This is my longest episode I have done so far. In it I discuss my favorite polyphenol, resveratrol. It is commonly found in wine and for a long time was thought to be the primary contributor to many of the health benefits of wine. This episode is actually the main episode, which is only a little bit longer than normal, and then a bonus section where I focus a bit more technically on three of the proposed cellular mechanisms for resveratrol. In it I discuss a paper I wrote, and if you would like to read the paper you can find it in the Scientific Nutrition Group on Facebook. Without further ado, see why this is my favorite polyphenol, and why I continue to quixotically yell about how we are not mice.
Script (remember I ad-lib, and my script is often less than complete, listen to the episode for accuracy):
For today’s episode I am going to talk about one of my favorite polyphenols. It is found in wine, and for a long time was one of the favorite candidates of the health benefits of red wine, resveratrol. And especially for this episode, after the normal episode ends I will be including some bonus content for people who want to learn more about the cellular mechanisms of resveratrol. I wrote a paper on this my junior year of college, that was supposed to be 10-12 pages and ended up being 26. I was so excited to talk about it, and got way too into researching it. This episode is also going to serve to help to remind us THAT WE ARE NOT MICE. So let’s do a quick comparison and go down the list of the things it does in mice and compare it to what it does in humans, and then at the end I’ll dangle a little bit of hope. Just a warning this episode is a little bit longer than normal, but I think it is interesting and one of the better episodes I have put together so far.
Let’s start with diabetes. In mice resveratrol is very effective at changing the glucose and insulin responses, and in humans it does practically nothing. There are computer simulations that show it could technically interact with the islet amyloid protein and may help prevent the advancement of type 2 diabetes because of that, but in actual studies it either shows a small effect or basically no effect at all. Though there are studies that have shown improved insulin sensitivity which is obviously a good thing. However, even in that studies there was no changes to the b islet cells, and the authors believe that any benefits that arose may have arisen due to a decrease in oxidative stress because resveratrol is a paradoxical antioxidant (which I will explain in the bonus material if you tune in). There was another small study that looked at glucose tolerance, and in that one glucose tolerance did seem to improve, but fasting glucose did not, so it is difficult to say exactly what the overall effect would be. This is why we need to be so careful drawing conclusions from mouse studies, mice have distinctly different physiologies than we do. They are a useful organism for early trials, but there is way too much of a tendency to draw large conclusions from them that is just not justified.
Let’s look at one of the big diseases that makes people nervous, cancer. In mice resveratrol has proven to be an effective anti-cancer agent, and it has even been effective against human cell lines and against murine models of human cancers. The problem? I cannot find a single study done in vivo in humans that showed any real effect. Yet I still have seen people market it as an anti-cancer supplement. That is only true if we are mice, and last time I checked we are not. There was actually a Phase 1 clinical trial done in humans for colon cancer several years ago that found that resveratrol had no effect on the gene products they were looking at, but a grape powder did, suggesting that it is possible that there are compounds in wines and grapes that may be useful but it is not useful alone.
So now let’s look at heart disease. Resveratrol seems to have some interesting effects here we should talk about. There was some early promising studies in mice, many of which seemed to focus on the fact that it had a potent antioxidant effect. A reduction in reactive oxygen species by antioxidants is one promising avenue for helping with heart disease. However, this in one case where in humans we have some results that actually got me really excited. There was a clinical trial done in humans that showed left ventricle diastolic function was improved, lowered LDL cholesterol in patients with coronary heart disease. This was an actual double blinded, placebo controlled, clinical trial so these results are quite exciting, and suggest to me that there is evidence that resveratrol can be a seriously useful compound in human health.
Let’s look at metabolic changes. Mice on a high-calorie diet have been shown to survive longer when they are supplemented with resveratrol. Resveratrol has actually been called a calorie restriction mimetic in small mammals because it seems to mimic many of the metabolic and physiological changes of calorie restriction for them. For example we see improved glucose tolerance, and improved lipid metabolism. In humans that are obese or have metabolic diseases there are actually some promising signs from resveratrol, although they are far from conclusive in my opinion. We have already discussed some of the changes in glucose and insulin responses, but there are also seems to be some other changes including the predicted Sir1 increase and AMPK increase that is seen in mice. In non-obese women we seem to so no changes at all, whereas in non-obese mice we do see some changes to transcriptional factors, but no changes to glucose tolerance or other more macro changes. This suggests that there is still some significant gap here between human metabolism and mouse metabolism, which I feel like is a point I keep making. However, some of the evidence is in my opinion promising.
Now finally let’s look at aging. In mice we see several physiological and biochemical changes including with AMPK and Sir1 and cAMP that would seem to suggest a reduction in aging related damage. This effect seems to hold pretty consistent over multiple studies. In humans, especially obese humans, there is limited evidence that these compounds will have that same effect. The issue with humans is it much harder to measure lifespan extension because we have such a longer life than mice. Furthermore, I worry about some features of resveratrol itself which also may be contributing to the problem, and I will discuss that lters.
The important thing to keep in mind with all of these studies is also that you cannot conclude that you need more red wine from them. The amount of resveratrol being used in these studies would be the equivalent of drinking liters and liters of wine each and every day which is obviously not desirable or healthy.
So why do all of these keep failing? Resveratrol has an incredibly low biovailability in humans, meaning that very little actually enters the cells or is usefully metabolized. So what could we do to improve this? Well glad you asked because this is where I get really excited, there is currently work being done to develop analogs of resveratrol that may be more biovailable and the early evidence suggests a significant but not necessarily large increase in biovailability. Besides that there has also been work on pro-drugs. Now pro-drugs are an interesting item, because they are a compound that when metabolized release the active form, in this case resveratrol. The reason these are interesting is that these have again been shown to significantly, but not necessarily large increase in biovailability. Finally there is work being done on coatings and stuff that hope to promote the metabolism of this compound, and again these have shown some early success. The point of all of this is that developing a truly useful compound is hard, WE ARE NOT MICE, and there are often ways to work arounds an issue in biovailability. That’s all I have for this main episode, but if you stay tuned in after my goodbye, I’m including a brief bonus feature where I discuss SOME of the proposed mechanisms of how resveratrol functions and which one is my favorite.
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It’s bonus content, this part is all based on things I researched for a paper my junior of college. If you want to see the paper I put it up in the Scientific Nutrition Group on Facebook and you can check it out there if you would like. So in this part we are going to focus on 3 primary mechanisms, interactions with amyloid proteins, interactions with the mitochondria, and interactions with the cell membrane.
First let’s start with the amyloid proteins. Amyloid proteins are those proteins that accumulate in your brain and can contribute to like Alzheimer’s. The islet variation of this can accumulate in the beta pancreatic cells, where insulin is produced, and when they accumulate can contribute to the death of beta pancreatic cells. When enough beta pancreatic cells diet, type 2 diabetes basically becomes irreversible because the body can no longer produce enough insulin. Resveratrol is able to bind to this polypeptide and make it such that it can no longer accumulate. This could potentially explain the longer lifespan and some of the improved diabetes markers with resveratrol.
The second one is the interaction with the mitochondria, and this is why I called resveratrol a paradoxical antioxidant in the main episode. Basically the way this functions is that resveratrol could potentially interact with the electron transport chain, and actually oxidize it, meaning that it pulls electrons out of the electron transport chain and into itself. When this happens resveratrol can then produce H2, or elemental hydrogen. The reason this is important is because H2 is one of the smallest, simplest, and most potent clinical antioxidants. So resveratrol may act as an antioxidant by inducing targeted oxidation and then releasing this potent antioxidant. Thus a paradoxical antioxidant.
The third mechanism involves interactions with the lipid bilayer, the cell membrane. This is the most interesting one to me, and I’ll explain why. Resveratrol effect changes based on the fluidity of the membrane. In a very fluid membrane, resveratrol makes it stiffer. In a stiff membrane, resveratrol makes it more fluid. The proposed mechanism for how this would work is in a similar manner to cholesterol, which can form lipid rafts. So to explain it more simply here, imagine a stiff membrane where the fatty acids are almost all saturated fatty acids and fit in really close together. What happens is the resveratrol is able to fit in between them, and because they are no longer so tightly fit together there is now a lot more fluidity. With a more fluid membrane what happens is that resveratrol actually helps link them together, and makes them more tightly associated. This increases the stiffness of the membrane. So why is this the most interesting mechanism to me? Well because there are a huge number of membrane bound proteins, meaning proteins that are a part of the membrane. So as the membrane changes it can induce changes in these proteins which can then change their signaling cascades and cause the varied physiological effect. It is also possible for this one to be working in concert with the mitochondrial one I have already discussed, because the mitochondria has its own membrane! This could also help explain how it is interacting with so many different pathways.
This is far from an exhaustive look at the proposed mechanisms for resveratrol. There are others, but these are the ones that most interested me, and I hope they interested you too. Thank you for tuning into this bonus content, and if you enjoyed this episode please share it with a friend. Thank you.
Bibliography (I may not directly address these studies in the episode but I looked at them and thought they might be valuable):
Alayev A, Doubleday PF, Berger SM, Ballif BA, Holz MK. 2014. Phosphoproteomics reveals resveratrol-dependent inhibition of akt/mTORC1/S6K1 signaling. J Proteome Res 13(12):5734-42.
Baur J and Sinclair D. 2006. Therapeutic potential of resveratrol: The in vivo evidence. Nature Reviews 5.
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, López-Lluch G, Lewis KN, et al. 2006. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117):337-42.
Brasnyó P, Molnár GA, Mohás M, Markó L, Laczy B, Cseh J, Mikolás E, Szijártó IA, Mérei Á, Halmai R, et al. 2011. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the akt pathway in type 2 diabetic patients. British Journal of Nutrition 106(3):383-9.
Cardullo N, Spatafora C, Musso N, Barresi V, Condorelli D, Tringali C. 2015. Resveratrol-related polymethoxystilbene glycosides: Synthesis, antiproliferative activity, and glycosidase inhibition. J Nat Prod 78(11):2675-83.
Chang CH, Lee CY, Lu CC, Tsai FJ, Hsu YM, Tsao JW, Juan YN, Chiu HY, Yang JS, Wang CC. 2017. Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: A key role of AMPK and akt/mTOR signaling. Int J Oncol 50(3):873-82.
Chen T, Sheng J, Fu Y, Li M, Wang J, Jia A. 2017. 1H NMR-based global metabolic studies of pseudomonas aeruginosa upon exposure of the quorum sensing inhibitor resveratrol. J Proteome Res 16(2):824-30.
Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M, Cohen HW, Barzilai N. 2012. Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci 67(12):1307-12.
Davidov-Pardo G, Perez-Ciordia S, Maria-Arroyo MR, McClements DJ. 2015. Improving resveratrol bioaccessibility using biopolymer nanoparticles and complexes: Impact of protein & carbohydrate maillard conjugation. J Agric Food Chem 63(15):3915-23.
Fernández AF and Fraga MF. 2011. The effects of the dietary polyphenol resveratrol on human healthy aging and lifespan. Epigenetics 6(7):870-4.
Giovannini L and Bianchi S. 2017. Role of nutraceutical SIRT1 modulators in AMPK and mTOR pathway: Evidence of a synergistic effect. Nutrition 34:82-96.
He X, Deng Q, Cai L, Wang C, Zang Y, Li J, Chen G, Tian H. 2014. Fluorogenic resveratrol-confined graphene oxide for economic and rapid detection of alzheimer’s disease. ACS Appl Mater Interfaces 6(8):5379-82.
Jamie L Barger, Tsuyoshi Kayo, James M Vann, Edward B Arias, Jelai Wang, Timothy A Hacker, Ying Wang, Daniel Raederstorff, Jason D Morrow, Christiaan Leeuwenburgh, et al. 2008. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3(6):e2264.
Jeandet P, Bessis R, Sbaghi M, Meunier P, Trollat P. 1995. Resveratrol content of wines of different ages: Relationship with fungal disease pressure in the vineyard. Am J Enol Vitic 46(1):1-4.
Liu P, Chong I, Lee Y, Tsai J, Wang H, Hsieh C, Kuo H, Liu W, Chen Y, Chen H. 2015. Anti-inflammatory effects of resveratrol on hypoxia/reoxygenation-induced alveolar epithelial cell dysfunction. J Agric Food Chem 63(43):9480-7.
Magyar K, Halmosi R, Palfi A, Feher G, Czopf L, Fulop A, Battyany I, Sumegi B, Toth K, Szabados E. 2012. Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease. Clinical Hemorheology and Microcirculation 50(3):179.
Markus MA and Morris BJ. 2008. Resveratrol in prevention and treatment of common clinical conditions of aging. Clinical Interventions in Aging 3(2):331-9.
Mattarei A, Azzolini M, Carraro M, Sassi N, Zoratti M, Paradisi C, Biasutto L. 2013. Acetal derivatives as prodrugs of resveratrol. Mol Pharmaceutics 10(7):2781-92.
Mishra R, Sellin D, Radovan D, Gohlke A, Winter R. 2009. Inhibiting islet amyloid polypeptide fibril formation by the red wine compound resveratrol. Chembiochem 10(3):445-9.
Nazar Labinskyy, Anna Csiszar, Gabor Veress, Gyorgyi Stef, Pal Pacher, Gabor Oroszi, Joseph Wu, Zoltan Ungvari. 2006. Vascular dysfunction in aging: Potential effects of resveratrol, an anti- inflammatory phytoestrogen. Current Medicinal Chemistry 13(9):989-96.
Neves AR, Nunes C, Reis S. 2015. New insights on the biophysical interaction of resveratrol with biomembrane models: Relevance for its biological effects. J Phys Chem B 119(35):11664-72.
Neves AR, Nunes C, Amenitsch H, Reis S. 2016. Resveratrol interaction with lipid bilayers: A synchrotron X-ray scattering study. Langmuir 32(48):12914-22.
Nguyen AV, Martinez M, Stamos MJ, Moyer MP, Planutis K, Hope C, Holcombe RF. 2009. Results of a phase I pilot clinical trial examining the effect of plant-derived resveratrol and grape powder on wnt pathway target gene expression in colonic mucosa and colon cancer. Cancer Manag Res 1:25-37.
Nicoletti NF, Rodrigues-Junior V, Santos AA, Leite CE, Dias ACO, Batista EL, Basso LA, Campos MM, Santos DS, Souto AA. 2014. Protective effects of resveratrol on hepatotoxicity induced by isoniazid and rifampicin via SIRT1 modulation. J Nat Prod 77(10):2190-5.
Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S. 2007. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 13(6):688-94.
Pantusa M, Bartucci R, Rizzuti B. 2014. Stability of trans-resveratrol associated with transport proteins. J Agric Food Chem 62(19):4384-91.
Park S, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R, Brown A, et al. 2012. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148(3):421-33.
Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, et al. 2008. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metabolism 8(2):157-68.
Pollack R and Crandall J. 2013. Resveratrol: Therapeutic potential for improving cardiometabolic health. Am J Hypertens 26(11):1260-8.
Pshenichnyuk SA and Komolov AS. 2015. Dissociative electron attachment to resveratrol as a likely pathway for generation of the H2 antioxidant species inside mitochondria. J Phys Chem Lett 6(7):1104-10.
Sánchez-Fidalgo S, Cárdeno A, Villegas I, Talero E, de la Lastra, Catalina Alarcón. 2010. Dietary supplementation of resveratrol attenuates chronic colonic inflammation in mice. European Journal of Pharmacology 633(1):78-84.
Sarpietro MG, Spatafora C, Accolla ML, Cascio O, Tringali C, Castelli F. 2013. Effect of resveratrol-related stilbenoids on biomembrane models. J Nat Prod 76(8):1424-31.
Shi Y, Hou X, Zhang X, Wang Y, Chen Y, Zou J. 2013. Inhibition of oxidized-phospholipid-induced vascular smooth muscle cell proliferation by resveratrol is associated with reducing Cx43 phosphorylation. J Agric Food Chem 61(44):10534-41.
Timmers S, Auwerx J, Schrauwen P. 2012. The journey of resveratrol from yeast to human. Aging 4(3):146-58.
Timmers S, Hesselink MKC, Schrauwen P. 2013. Therapeutic potential of resveratrol in obesity and type 2 diabetes: New avenues for health benefits? Ann N Y Acad Sci 1290(1):83-9.
Timmers S, Konings E, Bilet L, Houtkooper R, van de Weijer T, Goossens G, Hoeks J, van der Krieken S, Ryu D, Kersten S, et al. 2011. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metabolism 14(5):612-22.
Toppozini L, Meinhardt S, Armstrong CL, Yamani Z, Kucerka N, Schmid F, Rheinstadter MC. 2014. Structure of cholesterol in lipid rafts. Phys Rev Lett 113(22):228101.
Wang Q, Ning L, Niu Y, Liu H, Yao X. 2015. Molecular mechanism of the inhibition and remodeling of human islet amyloid polypeptide (hIAPP1–37) oligomer by resveratrol from molecular dynamics simulation. J Phys Chem B 119(1):15-24.
Wang W, Qi Y, Rocca JR, Sarnoski PJ, Jia A, Gu L. 2015. Scavenging of toxic acrolein by resveratrol and hesperetin and identification of adducts. J Agric Food Chem 63(43):9488-95.
Yoshino J, Conte C, Fontana L, Mittendorfer B, Imai S, Schechtman K, Gu C, Kunz I, Fanelli F, Patterson B, et al. 2012. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metabolism 16(5):658-64.
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