There’s a good reason to raise a glass. Of red wine, that is. You may know red wine to have health benefits when consumed in moderation. That’s largely because it contains an antioxidant-rich compound called resveratrol (pronounced rez-vera-trol). 

Resveratrol, which is a plant compound that belongs to a class called polyphenol stilbenoids, is produced in response to injury or when the plant is under attack by invaders such as bacteria or fungi, and even protects the plant from the ultraviolet rays of the sun (1). 

It was only around 1992 that researchers really began looking into the effect of resveratrol on human health, and it has been suggested that it may be protective against many of the most debilitating diseases,  including diabetes, heart disease, cancer and Alzheimer’s (2). 

Resveratrol itself, however, is rapidly metabolized by the liver, meaning it is not very bioavailable (3) as it is used up too quickly and then eliminated before it has any chance to exert any real effect. In our formula, we have combined resveratrol with one of its chemically similar cousins, called pterostilbene (pronounced tear-oh-still-bean) as a buffer. 

Pterostilbene is a primary compound called a polyphenol that is found in blueberries. Because of just a slight difference in its molecular structure, it is far more bioavailable than resveratrol. This means it can cross through cell membranes more easily than its cousin, which allows it to exert its numerous health benefits (4).  

The combination of pterostilbene and resveratrol are thus able to act upon an essential enzyme that’s responsible for ageing and longevity, called sirtuin 1 (SIRT1) (5), through their anti-inflammatory and antioxidant processes. It’s through this mode of action that these nutrients may have a significant effect on the development and progression of disease. 

Resveratrol plays a role in health and disease  

Heart health 

Cardiovascular disease (CVD) is the number one cause of death around the world, and so there’s little surprise that researchers have looked into resveratrol as a natural means to reduce its occurrence, both when used independently and when combined with traditional pharmaceutical medications and therapies. 

In studies conducted on mice, resveratrol has proven to be an effective treatment for heart failure through its action on various essential mechanisms that are involved in heart function (6). Multiple other animal studies have also shown resveratrol’s mechanism of action to increase SIRT1, which has protective effects on heart disease due to a decrease in inflammation. Inflammation is one of the leading causes of CVD (7), playing a role in both its development and severity. 

Clinical trials have corrected the same findings in humans following resveratrol supplementation, with positive decreases being noted in multiple inflammatory markers such as IL-6, TNFa, hs-CRP, plasma interferon and IL-8 (8). 

Multiple other attempts to produce the same clinical results in humans have proven difficult. The doses used in clinical trials vary widely, as does the bioavailability of the products used. Despite often contradictory findings, the effects of oral supplementation with resveratrol on cardioprotective effects are overall positive due to its impact on inflammatory status (9). 

There are generally larger variables in human studies than would be found in animal studies, which may be one reason that there is currently a lack of consensus on dosing and treatment periods when it comes to the variable factors such as cholesterol, endothelial function and high blood pressure, all of which are implicated in the development of CVD (10,11). 

Metabolic health

Diabetes is a common lifestyle disease that is associated with insulin and blood sugar dysregulation. Both rodent and non-human primate studies have shown that resveratrol improved insulin sensitivity and blood sugar metabolism in type 1 and type 2 diabetics (12). The mechanism of action has been shown to involve activation of the AMPK pathway, which decreases glucose release from the liver, a major contributing factor to soaring blood sugar levels in diabetics. Additionally, resveratrol has proven to increase glucose movement across cell membranes and reduce oxidative stress and tissue damage (13). 

There is mounting evidence that resveratrol may also be useful in the therapeutic targets to either prevent or treat metabolic syndrome, which is a combined disease of glucose dysregulation, high blood pressure, high cholesterol and increased body weight. Several mechanisms have been explored in this regard. 

Changes in sirtuin expression have been implicated in the development of metabolic syndrome, and due to resveratrol’s effect on SIRT1 enhancement, research shows it may be useful in treating the condition (14). The benefits of SIRT1 activation have been shown to overlap AMPK activation, which we know is a key metabolic regulatory pathway. In this way, resveratrol has been shown to improve metabolic homeostasis in metabolic syndrome (15). More recently, the effects of resveratrol on gut bacteria has been shown. Resveratrol appears to influence metabolic syndrome through pathways associated with the production of short-chain fatty acids (SCFAs), which are essential metabolites produced by gut bacteria and that affect metabolic balance (16). 

Clinical trials conducted in humans support these findings: a small trial including 24 patients saw a significant decrease in their body weight, a main feature of metabolic syndrome, as well as improved insulin balance following resveratrol supplementation (17). Another study in men concluded that resveratrol has a positive effect on body composition and enhancement in the function of gut bacteria (18). 

Resveratrol has shown to have protective effects against insulin resistance, high blood insulin levels and high blood sugar levels (19,20). 

Brain health 

Diabetes and metabolic syndrome have a significant effect on brain health. Research shows that not only does resveratrol provide benefits in the regulation of metabolic processes, it may reduce the risk of the cognitive effects of metabolic diseases on the brain. The pathways involved in these beneficial aspects include positive effects on brain-derived neurotrophic factor (BDNF) and SIRT1, which has been shown to improve cognitive deficits and spatial memory (21) in diabetics and those individuals with metabolic disease. 

The effects that resveratrol has a positive influence on the brain through other pathways. It’s effect on the gut microbiome has been shown to be beneficial in the treatment of brain disorders with its mode of action via the gut-brain axis (22). This aspect of resveratrol translates significant benefit in those with irritable bowel syndrome as many IBS sufferers have a higher risk of depression and anxiety, which increases the burden of disease. In a rodent model of IBS, rats that exhibited depression and anxiety-like behavior had normalization of their symptoms following chronic treatment with resveratrol (23). 

Stroke is another serious and debilitating condition to consider. The use of resveratrol alongside current therapies suggest there may be a more positive outcome in patients with stroke. Most studies have been conducted in rodent models, which shows how resveratrol and its effects on the SIRT1 and AMPK pathways may reduce brain cell destruction in the event of a stroke and the blood flow restriction to the area of damage (24). In humans, there are no clinical trials to show the effects of resveratrol in stroke patients, however, with evidence to support its use in improving blood flow to the brain in healthy people, there may be potential benefits of using resveratrol in stroke patients (25). 

Both Parkinson’s and Alzheimer’s disease are concerning conditions that affect a large cohort of the elderly population. Research conducted on resveratrol shows promise as an effective treatment therapy for both, where supplementation may protect brain cells against oxidative damage and toxicity, which reduces cell death (26). 

Parkinson’s disease has been simulated in animal models using a neurotoxin. In the common fruit fly, the effects of this toxin involving mechanisms of oxidation and inflammation are investigated and the role of resveratrol on the attenuation of these mechanisms observed. In insects treated with resveratrol, lifespan was increased in a dose-dependent manner, and, in addition, resveratrol appeared to inhibit neurotoxin-related cell death, cellular changes, behaviour deficits and accumulation of oxides, which further contributed to healthspan and lifespan in this sample (27). 

The mode of action in Alzheimer’s, which is the most common form of dementia, offers more insight into resveratrol’s role in brain health and disease. A review study suggests there are various mechanisms that come into play, including antioxidant activity (28) and reduced toxicity in brain cells (29), prevention of NF-kB activation (30) (a compound that is involved in the inflammatory response), and reducing cell death. Additionally, resveratrol may impact the formation and aggregation of misfolded proteins, which is one of the hallmarks of the disease (31). 

In an Alzheimer’s model, mice fed with a resveratrol supplement, there was evidence to show that it induced complete protection against memory loss and disease-related brain deterioration. Additionally, there was a marked reduction in Alzheimer’s related tau protein accumulation, as well as an increase in the enzymes that degrade amyloid proteins. In healthy mice, there was evidence for cognitive enhancement in the resveratrol-fed group. In both samples, there was further indication of wellbeing with the reduction of anxiety and increased efforts to explore their surroundings (32). 

Cancer

Cancer is a leading cause of death around the globe with the World Health Organization stating that 1 in 6 deaths is related to complications linked to cancer (33). Numerous studies have observed the antitumor effects of resveratrol, which provides promising evidence for its use not only in the treatment of cancer, but in its prevention (34). 

Clinical trials conducted on the effects of resveratrol in this case have shown positive results in multiple types of cancer. In a small pilot study on eight patients with colon cancer, resveratrol in the form of dried grape powder was given to the study participants. While the outcomes suggested that there was no effect on the Wnt pathway (that causes the initiation of cancer cells) of cancer cells, there was significant inhibition of the Wnt pathway in healthy colon cells, which may prevent the spread of colon cancer (35). 

Another pilot study included nine patients scheduled to undergo surgery to remove their liver tumor. This time, a resveratrol therapy that used microionization techniques to improve the bioavailability of the compound, determined that a marker of apoptosis, called cleaved caspase-3, was significantly increased by 39% in liver cancer cells when compared to patients that received a placebo. Additionally, with the use of microionized resveratrol, markers of resveratrol concentration were 3.6 times higher than were seen in healthy volunteers receiving non-ionized doses (36). 

Yet another human rtrial, to determine the effects of resveratrol on cancer, this time on how it would impact insulin-like growth factor (IGF1), was conducted in healthy volunteers. IGF1 is an important hormone for growth and development, and higher levels have implications in the development and growth of tumor cells. Various doses of resveratrol from 0.5g to 5g daily were given to the volunteers for 29 days. At a daily dose of 2.5g, the levels of circulating IGF1 were decreased the most, which is believed to be one of the mechanisms of action that resveratrol may have as being a protective agent against cancer when taken daily for extended periods of time (37). 

These small-scale studies offer promising information on the use of resveratrol in cancer prevention and treatment, however, researchers note the need for further clinical exploration and, more importantly, large-scale clinical trials. 

Ageing and longevity

Humans are innately fascinated by the idea of living longer. However, it’s important to take into account whether extended years on earth would be in a healthy or a diseased state. This is where resveratrol comes in, where there’s mounting evidence to suggest that it plays a role in promoting health by preventing or treating disease. In addition to the information about, there’s even more evidence to support the role of resveratrol in promoting healthy ageing and longevity. 

Take osteoarthritis (OA), for example. OA is one of the most common inflammatory-induced conditions associated with ageing, which affects the joints as a result of wear and tear degradation. We have already discussed SIRT1 in terms of inflammation, but it has also been referred to as the longevity gene. It has consistently been shown to actively participate in the pathways involved in the etiology of osteogenesis where its expression decreases as the disease progresses. Resveratrol has been found to activate SIRT1 and reduce inflammation in a dose-dependent manner, which offers a protective role against OA (38). 

Multiple studies to this effect have been conducted using non-human models, but even the smaller studies in humans present promising effects. In a small-scale trial performed in Iraq, patients receiving 500mg resveratrol daily for 90 days showed significantly decreased pain severity and OA markers compared to the placebo group. In addition, there was an improvement in function of the associated joint and a reduction in overall symptoms associated with OA of the knee (39,40). 

In humans, additional effects of SIRT1 and its role in the process of ageing have been investigated. Since SIRT1 is involved in stress resistance, insulin signaling and longevity, the activating effect of resveratrol on SIRT1 shows promise in human lifespan (41). 

Another interesting area of research on resveratrol is the effect it has on telomere length. Telomeres are essentially caps at the end of chromosomes that make up DNA, and they become shortened with ageing. Those who have longer telomeres typically have longer lifespans (42). 

While research in rodent models have shown that resveratrol delays the development of senescent cells, which are hallmarks of ageing, as well as having positive effects on telomere length and telomerase activity, resveratrol does not appear to extend the lifespan of healthy rodent, or rodents that are a model of premature ageing (43). 

Resveratrol acts on physiological processes through various mechanisms of action 

The way in which polyphonols like resveratrol and pterostilbene work is through the modulation of the hallmarks of ageing. These include oxidative damage, higher levels of inflammation, shortening of telomere length and cell death (44). 

The effects of resveratrol in the ageing process have been proposed as being involved in these primary mechanisms of action (45):

1. Via SIRT1 activation

The sirtuin family of proteins are NAD+-dependent, and are important for many cellular processes including genetic function, regulation of metabolic compounds, cell regulation and lifespan. Resveratrol has been shown to have a significant effect on SIRT1 in particular, which has positive implications on health, especially when it comes to those diseases that are associated with SIRT1 inhibition (46). 

2. Promoting autophagy

Autophagy is a critical physiological function in which cells are able to remove the damaged components of other cells in an effort to promote new cells growth and essentially, ‘clear out’ cells that are no longer useful or needed (47). While the process of cleaning has been shown to involve the most well known pathway, SIRT1 expression (48), which confers the other health benefits of resveratrol, autophagy has also been shown to happen independently of this pathway, and more precisely, via downregulation of the mTOR pathway (49). 

3. Inducing cell stress (hormesis)

Stress as we know it can have detrimental effects on health and stimulate pathways that lead to disease. Short periods of controlled cell stress, however, referred to as hormesis, stimulate the production of heat shock proteins (HSPs), which improve the body’s resilience to higher degrees of stress. Resveratrol has been shown to induce hormetic responses in a variety of studies in animals and humans, which has therapeutic implications that promote health and protect from disease (50). 

4. As a calorie restriction mimetic

Calorie restriction has been shown to have a positive effect on lifespan (51), however, in an environment where overfeeding and access to food is rife, it is difficult for most individuals to practice CR continuously. Research into calorie restriction mimetics have therefore provided a means to reap the benefits of calorie restriction without physically restricting calories. Resveratrol, amongst other natural compounds, has proven to mimic the effect of calorie restriction with positive implications on metabolic health (52). 

5. Through antioxidant activity. 

Accumulation of reactive oxygen species (ROS) over the lifespan causes cell and tissue damage that leads to the effects of ageing. Resveratrol has been shown to reduce the production of these ROS, scavenge free radicals and improve antioxidants profiles in the organism (53). In mice, resveratrol has been shown to decrease the production of nitric oxide and increase the activity of superoxide dismutase (SOD), which reduces tissue damage (54). 

6. Via anti-inflammatory pathways. 

When the body’s inflammatory mechanisms favour the pro-inflammatory pathways, it causes ageing through tissue damage. The pathways through which resveratrol work are believed to involve those that traditional anti-inflammatory medications work, for example, the COX-1 and COX-2, as well as LOX pathways, where resveratrol appears to directly inhibit their activation (55). In mice, resveratrol reduces the capacity of their liver to make inflammatory chemicals, thereby naturally suppressing inflammation (56). 

7. Increasing telomere length. 

The continuously sequencing portions of the DNA, called telomeres, shortened with advancing age, which causes dysfunction and is a hallmark of the ageing process. Resveratrol may protect from telomere shortening by inducing maintenance factors for the structures (57). 

Resveratrol’s high safety profile

There’s no shortage of research to support the use of resveratrol in health and disease. It is, however, important to note that a large amount of the evidence supporting the use of resveratrol, in addition to the animal studies, has come from a laboratory setting on individual cells and cell lines. In the application in human physiology, it is critical to consider the limitations and challenges of using oral preparations owing to the poor solubility and bioavailability of the compound in digestion.

These limitations may be overcome by changing how resveratrol is delivered into the body. One way to do this is to add pterostilbene to the mix. This compound that is similar to resveratrol, has been shown to improve and enhance resveratrol’s activity, with research showing the greatest benefit in age-related diseases like cancer, high cholesterol, diabetes, heart disease and many more. It’s in this way that we are confident in the effects of resveratrol in the enhancement of health- and lifespan (60,61,62,63).

Another way to improve the delivery of resveratrol is to pair it with another compound called piperine. Piperine is an extract that comes from black pepper and has been shown to stop the liver from metabolizing resveratrol too quickly. Studies in mice have shown that this simple extract can improve blood concentrations of resveratrol by more than 1500%. It’s important to note that these results have not been replicated as successfully in humans, but one thing has been shown to be true when piperine is combined with resveratrol, and that’s the increase in blood flow to the brain, which enhances cognitive function (64). 

Many bodies of research conclude the high safety profile of resveratrol, with doses as high as 5g per day showing no development in toxicity or serious side effects. Overweight older adults, who took 2g of resveratrol for 90 days tolerated the dose well, with no adverse effects being reported. Another study, however, showed that repeated daily doses of 2.5g of resveratrol were associated with nausea, gas, digestive discomfort and diarrhea (65). 

As an antioxidant, there are potential adverse effects of very high doses that need to be taken into account. In rats, a dose of 25g caused serious health risks, which has as yet not been tested in humans. Additionally, research is still ongoing into a potential for resveratrol to act as a pro-oxidant in some instances, which means it can both defend and be implicated in the process of several diseases (58). 

For this reason, the lower recommended dose has been used in our formulation, which provides 150mg of resveratrol a day (59). 

Conclusion

Through various mechanisms we have demonstrated the broad action of resveratrol on a range of physiological processes. From its anti-inflammatory and antioxidant responses and enhancing activity of the SIRT1 pathway, we have a better idea of the functional benefits that resveratrol can have on health and how it may be used in the prevention of or improve the outcomes of various chronic diseases. 

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