Tuesday, November 12, 2013

Lost in translation: Why resveratrol supplements are not the same as drinking wine

Resveratrol, the miracle molecule from red wine, has rocketed from relative obscurity to celebrity status in the supplement market. Its multiple anti-aging properties are given credit for this, and I used resveratrol research in my book “Age Gets Better with Wine” to explain why moderate regular consumption of red wine is a healthy thing. Supplement marketers now proclaim that resveratrol pills have “all the benefits of wine without the alcohol” and tout their own special formulas. Yet there remains a lack of large well-controlled clinical studies to back up these claims.

A relatively new field of medical science called translational medicine helps explain the problem. Often called “bench to bedside” research, translational medicine seeks to bridge the gap between laboratory studies and validated clinical treatments. The challenge of translational medicine is enormous, given that more than 90% of treatments (say for example a drug or supplement) fail in human trials after successful runs in animal studies. It’s an astonishing  statistic, but this percentage has actually been increasing despite improvements in methodology. Dr. Richard Klausner, former Director of the National Cancer Institute, summed up the problem: “We have cured cancer in mice for decades—and it simply didn’t work in humans.”

So what does this mean for resveratrol? Despite the thousands of scholarly publications on resveratrol, it is still not clear. If you are a fruit fly, then resveratrol will activate your anti-aging sirtuin genes and you will live longer (and apparently have a more vigorous sex life.) If you are a mouse on a high fat diet, resveratrol is what you want in order to set your metabolism in order. But translating these findings to humans is deceptively difficult. A recent article highlighted some of the problems: Natural compounds such as resveratrol afford no intellectual property that could be leveraged to fund the large clinical trials needed to determine their effectiveness; nutraceutical companies complicate the problem further by developing their own proprietary blends with multiple ingredients; and resveratrol has multiple therapeutic “targets” each with its own dose-response curve, tissue affinity, and metabolism.

Resveratrol research may still pan out however, and some therapeutic applications are well validated, such as in skin care. Evidence is certainly adequate to continue with clinical research on resveratrol on a wide range of conditions, including Alzheimer’s disease, diabetes, and cardiovascular disease. But a glass of red wine with dinner is still a good thing and likely to remain so.

Tuesday, October 22, 2013

Versatile Resveratrol Part 2: The ultimate skin care ingredient?

What would the ideal anti-aging skin care product look like? To begin with, it would need to provide protection against sun damage from UV exposure.[i] Of course any sunscreen does that, so what we really want is something that can help reverse the effects of UV exposure, which include mutations in the DNA of skin cells. This is where the idea of working at a molecular level comes into play. While many products talk about “DNA repair” the evidence for a role for resveratrol is particularly strong. There are several ways that resveratrol functions in this regard, the best known of which is its powerful antioxidant effects.

Healthier DNA means not only more attractive skin but a lower risk of skin cancers. The use of antioxidants such as resveratrol to lower risk of skin cancer is known as chemoprevention. There is evidence that it may help prevent many other types of cancer as well.

Another measure of aging has to do with integrity of sequences on the ends of the chromosome known as telomeres[ii]. Each time a cell replicates, the DNA must “unzip” to provide a template for the chromosomes in the new cell. It is prevented from unraveling by telomeres, which are sort of like the caps on shoelaces, but with each cycle the telomeres get shorter.. Restoring telomeres is a major effort in anti-aging, and it appears that resveratrol may activate the enzyme that restores telomeres (telomerase), thereby improving cellular health and longevity.

Nothing will magically undo every DNA mutation or the visible manifestations of them in the skin (such as discoloration, wrinkles, and other blemishes) so our ideal product should help with those too. One way that resveratrol improves skin is by inhibition of the enzyme that makes pigment, which results in lightening of dark spots and overall brightening[iii] of the skin.

Facial redness[iv] is another manifestation of the type of inflammation associated with accelerated aging. Resveratrol has also been shown to reduce facial redness with a twice daily application for 6 weeks, and continued improvement beyond that.

We all know that good skin is built by good collagen and elastin (a type  of collagen.) These proteins are constantly being rebuilt by enzymes known as matrix metalloproteinases, referred to as “MMP’s.” Regulation of MMP activity is critical to skin health and aging. It should come as no surprise then that resveratrol is implicated in regulation of MMP via SIRT activation[v], improving the skin’s stress response to UV exposure. This translates into healthier collagen and more elastic skin.

Sometimes however collagen rebuilding is overly exuberant, resulting in thickened scars. An extreme form of scarring is keloid, and treatment of keloids remains a challenge for plastic surgeons. An effective weapon   may be found in resveratrol, which has been shown to inhibit the cells (fibroblasts) that are overly active in keloids, while having no adverse effect on normal fibroblasts.[vi]

Acne is another common problem, and not one limited to teenagers. While there are effective treatments for acne such as benzoyl peroxide and tretinoin (Retin-A), these can cause irritation. Resveratrol is proving to be a useful adjunct to acne treatment,[vii] with more than one mode of action: It is antibacterial with specific effects on the type of bacteria associated with acne, while its anti-inflammatory properties reduce the redness and irritation.

A later life issue is changes in the skin with menopause. These include thinning due to lowered collagen production, dryness due to lessened moisture retention, and others. Given the controversies with estrogen replacement therapy, the need for a product providing estrogen-like effects in the skin is substantial. Resveratrol is one of the few ingredients capable of stimulating collagen production through estrogen-like effects.[viii]

If resveratrol is going to accomplish all of these anti-aging feats in a skin care product, it has to permeate the skin and reach the cells active in regeneration (bioavailability.) resveratrol is uniquely suited to traverse the barrier of hardened surface cells known as the stratum corneum because of a few features. One is the small size of the molecule, probably the smallest of the antioxidant polyphenols; the other is that it is hydrophobic, meaning that it is more comfortable in lipids (fatty molecules.) These types of molecules are able to penetrate better.

[i] Nichols JA, Katiyar SK. Skin photoprotection by natural polyphenols: anti-inflammatory, antioxidant and DNA repair mechanisms. Arch Dermatol Res. 2010 Mar;302(2):71-83
[ii] Xia L, Wang XX, Hu XS, Guo XG, Shang YP, Chen HJ, Zeng CL, Zhang FR, Chen JZ. Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms. Br J Pharmacol. 2008 Oct;155(3):387-94.
[iii] Park J, Boo YC. Isolation of Resveratrol from Vitis Viniferae Caulis and Its Potent Inhibition of Human Tyrosinase. Evid Based Complement Alternat Med. 2013;2013:645257
[iv] Ferzil G, Patel M, Phrsai N, Brody N. Reduction of facial redness with resveratrol added to topical product containing green tea polyphenols and caffeine. J Drugs Dermatol. 2013 Jul 1;12(7):770-4.
[v] Lee JS, Park KY, Min HG, Lee SJ, Kim JJ, Choi JS, Kim WS, Cha HJ. Negative regulation of stress-induced matrix metalloproteinase-9 by Sirt1 in skin tissue. Exp Dermatol. 2010 Dec;19(12):1060-6.
[vi] Ikeda K, Torigoe T, Matsumoto Y, Fujita T, Sato N, Yotsuyanagi T. Resveratrol inhibits fibrogenesis and induces apoptosis in keloid fibroblasts. Wound Repair Regen. 2013 Jul-Aug;21(4):616-23.
[vii] Fabbrocini G, Staibano S, De Rosa G, Battimiello V, Fardella N, Ilardi G, La Rotonda MI, Longobardi A, Mazzella M, Siano M, Pastore F, De Vita V, Vecchione ML, Ayala F. Resveratrol-containing gel for the treatment of acne vulgaris: a single-blind, vehicle-controlled, pilot study. Am J Clin Dermatol. 2011 Apr 1;12(2):133-41.
[viii] Giardina S, Michelotti A, Zavattini G, Finzi S, Ghisalberti C, Marzatico F. [Efficacy study in vitro: assessment of the properties of resveratrol and resveratrol + N-acetyl-cysteine on proliferation and inhibition of collagen activity]. Minerva Ginecol. 2010 Jun;62(3):195-201.

Friday, October 4, 2013

Versatile resveratrol: the ultimate skin care ingredient?


Part 1
Recently I was honored to join Professors David Sinclair of Harvard and Joseph Vercauteren of the University of Montpelleir at an anti-aging symposium at the invitation of Mathilde Thomas of Caudalie in Paris. Caudalie has been using wine extracts (and specifically resveratrol) in their products for more than 15 years, after Vercauteren identified it in wine grape vines. Sinclair has become well known for his work identifying the role of sirtuin (SIRT) genes in anti-aging, and resveratrol as a natural sirtuin activator. While much remains to be proven, it is fair to say that science is finally beginning to have an impact on skin care. With an increasing understanding of what causes aging in skin cells and how botanical antioxidants such as resveratrol work at a molecular level, there is no excuse to use anti-aging skin care products that don’t multitask.

Before delving into the potential benefits of resveratrol in skin care, it may help to review how resveratrol came into the spotlight in the first place. By just about any measure, moderate wine consumption is among the most potent anti-aging lifestyle habits known. And although resveratrol is present in only small amounts in wine, it is the best known source; coupled with an impressive array of anti-aging properties identified in laboratory conditions, resveratrol has been offered as the mediator of wine’s benefits. Sales of resveratrol supplements have soared. (One study noted that 2/3 of people who take supplements include resveratrol.)
Wine drinkers do enjoy healthier skin. For example, a study from Australia (where skin damage from sun exposure is a big deal) found that wine drinkers had a 27% lower risk of developing premalignant lesions known as actinic keratoses (AK’s.) Another study, from Germany, found that wine consumption – but not topical application of wine to the skin – reduced the redness from controlled exposure to UV light; in other words, a sunscreen you can drink.
From here the picture gets a bit more complicated, so bear with me for a moment. Topically applied resveratrol confers protection against damage from UV light in skin, just as it provides a handy explanation for why wine drinkers have healthier hearts and brains, and live longer. But remember that there isn’t enough resveratrol in wine to produce the effects seen under lab conditions without consuming enormous amounts, and supplements of resveratrol have a problem with what is known as “bioavailability.” That means that enough of it has to be absorbed into the circulation and distributed to the target tissue (in our case, skin) before being metabolized. Our digestive systems are pretty efficient at disposing of resveratrol (or at least metabolizing it into other compounds), and there is a high degree of variability between people.
To make matters even more confused, there is the issue of a phenomenon known as hormesis. This refers to paradoxical effects from the same thing in different amounts. Resveratrol has demonstrated hormesis in several cancer types wherein it promotes growth at low levels but inhibits at higher ones; the opposite may occur with Alzheimer’s and osteoporosis. Balancing these opposing effects is a considerable challenge, even if predictable levels of resveratrol in target tissues could be achieved.
The upshot is that if you are looking for the effects of resveratrol in the skin, it may be best to just put it there in the first place. Fortunately, there is good evidence that resveratrol is absorbed into the skin when applied topically. In Part 2 of this post I will detail the ways in which resveratrol functions as the ideal anti-aging skin care ingredient.

Tuesday, August 13, 2013

Red wine vs resveratrol as cancer fighters

Headline August 8, 2013: Red wine protects from colon cancerAccording to a study from researchers at SUNY Stony Brook which compared the drinking habits of red and white wine drinkers with similar lifestyles consuming three or more glasses of red wine a week may help to reduce the risk of colon cancer. They found that drinking red wine reduced the risk of colon cancer by 68 per cent while drinking white wine did not. The researchers believe it is the resveratrol in red wine that provides the protection.”

Headline August 10, 2013: Dietary supplement resveratrol is unlikely to have impact on cancer “…researchers at the Medical University of South Carolina, USA, report results from a study of resveratrol in healthy human volunteers. They found that oral resveratrol is actually broken down to an inactive form very rapidly, so it’s unlikely that supplements have any effect.”

Is it possible that both of these findings are true? The answer is yes, but only if it is something other than the resveratrol that is providing the protective effect of drinking red wine – contrary to the presumption of the researchers at SUNY. These two seemingly contradictory headlines point to a dilemma that has come to define the issue of healthy drinking: the assumption that resveratrol is the whole story, a proxy for red wine without the alcohol.

It’s an easy enough assumption to make, and in fact I gave it a fair amount of consideration in my book. We know that red wine drinkers have better cognition as they get older, lower overall rates of cancer, diabetes, osteoporosis, Alzheimer’s, and a host of other scourges of aging. Conveniently, resveratrol has specific effects in laboratory studies to explain each of these benefits: breaking down the amyloid plaques in neural tissue associated with Alzheimer’s, estrogen-like properties for osteoporosis, or down-regulating overactive genes in cancer cells. The problems are that levels of resveratrol needed for these effects are generally much higher than what is achievable with healthy wine consumption, and absorption of resveratrol after oral ingestion is highly variable (and quickly metabolized, as the group at South Carolina determined.)

It may turn out that resveratrol is indeed useful as a cancer fighter, and there are a handful of clinical trials on the subject (full list available here.) Because the two studies mentioned in this article are both clinical trials, they deserve a higher level of consideration than lab studies on animals or cells in tissue culture. Interestingly, both trials largely confirm what previous ones have found: drinking red wine in moderation is healthy, resveratrol supplementation remains to be proven beneficial.

Wednesday, July 24, 2013

Resveratrol and exercise: a good thing or bad?

An article just out this week suggests that resveratrol actually cancels the beneficial effects of exercise in older men. This widely cited study, not yet even in print, was a randomized prospective clinical trial in which healthy but inactive men were placed on an exercise program and given either a 250 mg resveratrol supplement or placebo.  Exercise tolerance (measured by maximum oxygen uptake), improved cholesterol profiles, and blood pressure indicators in a group of men average age 65 were all improved after 6 weeks in the placebo group as compared to those taking resveratrol , who had no significant changes.  This runs counter to expectations from several previous studies (mostly on mice) that suggested the opposite. Resveratrol has even been touted as a performance-enhancing supplement!

This is one reason why use of supplements based primarily on animal studies is problematic; when tested in humans, data may be contradictory. The real questions are how and why such different effects can occur. One explanation is a phenomenon called hormesis. This is sort of the inverse of the J-shaped curve of healthy drinking, with low concentrations yielding a neutral or negative effect, increasing doses having a greater effect up to a point, then adverse or even opposite effects at doses above that. It is important to recognize that paradoxical effects can occur at concentrations either low or high, and the optimal range (in pharmacology called the “therapeutic window”) may vary with different types of tissues. So the best dose for exercise training (if any) could be entirely at odds with what brain cells or blood vessels respond to.  Also called a “biphasic response,” the effect has been seen in cancer cell cultures, osteoporosis, and other systems.

All this presumes of course that resveratrol in supplement form is evenly absorbed and distributed, which seems also to be highly variable. Even if resveratrol enhanced the beneficial aspects of exercise in men, there are the hormetic estrogen properties to sort out. If all this is enough to drive one to drink, I suggest a glass (or 2 at the most) of red wine.

Friday, July 19, 2013

From grapes to great skin: new evidence for resveratrol

When I first developed our resveratrol-based antioxidant skin care product Veraderma in conjunction with Calidora Skin Clinics in 2008, I had good reason to believe in its potent anti-aging capabilities. Resveratrol , the multipurpose miracle molecule whose most familiar source is wine grape skins (hence red wine because it is fermented with the skins), has become a bit of a sensation since then. Several major skin care companies now include wine compounds in their products, and the science continues to reinforce the role of resveratrol in healthy skin (even if its use as an oral supplement remains to be proven.)

One example comes from independent research underwritten by L’Oreal, which found that there are specific resveratrol “binding sites” in human skin cells that mediate resveratrol’s protective properties. These binding sites appear to trigger changes within the cells rendering them resistant to damage from environmental toxins. Notably, resveratrol was more effective than the green tea-derived antioxidant compound EGCG, and the resveratrol derivative piceatannol.

This latter finding may actually be the most significant aspect of the study because it makes the case for resveratrol as a skin care ingredient as opposed to a supplement. One of the concerns with use of resveratrol as a supplement is that it is rapidly metabolized into other compounds such as piceatannol, so if it ever reaches the skin through the bloodstream it may have either changed into something else or not reach high enough levels to be meaningful. (Another recent study found however that resveratrol combined with other wine polyphenols improved skin moisturization and elasticity,  and diminished skin roughness and depth of wrinkles after 60 days of taking the supplement.)

Another somewhat confused issue is whether resveratrol is a true activator of anti-aging enzymes called sirtuins. You will recall that resveratrol was hailed as an anti-aging breakthrough when it was first reported to be a situin activator –at least in yeast, roundworms, and fruitflies – and an industry was born. The picture turns out to be considerably more complicated however, but sirtuins have been recently shown to promote healthy skin. It is possible that resveratrol works via this pathway as well. There is clearly much to be learned still about resveratrol despite the hundreds of published studies, but if your skin care plan doesn’t include wine polyphenols, you may be missing out.

Tuesday, March 12, 2013

Revisiting resveratrol: new findings rekindle anti-aging debate

Just when we thought the bloom was off the rosé for resveratrol, the anti-oxidant polyphenol from red wine with multiple anti-aging properties, along comes new research giving life to the debate. But first a bit of background: As I detailed in my book Age Gets Better with Wine, it is well-documented that wine drinkers live longer and have lower rates of many diseases of aging. Much or the credit for this has been given to resveratrol, though there isn’t nearly enough of it in wine to explain the effects. Nevertheless, I dubbed it the “miracle molecule” and when it was reported to activate a unique life-extension phenomenon via a genetic trigger called SIRT, an industry was born, led by Sirtris Pharmaceuticals, quickly acquired by pharma giant Glaxo. The hope was that resveratrol science could lead to compounds enabling people to live up to 150 years and with a good quality of life.

But alas, researchers from other labs could not duplicate the results, and clinical studies disappointed. After a few short years, Glaxo pulled the plug on the project. But SIRT still seemed to be a key to lifespan extension even if resveratrol was not a direct activator of it. But the latest study from the Sirtris/Glaxo scientists suggests that maybe resveratrol may play a role here after all, at least on individual cells under laboratory conditions. Whether this applies to clinical use of resveratrol (or routine use of resveratrol supplements) remains speculative however.

Which brings us back to the central question of wine and health. Because the amount of resveratrol in wine is much lower than levels required to produce effects on cells in the lab, whatever benefits accrue to wine consumption cannot be attributed to resveratrol. So for now I will continue to take my medicine in the liquid and more palatable form.

Wednesday, January 16, 2013

Is red wine a performance-enhancing drug?

Lance Armstrong’s doping revelation aside, a recent study added controversy to the question of whether quercetin, a red wine-derived substance, can boost athletic performance by boosting testosterone levels. Though it was a test-tube study not backed up by any human subject data, the researchers thought it significant enough to inform the World Anti-Doping Agency. Quercetin has been reported in reputable publications to enhance oxygen uptake and endurance, and since many of these have come out since my review in "Age Gets Better with Wine," so I thought it might be worth another look.

For starters, quercetin is an antioxidant bioflavanoid that can be found in foods other than wine (apples for instance.) It first caught researchers’ attention as a component of red wine, being a possible contributor (along with other compounds such as resveratrol) to the famous “French paradox.” Like other wine-derived compounds, quercetin seems to alter energy metabolism at a cellular level. But does this translate to measureable changes in athletes? The data is conflicting. One well-designed clinical trial examined the effects of a quercetin + vitamin C supplement on 60 male athletes. After 8 weeks of using the supplement, no changes in exercise endurance were found, but there were slightly reduced markers of post-exercise muscle damage and a reduction in body fat (compared to placebo.) Another study by the U.S. Army evaluated a high-dose quercetin supplement on aerobically demanding soldier performance. No measurable benefit was found, though this was a shorter trial (just over a week.) Still another trial on endurance runners found no benefit.

One way to troll for meaningful data from conflicting study results is what is called a meta-analysis, which combines the results of all properly designed published studies. The School of Applied Physiology at Georgia Institute of Technology in Atlanta conducted such a review, concluding that “On average, quercetin provides a statistically significant benefit in human endurance exercise capacity (VO2max and endurance exercise performance), but the effect is between trivial and small.” So whether red wine or quercetin supplements boost testosterone or not, the effect seems unlikely to be enough to affect the outcome of the Tour de France or explain the French paradox by itself. There are plenty enough healthy reasons to have a glass of wine anyway.