Myth: Resveratrol can replace calorie restriction to improve vascular health.
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Caloric Restriction and CR Mimics?
Caloric restriction, or CR in short, is the one of the most well-known strategy to expand lifespan and delay chronic diseases related to ageing. To perform CR, one needs to reduce his or her caloric intake by 20-50% (1) without altering the levels of essential nutrients such as vitamins, minerals and proteins to prevent malnutrition. In fact, a recent clinical study (2) has shown that just 15% reduction in daily caloric intake is sufficient to control obesity and ageing. For many, this is equivalent to 1 packet of peanut butter sandwich biscuit or ¾ bowl of cooked rice (150kcal).
While we all know that appropriate amount of dieting is good for our physical and emotional health, CR can work specifically on our cardiovascular system by reducing blood cholesterol, inflammation and oxidative stress.
Performing CR is easy, all you have to do is to eat less. This makes CR the most reproducible intervention against many chronic health problems. However, CR can also be the least reproducible option for many city dwellers. We are living in an age of food abundancy. Sometimes having plenty of choices is equivalent to no choice. Think of the busy schedule you have at work and the oily take away food you have on your order, or the expensive salads with prices that never match with the number of lettuce leaves, it’s either you eat unhealthy food or starve. Adjustments to dietary plans need time, money and a decent amount of self-determination. This is when scientists and publics start to shift focus from CR to CR mimics – supplements that have similar effects to CR but are much more convenient to take.
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Debunking the myth
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Atherosclerosis: deposits of cholesterol, blood cells and fats form a plaque that stiffens and blocks the artery
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There is some truth in the myth...
How does Resveratrol work as a CR mimic?
Many studies have reported the anti-inflammatory and anti-oxidant effects of resveratrol on endothelial cells (1), which are one of the main cells found at the vessels of our body.
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Anti-Oxidant
Increase oxidative stress depletes the vasodilator in the blood vessel walls and leads to hypertension (5) due to enhanced vasoconstriction. Oxidative stress also induces inflammation.
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Aneurysm: balloon-like bulges of weakened blood vessel, leads to stroke when bursts
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How can the anti-oxidant and anti-inflammatory effects of Resveratrol be studied?
We take a look at pre-clinical studies.
As early as 2008, scientists from the National Institute of Health (NIH) had proved the the high potential of resveratrol as a caloric restriction mimic on the mice model (6). Mice supplemented with resveratrol showed an increase in health status of the vascular tissue with reduction in blood cholesterol level, increase responsiveness to vasodilator and decreased cell death, oxidative stress and inflammation.
These results seem comprehensive and satisfactory. However, on the evolutionally view, mice are barely distantly related to us. Also, from the past experimental data, the translational success from the mice model to human is unpredictable. This means there is a high chance that whatever works on them will not work on us. Just like how the vaccines have to be put under reliable pre-clinical trails before the actual clinical trails are conducted, we need to back up our results with test subjects who are of closer resemblance to us.
Having thought of living a scrumptious life without adding so much burden to your vascular health? Resveratrol pills might just be what you need, at least for our primate cousins.
In 2015, NIH published another 2-year long study on the benefits of resveratrol supplement on vascular heath (7). This time, 24 Rhesus monkeys were randomised into 3 groups - standard diet, high fat high sucrose diet and high fat high sucrose diet with resveratrol supplements.
Not surprisingly, their results have shown that resveratrol is able to prevent the increase in aortic pause wave velocity (PWV) that was shown in the high fat high sucrose group. PWV is the gold standard in measuring one's artery stiffness. As PWV increases throughout a person's life time, maintaining PWV in the healthy range is essential for one's cardiovascular health.
The later follow up experiments from the study showed that there was a significant decrease in inflammation and aortic cell death activities, and an increase in anti-oxidant biomarkers in the resveratrol supplemented monkeys - complies with the results from the previous study.
Interestingly, this time, resveratrol failed to control the blood cholesterol level in these poorly eating monkeys. The effect of PWV reduction also decline from the second year onwards. Scientists suggested that this may be due to the long term impact of the poor dietary structure overwhelms the system, blunting the beneficial effects of resveratrol.
In conclusion, the pre-clinical studies on animal models show us great potential of resveratrol in acting as a caloric restriction mimic. Resveratrol may complement with a heathy or standard diet to bring out better vascular health. It may even rescue our vascular health from a detrimental diet that is high in fat and sugar. However, we need to be aware that it is not an elixir to fully reverse the impact of unhealthy eating.
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Now, if animal studies also support the use of resveratrol, is it safe to conclude that it is translatable to humans? Animals and humans are different after all.
Results from clinical trials gives hope for the replacement of calorie restriction with resveratrol.
Why is a placebo important?
What exactly is CAVI and FMD?
Large amounts of clinical trials have been performed on populations with existing metabolic conditions such as patients with hypertension, diabetes and healthy smokers.
A one-time supplementation of 300mg resveratrol to hypertensive patients increased the flow-mediated dilation (FMD) of the arteries as compared to the group that was given a placebo, which is a pill that contained no resveratrol. Hence, resveratrol appeared to be able to improve the arteriole function in hypertensive patients.
Interestingly, results demonstrated a significant improvement in FMD in women but not men. Patients with higher low density lipoprotein (LDL) had greater improvement in FMD than those with initial lower LDLs (12). However, further studies are needed to warrant the validity of this point.
What about a longer period of resveratrol consumption?
The consumption of resveratrol daily for 3 months improved the vascular health of diabetic participants in a 2017 clinical study (8). Markers of an unhealthy vascular profile include high oxidative stress and an increase in the stiffness of the arteries in our body. Resveratrol successfully reduced the oxidative stress levels of the blood vessels as observed from the reduced levels of diacron reactive oxygen metabolites, a marker for oxidative stress after resveratrol consumption. Arterial stiffness was also decreased significantly as seen from the reduction in CAVI, which is a measurement for arterial stiffness.
Well, the above clinical trials are all performed on people with existing health conditions...Are there any clinical trials performed on healthy adults?
A 2013 clinical study showed promising results of resveratrol consumption on the vascular health of 41 healthy adults (10). Blood plasma serum was taken from participants after consumption of RESV (containing trans resveratrol, grapeskin extract and quercetin) or cellulose placebo, and incubated with human coronary endothelial cells. Analysis of the cell culture showed a significant decrease in levels of inflammatory-related proteins, namely VCAM, ICAM, IL-8, thereby proving a protective anti-inflammatory effect of resveratrol on those who are at low-risk for cardiovascular diseases. This suggests the potential of resveratrol as a protective supplement against age-related declines in the vascular system.
A closer step to the possibility of resveratrol replacing calorie restriction lies in a 2018 clinical trial which compared the effects of resveratrol and calorie restriction in a single experiment.
In the clinical trial, both calorie restriction and resveratrol groups showed similar levels of the increase in expression of SIRT1 and esRAGE proteins which are molecules linked to vascular protection (9). Therefore, this study provided some evidence for the similarities of resveratrol to calorie restriction.
Are we there yet?
Despite the great amount of research of resveratrol in clinical trials, various shortcomings and limitations of the current research prevents the full replacement of calorie restriction by resveratrol.
Current clinical trials on resveratrol have produced mixed results. For instance, a clinical trial on middle-aged adults that are moderately insulin resistant proved no significant changes in circulating high-sensitivity C-reactive protein (hs-CRP) or IL6 after 4 months of resveratrol consumption (11). hs-CRP and IL-6 are inflammatory markers that can possibly contribute to vascular dysfunction.
This could be attributed to the largely variable protocols adopted in different clinical trials. For example, different trials used different indicators of inflammatory markers and oxidant levels. Just like how giving only multiple choice questions to some students while only open-ended questions to others would not be a fair or reliable procedure to evaluate students' academic abilities, there needs to be a more standardised procedure to evaluate the effects of resveratrol on vascular health.
Additionally, most clinical trials are conducted over a relatively short period of time, ranging from a one-time off to a maximum of a year of supplementation. You probably wouldn’t want to consume resveratrol only to find out that in the much longer term they do not have much beneficial effects or may instead even have side effects that only manifest in the long run.
Furthermore, the sample sizes of the current clinical trials would be too small to make meaningful conclusions, even though they have been double-blinded. randomised, and placebo-controlled. Imagine one experiment conducted on 10 individuals versus another with 100, which one would you trust more? Larger scaled clinical trials need to be conducted in order for the effects of resveratrol to be generalised to people of various ages, ethnicity and countries.
Most importantly, few studies touch on the comparison between effects of resveratrol and calorie restriction in the same experiment. It would be less accurate to conclude the degree of similarity of resveratrol and calorie restriction from separate clinical trials since the protocols and sample sizes vary across studies.
All in all, it seems that we are progressing, but it is still not there yet.
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A placebo is commonly used in drug experiments to test whether a drug truly has an effect. It can be a “fake drug” that is harmless and possesses no therapeutic or harmful effects [13]. The idea of placebo builds on the fact that the mind may play an important role in altering physical outcomes. Without the presence of a placebo, how can we be sure that the group consuming the medication improved truly because of the therapeutic effects of the drug and not due to the psychological effects of simply taking a medication? Hence, having a placebo group eliminates the possibility of the latter and gives greater reliability to experiments.
Flow-mediated dilation (FMD) is a measure of the functioning of the endothelial dilation capacities in response to a shear stress from the sudden blood flow to a previously constricted region of the arteries. Improvement in FMD, represented by higher FMD values, portrays greater endothelial functioning. Cardio‐ankle vascular index (CAVI) is a relatively new measure of arterial stiffness. It is less affected by changes in blood pressure compared to PWV (14). Regardless of whether FMD, CAVI or PWV, these measurements have been reliable predictors of cardiovascular diseases and are used widely in both clinical and experimental settings.
What is considered a good clinical trial?
Randomised, double-blinded and placebo-controlled studies are the ideal features that a good clinical study should comprise (13). Randomisation involves the non-specific selection and grouping of participants. A double-blinded study would have both participants and investigators kept unaware of the intervention. Some studies go further to adopt a triple-blinded study where data analysers of the study are also kept in the dark. Though these factors are considered the gold standard of any experimental study, a comprehensive compliance will require a large amount of time, resources and effort.
Truth: Resveratrol cannot fully replace calorie restriction at the moment.
Nutraceuticals like resveratrol have the potential to improve vascular health but considerations need to be undertaken on various levels - clinically and individually.
Until more large-scale studies comparing the direct effects of resveratrol and calorie restriction are made, perhaps calorie restriction would be a more natural means of improving vascular health compared to the deliberate consumption of resveratrol supplements whose efficacies have not been strongly supported yet.
Some studies have reported the potential interaction of resveratrol with other drugs. For example, resveratrol may interact with cytochrome P450 when consumed in high doses (15). Cytochrome P450 is a family of enzymes involved in the metabolism of many drugs. Therefore, the uncareful consumption of resveratrol with another drug simultaneously may interfere with the efficacies of the other drug. Thus, an individual on current medication may have to be careful in taking resveratrol.
Even if future studies warrant the replacement of calorie restriction with resveratrol, it should be noted that it is unlikely that consumption of resveratrol can make up for the effect of an unhealthy diet as proven in the 2015 pre-clinical trial. Moderation is always the key and consultations with a professional on the appropriate usage of resveratrol would be crucial.
If you would like to slow down the aging of your vessels starting from today, a moderate cut-down of calories from your daily meals can be a good start and go a long way.
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Done by: MeiQi and An Ping
References
1. Redman, L. M., Smith, S. R., Burton, J. H., Martin, C. K., Il’yasova, D., & Ravussin, E. (2018). Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging. Cell Metabolism, 27(4), 805-815.e4. https://doi.org/10.1016/j.cmet.2018.02.019
2. Vernon W. Dolinsky, Jason R.B. Dyck. (2011). Calorie restriction and resveratrol in cardiovascular health and disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1812, Issue 11, ISSN 0925-4439, 1477-1489. Retrieved from https://doi.org/10.1016/j.bbadis.2011.06.010.
3. Galkina, E., & Ley, K. (2009). Immune and inflammatory mechanisms of atherosclerosis. Annual Review of Immunology. https://doi.org/10.1146/annurev.immunol.021908.132620
4. Chalouhi, N., Ali, M. S., Jabbour, P. M., Tjoumakaris, S. I., Gonzalez, L. F., Rosenwasser, R. H., Koch, W. J., & Dumont, A. S. (2012). Biology of intracranial aneurysms: role of inflammation. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 32(9), 1659–1676. https://doi.org/10.1038/jcbfm.2012.84
5. Rodrigo, R., González, J. & Paoletto, F. The role of oxidative stress in the pathophysiology of hypertension. Hypertens Res 34, 431–440 (2011). https://doi.org/10.1038/hr.2010.26
6. Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., Swindell, W. R., Kamara, D., Minor, R. K., Perez, E., Jamieson, H. A., Zhang, Y., Dunn, S. R., Sharma, K., Pleshko, N., Woollett, L. A., Csiszar, A., Ikeno, Y., le Couteur, D.,Elliott, P. J., Becker, K.G., Navas, P., Ingram, D.K, Wolf, N.S, Ungvari, Z., Sinclair, D.,A.. de Cabo, R. (2008). Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metabolism, 8(2), 157–168. https://doi.org/10.1016/j.cmet.2008.06.011
7. Mattison, J. A., Wang, M., Bernier, M., Zhang, J., Park, S., Maudsley, S., An, S. S., Santhanam, L., Martin, B., Morrell, C., Baur, J. A., Peshkin, L., Csiszar, A., Herbert, R. L., Tilmont, E. M., & Ungvari, Z. (2015). Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. NIH Public Access. 20(1), 183–190. https://doi.org/10.1016/j.cmet.2014.04.018.Resveratrol
8. Imamura, H., Yamaguchi, T., Nagayama, D., Saiki, A., Shirai, K., & Tatsuno, I. (2017). Resveratrol Ameliorates Arterial Stiffness Assessed by Cardio-Ankle Vascular Index in Patients With Type 2 Diabetes Mellitus. International Heart Journal, 58(4), 577–583. https://doi.org/10.1536/ihj.16-373
9. Roggerio, A., Strunz, C., Pacanaro, A., Leal, D., Takada, J., Avakian, S., & Mansur, A. (2018). Gene Expression of Sirtuin-1 and Endogenous Secretory Receptor for Advanced Glycation End Products in Healthy and Slightly Overweight Subjects after Caloric Restriction and Resveratrol Administration. Nutrients, 10(7), 937. https://doi.org/10.3390/nu10070937
10. Agarwal, B., Campen, M. J., Channell, M. M., Wherry, S. J., Varamini, B., Davis, J. G., Baur, J. A., & Smoliga, J. M. (2013). Resveratrol for primary prevention of atherosclerosis: Clinical trial evidence for improved gene expression in vascular endothelium. International Journal of Cardiology, 166(1), 246–248. https://doi.org/10.1016/j.ijcard.2012.09.027 .
11. Kjær, T. N., Ornstrup, M. J., Poulsen, M. M., Stødkilde-Jørgensen, H., Jessen, N., Jørgensen, J. O. L., Richelsen, B., & Pedersen, S. B. (2017). No Beneficial Effects of Resveratrol on the Metabolic Syndrome: A Randomized Placebo-Controlled Clinical Trial. The Journal of Clinical Endocrinology & Metabolism, 102(5), 1642–1651. https://doi.org/10.1210/jc.2016-2160
12. Marques, B., Trindade, M., Aquino, J., Cunha, A., Gismondi, R., Neves, M., & Oigman, W. (2018). Beneficial effects of acute trans-resveratrol supplementation in treated hypertensive patients with endothelial dysfunction. Clinical and Experimental Hypertension, 40(3), 218–223. https://doi.org/10.1080/10641963.2017.1288741
13. Harvard Health. (2019, August 9). The power of the placebo effect. https://www.health.harvard.edu/mental-health/the-power-of-the-placebo-effect
14. Bruno, R. M., Bianchini, E., Faita, F., Taddei, S., & Ghiadoni, L. (2014). Intima media thickness, pulse wave velocity, and flow mediated dilation. Cardiovascular Ultrasound, 12(1). https://doi.org/10.1186/1476-7120-12-34
15. Chow, H. H., Garland, L. L., Hsu, C. H., Vining, D. R., Chew, W. M., Miller, J. A., Perloff, M., Crowell, J. A., & Alberts, D. S. (2010). Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer prevention research (Philadelphia, Pa.), 3(9), 1168–1175. https://doi.org/10.1158/1940-6207.CAPR-09-0155
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