Resveratrol: A Powerful Polyphenol That Slows Cellular Aging

Authored by Allison DeMajistre via The Epoch Times (emphasis ours),

Resveratrol is one of the most studied natural polyphenol compounds and is found in the skins and seeds of red and purple grapes, berries, peanuts, and pistachios.

When plants face constant environmental stress such as from fungus, drought, ultraviolet radiation, and insect infestation, their intrinsic defense mechanism is to produce polyphenols.

Resveratrol was isolated by a Japanese scientist in 1939 from the roots of the white hellebore plant. It gained attention in 1992 when researchers suggested that this component found in red wine had cardioprotective qualities that might explain the “French paradox,” the observation that the French drink a lot of red wine and have low rates of heart disease despite a high-fat diet.

Since then, resveratrol has been studied more broadly and has shown tremendous protective potential at the cellular level.

“The in vitro and in vivo studies point to the exact mechanisms of how it works in terms of being cardioprotective, cancer preventative, cancer therapeutic, neuroprotective, helpful in people who are obese, [helpful for] glucose metabolism, anti-inflammatory, and an antioxidant,” Dr. Nathan Goodyear, a medical doctor and integrative cancer expert, told The Epoch Times.

Longevity and Disease Prevention

Research has shown that calorie restriction can delay or prevent many age-related diseases and extend lifespan, and resveratrol can mimic the action of calorie restriction.

Although calorie restriction has many benefits, including increased insulin sensitivity and improved overall metabolic health, most people don’t want to spend the day counting calories or fasting.

Resveratrol mimics calorie restriction by activating signaling proteins called sirtuins, which can regulate inflammation, repair DNA, promote insulin sensitivity, and help form neurons in the brain. These proteins are also associated with healthy aging and longevity.

“The sirtuin system is a complex regulatory process involving seven sirtuin genes expressed in multiple tissues,” registered dietician nutritionist Kelsey Costa told The Epoch Times by email.

Silent information regulator 1 (SIRT1) is one of the seven sirtuin genes activated by resveratrol. It promotes longevity through metabolic processes such as insulin release, lipid mobilization, and healthy stress response. A review published in the Annals of the New York Academy of Sciences found that people who had fasted for one week had a twofold increase in the SIRT1 gene in their fat cells.

The review also mentioned studies involving resveratrol and the activation of SIRT1 that showed a 70 percent increase in yeast lifespan, life-extending potential in worms and flies, and an increase in the survival of obese middle-aged mice.

“SIRT1 is abundant in the blood vessel system, plays a crucial role in creating and growing new blood vessels, and is significantly stimulated by resveratrol,” Ms. Costa said. “Ultimately, sirtuin genes create proteins that affect heart-related functions like growing new blood vessels, decreasing hypertension, and preventing atherosclerosis, which provides a plausible explanation for resveratrol’s diverse health benefits.”

Cardiovascular Benefits

Cardiovascular disease is primarily the result of a chronic low-grade inflammatory condition that can cause atherosclerosis, high blood pressure, heart attacks, and heart failure.

A 2022 systematic review and meta-analysis of six randomized controlled studies concluded that “resveratrol can be used as a potential treatment in patients with [cardiovascular disease] by reducing inflammatory conditions.” It is also a potent vasodilator that releases nitric oxide and lowers blood pressure.

According to Ms. Costa, “resveratrol decreases the serum concentrations of pro-inflammatory cytokines, which are critical compounds involved in the body’s inflammatory response, suggesting resveratrol may be beneficial as an adjuvant therapy for chronic inflammation and cardiovascular disease.”

Most studies have been performed in the lab or on animals and show the positive effects of resveratrol on the heart, prompting several randomized controlled trials in humans over the past decade to determine if the same benefits apply to both healthy and chronically ill humans. The results in humans have been variable, possibly due to inconsistent protocols and doses of resveratrol. Yet many studies have shown positive effects on coronary artery disease, including decreased arterial stiffness, hypertension, inflammation, and cholesterol.

Dr. Goodyear believes resveratrol can also protect the heart from certain types of chemotherapy that may damage it. “Although we primarily use natural and holistic treatments for cancer, we will use some conventional therapies, including chemotherapy,” he said. “If we ever use a low-dose form of chemotherapy with a potential impact on the heart or kidneys, resveratrol can be added in to protect these patients.”

May Regulate the Gut Microbiome

The gut microbiome, a community of trillions of microorganisms living in the digestive tract, is believed by many to be the most critical factor in overall health. It consists of bacteria, viruses, fungi, and other microbes; when they live in concord in the gut, all body systems work harmoniously. But when those microorganisms are unhealthy and unbalanced, it can lead to several acute and chronic illnesses, including gastrointestinal problems, obesity, Type 2 diabetes, cancer, and autoimmune diseases.

Recent research suggests that resveratrol’s antioxidant, anti-inflammatory, and other beneficial properties can help regulate the microbiome and protect the intestinal tract from inflammation and impending disease. While researchers are still investigating resveratrol and its role in regulating overall health through the gut microbiome, they believe it can protect the intestines by strengthening the tight junctions of the intestinal wall. A strong intestinal barrier helps with nutrient absorption and prevents a “leaky gut,” which allows bacteria, toxins, and undigested food particles to pass through and enter the bloodstream.

Resveratrol’s antioxidant and anti-inflammatory properties can also prevent pathogenic bacteria and fungi from growing inside the intestine and increase immune cells to ward off possible diseases further, including many types of cancer.

May Suppress Cancer Cells

In 1997, researchers found that resveratrol prevented cancer cell growth on the skin of mice. Since then, an overwhelming number of studies have focused on resveratrol’s anti-cancer properties.

Resveratrol affects cancer at different stages, from initiation to progression, through various signaling pathways regulating cell growth, cell destruction, inflammation, metastasis, and the development of new blood vessels. An interesting aspect of resveratrol is that it can protect normal cells while causing cancer cell death. Researchers have also found that lower concentrations of resveratrol can increase the expression of cell survival proteins, while higher concentrations stimulate cancer cell death.

A 2015 study suggests that resveratrol may inhibit the growth of gastric cancer cells and induce programmed death of potentially cancerous cells. Human gastric cancer cells were injected into mice, and resveratrol was injected near the tumor cells, significantly inhibiting their growth. The researchers suggested that even though resveratrol’s bioavailability is low in humans and it’s quickly processed and excreted by the body, it has metabolites, or byproducts, that may continue to have beneficial effects.

Another study found that resveratrol may help actinic keratosis—rough, scaly patches of skin that are potentially cancerous.

Studies have shown that resveratrol can target the p53-mediated pathway to induce apoptosis, inhibiting the growth of colorectal cancer cells. Tumor suppressor p53 is a crucial protein involved in DNA repair and apoptosis (cancer cell death). Even in tumor-suppressor p53 mutations where cancers don’t respond well to chemotherapy, resveratrol treatment was found to stop cell growth in cervical cancer. It was also shown to inhibit prostate cancer cell growth and induce apoptosis by inhibiting a major protein signaling pathway.

Clinical trials involving resveratrol and other cancers, including colon and liver cancers, are ongoing and continue to have encouraging results.

Resveratrol may also be chemoprotective, meaning that it may protect healthy cells from damage during chemotherapy treatment.

In lab studies, resveratrol demonstrates several mechanisms that induce programmed cell death in several cancer lines and shows clear anti-cancer effects. Since natural resveratrol has clear drawbacks because of its limited bioavailability, there is interest in the development of resveratrol derivatives.

Dr. Goodyear told The Epoch Times that despite the limited studies, there are advances in solving resveratrol’s problems with administration and bioavailability. Still, more studies are needed that look specifically at women with breast cancer, men with prostate cancer, people with cardiovascular disease, or those who have had a stroke.

“The problem with that is it takes time and money,” he said. “Most people who have a lot of interest in these natural therapies unfortunately don’t have the money to put into the large clinical trials we need to solve the limitations.”

May Protect Against Alzheimer’s and Parkinson’s

Unlike other antioxidants, resveratrol has the unique ability to cross the blood-brain barrier. Studies are ongoing, and researchers believe there is tremendous potential for resveratrol to become a viable therapy for Alzheimer’s disease and Parkinson’s disease through its antioxidant and anti-inflammatory actions.

Five of the primary causes of Alzheimer’s disease progression have shown potential for control with targeted resveratrol treatment. These include protein misfolding, cellular metabolism, inflammation, mitochondrial dysfunction, and telomere shortening.

Protein Misfolding

Proteins can’t work effectively when they aren’t in the correct formation. The protein misfolding in Alzheimer’s disease involves accumulating abnormally folded beta-amyloid and tau proteins. Resveratrol has been shown to inhibit beta-amyloid malformation by decreasing its production through sirtuin pathways. It interferes with the amyloid pathway via its antioxidant and anti-inflammatory properties and reduces amyloid plaque production of free radicals and neuroinflammation.

Although the effects of misfolded tau proteins aren’t as widely studied as beta-amyloid proteins, resveratrol’s activation of SIRT1 and the following mechanisms can reduce tau levels and improve cognitive function.

Cellular Metabolism

Researchers have found that fasting can benefit cognitive performance and Alzheimer’s disease prevention by releasing brain-derived neurotrophic factor, which regulates cellular processes involved in normal brain function; reduced levels are often associated with degenerative brain disorders.

Just as resveratrol can benefit the heart by mimicking calorie restriction through the expression of SIRT1, it can also improve cognition by enhancing mitochondrial function, helping to boost the destruction of free radicals that promote cognitive decline.

Inflammation

Localized inflammation and microglia, the immune cells of the brain that regulate the brain’s response to illness through inflammation, contribute to neurodegeneration and cognitive decline in the brain. Reducing this brain inflammation appears to be effective in slowing and even modifying the progression of Alzheimer’s disease in animal models.

Although the mechanism is still unclear, laboratory and animal studies have shown that resveratrol effectively reduces neuroinflammation.

Mitochondrial Dysfunction and Free Radicals

Mitochondria are called the “powerhouse of the cell” for good reason. Their primary function is to produce adenosine triphosphate (ATP), the prime cellular energy source essential for muscle contraction, cell membrane potential, maintaining the proper electrical pathways between cells, and overall cellular metabolism.

Healthy mitochondria have antioxidant defense mechanisms that protect cells from free radicals that damage cells and lead to aging and disease. Mitochondria’s control over apoptosis (programmed cell death) is crucial for eliminating damaged or malfunctioning cells that may contribute to neurodegeneration.

Brain cells (neurons) have high energy requirements and contain thousands of mitochondria to generate ATP to maintain cellular metabolism and keep the brain working properly. An alteration in the mitochondrial function of neurons can start a cascade of cellular damage by inhibiting neuronal defense against free radical production. As neurons are damaged and begin to die, progression into the early stages of Alzheimer’s begins. Resveratrol can counteract free radical production by activating a pathway involving the SIRT1 protein and boosting mitochondrial energy and efficiency.

Telomere Shortening

Telomeres are the repetitive DNA sequences on the end of chromosomes that act as protective caps, preventing the loss of fundamental genetic information as cells divide. Every time cells divide, telomeres become shorter and shorter. Eventually, when they are so small and can no longer divide, they die. Although inevitable and part of aging, protecting telomeres from becoming reduced prematurely promotes more youthful cells and prevents age-related diseases.

Shortened telomeres play a significant role in Alzheimer’s by increasing the potential for DNA damage, cellular dysfunction and impaired regeneration, neuroinflammation, and eventual neuronal death.

Polyphenols such as resveratrol preserve telomere length, promoting the expression of necessary enzymes within the brain that help maintain telomeres. Resveratrol activates a SIRT1 pathway to protect DNA from free radical damage.

May Increase Insulin Sensitivity

Increasing evidence suggests that oxidative stress plays a critical role in diabetes progression. Resveratrol’s potent antioxidant properties and ability to activate sirtuins, particularly SIRT1, make it a potential candidate for targeting the underlying cellular abnormalities of Type 2 diabetes, obesity, and metabolic disease.

Studies have found that resveratrol can safely reduce the chronic inflammatory properties often associated with obesity while restoring insulin sensitivity, reducing inflammatory injury to blood vessels, and attenuating oxidative stress on the pancreas as insulin levels increase. These studies also show that resveratrol can help save pancreatic beta cells and improve glucose tolerance with SIRT1 activation.

Clinical studies lasting from four weeks to one year revealed that supplementing with grape extract and resveratrol for one year had beneficial effects on Type 2 diabetes and high blood pressure. Resveratrol supplementation for more than 45 days lowered blood pressure, glycated hemoglobin (HbA1c), fasting blood glucose, insulin levels, and insulin resistance, and even improved HDL “good” cholesterol levels.

May Relieve Joint Pain

Resveratrol’s anti-inflammatory properties have been shown to slow down or stop the degeneration of rheumatoid arthritis and osteoarthritis.

Rheumatoid Arthritis

Resveratrol has shown the potential to mediate pathways and enzymes that can inhibit the production of inflammatory molecules in the body. Its antioxidant properties can also help protect joints from rheumatoid arthritis-related oxidative stress.

One study found resveratrol effective when used in combination with methotrexate, a traditional medication used to treat rheumatoid arthritis, showing a synergy between the two therapeutics.

Osteoarthritis

A recent study suggests that resveratrol can potentially prevent and treat knee osteoarthritis (KOA) by reducing inflammation, apoptosis, and cartilage degeneration. The study concluded that resveratrol will become an alternative therapy for preventing and treating KOA.

A 90-day pilot study of 110 men and women with KOA treated with both meloxicam, a nonsteroidal anti-inflammatory, and resveratrol significantly reduced knee pain. The levels of inflammatory biomarkers in their blood were also reduced considerably compared to the placebo group. The researchers suggested resveratrol may be an effective adjunct supplement for patients taking meloxicam for KOA.

Potential Risks

“While resveratrol has been linked to various health benefits, it’s important to consider potential risks and adverse outcomes,” Ms. Costa said. “At high doses, resveratrol has been reported to have toxic effects, cause gastrointestinal issues, and interfere with certain enzymes, which can lead to interactions with other drugs.”

Potential medication interactions include anticoagulants and anti-platelet drugs since resveratrol may cause clotting and, therefore, may be contraindicated. It’s best to consult a physician before taking resveratrol to determine the proper dosing and potential drug interactions.

Overall, resveratrol’s adverse effects have been minor, and many studies have established that resveratrol is well-tolerated and safe for humans, though dosing levels remain inconclusive.

The Bottom Line

Resveratrol is a powerful antioxidant and anti-inflammatory that has shown tremendous promise across extensive clinical studies in lab animals and humans, yet there’s much to learn about its potential in preventing and treating future chronic health conditions.

For instance, there is no established therapeutic dosage of resveratrol. According to Ms. Costa, “The dose of resveratrol administered in research studies is much higher than what one would typically consume in a daily diet or from drinking red wine and seems to have a more pronounced effect when taken as a daily supplement.”

Much of the research to date has been in animals and test tubes using higher levels of resveratrol than found in a normal diet. These studies have led to significant progress in identifying its mechanisms of action and how it translates into various health benefits. However, further human studies are needed to confirm its efficacy, potential adverse effects, and the dose–effect relationship.

“When you look at resveratrol broadly, it’s super exciting, and there is so much we don’t understand about it,” Dr. Goodyear said. “I think there is no doubt resveratrol will positively impact a wide spectrum of diseases preventatively and in targeted treatments.”