Resveratrol/Pterostilbene - When to Use to Improve Your Health

Resveratrol (3,5,4’-trihydroxy-trans-stilbene) was one of the first supplements to gain widespread popularity and research in the 1990s. Many controversial claims over the years have been made about the anti-aging effects of the supplement. Initial claims were that the compound can increase life expectancy in humans. Recent in vivo studies have cast some doubt on these claims. However, it is anti-inflammatory, scavenges excessive free iron, and improves mitochondrial function to help improve our health.

Resveratrol is a polyphenolic compound (phytoalexin) that is found in a few foods that we consume in our everyday life. It is produced by plants to defend themselves from infections, including the fungus Botrytis cinerea. Resveratrol is found in grapes, red wine, raspberries, plums, grape tomatoes, Japanese knotweed, Cissus quadrangularis, and peanuts. Dietary intake of resveratrol is deficient in our Standard American Diet unless you consume red wine frequently, which per studies, equates to a daily dosage of .2 milligrams on average.[1] [2]

Resveratrol is poorly soluble in water but is absorbed through diet and supplementation per in vivo studies. Resveratrol does have low bioavailability within our body (half-life of one to three hours); per studies, it does appear to be more bioavailable when it is taken with a meal containing fat. Proper melatonin production and quercetin supplementation synergize with resveratrol for neuroprotection and improved mitochondrial health. Trans-resveratrol is the active form and is linked to a more significant reduction of excessive inflammation and cancer cell apoptosis than cis-resveratrol.[3] [4] [5] [6] [7] [8] [9]

Resveratrol Improves Mitochondrial Health by Many Different Complex Mechanisms:

Resveratrol mimics caloric restriction mechanisms by possibly activating SIRT1 (sirtuin one gene) directly or by acting on AMPK, increasing NAD⁺, which is a cofactor of sirtuin one, therefore, increasing its expression. Sirtuin one proteins improve insulin sensitivity in our cells, reduce Th1 (https://selfhacked.com/blog/supplements-foods-exercise-right-type-th1-vs-th2-dominance/),[10] and Th2 (https://selfhacked.com/blog/supplements-foods-exercise-right-type-th1-vs-th2-dominance/)[11] dominance (enhances Th17 (https://health.selfdecode.com/blog/th17/)^{^[12]} dominance), improves mitochondrial function by reducing oxidative stress, and increases longevity (at least in yeast). SIRT1 may increase the production of Th17 cells, worsening Th17 dominance in some people. SIRT1 inhibition is being investigated as a possible cancer treatment because activation of SIRT1 promotes cell survival over apoptosis by inhibiting apoptosis proteins. Inhibiting apoptosis proteins is not good for cancerous or unhealthy cells because you want them to die. Finally, SIRT1 over activation may impair nightly liver regeneration.[13] [14] [15] [16] [17] “Dietary restriction (a dietary regimen that restricts calorie intake), when not associated with malnutrition, has been shown to improve health and to slow the aging process in a wide range of animals. Sirtuin enzymes are nicotinamide adenine dinucleotide (NAD)-dependent deacetylases that are conserved from yeast to humans, influence lifespan in lower organisms, and appear to mediate at least certain effects of dietary restriction. Resveratrol has been proposed to mimic protective effects of dietary restriction, based on the observation that it can activate the mammalian sirtuin SIRT1 (silent mating type information regulation 2, S. cerevisiae, homolog 1) in an in vitro assay. However, the precise importance of sirtuins in the effects of dietary restriction and the ability of resveratrol to directly activate these enzymes in vivo remain controversial. Even while the rationale for testing resveratrol as a dietary restriction mimetic has been challenged, evidence for dietary restriction-like effects has continued to emerge. Resveratrol has been shown to extend life in yeast, worms, and flies in a sirtuin-dependent manner, although not all groups have reproduced these results. Further, it prevents insulin resistance, enhances mitochondrial biogenesis, improves vascular function, delays functional decline and restores normal longevity in obese mice. Perhaps most impressively, resveratrol induces transcriptional profiles in multiple tissues that resemble those of animals consuming fewer calories. At the same time, it is clear that it fails to mimic other aspects of dietary restriction, such as slowing heart rate and decreasing core body temperature, or thus far, extending lifespan in non-obese animals. Therefore, it appears to mimic some, but not all, effects of dietary restriction, and much remains to be learned about the mechanisms responsible. A common theme that emerges from studies on mammals is that both dietary restriction and resveratrol treatment can elicit changes in cellular mitochondrial content and alter mitochondrial production of reactive oxygen species (ROS). These effects are likely to have significant, possibly synergistic, impact on cellular aging processes.”[18]
Resveratrol promotes healthy mitochondrial biogenesis (creation of new mitochondria) within our brain, liver, and skeletal muscle. Resveratrol causes a post-translation regulation of PGC-1α, where PQQ (pyrroloquinoline quinone) upregulates PGC-1α mRNA transcription, so both could be taken simultaneously to improve mitochondrial biogenesis.[19] [20] “Multiple mechanisms may explain resveratrol-induced mitochondrial biogenesis and its contribution to cytoprotection and organismal health. Activation of SIRT1 by resveratrol can promote deacetyation and activation of peroxisome proliferator activator gamma coactivator 1 alpha (PGC-1α), the “master regulator” of mitochondrial biogenesis. Alternatively, other pathways, such as activation of the energy sensor AMP-activated protein kinase (AMPK) may allow PGC-1α to be activated independently of SIRT1, or many mechanisms may act in concert. Impaired mitochondria (e.g. in diabetes and in aging) may alter ATP production, the synthetic and secretory function of cells, cellular redox homeostasis and nuclear gene expression (by changing retrograde signaling pathways). Resveratrol-induced mitochondrial biogenesis would correct this impairment. Furthermore, because mitochondrial proliferation reduces the flow of electrons per unit mitochondria, resveratrol-induced mitochondrial biogenesis may reduce mitochondrial ROS production in the cells. Indeed, resveratrol, at physiologically relevant concentrations, attenuates mitochondrial oxidative stress in endothelial cells.”[21]
Resveratrol reduces mitochondrial oxidative stress, increases SIRT1 expression (which might be what activates endothelial NOS (eNOS) expression), and increases nitric oxide production in endothelial cells, improving blood flow, blood pressure, and cardiovascular health.[22] [23]
Resveratrol reduces endotoxin-induced mitochondrial dysfunction by reducing inflammatory cytokines, including tumor necrosis factor-alpha (TNFa), nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), and by reducing Gram-negative (might be very useful against H. pylori dysbiosis) bacterial colonies from its antibacterial properties.[24] [25]
Resveratrol helps to protect the mitochondria of our brain, ears (works well for people suffering from tinnitus and hearing loss), eyes (might protect or improve eye function for people suffering from macular degeneration, visual snow, and diabetic retinopathy), heart, kidneys, liver, nervous system, pancreas (might improve pancreatic and insulin function if you suffer from diabetes), skeletal muscle, and vascular system (good for restoring proper circulation so it might improve Reynaud’s phenomenon symptoms).[26] [27] [28] [29] [30] [31]
Resveratrol increases mitochondria energy by reducing oxidative stress. Increased oxidative stress in the mitochondria hinders the electron transport chain, reducing mitochondrial output. “Increased ROS levels in the mitochondria are known to inactivate critical enzymes involved in mitochondrial metabolism (e.g. α-ketoglutarate dehydrogenase and aconitase), which may diminish ATP production. It is also likely that mitochondrial oxidative stress results in direct injury to mitochondrial DNA, which may play a further role in the development of age-related diseases.”[32]

Resveratrol rapidly crosses our blood-brain barrier and has many neuroprotective effects. Trans-resveratrol was found in studies to increase cerebral blood flow, which may be useful for people with cerebrovascular disease. However, cognitive performance enhancement was not noted within the studies. Resveratrol supplementation might be useful for stroke prevention and recovery. Resveratrol might suppress glutamate excitability within our brain (there are a few studies that show it may sensitize our neural cells further to glutamate excitotoxicity; nonetheless, it is worth trying) and, in doing so, might help with seizure disorders, brain trauma, Alzheimer’s, Parkinson’s, cerebrovascular disease, schizophrenia, autism, brain fog, and anxiety. Resveratrol increases the glutathione content of glial cells (neuronal support cells), which helps protects them from ammonia neurotoxicity (many people suffering from upper gut bacterial dysbiosis or if you take valproic acid suffer from differing degrees of hyperammonemia). Resveratrol combined with proper melatonin production or supplementation has been shown to reduce beta-amyloid plaque formation (plaques of amyloid-beta peptides that increase oxidative stress in the brain and reduce neural mitochondria) within our brain, which may prevent or may alleviate Alzheimer’s disease.[33] [34] [35] [36] [37] [38] [39]

Pterostilbene is a dimethylated derivative of resveratrol. Two methoxy groups on the pterostilbene molecule replace the hydroxyl groups on a resveratrol molecule. Blueberries are the main source of dietary pterostilbene within our diet, which are well known for their neurological protection capabilities. Pterostilbene is also found in grapes and peanuts. Pterostilbene absorption is better than resveratrol (eighty percent bioavailability compared to the noted twenty percent of resveratrol), and it should be taken with meals to improve absorption. Pterostilbene also has a longer half-life than resveratrol at one hundred and five minutes, instead of resveratrol’s fourteen minutes.[40] [41] [42]

Pterostilbene has many of the same benefits as resveratrol. Pterostilbene has powerful anti-inflammatory capabilities, may improve insulin sensitivity, cognitive function, and our cerebrovascular system’s health. Pterostilbene is a newer supplement and has been studied less compared to resveratrol. It is unknown if it is better to supplement with pterostilbene instead of trans-resveratrol to improve your health but it might be worth trying because of its longer half-life and increased bioavailability.[43] [44] [45]

There are some side effects associated with supplementation. Resveratrol does not appear to have side effects at around a one-gram daily dose. Doses of more than two and a half grams daily have been associated with side effects, including nausea, vomiting, diarrhea, and liver dysfunction in people with non-alcoholic fatty liver disease. These side effects may occur in people dealing with dysbiosis because it is an antimicrobial supplement, and many symptoms are similar to when gut microbes die off. Taking it with food for people with gastrointestinal issues may reduce gastrointestinal side effects. Resveratrol supplementation is relatively safe and well-tolerated at up to five grams daily, either as a single dose or divided into multiple doses throughout the day for most people who are healthy. Orally administrated resveratrol gets metabolized by our gut microbiota, which makes it difficult to determine which effects are solely due it and/or its metabolites.[46]

Resveratrol has been reported to hinder human platelet aggregation during in vitro studies. Supplementing with resveratrol could enhance both bruising and bleeding risk when taken with anticoagulant drugs, antiplatelet drugs, and non-steroidal anti-inflammatory drugs (NSAIDs). It is also best because of its potential blood-thinning properties resveratrol should be discontinued a few weeks before elective surgery. Resveratrol has been reported to inhibit CYP3A4 activity. Therefore, high intakes could reduce metabolic medication clearance that undergoes extensive first pass CYP3A4 metabolism, increasing these medications’ bioavailability and toxicity risk. Finally, if you are taking any medications, ask your healthcare professional if supplementation may interact with any medications you are currently taking.[47] [48]

Supplemental doses of pterostilbene of up to two hundred and fifty milligrams daily are considered safe per studies. Pterostilbene also appears to block the activity of several metabolic enzymes, most notably CYP2C8 and UGT1A6, and will increase the effects of any drug they metabolize. Finally, pterostilbene may increase the effects of the medication’s sertraline and gefitinib as well. Finally, if you are taking any medications, ask your health care professional if pterostilbene supplementation may interact with any medications you are taking.[49] [50] [51] [52]