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

Introduction

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.
 
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