Written by Johannes Haerle, PhD, Senior Technical Manager, Evolva
Thanks to many researchers and clinicians worldwide, resveratrol continues to shine in the spotlight with new positive findings collected in preclinical and clinical studies every day. For over a decade, this steady stream of knowledge highlights resveratrol as one of the most well studied dietary supplements today within this fast evolving field. In May 2019, researchers from King’s College London highlighted new further insights of resveratrol, which documented its vasodilation properties and ability to lower blood pressure. Their findings indicate that a specific protein modulating activity can positively impact blood circulation through the oxidation of a protein called cGMP-dependent protein kinase (PKG).
With this new theory from King’s College London capturing headlines, we thought it was a good opportunity to compare these preclinical-derived insights to existing clinical studies. Prior work continues to underline the crucial role of resveratrol in improving blood circulation and its relevance to healthy aging.
One of the most studied ingredients
The polyphenol resveratrol known as phytoalexin produced in plants as a response to stress1 is well established in dietary supplements and food and beverages, found in products as a single active ingredient or in combination with others.2 Cognitive and cardiovascular health are often the targeted focus of these consumer products based on the great body of scientific studies counting more than 170 human clinical trials and 12,000 publications on NCBI PubMed. Other areas of focus in these clinical trials and publications include sports, bone and joint, eye, oral, skin and overall women’s health.3 Some people may ask the question “How can just one active ingredient, resveratrol, exhibit such a wide range of health benefits?” We have compiled this summary to highlight why resveratrol is so impactful for health aging and answer this common question.
Healthy blood flow as a basis for healthy living
One of the main fundamental functions to support healthy living is to maintain a healthy blood flow in the body and in the brain. Resveratrol has been characterized as being one of the most potent vasoactive molecules responsible for effectively increasing blood flow.4 Emerging research has highlighted that resveratrol follows a multifaceted approach and its beneficial effects are based on its molecular structure, cellular and systemic functions.5 More specifically, resveratrol has been characterized to interact with over 20 cellular targets directly and on a number of cellular processes indirectly by modulating cellular signals.6,7
Four mechanisms of action are key to understanding how resveratrol mediates healthy blood circulation
By targeting blood vessels and healthy circulation, scientific insights have identified 4 key molecular mechanisms of resveratrol which include the activation of:
- both estrogen receptors,
- the cell cycle and stress regulator protein SIRT1 associated with longevity and healthy aging,
- the antioxidant and anti-inflammation capacity regulator Nrf2 and
- the blood sugar and energy expenditure regulating protein AMPK.7,8
All four key functions can be involved in the activation of an enzyme called endothelial nitric oxide synthase (eNOS), which is known to be responsible for blood vessel dynamics by producing nitric oxide (NO).9 The enzyme eNOS is located in endothelial cells which cover the inner walls of blood vessels and the produced NO has been characterized to fulfill antithrombotic, antihypertensive and anti-atherosclerotic functions which will be briefly clarified below.10
Vasodilation helps blood flow
NO reaches the smooth muscle cells surrounding the blood vessels, which causes vasodilation and the widening of blood vessels through a cascade of reactions. Three different signaling pathways have been reported in literature to be involved in this process, and the cGMP dependent protein kinase (PGK) seem to have a crucial role in smooth muscle relaxation and blood vessel widening.
Based on the just recently published observation by researchers from the King’s College London, resveratrol can directly activate PGK and trigger vasodilation in a mouse model.11 This observation represents a great example of the multilevel modulating feature of resveratrol acting directly via protein modification, but also indirectly via the signaling molecule NO on proteins like PGK. This mechanism improves the blood circulation.
Once diffused into the blood, NO prevents platelet aggregation, as well as the adhesion of lipids and the overload of immune cells, all processes known to potentially cause arteriosclerosis and blood vessel stiffening.12 NO has also been shown to act as a messenger triggering mitochondrial biogenesis, which might be involved in the antiaging effects observed in resveratrol calorie restriction studies.13
Resveratrol can be key to maintaining healthy blood flow
Resveratrol effectively increases NO production on several levels, primarily by upregulating the NOS expression enabling more copies of this enzyme in endothelial cells. Secondly, resveratrol also enhances the NOS enzymatic activity and higher NO production by preventing the NOS enzyme from generating unwanted side products which could otherwise cause oxidative stress.14
Based on these preclinical and clinical derived insights, we at Evolva believe that one of the key functions of resveratrol is improving blood flow and circulation in the body and in the brain which ultimately might be one of the basics for healthy living. Therefore, we continue to investigate this function and the resulting health benefits with Veri-te™ resveratrol supported human clinical studies.
- Catalgol, B., Batirel, S., Taga, Y. & Ozer, N. K. Resveratrol : French paradox revisited. 3, 1–18 (2012).
- Pezzuto, J. M. Resveratrol: Twenty Years of Growth, Development and Controversy. Biomol. Ther. (Seoul). 14, 1–14 (2018).
- Singh, A. P. & Kaschula, C. H. Health benefits of resveratrol : Evidence from clinical studies. 1–41 (2019). doi:10.1002/med.21565
- Wong, R. H. X. et al. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr. Metab. Cardiovasc. Dis. 21, 851–856 (2011).
- Galiniak, S., Aebisher, D. & Bartusik-aebisher, D. Health benefits of resveratrol administration. Acta Biochim. Pol. 66, (2019).
- Tomé-Carneiro, J. et al. Resveratrol and Clinical Trials: The Crossroad from In Vitro Studies to Human Evidence. Curr. Pharm. Des. 19, 6064–6093 (2013).
- Harikumar, K. B. & Aggarwal, B. B. Resveratrol: A multitargeted agent for age-associated chronic diseases. Cell Cycle 7, 1020–1035 (2008).
- Li, H., Xia, N., Hasselwander, S. & Daiber, A. Resveratrol and Vascular Function. 1, 1–16 (2019).
- Zhao, Y., Vanhoutte, P. M. & Leung, S. W. S. Vascular nitric oxide : Beyond eNOS. J. Pharmacol. Sci. 129, 83–94 (2015).
- Li, H. & Fo, U. Nitric oxide in the pathogenesis of vascular disease. J Pathol 190, 244–254 (2000).
- Prysyazhna, O. et al. Blood Pressure – Lowering by the Antioxidant Resveratrol Is Counterintuitively Mediated by Oxidation of cGMP-Dependent Protein Kinase. Circulation 126–137 (2019).
- Li H, Horke S, F. U. Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis 237, 208–219 (2014).
- Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, C. M. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science (80-. ). 14, 314–317 (2005).
- Xia, N., Förstermann, U. & Li, H. Resveratrol and Endothelial Nitric Oxide. Molecules 19, 16102–16121 (2014).