This is the last post in our series dedicated to sirtuins – tiny superheroes operating within us and potentially impacting our lifespan. Here, we will introduce you to the poster child of sirtuin modulators, a molecule named resveratrol. Resveratrol’s ability to activate sirtuins, particularly SIRT1, has led to extensive research into its potential health benefits, including its effects on lifespan and age-related diseases. While the exact extent of its impact on sirtuins and human health is still a topic of ongoing research and debate, resveratrol remains one of the most well-known sirtuin modulators in the scientific community.

If you still need to explore our introduction to sirtuins, or if you are curious to learn how diet and exercise can affect sirtuins, follow our earlier posts. 

What is resveratrol? Origins, Forms, and Natural Sources

Resveratrol is a polyphenol that occurs in nature. It was first isolated from the roots of a flower called white hellebore in 1939 (1). There are two forms of resveratrol- cis and trans, with trans-resveratrol being the more stable form and, therefore, more prevalent in nature (Figure 1). Both forms exhibit different biological activities. Since its discovery, it has been found in many different edible parts of plants, such as berries, grapes, peanuts, pistachios, and plums (1). During the last three decades, resveratrol has received considerable attention for its potential beneficial health effects (1).

Figure 1: Resveratrol chemical structure (cis and trans forms)

Resveratrol in Red Wine: Unveiling the French Paradox

The interest in resveratrol started in the early 1990s, when the moderate red wine intake of the French population was found to correlate with a decreased incidence of heart disease and obesity, which appeared to contradict their relatively high‐fat diet. This relationship, termed the “French Paradox,” was initially attributed solely to the presence of resveratrol in red wine (1). Since then, when resveratrol was a topic of public discussion, it was often linked to wine, and the idea that wine could have positive effects because of this compound (2). However, it’s important to note that the resveratrol content in wine is too minimal to significantly impact human longevity, even though the media often used wine to capture public attention (2).

Resveratrol dosage per day: How much is necessary for health benefits?

Resveratrol is present in many healthy foods, in addition to red wine. However, it is in very small amounts. One needs to consume impractical amounts of food or drinks to get the estimated amount of resveratrol required to generate a pharmacological response (Figure 2) (3).  Although there have been extensive studies on resveratrol, how much one needs depends on the indication, and it is still a controversial topic. Some studies report using just a few milligrams and others grams (3). As resveratrol is not present in sufficient quantities in food, it’s available in various forms, typically as tablets, powders, or topical creams, and is marketed as a dietary supplement.

Figure 2 (adopted from (3)): The amount of food and drinks needed to achieve therapeutic levels of resveratrol is substantial. Drawing from animal studies, it has been suggested that daily doses ranging from hundreds of milligrams to several grams of resveratrol are necessary for therapeutic purposes. To put this into perspective, if someone aims to consume 1 gram of resveratrol daily, they would need to ingest the quantities of food or beverages shown here.

How does resveratrol work in the body?

We present resveratrol as part of our sirtuin series. Although it has been considered that resveratrol is influencing different sirtuin pathways, that is only one of the ways it affects our bodies. Based on preclinical data, resveratrol has been found to affect many different molecules and processes in the body. It can interact with a wide range of signaling molecules, such as Wnt, NF-kB, citokines and caspases.  This versatility is why resveratrol has so many different effects on health and is considered to have multiple beneficial properties (1). Due to its multitargeting capabilities, it was believed to be a promising agent for cancer therapy, showing positive responses in common cancer types such as colon cancer, breast cancer, and multiple myeloma (1).

Prolonging lifespan: Myth or reality? 

Resveratrol is well-known for its potent antioxidant, anti-inflammatory, anticarcinogenic, cardioprotective, and neuroprotective properties (3), (4). One of the most remarkable aspects of resveratrol is its ability to extend lifespan in model organisms. Resveratrol was found to prolong lifespan by 70% in yeast (Saccharomyces cerevisiae), a typical model for aging studies (5). It has also been shown to extend the lifespan in worms and fruit flies (6). Additionally, a study showed increased survival of a mouse fed with resveratrol and high fet diet compared to mice fed with high fat only, and their life expectancy matched mice fed on a normal diet (7). More specifically, 58 % of mice fed with a high fat diet have died, compared to 42 % of mice fed with resveratrol and high fat and 42 % of mice of the standard diet control.

There are no studies directly relating to lifespan extension of humans by using resveratrol at the moment but there are studies investigating the effect of resveratrol in different diseases as discussed below.

Resveratrol’s Role in Disease Management: Promising Insights

Resveratrol is reported to potentially improve the therapeutic outcome in patients suffering from diabetes, obesity, colorectal cancer, breast cancer, multiple myeloma, metabolic syndrome, hypertension, Alzheimer’s disease, stroke, cardiovascular diseases, kidney diseases, inflammatory diseases, and rhinopharyngitis (1).

  • Diabetes, obesity, and metabolic syndrome

Research has indicated that resveratrol may improve insulin sensitivity and glucose metabolism, making it a topic of interest in diabetes management (1). In a placebo controlled clinical trial involving individuals with type 2 diabetes mellitus, the administration of 1 g of resveratrol for 45 consecutive days resulted in notable antidiabetic effects, including reduced fasting blood glucose, hemoglobin A1c, insulin levels, and insulin resistance, along with a significant increase in high-density lipoprotein cholesterol (8). Lower doses of resveratrol (10 mg/day for 4 weeks) also demonstrated the ability to lower blood glucose levels and enhance insulin sensitivity in diabetic patients. A study taking into account multiple randomized controlled trials on the effect of resveratrol on glucose control and insulin sensitivity (meta-analysis)  also confirmed resveratrol’s effectiveness in improving outcomes for diabetic patients compared to healthy participants, particularly at lower doses (9).

  • Cancer 

Some research suggests that resveratrol might have anticancer properties, potentially inhibiting the growth of cancer cells. Notably, resveratrol has shown positive responses in common cancer types like colon cancerbreast cancer, and multiple myeloma (1). While preclinical research (research in model organisms such as worms and mice) has shown that resveratrol can influence various cancer-related genes, clinical studies(studies in humans) have observed only a few of these effects in patients. Currently, there are only a fewpublished clinical trial reports on resveratrol (total of 152), compared to thousands of preclinical studies (1). To really know if resveratrol helps treat cancer, we need more careful and larger clinical trials. These studies should also help us understand how resveratrol works in the body (pharmacokinetics) and what it does to the disease (pharmacodynamics).

  • Neurological diseases

Resveratrol seems to have some promise in helping with brain diseases like Alzheimer’s and memory problems. It does this by affecting different genes and processes linked to these diseases and protecting the brain from damage. But in studies with Alzheimer’s patients, not everyone benefited from it, even though some signs improved (10). Also, when combined with another treatment for stroke, it might make the treatment work better and be safer (11). Resveratrol could also help with memory, sugar control, and mood problems, potentially helping with conditions such as anxiety, depression, and cognitive impairment (1).

  • Cardiovascular diseases

Resveratrol could be beneficial for heart health because it can target many different things, although the evidence supporting its effectiveness in treating cardiovascular diseases (CVDs) in humans remains limited(1). In a triple-blind clinical trial involving CVD patients, a combination of resveratrol (8 mg) with grape extract showed promising results as it seemed to lower “bad” cholesterol and inflammation when compared to placebo (12). Other trials indicated that resveratrol supplementation improved various cardiovascular risk factors like blood lipid profiles, fasting blood glucose, and markers of inflammation although its precise contribution when used alongside other compounds remains unclear (13), (14).  To enhance our knowledge of how effective resveratrol is in treating CVDs, additional clinical research should take into account variables such as patient characteristics, blood pressure, and the possible combined effects of different treatments.

  • Inflammatory diseases

Resveratrol seems to reduce inflammation in a condition called takayasu arteritis – a rare inflammatory condition that primarily affects the aorta and its major branches (15). Resveratrol might do this by lowering a specific inflammation-causing molecule called TNF-α. However, in other trials, especially with a high dose (5 grams), it could actually increase this inflammation-causing molecule in healthy people (16). So, the amount, duration, and a person’s health might affect how resveratrol works with inflammation. More research is needed to fully understand this dual role of resveratrol in different situations.

In addition to the discussed studies, currently there are more clinical trials involving resveratrol – 6 active trials and 10 trials currently recruiting patients (www.clinicaltrials.gov). Some of the diseases targeted include cardiovascular, ovarian insufficiency, insulin resistance, ulcerative colitis, skin rejuvenation, and as antiaging dietary supplement. That highlights the continuous investigation into resveratrol’s potential benefits. 

Potential side and adverse effects from resveratrol

Resveratrol has shown potential health benefits in clinical trials, but it’s also been associated with some side and adverse effects. 

  • Headaches and dizziness

In trials with healthy individuals, mild side effects like headaches and dizziness were reported at higher dosesof resveratrol (17). 

  • Elevated liver enzymes, skin rash, diarrhea

Some medications may cause unwanted pharmacologic reaction in the body and that is termed adverse effects. In obese postmenopausal women, taking 1 gram of resveratrol for 12 weeks led to adverse effects including elevated liver enzymes, skin rashes, diarrhea, and increased cholesterol in some subjects (18). 

  • Bleeding and bruising

Resveratrol can have antiplatelet effects, potentially causing bleeding or bruising, especially when combined with blood anticoagulants or nonsteroidal anti-inflammatory drugs (19). 

Therefore, while resveratrol has promise, its safety and potential side effects should be considered when used as a dietary supplement (1).

Bioavailability concerns 

In most clinical trials, the major challenge is the limited bioavailability of resveratrol. It is readily absorbed, metabolized and excreted from the body thus remaining in the cell for only limited time. Researchers are working on developing compounds that are similar to resveratrol but are expected to have better bioavailability (1) (20).

Resveratrol supplements: Navigating the landscape for better health

Finally, it is worth noting that resveratrol is sold as a supplement meaning that it does not need to undergo the rigorous approval process as pharmaceuticals do. Despite the many regulations in place, there are still frequent instances of non-compliance and food fraud within the supplement industry. In a study evaluating 20 resveratrol food supplement products in Slovenia, it was found that 95% of these products did not contain the amount of resveratrol declared on their labels, and 55% had more than declared (21). Furthermore, 25% of the products exceeded the maximum resveratrol level permitted for food supplements according to EU regulations. The analysis of labels also revealed various errors, including typos and misleading information, highlighting the need for improvement in the food supplement industry to ensure safety and accuracy.

Resveratrol in Review: Balancing Promise and Caution for Health

In conclusion, resveratrol has been extensively studied for its varied effects. While traditional drugs often target single molecules, resveratrol’s multitargeting properties, and long history of safe consumption make it a promising candidate for various health conditions. However, its rapid metabolism and limited bioavailability pose challenges, and more research is needed to fully understand its clinical applications. Currently, while resveratrol is accessible as a supplement, it is not prescribed for treatment for any human disease. So, consult with a healthcare professional to determine if resveratrol aligns with your unique health goals and needs. Embracing such personalized strategies can pave the way for a healthier and more fulfilling life journey.

Silviya Demerzhan, Ph.D.

Chief Scientific Officer, Nordic Executive Medicine
Medical review by: Dr. Mahir Vazda MD

References

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