Nutraceuticals and nootropics for anti-aging

I keep hearing about a drug called ‘resveratrol’ on TV and in magazines and newspapers. It supposedly prevents heart disease and stops the aging process. Claims like this have been made about lots of other products for many, many years, but mostly they have turned out to be a lot of hype. Is there any reason to think that resveratrol is any different? What does it really do?

While it’s true that the supplement industry sometimes promotes products whose benefits fall far short of the claims made for them, resveratrol is not one of those. It really is different. Much of what sounds like ‘hype’ is actually the enthusiasm of medical researchers finding its way into promotional materials created by supplement companies. Resveratrol, and related compounds found in grapes and other plants, have shown remarkable abilities to interfere with processes responsible for cancer and age-related illnesses. So great is the interest in these substances that a search of the medical literature on resveratrol turns up more than 2500 research studies, most of them published in the past four years.

What has prompted the excitement over this substance? Initially, resveratrol was seen as a possible prevention for ‘hardening of the arteries’ — the build-up on arterial walls of plaque-like deposits of cholesterol and other materials which restrict blood flow. The early evidence was indirect — populations who normally consume more than average amounts of resveratrol in red wine were found to have a lower risk of heart disease.¹ Then tissue studies^2,3 showed that resveratrol and similar substances have properties considered desirable in cardiovascular treatments. And when resveratrol was actually fed to living animals, it did indeed turn out to have cardiovascular benefits.⁴

Once resveratrol’s cardiovascular potential was realized, researchers began studying it in other medical contexts. There is a long list of these on the LifeLink website at Illuminol.asp. Most of the ailments on that list look like good candidates for resveratrol treatment, but the applications that are generating the most excitement are:

• Cardiovascular disease
• Cancer
• Aging

Let’s look at each of these three areas.

Cardiovascular disease

The first hint that resveratrol might be useful for cardiovascular disease came in 1992 when it was discovered that it had the ability to inhibit blood platelet aggregation⁵ — a process implicated in plaque formation in arteries. In the years since then researchers have studied resveratrol’s cardiovascular effects in cells, in cell components, in tissues, and in whole animals. Like many other polyphenols, it inhibits the oxidation of lipids and interferes with inflammatory processes involved in atherosclerosis. It suppresses arrhythmias, and relaxes blood vessels. Its effects on cell-signaling and gene action have been explored in considerable detail.⁶ Clinical studies on lab animals showed that resveratrol prevents plaque formation in the arteries of live animals.^7,8

Despite this strong evidence that resveratrol might prevent the primary cause of heart disease, human clinical trials are almost non-existent. No effort has been made to directly test whether resveratrol actually reduces cardiovascular disease in humans. Instead there have been a handful of small studies, each focused on certain factors known to be correlated with heart disease, and each producing positive results — such as the small 8-week study performed by researchers at the University of Connecticut, in which inflammatory factors were measured in 44 women who were given grape polyphenols or placebo; it was found that resveratrol “beneficially affected key risk factors for coronary heart disease…”.⁹

Although the evidence is indirect, it is quite convincing to me. I believe that resveratrol is a significant preventative for cardiovascular disease, in addition to its other activities. And I think it’s great to have a single supplement that works against multiple ailments — this saves a lot of money and hassle compared to buying several separate supplements to get these same benefits.

Cancer

Two different supplements have recently captured the attention of forward-looking cancer researchers: vitamin D3 and resveratrol. Both show strong anti-cancer effects that apparently result from the fact that these substances affect the activities of genes involved in the growth of cancerous cells. Although the details of this gene regulation are not known, it is most likely that vitamin D3 and resveratrol regulate different sets of genes — and therefore may act synergistically.

The claim that resveratrol and associated polyphenols inhibit cancer growth is based on abundant evidence from cell studies and experiments with lab animals. These are nicely summarized in a review in The International Journal of Molecular Sciences.¹⁰

As for clinical trials to prove that resveratrol has the same anti-cancer benefits in humans... well, there haven’t been any. (I’ll have more to say about that below.) Nevertheless, the molecular mechanisms leading to cancer are the same in lab animals as they are in humans. What holds for them undoubtedly holds for us.

The evidence for resveratrol’s anti-cancer activity is, in my opinion, strong enough to justify its cost as a cancer preventative even if it had no other benefits. I use resveratrol (250 mg/day), along with vitamin D3 (25000 i.u. every other day) for protection from cancer as well as from other age-related diseases, including aging itself.

Aging

There is a small but very enthusiastic research community devoted to understanding the mechanisms of aging and finding ways to block these mechanisms. Resveratrol is one of the substances that these researchers have developed a strong interest in. Well over a hundred research papers have appeared on this subject during the past ten years.

Does resveratrol slow, halt, or reverse the aging process? In various other species it does.^11,12 The same basic aging mechanisms operate in humans, so there is no reason to think that the same treatments would not also work for us. Trouble is, a clinical trial to prove this would require about ten years to carry out and might have difficulty recruiting participants. (Why volunteer for a clinical trial and risk getting a placebo, when you can just buy resveratrol and use it on your own?)

One of the more intriguing pieces of evidence that resveratrol is an aging-suppressor in humans is the work done on human skin cells at the University of Sidney.¹³ The researchers grew the cells in tissue culture and then followed the activities of 19000 genes as resveratrol was provided to the cells. They found that the activities of 47 genes changed significantly in response to the resveratrol. These included genes for growth, cell division, cell signaling, programmed cell death, and for the making of proteins — in fact, many were genes involved in aging and decrepitude at the cellular level.

I consider resveratrol to be a breakthrough in the prevention of aging. While it’s far from 100% effective, it is an important step in the right direction. Modified versions of resveratrol are now being developed, and in the coming years we should expect to see some of them come to market — first as high-priced prescription drugs, then as black-market knock-offs, and eventually as over-the-counter aging-inhibitors. Meanwhile, I’m going to be buying time by using resveratrol itself until something better comes along.

Problems with resveratrol stability and absorption

Many resveratrol products are now on the market, and most of them are worth a lot less than they cost. There are three problems:

• resveratrol is unstable in the presence of bright light;
• resveratrol is unstable in the presence of oxygen unless it is kept cold;
• resveratrol is poorly absorbed in the digestive tract.

Since most resveratrol products on the market are processed, packaged, and shipped under ordinary conditions, they are highly degraded by the time they reach the end-user. When an impartial analytical lab analyzed a random selection of resveratrol products in 2007, the results revealed that most of them contained far less of the active ingredient than is thought to be a useful dose. LifeLink considered adding a resveratrol product to its product line back in 2006, but delayed doing so until a practical solution to the stability problem could be found. The resulting product, ilLuminol, is kept at temperatures cool enough and at light levels low enough to prevent oxidation.

The poor absorbability of resveratrol means that only those products containing bioavailability enhancers are able to put resveratrol into the body in an active state. But most resveratrol products on the market contain no bioavailabity enhancers. When LifeLink asked me to come up with a formula for ilLuminol, I suggested two such enhancers: quercetin and piperine. These two bio-enhancers inhibit the conversion of resveratrol to other substances, and also inhibit the molecular ‘pumps’ that the body uses to prevent resveratrol from entering the bloodstream and from entering cells where it can take effect.

Why haven’t there been any clinical trials in humans?

Actually there have been a small number of clinical trials that tested resveratrol in the human body. But these were not tests of resveratrol as a treatment for cancer, heart disease, or aging, but rather as studies of resveratrol's physiological effects. For example, cardiologists at University General Hospital in Attikon measured the effects of a dose of resveratrol on arterial flow.⁴ Similarly, researchers at the University of Toronto studied arterial flow, heart rate, cardiac output, and nerve activity.¹⁴ These may be useful experiments, but they are a far cry from direct tests of the ability of resveratrol to protect patients from life-threatening ailments.

Given the fact that cancer kills 7 million people per year,¹⁵ and cardiovascular disease kills 16 million,¹⁶ one would think that the medical research establishment would be johnny-on-the-spot whenever a promising new treatment turns up. And one would expect that by now hundreds of clinical trials would already have been conducted, specifically aimed at determining how best to use resveratrol and related polyphenols for dealing with cancer, cardiovascular disease and a host of other ailments. Yet nothing of the sort has happened. The establishment is mainly interested in ‘established’ research approaches, and this is where almost all of the money goes — billions of dollars every year for minor improvements in cholesterol suppression, radiation therapy and chemotherapy, for example. Something seems very wrong here.

In my view, this problem stems from several causes, but the one I want to rail against here is the stifling influence of traditional medical philosophy.

Some of the principles used by the medical community to make fundamental decisions are rooted in tradition. They were formulated in ancient times, before anyone understood anything at all about how the body works, and when patients were more likely to die than to survive ailments that we now consider trivial. Physicians knew that to do anything innovative was to risk being blamed if the patient died, so they adopted this principle: “Above all, do no harm.” In practice, this meant “Don’t try anything new.” This principle still plays a major role in medical decision-making because superficially “Do no harm!” sounds good. But it leads to outrageously bad decisions because it only takes into account the well-being of people who might be harmed by a treatment — it fails to take into account the well-being of people who would benefit from the treatment. For example, the U.S. FDA routinely refuses to approve drugs that have serious side effects in a few people but which would benefit many others. FDA officials will choose to let a hundred thousand people die needlessly from not having access to a beneficial new drug than to risk having a hundred people die from its side effects. Does this make any sense? Only if you accept the idea of “Above all, do no harm.”

In conclusion

Resveratrol, in my opinion, is a very important nutritional discovery. I use it myself — LifeLink’s enhanced resveratrol formula ‘ilLuminol’ — and will continue to do so even though I don’t expect the benefits to my body to be noticeable for a few years — just as aging itself is usually noticeable only with the passage of years. I’m willing to act on the basis of indirect evidence rather than direct proof of efficacy because the indirect evidence is pretty good, the potential benefits are enormous, there aren’t any negative side effects, and the cost is affordable.

For specific information about LifeLink’s resveratrol product, ilLuminol™, see the monograph About ilLuminol.

— Dr. Alexis Zarkov, Ph.D.

You can contact Dr. Zarkov at AskDrZarkov@yahoo.com.

Last modified 2009.May.19

References

[1]  French paradox wikipedia

[2]  Effects of resveratrol on vascular tone and endothelial function of human saphenous vein and internal mammary artery. Int J Cardiol. 2005 Nov 2; 105(2):209-15 Rakici O, Kiziltepe U, Coskun B, Aslamaci S, Akar F

[3]  Effect of resveratrol on platelet aggregation in vivo and in vitro. Chin Med J (Engl). 2002 Mar; 115(3):378-80 Wang Z, Zou J, Huang Y, Cao K, Xu Y, Wu JM

[4]  Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. Eur J Cardiovasc Prev Rehabil. 2005 Dec; 12(6):596-600 Lekakis J, Rallidis LS, Andreadou I, Vamvakou G, Kazantzoglou G, Magiatis P, Skaltsounis AL, Kremastinos DT

[5]  An antiplatelet principle of Veratrum formosanum. Planta Med. 1992 Jun; 58(3):274-6 Chung MI, Teng CM, Cheng KL, Ko FN, Lin CN

[6]  Cardioprotective actions of grape polyphenols. Nutr Res. 2008 Nov; 28(11):729-37 Leifert WR, Abeywardena MY

[7]  Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Atherosclerosis. 1999 Jan; 142(1):139-49 Yamakoshi J, Kataoka S, Koga T, Ariga T

[8]  Red wine, dealcoholized red wine, and especially grape juice, inhibit atherosclerosis in a hamster model. Atherosclerosis. 2001 May; 156(1):67-72 Vinson JA, Teufel K, Wu N

[9]  Grape polyphenols exert a cardioprotective effect in pre- and postmenopausal women by lowering plasma lipids and reducing oxidative stress. J Nutr. 2005 Aug; 135(8):1911-7 Zern TL, Wood RJ, Greene C, West KL, Liu Y, Aggarwal D, Shachter NS, Fernandez ML

[10]  Red wine polyphenols for cancer prevention. Int J Mol Sci. 2008 May; 9(5):842-53 He S, Sun C, Pan Y

[11]  Trans-resveratrol: a magical elixir of eternal youth? Curr Med Chem. 2008; 15(19):1887-98 Orallo F

[12]  Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004 Aug 5; 430(7000):686-9 Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D

[13]  The effect of resveratrol on a cell model of human aging. Ann N Y Acad Sci. 2007 Oct; 1114:407-18 Stefani M, Markus MA, Lin RC, Pinese M, Dawes IW, Morris BJ

[14]  Dose-related effects of red wine and alcohol on hemodynamics, sympathetic nerve activity, and arterial diameter. Am J Physiol Heart Circ Physiol. 2008 Feb; 294(2):H605-12 Spaak J, Merlocco AC, Soleas GJ, Tomlinson G, Morris BL, Picton P, Notarius CF, Chan CT, Floras JS

[15]  Report sees 7.6 million global 2007 cancer deaths Reuters news agency website, Mon Dec 17, 2007

[16]  International Cardiovascular Disease Statistics American Heart Association Statistical Fact Sheet, 2007 Update

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Disclaimer: The information provided in this “Ask Dr. Zarkov” article contains no medical advice whatsoever — it contains biological information. Nothing in the article constitutes an effort to persuade readers to use, or not to use, this biological information as a basis for action.