, Sweet TJ, Bailey E, Booth T, Docherty JJ. Resveratrol suppresses nuclear factor-kappaB in herpes simplex virus infected cells. Antiviral Res 2006 Dec ;72 (3):242 -51 Epub 2006 Jul 14 2006;72:242-51.

(19) Palamara AT, Nencioni L, Aquilano K, De CG, Hernandez L, Cozzolino F, et al. Inhibition of influenza A virus replication by resveratrol. J Infect Dis 2005 May 15 ;191 (10):1719 -29 Epub 2005 Apr 13 2005;191:1719-29.

20) Ferretta A, Gaballo A, Tanzarella P, Piccoli C, Capitanio N, Nico B, et al. Effect of resveratrol on mitochondrial function: implications in parkin-associated familiar Parkinson's disease. Biochim Biophys Acta 2014 Jul ;1842 (7 ):902 -15 doi : 10 1016 /j bbadis 2014 02 010 Epub 2014 Feb 25 2014;1842:902-15.

(21) Wang H, Yang YL, Zhang H, Yan H, Wu XJ, Zhang CZ. Administration of the Resveratrol
Analogues Isorhapontigenin and Heyneanol-A Protects Mice Hematopoietic Cells against Irradiation Injuries. Biomed Res Int 2014 ;2014 :282657 doi : 10 1155 /2014 /282657 Epub 2014 Jun 24 2014;2014:282657.

(22) Wu EJ, Goussetis DJ, Beauchamp E, Kosciuczuk EM, Altman JK, Eklund EA, et al. Resveratrol enhances the suppressive effects of arsenic trioxide on primitive leukemic progenitors. Cancer Biol Ther 2014 Apr;15 (4):473 -8 doi : 10 4161 /cbt 27824 Epub 2014 Feb 4 2014;15:473-8.

(23) Hosoda R, Kuno A, Hori YS, Ohtani K, Wakamiya N, Oohiro A, et al. Differential cell-protective function of two resveratrol (trans-3,5,4'-trihydroxystilbene) glucosides against oxidative stress. J Pharmacol Exp Ther 2013 Jan ;344 (1):124 -32 doi : 10 1124 /jpet 112 198937 Epub 2012 Oct 5 2013;344:124-32.

(24) Silva AM, Oliveira MI, Sette L, Almeida CR, Oliveira MJ, Barbosa MA, et al. Resveratrol as a natural anti-tumor necrosis factor-alpha molecule: implications to dendritic cells and their crosstalk with mesenchymal stromal cells. PLoS One 2014 Mar 10;9 (3):e91406 doi : 10 1371 /journal pone 0091406 eCollection 2014 2014;9:e91406.

(25) ZhuGe CC, Xu JY, Zhang J, Li W, Li P, Li Z, et al. Fullerenol protects retinal pigment epithelial cells from oxidative stress-induced premature senescence via activating SIRT1. Invest Ophthalmol Vis Sci 2014 May 20 pii : IOVS -13-13732 doi : 10 1167 /iovs 13-13732 2014;68:215-26.

(26) Delucchi F, Berni R, Frati C, Cavalli S, Graiani G, Sala R, et al. Resveratrol treatment reduces cardiac progenitor cell dysfunction and prevents morpho-functional ventricular remodeling in type-1 diabetic rats. PLoS One 2012 ;7 (6 ):e39836 doi : 10 1371 /journal pone 0039836 Epub 2012 Jun 29 2012;7:e39836-e39858.

(27) Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006 Jun ;5(6 ):493 -506 Epub 2006 May 26 2006;5:493-506.

(28) Tresguerres IF, Tamimi F, Eimar H, Barralet J, Torres J, Blanco L, et al. Resveratrol as anti-aging therapy for age-related bone loss. Rejuvenation Res 2014 Jun 23 2014.

(29) Hsu SC, Huang SM, Chen A, Sun CY, Lin SH, Chen JS, et al. Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway. Int J Biochem Cell Biol 2014 Jun 6 ;53C :361 -371 doi : 10 1016 /j biocel 2014 06 002 2014;53C:361-71.

(30) ZhuGe CC, Xu JY, Zhang J, Li W, Li P, Li Z, et al. Fullerenol Protects Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Premature Senescence via Activating SIRT1. Invest Ophthalmol Vis Sci
2014 May 20 pii : IOVS -13-13732 doi : 10 1167 /iovs 13-13732 2014.

(31) Takada Y, Bhardwaj A, Potdar P, Aggarwal BB. Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 2004 Dec 9 ;23(57 ):9247 -58 2004;23:9247-58.

(32) Takada Y, Bhardwaj A, Potdar P, Aggarwal BB. Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 2004 Dec 9 ;23(57 ):9247 -58 2004;23:9247-58.

(33) Holmes-McNary M, Baldwin AS, Jr. Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IkappaB kinase. Cancer Res 2000 Jul 1;60 (13):3477 -83 2000;60:3477-83.

(34) Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J, et al. Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc Natl Acad Sci U S A 2000;97:3207-12.

(35) Murias M, Handler N, Erker T, Pleban K, Ecker G, Saiko P, et al. Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationship. Bioorg Med Chem 2004 Nov 1;12 (21):5571 -8 2004;12:5571-8.

(36) Hirschey MD, Shimazu T, Capra JA, Pollard KS, Verdin E. SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2. Aging (Albany NY) 2011 Jun ;3(6 ):635 -42 2011;3:635-42.

(37) Sayd S, Junier MP, Chneiweiss H. [SIRT2, a multi-talented deacetylase]. Med Sci (Paris) 2014 May ;30 (5):532 -6 doi : 10 1051 /medsci /20143005016 Epub 2014 Jun 13 2014;30:532-6.

(38) Sayd S, Thirant C, El-Habr EA, Lipecka J, Dubois LG, Bogeas A, et al. Sirtuin-2 activity is required for glioma stem cell proliferation arrest but not necrosis induced by resveratrol. Stem Cell Rev 2014 Feb ;10(1):103 -13 doi : 10 1007 /s12015 -013 -9465 -0 2014;10:103-13.

(39) Pervaiz S. Resveratrol: from grapevines to mammalian biology. FASEB J 2003 Nov ;17(14):1975 -85 2003;17:1975-85.

(40) Hwang D, Fischer NH, Jang BC, Tak H, Kim JK, Lee W. Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases. Biochem Biophys Res Commun 1996;226:810-8.
(41) Elmali N, Baysal O, Harma A, Esenkaya I, Mizrak B. Effects of resveratrol in inflammatory arthritis. Inflammation 2007 Apr;30 (1-2):1-6 2007;30:1-6.

(42) Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997;275:218-20.

(43) Kitada M, Koya D. Renal protective effects of resveratrol. Oxid Med Cell Longev 2013 ;2013 :568093 doi : 10 1155 /2013 /568093 Epub 2013 Nov 28 2013;2013:568093.

(44) Scherz-Shouval R, Elazar Z. ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 2007 Sep ;17(9 ):422 -7 Epub 2007 Sep 4 2007;17:422-7.

(45) Avolio E, Gianfranceschi G, Cesselli D, Caragnano A, Athanasakis E, Katare R, et al. Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction. Stem Cells 2014 May 6 doi : 10 1002 /stem 1728 2014.

(46) Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006 Jun ;5(6 ):493 -506 Epub 2006 May 26 2006;5:493-506.

(47) Wallerath T, Deckert G, Ternes T, Anderson H, Li H, Witte K, et al. Resveratrol, a polyphenolic phytoalexin present in red wine, enhances expression and activity of endothelial nitric oxide synthase. Circulation 2002 Sep 24 ;106 (13):1652 -8 2002;106:1652-8.

(48) Fukao H, Ijiri Y, Miura M, Hashimoto M, Yamashita T, Fukunaga C, et al. Effect of trans-resveratrol on the thrombogenicity and atherogenicity in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Blood Coagul Fibrinolysis 2004 Sep ;15 (6 ):441 -6 2004;15:441-6.

(49) Wang Z, Zou J, Huang Y, Cao K, Xu Y, Wu JM. Effect of resveratrol on platelet aggregation in vivo and in vitro. Chin Med J (Engl ) 2002 Mar ;115 (3):378 -80 2002;115:378-80.

(50) Chaturvedi RK, Beal MF. Mitochondria targeted therapeutic approaches in Parkinson's and Huntington's diseases. Mol Cell Neurosci 2013 Jul ;55 :101 -14 doi : 10 1016 /j mcn 2012 11 011 Epub 2012 Dec 5 2013;55:101-14.

(51) Zhang F, Wang YY, Liu H, Lu YF, Wu Q, Liu J, et al. Resveratrol produces neurotrophic effects on cultured dopaminergic neurons through prompting astroglial BDNF and GDNF release. Evid Based Complement Alternat Med 2012 ;2012 :937605 doi : 10 1155 /2012 /937605 Epub 2012 Nov 28 2012;2012:937605.

(52) Pezet S, Malcangio M. Brain-derived neurotrophic factor as a drug target for CNS disorders. Expert Opin Ther Targets 2004 Oct ;8 (5):391 -9 2004;8:391-9.

(53) Linker R, Gold R, Luhder F. Function of neurotrophic factors beyond the nervous system: inflammation and autoimmune demyelination. Crit Rev Immunol 2009 ;29 (1):43 -68 2009;29:43-68.

(54) Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 2006 Feb 7 ;16 (3):296 -300 2006;16:296-300.

(55) Quincozes-Santos A, Bobermin LD, Tramontina AC, Wartchow KM, Tagliari B, Souza DO, et al. Oxidative stress mediated by NMDA, AMPA/KA channels in acute hippocampal slices: neuroprotective effect of resveratrol. Toxicol In Vitro 2014 Jun ;28 (4):544 -51 doi : 10 1016 /j tiv 2013 12 021 Epub 2014 Jan 8 2014;28:544-51.

(56) Lofrumento DD, Nicolardi G, Cianciulli A, De NF, La P, V, Carofiglio V, et al. Neuroprotective effects of resveratrol in an MPTP mouse model of Parkinson's-like disease: possible role of SOCS-1 in reducing pro-inflammatory responses. Innate Immun 2014 Apr;20 (3):249 -60 doi : 10 1177 /1753425913488429 Epub 2013 Jun 13 2014;20:249-60.

(57) Ye J, Liu Z, Wei J, Lu L, Huang Y, Luo L, et al. Protective effect of SIRT1 on toxicity of microglial-derived factors induced by LPS to PC12 cells via the p53-caspase-3-dependent apoptotic pathway. Neurosci Lett 2013 Oct 11;553 :72 -7 doi : 10 1016 /j neulet 2013 08 020 Epub 2013 Aug 21 2013;553:72-7.

(58) Sohal RS, Forster MJ. Caloric restriction and the aging process: a critique. Free Radic Biol Med 2014 Aug ;73C :366 -382 doi : 10 1016 /j freeradbiomed 2014 05 015 Epub 2014 Jun 2 2014;73C:366-82.

(59) Renes J, Rosenow A, Roumans N, Noben JP, Mariman EC. Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta 2014 Sep ;1844 (9 ):1511 -22 doi : 10 1016 /j bbapap 2014 04 023 Epub 2014 May 5 2014;1844:1511-22.

(60) Kitada M, Koya D. SIRT1 in Type 2 Diabetes: Mechanisms and Therapeutic Potential. Diabetes Metab J 2013 Oct ;37 (5):315 -25 doi : 10 4093 /dmj 2013 37 5 315 2013;37:315-25.

(61) Marchal J, Dal-Pan A, Epelbaum J, Blanc S, Mueller S, Wittig KM, et al. Calorie restriction and resveratrol supplementation prevent age-related DNA and RNA oxidative damage in a non-human primate. Exp Gerontol 2013 Sep ;48 (9 ):992 -1000 doi : 10 1016 /j exger 2013 07 002 Epub 2013 Jul 13 2013;48:992-1000.

(62) Fouad MA, Agha AM, Merzabani MM, Shouman SA. Resveratrol inhibits proliferation, angiogenesis and induces apoptosis in colon cancer cells: calorie restriction is the force to the cytotoxicity. Hum Exp Toxicol 2013 Oct ;32 (10):1067 -80 doi : 10 1177 /0960327113475679 Epub 2013 Mar 27 2013;32:1067-80.

(63) Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009 Jul 10;325 (5937 ):201 -4 doi : 10 1126 /science 1173635 2009;325:201-4.

(64) Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003 Sep 11;425 (6954 ):191 -6 Epub 2003 Aug 24 2003;425:191-6.

(65) Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004 Aug 5;430 (7000 ):686 -9 Epub 2004 Jul 14 2004;430:686-9.

(66) Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006 Nov 16 ;444 (7117 ):337 -42 Epub 2006 Nov 1 2006;444:337-42.

(67) Murase T, Haramizu S, Ota N, Hase T. Suppression of the aging-associated decline in physical performance by a combination of resveratrol intake and habitual exercise in senescence-accelerated mice. Biogerontology 2009 Aug ;10(4):423 -34 doi : 10 1007 /s10522 -008 -9177 -z Epub 2008 Oct 1 2009;10:423-34.

(68) Kim HJ, Kim IK, Song W, Lee J, Park S. The synergic effect of regular exercise and resveratrol on kainate-induced oxidative stress and seizure activity in mice. Neurochem Res 2013 Jan ;38 (1):117 -22 doi : 10 1007 /s11064 -012 -0897 -8 Epub 2012 Oct 4 2013;38:117-22.

(69) Matsui K, Ezoe S, Oritani K, Shibata M, Tokunaga M, Fujita N, et al. NAD-dependent histone deacetylase, SIRT1, plays essential roles in the maintenance of hematopoietic stem cells. Biochem Biophys Res Commun 2012 Feb 24 ;418 (4):811 -7 doi : 10 1016 /j bbrc 2012 01 109 Epub 2012 Jan 28 2012;418:811-7.

(70) Li G, Rivas P, Bedolla R, Thapa D, Reddick RL, Ghosh R, et al. Dietary resveratrol prevents development of high-grade prostatic intraepithelial neoplastic lesions: involvement of SIRT1/S6K axis. Cancer Prev Res (Phila) 2013 Jan ;6 (1):27 -39 doi : 10 1158 /1940 -6207 CAPR -12 -0349 Epub 2012 Dec 17 2013;6:27-39.

(71) Hsu CL, Yen GC. Induction of cell apoptosis in 3T3-L1 pre-adipocytes by flavonoids is associated with their antioxidant activity. Mol Nutr Food Res 2006 Nov ;50 (11):1072 -9 2006;50:1072-9.

(72) Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De OR, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004 Jun 17;429 (6993 ):771 -6 Epub 2004 Jun 2 2004;429:771-6.

(73) Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006 Dec 15 ;127 (6 ):1109 -22 Epub 2006 Nov 16 2006;127:1109-22.

(74) Koo SH, Montminy M. In vino veritas: a tale of two sirt1s? Cell 2006 Dec 15 ;127 (6 ):1091 -3 2006;127:1091-3.

(75) Lu Y, Liu Y, Li Y. Comparison of natural estrogens and synthetic derivative on genioglossus function and estrogen receptors expression in rats with chronic intermittent hypoxia. J Steroid Biochem Mol Biol 2014 Mar ;140 :71 -9 doi : 10 1016 /j jsbmb 2013 12 006 Epub 2013 Dec 12 2014;140:71-9.

(76) Chung KW, Kim DH, Park MH, Choi YJ, Kim ND, Lee J, et al. Recent advances in calorie restriction research on aging. Exp Gerontol 2013 Oct ;48 (10):1049 -53 doi : 10 1016 /j exger 2012 11 007 Epub 2012 Nov 29 2013;48:1049-53.

(77) Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A 2004 Apr 27 ;101 (17):6659 -63 Epub 2004 Apr 2004;101:6659-63.

(78) Meyer TE, Kovacs SJ, Ehsani AA, Klein S, Holloszy JO, Fontana L. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol 2006 Jan 17;47 (2):398 -402 2006;47:398-402.

(79) Wang B, Yang Q, Sun YY, Xing YF, Wang YB, Lu XT, et al. Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice. J Cell Mol Med 2014 Jun 1 doi : 10 1111 /jcmm 12312 2014.

(80) Chen YJ, Chen YY, Lin YF, Hu HY, Liao HF. Resveratrol inhibits alpha-melanocyte-stimulating hormone signaling, viability, and invasiveness in melanoma cells. Evid Based Complement Alternat Med 2013 ;2013 :632121 doi : 10 1155 /2013 /632121 Epub 2013 May 23 2013;2013:632121.

(81) Shen YA, Lin CH, Chi WH, Wang CY, Hsieh YT, Wei YH, et al. Resveratrol impedes the stemness, epithelial-mesenchymal transition, and metabolic reprogramming of cancer stem cells in nasopharyngeal carcinoma through p53 Activation. Evid Based Complement Alternat Med 2013 ;2013 :590393 doi : 10 1155 /2013 /590393 Epub 2013 Apr 29 2013;2013:590393.

(82) Patties I, Kortmann RD, Glasow A. Inhibitory effects of epigenetic modulators and differentiation inducers on human medulloblastoma cell lines. J Exp Clin Cancer Res 2013 May 14;32 :27 doi : 10 1186 /1756 -9966 -32 -27 2013;32:27.

(83) Yang YP, Chang YL, Huang PI, Chiou GY, Tseng LM, Chiou SH, et al. Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis. J Cell Physiol 2012 Mar ;227 (3):976 -93 doi : 10 1002 /jcp 22806 2012;227:976-93.

(84) Ji Q, Liu X, Fu X, Zhang L, Sui H, Zhou L, et al. Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/beta-catenin signal pathway. PLoS One 2013 Nov 11;8 (11):e78700 doi : 10 1371 /journal pone 0078700 eCollection 2013 2013;8:e78700-e78755.

(85) Banerjee S, Bueso-Ramos C, Aggarwal BB. Suppression of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res 2002 Sep 1;62 (17):4945 -54 2002;62:4945-54.

(86) Tessitore L, Davit A, Sarotto I, Caderni G. Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. Carcinogenesis 2000 Aug ;21(8 ):1619 -22 2000;21:1619-22.

(87) Pandey PR, Xing F, Sharma S, Watabe M, Pai SK, Iiizumi-Gairani M, et al. Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer. Oncogene 2013 Oct 17;32 (42 ):5111 -22 doi : 10 1038 /onc 2012 519 Epub 2012 Dec 3 2013;32:5111-22.

(88) Hu FW, Tsai LL, Yu CH, Chen PN, Chou MY, Yu CC, et al. Impairment of tumor-initiating stem-like property and reversal of epithelial-mesenchymal transdifferentiation in head and neck cancer by resveratrol treatment. Mol Nutr Food Res 2012 Aug ;56 (8 ):1247 -58 doi : 10 1002 /mnfr 201200150 Epub 2012 Jun 13 2012;56:1247-58.

(89) Mimeault M, Batra SK. Altered gene products involved in the malignant reprogramming of cancer stem/progenitor cells and multitargeted therapies. Mol Aspects Med 2013 Aug 29 pii : S0098 -2997 (13)00059 -9 doi : 10 1016 /j mam 2013 08 001 2013.

(90) Mimeault M, Batra SK. New promising drug targets in cancer- and metastasis-initiating cells. Drug Discov Today 2010;15:354-64.

(91) Mimeault M, Batra SK. Recent concepts on cancer- and metastasis-initiating cells and their therapeutic implications in the development of novel effective cancer therapies. Anticancer Agents Med Chem 2010.

(92) Shankar S, Nall D, Tang SN, Meeker D, Passarini J, Sharma J, et al. Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One 2011 Jan 31 ;6 (1):e16530 doi : 10 1371 /journal pone 0016530 2011;6:e16530.

(93) Gweon EJ, Kim SJ. Resveratrol attenuates matrix metalloproteinase-9 and -2-regulated differentiation of HTB94 chondrosarcoma cells through the p38 kinase and JNK pathways. Oncol Rep 2014 Jul ;32 (1):71 -8 doi : 10 3892 /or 2014 3192 Epub 2014 May 16 2014;32:71-8.

(94) Mattison JA, Wang M, Bernier M, Zhang J, Park SS, Maudsley S, et al. Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab 2014 Jul 1;20 (1):183 -90 doi : 10 1016 /j cmet 2014 04 018 Epub 2014 May 29 2014;20:183-90.

(95) Park HR, Kong KH, Yu BP, Mattson MP, Lee J. Resveratrol inhibits the proliferation of neural progenitor cells and hippocampal neurogenesis. J Biol Chem 2012 Dec 14;287 (51 ):42588 -600 doi : 10 1074 /jbc M112 406413 Epub 2012 Oct 26 2012;287:42588-600.

(96) Saharan S, Jhaveri DJ, Bartlett PF. SIRT1 regulates the neurogenic potential of neural precursors in the adult subventricular zone and hippocampus. J Neurosci Res 2013 May ;91 (5):642 -59 doi : 10 1002 /jnr 23199 Epub 2013 Feb 13 2013;91:642-59.

(97) Zheng X, Zhu S, Chang S, Cao Y, Dong J, Li J, et al. Protective effects of chronic resveratrol treatment on vascular inflammatory injury in steptozotocin-induced type 2 diabetic rats: role of NF-kappa B signaling Eur J Pharmacol 2013 Nov 15 ;720 (1-3):147 -57 2013;720:147-57.

(98) Cheng Z, Schmelz EM, Liu D, Hulver MW. Targeting mitochondrial alterations to prevent type 2 diabetes-Evidence from studies of dietary redox-active compounds. Mol Nutr Food Res 2014 Feb 12 doi : 10 1002 /mnfr 201300747 2014.

(99) Sadi G, Bozan D, Yildiz HB. Redox regulation of antioxidant enzymes: post-translational modulation of catalase and glutathione peroxidase activity by resveratrol in diabetic rat liver. Mol Cell Biochem 2014 Aug ;393 (1-2):111 -22 doi : 10 1007 /s11010 -014 -2051 -1 Epub 2014 Apr 17 2014;393:111-22.

(100) Kowluru RA, Santos JM, Zhong Q. Sirt1, A Negative Regulator of Matrix Metalloproteinase-9 in Diabetic Retinopathy. Invest Ophthalmol Vis Sci 2014 Jun 3 pii : IOVS -14-14383 doi : 10 1167 /iovs 14-14383 2014.

(101) Konings E, Timmers S, Boekschoten MV, Goossens GH, Jocken JW, Afman LA, et al. The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men. Int J Obes (Lond) 2014 Mar ;38 (3):470 -3 doi : 10 1038 /ijo 2013 155 Epub 2013 Aug 20 2014;38:470-3.

(102) Bashmakov YK, Assaad-Khalil SH, Abou SM, Udumyan R, Megallaa M, Rohoma KH, et al. Resveratrol promotes foot ulcer size reduction in type 2 diabetes patients. ISRN Endocrinol 2014 Feb 20 ;2014 :816307 doi : 10 1155 /2014 /816307 eCollection 2014 2014;2014:816307.

(103) Xie S, Sinha RA, Singh BK, Li GD, Han W, Yen PM. Resveratrol induces insulin gene expression in mouse pancreatic alpha-cells. Cell Biosci 2013 Dec 13;3(1):47 doi : 10 1186 /2045 -3701 -3-47 2013;3:47.

(104) Liu K, Zhou R, Wang B, Mi MT. Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. Am J Clin Nutr 2014 Apr 2;99 (6 ):1510 -1519 2014;99:1510-9.

(105) Shetty AK. Promise of resveratrol for easing status epilepticus and epilepsy. Pharmacol Ther 2011 Sep ;131 (3):269 -86 doi : 10 1016 /j pharmthera 2011 04 008 Epub 2011 Apr 28 2011;131:269-86.

(106) Gorbunov N, Petrovski G, Gurusamy N, Ray D, Kim dH, Das DK, et al. Regeneration of infarcted myocardium with resveratrol-modified cardiac stem cells. J Cell Mol Med 2012 Jan ;16 (1):174 -84 doi : 10 1111 /j 1582 -4934 2011 01281 x 2012;16:174-84.

(107) Renaud J, Bournival J, Zottig X, Martinoli MG. Resveratrol protects DAergic PC12 cells from high glucose-induced oxidative stress and apoptosis: effect on p53 and GRP75 localization. Neurotox Res 2014 Jan ;25 (1):110 -23 doi : 10 1007 /s12640 -013 -9439 -7 Epub 2013 Nov 12 2014;25:110-23.
en de it ru fr sp +3630-6125826

eXTReMe Tracker

More information about Fasting&Cleansing program read here

Copyright © 2016-2024 Terms / Contact us / Home / Sitemap / Affiliate / Links / Shop