Wednesday, May 14, 2014

Yes Red Wine is Still Good for You

Recent reports that “red wine is not great for health after all” and that “no amount of alcohol is safe” are just plain wrong. This type of misguided reporting and misinterpretation of scientific studies is one of the reasons for my book Age Gets Better with Wine. How is it that the story is still so confused?
Kicking off the latest round of hype was a report issued bythe World Health Organization’s International Agency for Research on Cancer. Noting that the risk is dose-dependent, meaning that heavy drinking has a stronger correlation with some types of cancer, the authors of the report concluded that even moderate drinking carries some degree of risk. This was followed by release of a study in Italy that looked at dietary levels of resveratrol and incidence of diseases of aging. Since the most well-known source of resveratrol is red wine, the lack of a benefit from higher resveratrol consumption was reported as casting doubt on the benefits of red wine.
So here we go again: It is well-documented that people who consume red wine in moderation, on a daily basis, live longer, have lower rates of cancer and other diseases of aging, and have better mental function and higher quality of life as compared to nondrinkers. They are also healthier than heavy drinkers, so the relationship of wine consumption and disease risk is not a linear dose-response but a J-shaped curve. One reason why this is not recognized is what is called “self-reporting bias,” which means that heavy drinkers tend to under-report their true consumption and so are categorized as moderate drinkers. Another reason is that there are comparatively few true consumers of red wine in moderation and they are hard to isolate statistically. Most people tend to drink in more erratic patterns as compared to the more traditional habitual glass of wine with dinner. These types of things confound data but lumping this group in with all drinkers and declaring alcohol a carcinogen is sloppy science and wrongheaded.
The bigger problem with this report is that it looks only at cancer risk, not overall health and longevity. Even if we ignored the evidence that moderate wine drinkers actually have lower cancer risk and assumed it was a linear dose-response relationship, the major cause of mortality is heart disease. Since moderate drinkers have a larger benefit of reduced heart disease risk than potential increase in cancer, the net result is still clearly positive. Add to that the benefits of wine on Alzheimer’s, diabetes, osteoporosis, etc. etc. and you will see my point.
But the big C is a scary thing, and a major point of emphasis in the report is breast cancer. The widely held view, based on the many studies that have been done, is that a drink a day increases risk of breast cancer by 10%; 2 drinks, 20% and so on. Lifetime risk of breast cancer is around 12%, but the risk of a daily drink (if any) would not increase risk to 22%, but rather 10% of the 12%, so the net is just over 13% -  hardly measureable by statistical standards. Add to that the self-reporting bias and it is easy to see why alarmist reporting is unjustified. And as I have pointed out many times before, in populations where women drink primarily red wine, the incidence of breast cancer is substantially lower.
Which brings us to the question of whether red wine really is different. A study 783 elderly men in the Chianti region of Italy attemptedto answer this question by measuring resveratrol metabolites in the urine, and looking for a relationship of resveratrol to observed rates of cancer and longevity. The reasoning was that red wine’s benefits are due to resveratrol, which also occurs in other foods, so total resveratrol from all dietary sources should correlate to improved health. However, the study found no such correlation.

I could have told them that before they started the study, because there is not much resveratrol in any naturally occurring food including wine, so it was never the primary reason for red wine’s benefits. Remember the whole reason for doing the study was to try to find what it is about wine that would explain why wine drinkers fare so well; but it always comes back to just drinking the wine. 

Tuesday, February 4, 2014

Wine and chocolate lower diabetes risk

A perennial topic around Valentine’s Day is the health benefits of wine and chocolate, and this year we have new evidence that they may lower the risk of type 2 diabetes. Credit is given to high levels of anthocyanins, nutritional antioxidants found in red wine, berries, and of course dark chocolate. Anthocyanins are the pigments that give these foods their color, unlike resveratrol which also comes from the skins of wine grapes.

The study, from the University of East Anglia and Kings College London, consisted of a food questionnaire of 2000 women. Those with the highest intake of anthocyanin-rich foods had lower insulin resistance – a marker for type 2 diabetes - and better blood glucose regulation. But the researchers took it a step further, and documented that this group also had lower levels of markers of inflammation, believed to be associated with a wide range of age-related diseases including cancer, diabetes, and cardiovascular problems. Sweet news for your sweetheart indeed.

As with all population-based studies of this type, there are a few caveats. For one, dark chocolate high in anthocyanins and flavonoids is not what you would typically find in an assortment of confections, and high sugar or butterfat content may cancel out much of the benefits. And with wine of course, it is consumption in moderation that is the key to healthy drinking. And perhaps just as important, food intake surveys of this type may show more about what unhealthy foods are not being consumed, not just what is.

I’m looking for studies on the benefit of giving roses with chocolate and wine (I’m sure it has to contribute something) but for now we will have to take that on faith.

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.