#051 Is Resveratrol a Longevity Compound?

Resveratrol: Benefits

Hello friends, today is another special episode. Today I'm going to talk about resveratrol, probably one of the most studied plant compounds around.

"Hello friends, today is another special episode. Today I'm going to talk about resveratrol, probably one of the most studied plant compounds around."

Resveratrol: Benefits

This study design used a crossover design so that each participant served as their own control, and they only showed improvements on the resveratrol, not on placebo.

"This study design used a crossover design so that each participant served as their own control, and they only showed improvements on the resveratrol, not on placebo."

Longevity Discussion

It counters neuronal inflammation and improves cognitive performance by mitigating reactive oxygen species, inhibiting pro-inflammatory molecules such as COX-1, and inhibiting beta amyloid plaque formation and aggregation, a hallmark of Alzheimer's disease.

"This study design used a crossover design so that each participant served as their own control, and they only showed improvements on the resveratrol, not on placebo. When people with non-alcoholic fatty liver disease took a resveratrol supplement of either 300 or 500 milligrams per day for three months, their serum LDL levels, liver fat concentrations, and inflammatory biomarkers such as NF-kappa B all decreased, while their insulin sensitivity increased. In a study involving 75 people who were taking a statin, those who also took a 350 milligram resveratrol enriched grape extract daily for six months saw a decrease in multiple cardiovascular risk markers. LDL decreased by 4.5%. Oxidized LDL decreased by 20%. And apolipoprotein B decreased by 9.8%. After the six month treatment period, the people received double the original dose for another six months, which resulted in a decrease in inflammatory markers such as TNF-alpha and IL-6 while increasing the anti-inflammatory marker IL-10. Those are some pretty impressive results. When it comes to resveratrol and statins, however, there may be some more nuance to this because resveratrol, at least at high doses, may also slow drug metabolism, a factor we'll dig into a little bit more later. While all of these studies focused on people who were at risk for cardiovascular disease, in a study in which people who already experienced a heart attack were given a very low dose of 10 milligrams of resveratrol every day for three months, the participants showed significant decreases in LDL and improved left ventricle diastolic function and endothelial function, both which are overall measures of heart health. You might have noticed a common theme in many of these studies, an improvement in markers of inflammation, a key player in the development of chronic diseases, including cardiovascular disease. Some studies have focused specifically on the anti-inflammatory properties of resveratrol. In a study in which healthy people were given a six-week course of Japanese knotweed extract containing 40 milligrams of resveratrol, the study participants had lower levels of reactive oxygen species and suppressed expression of pro-inflammatory cytokines, TNF-alpha and IL-6. Studies in animals show similar beneficial effects. When monkeys were fed an obesogenic diet, they had a 40% increase in arterial stiffness and inflammation. But when those monkeys also were given a daily resveratrol supplement for two years, 80 milligrams per day for the first year, and then 480 milligrams per day for the second year, they had decreased inflammation due to diminished levels of NF-kappa B, decreased adipocyte size, and improved insulin sensitivity in their visceral adipose tissue. They also had completely reversed the arterial wall stiffness and inflammation induced by the obesogenic diet. Resveratrol also appears to promote neurological health. It counters neuronal inflammation and improves cognitive performance by mitigating reactive oxygen species, inhibiting pro-inflammatory molecules such as COX-1, and inhibiting beta amyloid plaque formation and aggregation, a hallmark of Alzheimer's disease. In a study of healthy adults aged 50 to 75 years old, 200 milligrams of resveratrol taken daily for 26 weeks improved the participant's ability to complete memory tasks. Resveratrol also showed promise in a phase two clinical trial for the treatment of Alzheimer's disease. The trial involved 56 patients diagnosed with Alzheimer's who were treated with 500 milligrams of resveratrol once daily with a dose escalation by 500 milligram increments every 13 weeks, ending with a thousand milligrams twice daily. The patients saw improvements in mental examination status scores, improved cerebral spinal fluid amyloid beta levels, and lowered cerebral spinal fluid levels of an enzyme called matrix metalloprotease 9, a mediator of neuroinflammation. These findings that resveratrol treatment may improve parameters associated with Alzheimer's disease are encouraging, but larger and longer studies are needed to determine whether resveratrol can promote cognitive and functional improvement either more broadly or definitively in the case of Alzheimer's disease. Let's talk about cancer. Some rodent studies have shown the potential of resveratrol for the treatment of various types of cancer, including pancreatic, prostate, colorectal, liver, and breast cancer. But there simply isn't enough evidence to suggest that resveratrol is a viable option for cancer therapy in humans. The good news is that resveratrol might be effective as a chemoprotective agent to prevent cancer. Two clinical studies in which healthy people received varying doses of resveratrol found that one gram or 2.5 grams reduced IGF-1, which is associated with tumor proliferation and metastasis. Resveratrol treatment also increased carcinogen detoxifying enzymes such as glutathione S-transferase and others, an effect also elicited by other useful compounds like sulforaphane, which isn't surprising since many PLAT compounds do act on partially overlapping genetic pathways. So that's just a sampling of the research showing resveratrol's beneficial effects. Let's talk a little bit about the physiological responses to resveratrol and the mechanisms that drive these responses. Probably one of the most well-known mechanisms by which resveratrol works is through sirtuin activation. Sirtuins have been shown to play a role in healthspan and longevity in multiple organisms. They are linked to the regulation of a whole slew of metabolic processes, including insulin release, lipid mobilization, stress responses, and lifespan modulation. They respond to physiological changes in energy levels and mediate many of the beneficial effects seen with calorie restriction. Caloric restriction has widely been shown to increase healthspan across a wide range of organisms from bacteria to primates. Resveratrol is thought to be a caloric restriction mimetic. A study in which mice were fed an obesogenic diet and treated with resveratrol found that the animals not only lived longer compared to mice that didn't receive resveratrol, but they experienced physiological changes typically seen with caloric restrictions such as reduced IGF-1 and increased AMP kinase activity. In a study in which healthy mice were fed a standard chow diet to test resveratrol's ability to mimic caloric restriction, resveratrol supplementation did not increase lifespan in the mice, but did exhibit changes in gene expression that mimicked caloric restriction. The mice also improved overall health as reflected by lower incidence of osteoporosis, cataracts, vascular dysfunction, and declines in motor skills, all signs of aging. As a calorie restriction mimetic, resveratrol promotes the induction of autophagy. Autophagy is an adaptive response mechanism that is activated upon cellular energy stress to remove unnecessary or dysfunctional cellular components and to mobilize stored energy reserves. Resveratrol promotes autophagy through its activation of sirtuins. It also induces autophagy independent of sirtuins by inhibiting the activity of mTOR, a key regulator of autophagy. Resveratrol's autophagy-inducing capacity likely has implications for both aging and cancer. More research is needed. One of the most intriguing mechanisms by which resveratrol, a plant compound, elicits its beneficial effects in humans is via activation of cytoprotective responses that turn on genes that promote resilience against stress, sometimes called stress response genes or longevity genes. Let's talk about this a bit. Humans are able to eat a wide range of plants. During both normal development and under conditions of stress, these plants produce a variety of compounds broadly referred to as phytochemicals. Examples include flavanols, anthocyanins, and resveratrol. In plants, these compounds attract pollinators or serve as antioxidants, or in some cases, act as anti-feedants, substances that adversely affect or deter insects. In humans, phytochemicals can activate cellular stress response pathways, which confer long-lasting protective effects. This biological phenomenon known as xenohormesis switches on protective mechanisms that not only protect our cells from the phytochemicals themselves, but also provide protection against the potential deterioration of our environment, as well as the presence of damaging factors that we are exposed to on a daily basis, things like air pollution or overexposure to UV radiation. The scientific community has speculated about why animals, including humans, should respond with a stress response to compounds with otherwise very low systemic toxicity. One school of thought suggests that humans and animals interpret signals of plant stress, the primary inducer of phytochemical synthesis, as indications that their environment may be demanding enhanced levels of biological fitness as a type of interspecies hormesis or communication."

Caloric Restriction Discussion

It counters neuronal inflammation and improves cognitive performance by mitigating reactive oxygen species, inhibiting pro-inflammatory molecules such as COX-1, and inhibiting beta amyloid plaque formation and aggregation, a hallmark of Alzheimer's disease.

"According to this theory, some ancient common ancestors of both animals and plants synthesized polyphenols. Even though humans and animals lost the ability to produce these chemicals entirely, selective pressure helped us maintain the genetic machinery necessary to not only interpret the signals associated with their synthesis in plants, but also to produce enzymes and receptors with binding pockets that allow the modulation of these molecules and their metabolites. Thus, we kept the advantage of being able to continue to usefully interpret signals of a harsher environment before the degradation of the environment becomes too severe, and more importantly, allowing ourselves to turn on the necessary genetic programs while conditions are still somewhat favorable. This, however, is a hypothesis. Regardless of whether it's true, the observation still stands that certain plant phytochemicals, such as polyphenols, are able to create a profound cellular response mediated by the interactions with enzymes that seem to be the sort of key meets lock interactions that you would expect from biological systems formed under selective pressure rather than just coincidental interactions. Resveratrol, which is produced in response to stress in some plants like grapes, activates a variety of cellular stress response pathways in humans, such as the activation of SIRT1, which is linked to anti-inflammatory activity, metabolic adaptations, and neurological protections. AMP activated protein kinase, a fuel-sensing enzyme that activates numerous pathways involved in catabolism and inhibits mTOR, leading to the downregulation of cellular growth pathways, and cyclic AMP phosphodiesterase, an intracellular signaling molecule that increases cellular NAD levels. The activation of these cellular stress response pathways may in part mediate some of the beneficial effects also seen with caloric restriction. The effects of resveratrol in exercise training are contradictory, however. For example, a study involving 27 men between the ages of 60 and 72 years who participated in an eight-week training program with two days of cycling and one day of CrossFit showed that a low dose of resveratrol, 250 milligrams daily, blunted the positive effects of exercise training on blood pressure, blood cholesterol, and maximal oxygen uptake. Another study in which 22-year-old men engaged in four weeks of high-intensity interval training three days a week and supplemented with 150 milligrams of resveratrol per day did not demonstrate increases in the men's aerobic or anaerobic capacity, exercise substrate utilization, or muscle fiber specific adaptations. But a study involving 30 men and women between the ages of 65 and 80 years who participated in a 12-week resistance and aerobic training plan three days a week and took 500 milligrams of resveratrol daily showed that participants experienced increases in mitochondrial density, muscle fibers, and maximal oxygen consumption compared to exercise training alone. So as you can tell, these are contradictory results. The exercise adaptation blunting effects also contradict some animal research where a high dose of resveratrol actually reduced fatigue, suppressed age-associated decline in performance, improved aerobic performance during endurance exercise, and increased mitochondrial biogenesis and function. So how do we reconcile these facts? Potential factors may include the type of exercise being investigated, the intensity and dose of resveratrol, all of these things may contribute to these contradictory results. Of particular interest is the dose of resveratrol used. Both of the human studies mentioned a moment ago that showed resveratrol had blunted some of the exercise-induced benefits used a low dose of resveratrol, either 150 milligrams or 250 milligrams per day, whereas researchers observe positive effects with 500 milligrams of resveratrol per day. At a low dose, resveratrol can be a mild direct antioxidant, but at a higher dose, it acts as an indirect antioxidant. There is a difference between direct and indirect antioxidants. Direct antioxidants can bind to and sequester damaging reactive oxygen species. Examples include vitamin C and E. High dose supplemental vitamin C and E have also been shown to blunt some exercise induced adaptations. That is because the reactive oxygen species that are generated during exercise are important for the exercise induced cardiorespiratory adaptations. Indirect antioxidants can activate the body's own cytoprotective proteins like the NRF2 pathway, which subsequently activate a wide array of genetic pathways, including endogenous antioxidant systems like glutathione, for example. The benefits of indirect antioxidants are much more longer lasting and, in general, seem to not run the same risk as direct antioxidants when it comes to blunting the effects or beneficial adaptations from exercise that seem to actually depend on the short bursts of oxidative stress acting as a signal that we generate from exercise. The bottom line is that more studies, particularly dose-dependent studies, are definitely needed to determine how resveratrol supplementation affects exercise-associated adaptations. Now let's talk about bioavailability. Resveratrol exists in two different molecular arrangements, trans and cis. Transresveratrol is the most predominant and stable of the two forms and elicits the major health benefits. Trans resveratrol should be protected from light because it converts to the less active cis resveratrol form after just a few hours of solar or UV exposure. The majority of resveratrol supplements sold in the U.S. contain the trans form of resveratrol according to their labeling. Resveratrol is only about 25% bioavailable due to rapid metabolism and excretion. Its metabolism varies in a circadian fashion with higher bioavailability occurring in the morning. It is also more bioavailable if taken with food. A study in Healthy Human Volunteers found that resveratrol bioavailability is increased when taken with a moderate fat breakfast versus a very high fat breakfast. Resveratrol is insoluble in water, but studies have shown that if it is enclosed in a nanocapsule, a shell that encapsulates the inner core, its stability and bioavailability are increased. Other studies have shown that when resveratrol is given with piperine, a natural compound found in black pepper, its bioavailability and efficacy may be enhanced because piperine inhibits enzymes involved in the metabolism of resveratrol. When mice were given a single dose of resveratrol at 100 milligrams per kilogram of body weight, along with piperine at 10 milligrams per kilogram of body weight, there was an over 14-fold increase in serum concentration of resveratrol compared to mice that received resveratrol alone. However, a study in which 23 adults took 250 mg of transresveratrol with 20 mg of piperine found that piperine didn't improve bioavailability, but it did improve efficacy in regard to improved cerebral blood flow, which may benefit cognitive function. Dose matters. People often talk about the beneficial effects of red wine due to its resveratrol content. It's important to note that a five ounce glass of red wine contains approximately 1.8 milligrams of resveratrol, while therapeutic doses typically range from approximately 100 milligrams to one gram. Dr. David Sinclair, one of the world's leading experts on the beneficial effects of resveratrol, recently tweeted, people often ask, how much red wine should I drink to get enough resveratrol? To get the same as our mice, you'd have to drink a barrel a day, which I definitely don't recommend, however tempting. Human trials of resveratrol supplementation have demonstrated that doses up to 5 grams of resveratrol daily don't cause toxicity or serious side effects. A repeat dose study for 29 days in healthy volunteers showed that resveratrol supplementation of up to 5 grams was not toxic, but doses above 2.5 grams were associated with mild to moderate GI distress, such as nausea, gas, abdominal discomfort, and diarrhea. Another study in which overweight adults who were 70 years of age or older took 2 grams of resveratrol for 90 days, resveratrol was well tolerated. Despite resveratrol's beneficial effects, resveratrol supplementation should still be considered with at least a little caution. Long-term toxicology studies in humans, longer than one year, have not been performed. Studies have also shown that resveratrol supplementation may interfere with the way in which the body metabolizes other drugs. In particular, resveratrol inhibits cytochrome P450 enzymes, which are involved with the metabolism of many drugs, such as statins, antiarrhythmic drugs, and antihistamines. This inhibition could reduce the metabolic clearance of these drugs and lead to increased bioavailability and risk of toxicity. Specifically, in a clinical study where participants were given one gram of resveratrol per day for one month, it changed the activity of several cytochrome P450 enzymes in the liver. For example, resveratrol caused a 33% inhibition of CYP3A4, which is involved in the metabolism of the vast majority of drugs, including cholesterol-lowering statin drugs, chemotherapeutics, immunosuppressive drugs for transplant patients, and HIV protease inhibitors. Inhibition of this enzyme could result in elevation of the systemic blood levels of these drugs metabolized by this isozyme, which could lead to increased drug toxicity. It also caused a 171% inhibition in CYP2C9, which is the second most abundant CYP in the liver and small intestine. It is involved in the metabolic clearance of a wide variety of drugs, including many non-steroidal anti-inflammatory drugs, COX-2 inhibitors, oral anticoagulants, and oral hypoglycemic drugs. Again, this raises the question of whether resveratrol would decrease the clearance of these drugs and lead to toxicity. Maybe it's not a problem, but it is certainly something worth being aware of otherwise. Another study I would like to mention is a pilot randomized placebo controlled study, which found that men with prostate cancer that were given one gram of resveratrol per day for four months had lower serum levels of some androgen precursors like DHEA, which was decreased by 41%, but had no effect on testosterone, dihydrotestosterone, PSA levels, or prostate volume. DHEA is made from the adrenal gland, and while it is difficult to know the exact mechanism by which resveratrol lowered DHEA, the authors of this study suggest that resveratrol may reduce the concentration of androgen precursors by inhibiting their production in the adrenal gland or by increasing urinary excretion of the androgen precursors, or a combination of both. It is also difficult to know if this is clinically relevant, particularly since there was no effect on testosterone levels, but it is one of those things that I still think it is important to mention. A quick wrap-up. Resveratrol elicits a broad range of physiological responses such as activating anti-inflammatory and antioxidant response pathways and promoting the activation of sirtuins. These responses have translated to functional health improvements when used to treat people diagnosed with various metabolic diseases, such as type 2 diabetes, but also in neurological disorders, such as Alzheimer's disease. The jury is still out with regard to resveratrol's effects on exercise, and questions still remain about the appropriate dose for humans. Given resveratrol's ability to activate cellular protective mechanisms and act as a calorie restriction mimetic, in my opinion, it does seem to have the potential to be used as a preventative supplement. That's it for today's episode. Thank you so much for listening. If you would like to learn more about the topics I discussed today, check out the resveratrol topic page my team and I put together. 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