Resveratrol, Multiple Bioactivities for a Wide Range of Health Benefits. New Innovative Extracts for Nutraceutical, Pharmaceutical, and Cosmetics Applications

Abstract

Resveratrol (trans-resveratrol or 3,4′,5-trihydroxystilbene) is a polyphenol naturally present in grape skin and seeds. New innovative concentrated extracts produced by microorganisms or with innovative, ecological extraction techniques allow a new generation of high-quality ingredients for a diversity of product applications in nutraceuticals, cosmetics, and pharmaceuticals. Resveratrol exerts antioxidant and anti-inflammatory properties while promoting sirtuins 1 activities and mitochondrial functions. It also modulates multiple cellular signaling molecules, such as VEGF, caspases, cytokines NF-kB, vascular cell adhesion molecule, IGF-1, PPARs, and COX-2. Its clinical benefits have been demonstrated mainly in cognitive health, menopause, bone health, cardiovascular health, glucose metabolism, sport nutrition, and skin health. This chapter reviews the bioactivities of resveratrol, its clinical benefits, and detail its potential applications in several product categories in the growing field of health and nutrition product innovation. Resveratrol-based products may participate to provide new natural and complementary solutions for a global approach to health support and maintenance.

1. Introduction

Resveratrol (3,5,4′-trans-trihydroxystilbene) is a polyphenolic phytoalexin, which enters into the stilbene category. It is a naturally occurring molecule that is commonly found in grape skin and seeds but is also present in wines and various other types of plant-based conventional foods, especially tea or berries. Resveratrol possesses two phenol rings (monophenol and diphenol) bonded together by a double styrene bond, and it exists in both cis and trans isomeric forms (Figure 1). Trans-resveratrol appears to be the more abundant and stable natural form for several months [1].

Figure 1.

Resveratrol chemical structure.

2. Resveratrol modulates a wide range of cellular pathways, which triggers multiple bioactivities relevant to human health

2.1 Antioxidant properties

Oxidative stress is defined as an imbalance between the generation of reactive oxygen species and the antioxidant defense system of the body in favor of oxidant production (Figure 2). Enhanced oxidative stress damages macromolecules, DNA, and cellular activities, and impairs cell metabolism, which underlies several age-related diseases, including cancer, diabetes, chronic kidney disease, and cardiovascular and neurodegenerative diseases. Overproduction of reactive oxygen species (ROS) induces inflammation, dysregulation of mitochondria, and cell death. Resveratrol has an inhibitory effect on excessive ROS production, aberrant mitochondrial distribution, and lipid peroxidation [2, 3]. Resveratrol decreases ROS production in epidermal keratinocytes [4] astroglial cells and prevents hepatic steatosis in HFD-induced obese mice by reducing chronic inflammation and oxidative stress [5]. Resveratrol intake by diabetic rats at a dose of 5 mg/kg/day leads to normalization of antioxidant status, exacerbated by oxidative stress induced by hyperglycemia [6]. Resveratrol also attenuates oxidative stress in rats with experimental periodontitis [7], induced early Alzheimer’s disease [8], and chronic obstructive pulmonary disease [9].

Figure 2.

Main cellular pathways modulated by resveratrol and mechanisms of actions involved.

2.2 Anti-inflammatory action

Resveratrol suppresses IL-6 production and secretion by macrophages [10]. Moreover, the administration of resveratrol to monocyte cultures leads to a decrease in the expression of inflammatory mediators, such as TNF-α and IL-8, without triggering cytotoxicity [11]. Resveratrol is involved in the inhibition of toll-like receptors (TLR), which in their active form may modulate proinflammatory cytokines production and chemokine expression, and stimulate the activation of innate and adaptive immunity [12]. Resveratrol reduces matrix-metalloprotease (MMP) expression and suppresses the production of IL-1, IL-6, and TNF-α in a dose-dependent manner in chondrocytes in a model of osteoarthritis. Resveratrol effectively inhibits NF-κB signaling by inhibiting the activity of NF-κB, as well as by suppressing the phosphorylation of JAK/STAT signaling pathways [13]. The supplementation with 500 mg resveratrol is associated with a reduction of the levels of proinflammatory mediators and the inhibition of NF-kB activity in patients with active ulcerative colitis, a chronic intestinal inflammatory disease [14]. The activation of the sirtuin 1 pathway by resveratrol triggers the decrease in NF-kB-induced pro-inflammatory mediators’ levels, such as TNF-a, IL1b, IL6, MMP-1, MMP-3, and COX-2.

Macrophages differentiate from blood monocytes and participate in both innate and adaptative immunity. Resveratrol triggers an anti-inflammatory profile in macrophages. Several studies demonstrated that resveratrol exerts anti-inflammatory effects by attenuating TLR4-TRAF6, mitogen-activated protein kinase (MAPK), and AKT pathways in LPS-induced macrophages. Another signaling pathway that has been linked to inflammation is the endoplasmic reticulum (ER) response. More recently, it was shown that resveratrol prevents the increase of acetylated α-tubulin caused by mitochondrial damage in macrophages stimulated with inducers of the nod-like receptor family, pyrin domain containing 3 (NLRP3) [15]. It may also dose-dependently increase NK cell activity considered a primary line of defense in innate immunity [12].

Resveratrol also strongly reduces the production of granulocyte-macrophage colony-stimulating factor (GM-CSF), a pro-inflammatory cytokine that acts at the interface between innate and adaptive immunity essential for survival, the differentiation and activation of pro-inflammatory macrophages, and a key marker of atheroma formation.

2.3 Anti-glycation activity

Glycation is a chemical reaction between reducing sugars and proteins, leading to the synthesis of advanced glycation end products (AGEs) molecules. They accumulate and trigger damage at cellular levels, including endothelial dysfunction, abnormal cellular activity, alterations of protein conformation, and lipid peroxidation. Increased glycation is associated with a higher prevalence of diabetes and related complications and is also present in neurodegenerative diseases. Glycation forms highly reactive dicarbonyl compounds, such as methylglyoxal and glyoxal, which are key precursors to the production of AGE, enhancing oxidative stress in the tissues. Resveratrol supplementation in drinking water to chronic MG-treated rats significantly reduces the level of advanced oxidation protein products (AOPP), AGEs, and protein carbonyl in plasma, as well as markers of oxidative stress in the liver [16]. Moreover, resveratrol at doses ranging from 1 to 100 μM displays a protective effect in endothelial cells exposed to a high glucose-induced damage challenge. Resveratrol also inhibits the production of methylglyoxal-induced endothelial alterations by the stimulation of eNOS in the thoracic aorta in aging rodent model. Resveratrol prevents opacification and formation of polyols in the bovine lens, and improves kidney function due to suppression of AGEs formation, suggesting that resveratrol may be considered a protective agent against diabetic complications, such as cataracts and nephropathy [17, 18].

2.4 Neuroprotective action

Administration of resveratrol improves cognition, learning, and memory in a rodent model of vascular dementia. This preliminary result constitutes an interesting and encouraging finding in cognitive health and healthy aging areas [19]. Resveratrol also improves cognition and induces neuroprotection in amyloid and tau pathologies in mice models of Alzheimer’s disease [20]. Resveratrol displays a neuroprotective effect in a rodent model of cerebral ischemia/reperfusion injury. Resveratrol supplementation decreases the cerebral infract volume and activates JAK2, PI3K, or Akt expression, as well as anti-apoptotic molecules. Moreover, it also inhibits the expression of pro-apoptotic caspase-3 and Bax. Interestingly, resveratrol enhanced novel object recognition performances of aged rats. In addition, resveratrol enhanced cerebral blood flow during novel object recognition task in aged rats. Several pathways related to inflammation and oxidative stress, such as eicosanoid signaling, IL6, NO and ROS synthesis, and MIF-induced innate immunity were decreased in treated groups compared to control group [21]. Several neuroprotective actions of resveratrol have been suggested in the studies of its effects in intracerebral hemorrhage [22], cerebral neurodamage [23], and central nervous system injuries, such as stroke [24]. Moreover, additional preclinical studies confirm these findings in neuroprotective and cognitive-enhancing properties. The protection of resveratrol treatment on hippocampal plasticity and memory performance in female Balb/C mice has revealed positive preliminary results. Resveratrol induced neuronal differentiation in adult hippocampal precursor cells without affecting the proliferation in vitro [25]. Also, resveratrol intervention improved behavioral performance, increased the production of new neurons, elevated the population of double cortin-expressing intermediate cells, and promoted hippocampal neurogenesis in vivo. Furthermore, after intraventricular injection of resveratrol for 7 days, the long-term memory formation and the long-time potentiation induction from hippocampus were improved in C57BL/6 J mice, while these effects were blocked in SIRT-1 mutant [26], suggesting the neuroprotective and cognitive support is mediated through SIRT-1 signaling in the aging brain. Resveratrol-treated animals showed improved learning, memory, and mood functions. Resveratrol also increased net neurogenesis and microvasculature, decreased astrocyte hypertrophy, and microglial activation in the hippocampus [27].

Resveratrol showed protective effects against neurodegenerative diseases by enhancing the secretion of neurotransmitters, increasing the production of new neurons, decreasing neuroinflammation and oxidative stress, reducing neuronal apoptosis, and promoting hippocampal neurogenesis [28, 29]. However, these results need to be confirmed at the clinical stage in further studies with a specific patient categorization to adapt the supplementation strategy.

2.5 Antiaging action

Resveratrol is a polyphenolic sirtuin activator (SIRT-1), the first step in the process of deacetylation of peroxisome proliferator-activated receptor-coactivator (PGC-1a), which further modulates the genomic transcription of genes involved in mitochondrial metabolism. Resveratrol through the signaling cascade may be a regulator of multiple metabolic processes by activating SITR-1, which is present in many tissues, such as muscles, pancreas, and adipose tissues [30]. Administration of resveratrol (500 mg/day) in healthy and overweight subjects resulted in higher gene expression and serum concentration of sirtuin-1 [31], confirming the preclinical findings. Sirtuins exhibit a broad spectrum of bioactivities, including antiaging and anti-inflammatory effects, inhibition of degenerative disorders, such as liver steatosis, as well as improvement of endothelial function. Resveratrol induces neuronal differentiation in murine neuroblastoma cells and the differentiation of monocytes to macrophages. Intragastric administration or resveratrol causes activation of cardiac stem cells, an increase of capillary density, and reduction of apoptosis of cardiomyocytes, which may be beneficial in myocardial regeneration after acute myocardial infarction. Furthermore, by reducing the expression of perilipin 5, resveratrol accelerates lipid hydrolysis in brown adipose tissue, which may cause a decrease in weight and myocardial steatosis of heart tissue [32]. Supplementation with 0.04% resveratrol for 6 months in aging mice also reduces fatigue and enhances skeletal muscle function. Moreover, a daily dose of 500 mg of resveratrol relieves joint pain and stimulates the daily activity of patients with knee osteoarthritis [33]. Farrokhi et al. [34] demonstrated that 120 μM resveratrol reduced the production of matrix metalloproteinase 9, involved in atherosclerosis etiology.

Moreover, supplementation may influence DNA methylation and histone modification, pertinent in the context of obesity and energy metabolism. Histones’ posttranscriptional modifications may be modulated by resveratrol. For instance, it influences histone deacetylation via sirtuins, and sirtuins activated by resveratrol can deacetylate sites on PGC1a [35].

Resveratrol may modulate different aspects of aging and tissue maintenance process through SIRT-1 signaling pathways from histone modification, DNA methylation, joint degenerative process, cardiac stem cells regulation, and anti-inflammatory pathways. However, these promising findings of mechanisms of action in aging-related pathologies need to be confirmed in large clinical studies to build new nutritional strategies for aging focused on prevention.

2.6 Action of resveratrol on gut microbiota

Upon ingestion, resveratrol migrates through the gastrointestinal tract. Approximately 70% of the resveratrol intake is absorbed. During digestion and absorption, resveratrol binds to several nutrients, such as proteins, and the solubility of these will influence resveratrol absorption or excretion [36]. About 70–75% may enter the enterocyte, while the remaining 25% is directly excreted. Once inside the cell, 60% is glucuronidated and 13.5% is sulfated. These conjugates partially return to the intestine, leaving 17% glucuronides and 1.5% sulfates in the bloodstream [35]. The gut microbiota actively participates in resveratrol metabolism by increasing its availability from resveratrol precursors and producing resveratrol derivatives. A fraction is absorbed in the colon, where they are metabolized by the gut microbiota into low molecular weight phenolic compounds to be then transported to the liver, where they undergo further metabolizations: leading to the production of dihydroresveratrol, 3,4′- dihydroxy-trans-stilbene, and 3,4′-dihydroxybibenzyl, as main known metabolites to date. The bioactivity of resveratrol metabolites may be higher for some than resveratrol itself, and the antioxidant and anti-inflammatory of dihydroresveratrol was detected both in vitro and in vivo [30]. The exact bioactivities of resveratrol derivatives are not exactly well known.

It has been reported that resveratrol may also modulate gut microbial composition, while microbiota also regulates resveratrol biotransformation. Resveratrol is known to modulate the composition of the gut microbiota with a decrease in opportunistic pathogenic bacteria in vivo. Qiao et al. demonstrated that resveratrol supplementation at the daily dose of 200 mg/kg/d for 12 weeks promotes a higher Bacteroidetes-to-firmicutes ratio in western-diet-fed mice. In addition, the number of lactobacillus and Bifidobacterium was significantly increased in resveratrol-fed animals [37]. They are closely linked with redox signaling in mucosal epithelial cells, which plays a critical role in maintaining gut homeostasis. Moreover, Enterococcus faecalis, a pathogenic bacterium, was significantly decreased in resveratrol-fed mice. Similarly, recent evidence suggests that the relative abundance of Bacteroides, lactobacillus, Bfidobacterium, and akkermansia is increased with resveratrol supplementation. These effects on the modulation of the gut flora may be associated with anti-obesity effect. Resveratrol administration leads to an increase in the number of lactobacillus species and a decrease in the number of E. faecalis and E. coli in high-fat diet (HFD) mice. Both E. faecalis and E. coli are positively correlated with colonic ROS and MDA levels. Resveratrol also inhibits the growth of Bacteroides and Desulfovibrionaceae spp.; enhancing the proportion of blautia and dorea in the lachnospiraceae family, participating in the improvement of lipid and glycemic profile in HFD-rodent model of metabolic alterations and obesity. This was confirmed in another study. In HFD mice, resveratrol supplementation modulated the microbiota composition, suggesting a prebiotic action. The microbiota changes were characterized by a decreased abundance of pathogenic bacteria, such as desulfovibrio, lachnospiraceae_NK4A316_group, and alistipes, as well as an increased abundance of short-chain fatty acid (SCFA)-producing bacteria, such as allobaculum, Bacteroides, and blautia. Moreover, transplantation of the HFD resv-microbiota into HFD group triggers a reduction in body weight, chronic inflammation, and improved liver steatosis and hepatic lipid metabolism [38]. Resveratrol treatment for 25 days in DSS-colitis rat model leads to beneficial effects on the colon, including the modulation of the inflammation-associated genes, colonic mucosa architecture normalization, and the modulation of NF-kB pathway. Resveratrol administration can also rebalance normal intestinal microbiota in bacterial composition.

These data suggest a prebiotic activity of resveratrol, which modifies the variability and composition of the intestinal microbiota, with a decrease in the firmicutes/Bacteroidetes ratio, which is increased in obese patients [39].

Resveratrol may reduce chronic inflammation through changes in the gut microbiota. Resveratrol and its microbial metabolites may inhibit the increased levels of ROS, activate Nrf2 signaling, and improve oxidative stress associated with chronic inflammatory conditions. They also protect epithelial barrier function and help decrease the activation of NF-𝜅B and intestinal inflammation. Resveratrol may also modulate gut microbiota composition by enhancing beneficial endogenous strains, such as bifidobacterial or lactobacillus, and inhibit harmful pathogens [40].

2.7 Cardiometabolic action of resveratrol

Oral administration of resveratrol activates SIRT-1 and its targets, such as nuclear factor kappa B (NF-kB) and (PGC-1a) in mammalian tissues. PGC1a, a key regulator of energy metabolism, leads to decreased glycolysis in muscle and the liver, and increased lipid catabolism. As a consequence, it influences both glucose metabolism and lipid metabolism, inhibiting their accumulation. Resveratrol promoted SIRT-1 and also SIRT-5, which are involved in cellular energy homeostasis and cellular longevity [41]. Its consumption improves insulin secretion, decreases insulin resistance by protecting pancreatic beta cells from oxidative stress and by improving insulin metabolism. Furthermore, resveratorl consumption is also associated with reduction in fasting blood glycemia and Hb1ac. Resveratrol activates AMPK, which upregulates insulin receptor substrate-1 as part of insulin signaling modulation. Resveratrol activated AMPK-a and promoted mitochondrial biogenesis in the skeletal muscle of diet-induced insulin-resistant rodents [42, 43]. Resveratrol reduces the expression of adiponectin, which regulates insulin sensitivity [44, 45, 46]. Franco et al., (2014) demonstrated that in a rodent model programmed to be at risk of obesity and leptin resistance by early weaning, resveratrol suppressed leptin resistance, which prevents body weight gain, hyperphagia hyperglycemia, insulin resistance and visceral obesity in adult rats. In tissues, where SIRT-1 is present, resveratrol controls the insulin responses of target cells [47]. In the liver, SIRT-1 acts on gluconeogenesis. Therefore, resveratrol is considered to mimic the effects of a low-calorie diet, which improves cell turnover by slowing down the aging process [48].

In adipose tissue, resveratrol inhibits the process of the formation and accumulation of fat in the white adipose tissue. Moreover, resveratrol has been demonstrated to decrease body fat accumulation and leptin messenger ribonucleic acid (mRNA) levels and improve insulin sensitivity [49]. Resveratrol-induced reduction in fat mass is due to the activation of lipolysis through the adipose triglyceride lipase and the inhibition of de novo lipogenesis with the modulation of lipogenic enzymes and sterol regulatory element-binding protein-1c [36]. Resveratrol stimulates the production of brown adipose tissue and activates its metabolism by enhancing AMPK-α1 signaling in HFD mice. Moreover, activation of AMPK and SIRT-1 signaling with resveratrol, induces the browning of WAT. Resveratrol supplementation triggers SIRT-1 induced activation of PPAR signaling and PGC-1α in adipocytes, leading to fat browning [41, 50]. Resveratrol treatment has been demonstrated to decrease lipogenesis and increase lipolysis; thus, having an anti-obesity effect. It has also been shown to increase the capacity of thermogenesis in brown adipose tissue. Resveratrol treatment inhibited preadipocyte proliferation, adipogenic differentiation, and inflammatory cytokines production in a SIRT1-dependent manner.

Resveratrol may activate SIRT-1 and SIRT-3, and further improve mitochondrial metabolism, which in turn decreases ROS production, increases FA oxidation, and inhibits the damage of fatty acid synthase (FAS). As a consequence, resveratrol increases mitochondrial biogenesis and decreases mitochondrial uncoupling protein-2 (UCP-2) expression by activating SIRT-1 in β-cells [51].

Resveratrol may also improve some risk factors of cardiovascular health. The administration of resveratrol results in a reduced formation of trimethylamine-N-oxide (TMAO), a metabolite of carnitine and choline, considered as a risk factor for heart attack and stroke as it activates platelet activity, enhancing the risk of thrombosis. IL-1, IL-6, C-reactive protein, and the transcriptional activity of nuclear factor kappa B (NF-kB), which regulate inflammatory processes and immune responses, are reduced in patients with cardiovascular diseases, showing improvements in hypertension and ischemic heart disease risk [52]. Moreover, resveratrol treatment significantly lowered aorta media thickness, inflammation, fibrosis, and oxidative stress in aged male C57BL/6 mice compared to the control group, protecting against arterial aging by modulating the activity of the renin-angiotensin system [41]. Resveratrol could reduce superoxide generation, enhance NO level, and improve oxidative stress; thus, protecting against aging-associated vascular diseases [53, 54].

Other animal studies, mainly conducted in rats, have shown a reduction of abdominal fat, lipoprotein lipase, and ACC activities after treatment with resveratrol the anti-obesity effect of resveratrol is partly due to alteration in the gut microbiome and its related consequences [55].

Various different studies have reported that resveratrol has a high value to decrease insulin resistance, and improve glucose, lipid homeostasis, and cardiometabolic risk [35, 51, 56] through sirtuine signaling pathways, antioxidant, anti-inflammatory, and gut microbiota modulation (composition and bioactivities).

3. Resveratrol consumption is associated with promising health benefits: review of clinical data

Resveratrol is associated with many preclinical benefits demonstrated in a wide range of health axis. At the clinical evidence stage, the strength of evidence differs depending on number of studies available, heterogeneity in trial design and methodology, duration of studies, and population profile. This part will summarize the clinical evidence available in diabetes, obesity, cardiovascular health, metabolic health, and women health, based on meta-analysis and Randomized Controlled Trials (RCT) (Figure 3).

Figure 3.

Main clinical benefits reported by resveratrol and associated conditions of use.

3.1 Diabetes

Diabetes is a silent disease that is associated with inappropriate eating habits and lifestyles. By 2045 more than 11% of the world population would be diagnosed. Diabetes is an important risk factor for mortality since it is associated with years of life lost. In addition to elevated fasting glycemia, diabetic patients often have metabolic syndrome comorbidities, such as obesity, hypertension, and dyslipidemia, all of which enhance the risk of diabetic complications, especially cardiovascular diseases. Moreover, clinical data also suggested that 30–40% of patients will have at least one complication about 10 years after the onset of diabetes, suggesting the importance of a new nutritional approach and complementary approach.

A first meta-analysis included randomized clinical trials with humans that evaluated the effects of resveratrol supplementation, compared to placebo, in type 2 diabetes treatment or prevention [57]. 24 RCT were included. Results showed that resveratrol supplementation had no significant effect on fasting blood glucose compared to placebo. However, results showed that there was a significant reduction in insulin resistance in individuals treated with resveratrol. Resveratrol also showed a significant reduction in Hb1ac after a duration of use of more than 8 weeks. A previous meta-analysis that included only individuals with diabetes showed benefits from resveratrol supplementation on diabetes parameters like fasting blood glucose and insulin resistance [58].

A third meta-analysis included 19 studies involving 1151 patients with type 2 diabetes, including 584 patients treated with resveratrol and 567 patients who received a placebo [59] gives interesting additional insights. Compared with the control data group, large doses of resveratrol (≥1000 mg) reduced fasting blood glucose levels. Additionally, resveratrol reduced systolic blood pressure and diastolic blood pressure in patients with type 2 diabetes but did not improve waist circumference triglyceride levels or high-density lipoprotein cholesterol levels in patients with type 2 diabetes. A daily dose of resveratrol ranging from 5 mg to 5 g for at least 12 months improves glycemia and insulin sensitivity in diabetic patients These meta-analysis pointed out promising results in DT2 patients supplemented with resveratrol for at least 8 to 12 weeks. The minimal effective dose needs to be determined for each DT2 patient profile, taking into account medical history and/or comorbidities.

3.2 Obesity

The first meta-analysis on 7 RCT on overweight and obese (BMI > 25) with or without comorbidities linked to obesity and daily doses ranging from 40 to 3000 mg/day [60] shows that the majority of studies were carried out with a supplementation superior to 150 mg/day for at least 4 weeks. A higher daily dose of resveratrol ranging from 400 to 600 mg was associated with improvements in insulin sensitivity, lipid profile, metabolic flexibility, total antioxidant capacity, increase in energy expenditure and reduction of ectopic accumulation of fat. Moreover, a lower dosage at 150 mg/day for 30 days significantly decreased the metabolic rate of sleep in obese patients without increaseing the energy expenditure. There was also an increase in 24 h respiratory quotient values, mainly during the day and postprandial period, suggesting an improvement in metabolic efficiency. After 4 weeks of supplementation at a daily dose of 150 mg in patients with obesity, there was an increase in SIRT-1 and an improvement in insulin sensitivity by lowering insulin concentration and HOMA-IR, compared to placebo.

A second meta-analysis included 28 randomized controlled trials, which were included on obese adults, healthy adults, and chronic inflammatory diseases including NAFLD, diabetes, and metabolic syndrome mainly [61]. Pooled effect sizes suggested a significant effect of resveratrol administration on weight, BMI, and waist circumference. No significant effect of resveratrol supplementation on fat mass was found. Subgroup analysis revealed a significant reduction in body weight and BMI for daily dosage <500 mg, those with long-term interventions (≥3 month), and performed on people with obesity.

A third meta-analysis on RCT was conducted to summarize the effect of resveratrol intake on weight loss [62]. Out of 831 reports, 36 RCTs were eligible for inclusion in our meta-analysis. The pooled results, using a random-effects model showed that resveratrol supplementation significantly decreased body weight, BMI, and waist circumference, which confirmed the results of Mousavi et al. The impact on weight loss was significant in sub-group analysis for obese and diabetic people. Overall, resveratrol intake significantly reduced weight, BMI, WC, and fat mass, and significantly increased lean mass, but did not affect leptin and adiponectin levels.

3.3 Cardiovascular health

In vitro and in vivo studies demonstrated that resvereatrol has antiatherogenic, antihypertensive properties. It also promotes vasodilatation through the increase of NO production. Moreover, resveratrol reduces vascular oxidative stress, prevents vascular remodeling and reduces arterial stiffness. In addition, resveratrol also inhibits immune cell infiltration into the vascular wall and mitigates vascular inflammation [63]. Two recent meta-analyses assessed the potential clinical benefits on cardiovascular health.

The first meta-analysis on 17 randomized clinical studies on 681 subjects [64]. The daily dose ranged from 75 to 3000 mg/day and the duration was from 4 weeks to 6 months. No significant effect was observed on BP, SBP, or DBP. A significant weight mean difference in the diabetic population was observed. A positive association between SBP and BMI was significant. The cardiovascular factors were improved, especially at higher doses than 300 mg/day in the diabetic population. Another meta-analysis, including 6 RCT, comprising a total of 247 subjects were selected. Resveratrol consumption may not significantly reduce SBP and DBP. Subgroup analyses indicated that higher-dose of resveratrol consumption (>150 mg/d) significantly reduces SBP, whereas the lower dose of resveratrol did not show a significant lowering effect on SBP. The meta-regression analyses did not indicate the dose effects of resveratrol on SBP or DBP [65].

It could be promising regarding the preliminary results observed in clinical studies but additional clinical studies for atherosclerosis, hypertension, stroke, and myocardial infarction are needed to estimate the minimal effective dose, and duration of supplementation for each target population [54]. The minimal effective dose for SBP regulation in hypertension may be >150 mg/day to be confirmed in additional clinical studies on hypertensive subjects.

3.4 Metabolic health

Chronic diseases are generally slow-progressing and long-duration diseases. They are also named noncommunicable diseases. Based on the definition of World Health Organization (WHO), there are four major noncommunicable diseases, including cardiovascular diseases, cancers, diabetes, and chronic respiratory diseases (World Health Organization, 2013), representing a leading cause of death.

A first meta-analysis reviewed the effect of supplementation on noncommunicable disease risk factors, such as fasted glycemia, lipid profile, and BP [66]. Out of the total, 29 RCTs with 1069 participants were included. The dose of resveratrol supplementation ranged from 10 to 3000 mg, and the duration of intervention lasted from 4 weeks to 12 months. Resveratrol supplementation significantly reduced blood fasting glucose, total cholesterol, and CRP. Resveratrol supplementation is associated with significant reductions in SBP and DBP in DT2 patients. Subgroup analysis demonstrated that the clinical studies with resveratrol intervention superior to 3 months significantly reduced the LDL-cholesterol, DBP, and HbA1c values. However, no significant improvement was found in HDL-C TG, and insulin resistance score (HOMA-IR) after resveratrol supplementation.

A second meta-analysis was performed on 21 RCT, including NAFLD, diabetic patients, healthy adults, and adults with dyslipidemia [67]. The daily doses range from 10 to 500 mg/day and the duration of supplementation is from 4 to 12 weeks. The results have shown that it may significantly reduce total cholesterol, but no significant effects on LDL-C, HDL-C, and TG were observed. The differences between both meta-analyses may vary in lipid profile, depending on the type of population selected in the analysis.

Resveratrol treatment has also demonstrated clinical benefits on glucose and lipid metabolism confirmed in a meta-analysis. Study population, resveratrol source, and daily dose have varied greatly, potentially explaining inconsistent findings. Improvements were mainly observed in endothelial function, systolic blood pressure, as well as markers of oxidative stress and chronic inflammation in several studies [68]. Resveratrol supplementation significantly decreased body weight, BMI, and waist circumference based on several recent meta-analyses. Further clinical studies are needed to optimize and adapt the conditions of use (dose, duration) for specific patients’ profile (diabetes, metabolic health, obesity, and cardiovascular health) but promising clinical evidence shows the potential of resveratrol for cardiometabolic health management as a complementary approach to medical usual care.

3.5 Cognitive health

The societal impact of age-related cognitive decline is likely to be compounded by the global aging population, with a predicted doubling in the number of persons aged >60 years by 2050. Resveratrol reduces inflammatory cytokine release, improves mitochondrial energetic function, and improves Ab-peptide clearance by activating SIRT-1 and AMPK [69]. Some positive findings on depression rodent models as a potential mood-enhancing agent are promising [70]. A meta-analysis was also conducted to determine the treatment effect on the following cognitive domains and mental processes: processing speed, number facility, memory, and mood [69]. In total, 10 studies were included on 372 individuals. Three studies found resveratrol supplementation significantly improved some measures of cognitive performance, two reported mixed findings, and five found no effect. When data were pooled, resveratrol supplementation had a significant effect on delayed recognition and negative mood. The results of this review indicate that resveratrol supplementation might improve select measures of cognitive performance. The dose of resveratrol used in the included studies ranged from 75–500 mg with no clear dose-dependent effect, suggesting that the differences in trial results may potentially not be due to the dosage used. Resveratrol shows promise as a complementary treatment in neuroprotection agents by improving cognitive function and reducing AD pathologies, such as Ab. These benefits seem to be driven by improvements in brain metabolism through the regulation of ROS production, inflammation, and by preventing mitochondrial dysfunction. The benefits of resveratrol on brain health highlight that alteration in brain metabolism drive the future potential severity of the cognitive decline. The impact of inflammation and mitochondrial dysfunction on neuronal health explains to the promise on cognition as a neuroprotective agent [71, 72]. Further clinical studies are needed in this field of research due to promising preliminary findings.

3.6 Women’s health

Menopausal women have an increased risk of developing NCDs due to hormonal dysregulation and the ongoing aging process. Menopause is also linked to various daily discomfort due to estrogen deficit and hormonal changes, such as vasomotor symptoms (diurnal hot flushes and night sweats), muscular and joint weakness or pain, sleep disorders, mood variations, vaginal dryness, skin dryness, and wrinkles appearance, which impacts the quality of life of women, body image, and their social interaction. The prevalence of dementia is from 14–32% higher for women than for men over 65 years old; by the age of 80, women account for 63% of dementia sufferers worldwide and this difference is expected to become more pronounced [73].

A pilot study in overweight and obese postmenopausal women with high body mass index (BMI ≥ 25 kg/m2) to determine the clinical effect of resveratrol on systemic sex steroid hormones [74]. Forty subjects initiated the resveratrol intervention (1 g daily for 12 weeks). Resveratrol intervention triggers a 10% increase in the concentrations of sex steroid hormone binding globulin (SHBG) notably. Resveratrol intervention resulted in 73% increase in urinary 2-hydroxyestrone (2-OHE1) levels leading to a favorable change in the urinary 2-OHE1/16α-OHE1 ratio.

Lymphocytes from 13 healthy menopausal women were isolated and then cocultured with hTERT-HME1, a breast cell line with a precancerous phenotype. The results demonstrated that resveratrol treated lymphocytes significantly increased TNF-a production, the formation of immune synapses, and the target cell lysis. No significant effect was observed in the lymphocyte total antioxidant capacity. These results demonstrate that resveratrol may stimulate immune surveillance in menopausal women by increasing the cytotoxic activity of lymphocytes [75].

A first meta-analysis analyzed the effect of resveratrol on bone health, and relevant to women’s health [76]. Pooling six RCTs (eight treatment arms with 264 subjects) together. The dose of resveratrol ranged from 150 to 1500 milligrams per day. The duration of intervention also varied from 6 to 24 weeks, and no significant reduction of serum calcium, osteocalcin, C-terminal telopeptide of type I collagen, and procollagen I N-terminal propeptide values after resveratrol supplementation over placebo treatment. However, a significant increase in serum alkaline phosphatase (ALP) and bone alkaline phosphatase (BAP) values was observed after resveratrol treatment relative to placebo. The findings of this meta-analysis indicate that resveratrol supplementation increased some key bone biomarkers, such as ALP and BAP. This was confirmed in another large RCT in chronic use. The resveratrol for healthy aging in women (RESHAW) trial was a 24-month randomized, double-blind, placebo-controlled, and two-period crossover intervention carried out to assess the effects of resveratrol supplementation (75 mg twice daily) on cognition, cerebrovascular function, bone health, and cardiometabolic markers in 129 postmenopausal women [77]. After 12 months of supplementation, there were positive effects on bone density measured in the lumbar spine and neck of the femur, which was accompanied by a 7.24% reduction in C-terminal telopeptide type-1 collagen levels, a bone resorption marker, and compared with placebo. The increase in bone mineral density in the femoral neck resulted in a reduction in the 10-year probability of major and hip fracture risk. In the crossover comparison, the benefit of resveratrol over placebo on lumbar spine BMD was enhanced in those who regularly supplemented with both vitamin D and calcium compared with the calcium-only group [78]. The chronic supplementation of resveratrol combined with vitamin D and calcium may be interesting as a prevention strategy for bone weakness, fractures, and falls in menopausal women.

Eighty postmenopausal women aged 45–85 years were randomized to consume trans-resveratrol at a daily dose of 150 mg or placebo for 14 weeks. The effects of resveratrol on cognitive performance, cerebral blood flow velocity, and pulsatility index (a measure of arterial stiffness) in the middle cerebral artery and cerebrovascular responsiveness (CVR) were measured. Mood questionnaires were also administered. Resveratrol displayed 17% increases in CVR to both hypercapnic and cognitive stimuli compared to placebo group. Significant improvements were also observed in mental performance in the domain of verbal memory and in overall cognitive performance, which correlated with the increase in CVR. Following resveratrol supplementation, anxiety was significantly reduced. No significant changes were observed in other components of the POMS or in depressive symptoms [79].

Another 14-week randomized, double-blind, placebo-controlled clinical trial with resveratrol (75 mg, twice daily) was carried out in 80 healthy postmenopausal women [77]. Pain, menopausal symptoms, sleep quality, depressive symptoms, mood, and quality of life were assessed by SF-36 questionnaire at baseline and end of treatment. Compared with the placebo treatment, there was a significant reduction in pain and an improvement in total well-being after resveratrol supplementation. Benefits in quality of life are correlated with improvements in cerebrovascular function.

A 24-month randomized, placebo-controlled study was carried out in 125 postmenopausal women, aged 45–85 years, who consume 75 mg of resveratrol and a placebo twice daily for 12 months for each treatment in a cross-over design [79]. Compared to placebo, resveratrol supplementation resulted in a significant 33% improvement in overall cognitive performance. Women >65 years of age showed a relative improvement in verbal memory with resveratrol compared to those younger than 65 years. Furthermore, resveratrol improved secondary outcomes, including resting mean CBFV (cerebral blood flow velocity), fasting insulin, and insulin resistance index (HOMA-IR); Regular supplementation with low-dose resveratrol may enhance cognition, cerebrovascular function, and insulin sensitivity in postmenopausal women, to be confirmed in additional studies.

Formulations with resveratrol may also be useful for skin health maintenance during menopause. It may enhance the proliferation of fibroblasts, contributing to the increase in collagen III production. Resveratrol can bind ERα and Erβ estrogen receptors, participating in the stimulation of collagen types I and II production. RESV-mediated effects on keratinocyte senescence and proliferation are regulated by the AMPK FOXO3 pathway besides than by SIRT-1 [80]. Moreover, resveratrol exerts antioxidant action and may protect cells against oxidative stress associated with the deleterious action of free radicals and UV radiation on the skin by reducing the expression of AP-1 and NF-kB factors. Resveratrol may downregulate the process of photoaging of the skin [81]. Resveratrol has been demonstrated to act on cellular signaling mechanisms related to UV-mediated photoaging, including MAP kinases, nuclear factor kappa B (NF-kB), and matrix metalloproteinases [82]. Additionally, it has antiproliferative, anti-angiogenic, anti-inflammatory, antioxidant, and antimicrobial properties for cosmetic use in topical use or nutricosmetic for improving skin metabolism especially during menopause when hormonal disbalance leads to skin metabolism alterations. Resveratrol, with its structural similarity with diethylstilbestrol, a synthetic estrogen, may be considered a phytoestrogen. Indeed, resveratrol may activate the transcription of estrogen-responsive reporter genes and its action was inhibited by specific estrogen antagonists. This estrogen like effect may increase skin moisturization, skin elasticity, and thickness, as well as reducing skin wrinkles size and increase skin collagen content and the level of vascularization [83].

4. Conclusion

Resveratrol has been clinically tested in a wide range of health axis from cardiometabolic health, including diabetes, obesity, cardiovascular risk factors, neurocognitive health, and women’s health with identified mechanisms of action implying various cellular pathways. Resveratrol is naturally occurring in wine but innovations also produce it as a purified substance from a specific patented chemical process. A novel food application has been granted for resveratrol by EFSA in Europe for use of 99% trans-resveratrol, and the intended intake level of 150 mg/day for adults does not raise safety concerns to be used in food supplements (EFSA Journal 2016;14(1):4368). The bioavailability of resveratrol may be enhanced through the use of a specific production process or the adjunction of quercetin, which is believed to inhibit the sulfation of resveratrol in the body and increase its bioavailability. A food supplement represents a concentrated source of actives to support physiological functions of the body, resveratrol may be used in food supplements targeting women’s health, cognitive health, and metabolic health, which mainly help in transient discomfort and support the natural functions in healthy adults, especially when the body is subject to mental or physical stress, seasonal changes, aging or as an adjunct complementary approach in metabolic in glycemic control, lipid profile, weight management, or cardiovascular risk management.

FSMP are foods for specific medical purposes regulated by European regulatory texts n° 609/2013 and regulation EC 2016/128. For specific pathologies, especially targeting aging, malnutrition, and chronic inflammatory diseases (neurodegenerative disease, NAFLD, diabetes, and IBD). Resveratrol may also be used to modulate physiological signaling pathways involving oxidative stress reduction, anti-inflammatory action, SIRT-1 modulation, and neuroprotective action notably. As a cosmetic ingredient to be used in topical use or in food supplements in nutricosmetics, resveratrol has promising beneficial effects on skin health. Resveratrol may be considered a valuable ingredient in a nutritional complementary approach for various health axis to be confirmed in further clinical and to be considered by healthcare practitioners, dieticians, and pharmacists as a prevention or complementary approach in the personalized nutritional program.