They looked as if they were either dieting successfully or engaged in endurance training …

Resveratrol Breakout
Makes Fat Men More Fit

Supplement mimics the health effects of
calorie restriction in obese men
By Will Block

C an the natural compound resveratrol make you younger and bring back your youth? These are questions that animal studies have left us pondering, and at last researchers are getting around to the human studies that can provide the answers. Currently, there at least 30 scientific studies either in preparation, recruitment stage, underway, or just completed (but yet to be published)—examining such conditions as resveratrol’s effects on diabetes, colon cancer, Alzheimer’s disease, and physical performance.1 First to arrive is a small but well-designed study which over the course of just one month, made the subjects appear to be either successful dieters or endurance trainees … without dieting or working out!

Resveratrol Produces Calorie Restriction Benefits In Humans

The Fountain of Youth
by Lucas Cranach the Elder, 1546
While lifestyle changes such as exercise and diet programs can avert obesity and many of its consequences, these are apparently too difficult for much of the population. Could there be an easier way? In what appears to an initial answer, a new study shows positive effects for the use of supplemental resveratrol by obese subjects.2 Published in Cell Metabolism (a well-respected Cell Press publication; see sidebar), the research was conducted at Maastricht University Medical Center in The Netherlands where pronounced health benefits for obese, but otherwise healthy, subjects taking 150 mg of resveratrol per day for 30 days were found. The subjects, all male volunteers, had no family history of diabetes or any other endocrine disorders.

The Quality of a Cell Press Publication

The 2011 Nobel Prize for Physiology or Medicine was divided, one half conjointly to Jules A. Hoffmann and Bruce A. Beutler “for their discoveries concerning the activation of innate immunity” and the other half to Ralph M. Steinman posthumously “for his discovery of the dendritic cell and its role in adaptive immunity.” Of the journal articles contributing to development of the ideas that led to the award, many were published in Cell Press publications such as Cell, Current Biology, Developmental Cell, Immunity, and Trends in Molecular Medicine. This says a lot about Cell Press, and is consistent with the high quality of the Dutch study that is the subject of this article.

Yet after 30 days of taking resveratrol—and without changing their diet or exercise habits—the men’s metabolism improved, with inflammation declining, fat deposits in their livers decreasing, and circulating triglyceride levels falling. Surprisingly, compared to themselves as controls (see the subsection “The Study Protocol” below), resveratrol enabled their bodies to burn the same amount of energy over a 24-hour period, while resting and sleeping metabolic rates were reduced, and their muscle efficiency increased. It was as if they were using and storing calories more like athletes in training than lazy potato couches lying around and gorging on junk food.

The Curse of Obesity

Obesity is exceedingly common today, so much so that nearly 34% of all American adults fit the category (a body mass index* of 30 or greater).3 And the trend is ratcheting up, from really bad to much worse. During the past 25 years, there has been a steady and dramatic increase in obesity in the United States. In fact, 2010 found no state with a prevalence of obesity less than 20%. Thirty-six states had a prevalence of 25% or more and 12 of these states (Alabama, Arkansas, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Oklahoma, South Carolina, Tennessee, Texas, and West Virginia) had a prevalence of 30% or more. If the obese were a voting bloc, they might control the election of a President, especially in a three party race in which diet became a political subject (a possibility that may not be so far-fetched!). The U.S. has already had five obese presidents: Taft, Cleveland, McKinley, Taylor, and T. Roosevelt.


*A common approximate measure of total body fat is the body mass index (BMI), which also provides a rough measure of health and life expectancy. To calculate your BMI, divide your weight in pounds by the product of your height in inches times itself. Then multiply the result by 703. (In metric units, divide your weight in kilograms by the square of your height in meters.) The ideal range is about 19–22, with normal being about 23–25. A range of 25–29 indicates overweight, a moderate threat to your health and longevity, but a value of 30 or more indicates obesity, a serious threat.


Obesity Nearly Guarantees Disease

Yet obesity is virtually an underwriter for disease—with increased risks for higher levels of high blood pressure, heart disease, high cholesterol, low HDL levels (“good cholesterol”), and high LDL levels (“bad cholesterol”). Obesity also practically guarantees atherosclerosis, diabetes, stroke, osteoarthritis (including joint pain and joint dysfunction), respiratory difficulties (including sleep apnea), and certain types of cancers (including colon, breast, prostate, and endometrial). Finally, there is an increased likelihood of depression, stress incontinence, menstrual irregularities, excessive hair growth, pregnancy complications, and gastrointestinal problems. Despite its extreme partiality for unhealthiness, obesity rates continue to climb. Even in youth, obesity is becoming less rare. And as we age, the tide turns even more radically against us, especially when food is a “bargain” in disguise.

Resveratrol Marches Up The Tree of Life

In a progression of studies conducted over the last decade, resveratrol has been shown to clearly alter energy metabolism and mitochondrial function for the better in a variety of organisms, marching from low order to higher order, from yeast to worms to rodents. And in the animal models of obesity, resveratrol has been found to mimic caloric restriction, especially with regard to overall health and longevity. Yet, there have not been many human trials. And there have been no human studies that have systematically examined the metabolic effects of resveratrol in vivo … until now.

The Study Protocol

Although the new study was small, its design was favorable for testing whether the calorie restriction health equivalencies were present. The researchers treated 11 healthy, obese men with placebo and 150 mg/day of resveratrol in a randomized double-blind cross-over study for 30 days. This meant that each of the 11 volunteers in the Dutch study served as a member of the control group. Each subject took either resveratrol or a placebo supplement for 30 days, after which upon waiting one month (the “wash-out period), each subject crossed-over and took the opposite item. After the cross-over, if the subject had started with resveratrol, the subject then took the placebo, or vice versa. Neither the giver (the researcher) nor the taker (the subject) knew which was which, fulfilling the double-blind criteria.

To ensure that the subjects adhered to the study protocol and to confirm systemic conversion of resveratrol to a metabolite, total the (sum of conjugated and unconjugated) resveratrol and free plasma levels of both compounds were analyzed over the course of the 30 day period, for both resveratrol supplementation and placebo. While no resveratrol or its metabolite could be detected in the placebo group, both compounds were present in plasma of resveratrol-supplemented subjects. Thus, compliance was demonstrated, also indicating that the compound was well absorbed. Furthermore, measurement of the metabolite confirmed that resveratrol was efficiently metabolized.

Although the 150 mg dose of resveratrol given to the men was actually much smaller than the equivalent dose given to obese mice in a similar past experiment (the Auwerx study4),* in the men it yielded similar blood concentrations of the plant extract. In the Auwerx study, 400 mg/kg/day of resveratrol significantly increased aerobic capacity of the obese mice, as evidenced by their increased running time and consumption of oxygen in muscle fibers. The larger equivalent dose also protected mice against diet-induced-obesity and insulin resistance. According to the Dutch researchers, “We cannot exclude, however, that the metabolism of resveratrol is different between mouse and man and, possibly more importantly, that timing of treatment (30 days in our study versus 4–6 months in mice [Baur et al., 2006 {Sinclair}; Lagouge et al., 2006 {Auwerx}]) significantly impacts physiological outcome.”

However, the 150 mg dose was the human equivalent of the amount given to mice in the Sinclair study, which found that resveratrol extends lifespan in obese middle-aged mice by providing the health and longevity benefits of caloric restriction—without caloric restriction.5


* To obtain the human equivalent of the amount used in the Auwerx study, the amount given to the mice (400 mg of resveratrol per kilogram of body weight, per day) should be multiplied by the appropriate mouse/human scaling factor of 3/37 (0.081), which gives a value of 32.4 mg per kg per day. Using an 80-kg person as an example, the human dosage would therefore be 32.4 x 80 = 2,592 mg/day.

† In the Sinclair study, the amount given to the mice (22.4 mg of resveratrol per kilogram of body weight, per day) should be multiplied by the appropriate mouse/human scaling factor of 3/37 (0.081), which gives a value of 1.82 mg per kg per day. Using an 80-kg person as an example again, the human dosage would therefore be 1.82 x 80 = 146 mg/day, an amount easily achieved with supplements.


Resveratrol Makes Fat Men More Fit

The new Dutch study found, as did the Auwerx study for mice, that resveratrol could make obese men more fit. In the Auwerx study, the mice receiving resveratrol could run twice as far as those not receiving it. According to Auwerx, “Resveratrol makes you look like a trained athlete without the training.” (See “Is Resveratrol an Exercise Pill?” in the January 2007 issue, in which we speculated that resveratrol—based on the findings of both the Sinclair and the Auwerx papers—“is a sort of ‘fountain of youth,’ at least for mice, and probably for humans.”)

Improved Sleep and Resting Efficiency; More Muscle Power

Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated 5' AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis. AMPK is expressed in skeletal muscle, as well as liver and brain tissues. When it is activated, the net result is stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, as well as modulation of insulin secretion by pancreatic beta-cells. These data strongly suggest that resveratrol mimics the effects of calorie restriction and endurance training.

Improved Muscle Function for Better Energy Resources

Resveratrol was also found to increase SIRT1 (sirtuin 1, thought to be the trigger for caloric restriction benefits) and PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) protein levels. If you remember (see “Importance of PGC-1alpha in Maintaining Skeletal Muscle Function and Integrity” in the January 2008 issue if you don’t), PGC-1α is a transcriptional coactivator that regulates the genes involved in energy metabolism. This protein interacts with the nuclear receptor PPAR-γ, which permits the interaction of this protein with multiple transcription factors. Higher expression of PGC-1α results in mitochondrial biogenesis, literally making more mitochondria, which improves energy function and blunts skeletal muscle atrophy that normally occurs through disuse. So, again the result is improved muscle function and better energy resources.

Other Calorie Restriction Mimetics

Also in the Dutch study, resveratrol increased citrate synthase activity without change in mitochondrial content and improved muscle mitochondrial respiration on a fatty acid-derived substrate. In other words, resveratrol improved production of biochemical energy at the cellular level.

Additionally, resveratrol elevated muscle cell lipid levels and decreased liver lipid content, better harnessing the energy of lipids. Resveratrol also decreased circulating glucose, triglycerides, and inflammation markers, all indicating better plasma biochemistry.

The Nature of Sir2

No Roadblock to Longevity

In September of 2011, a study appeared in Nature that has generated a lot of controversy.1 The gist of the tempest is that sirtuins’ status has lost its certainty as a progenitor of longevity effects. Technically, sirtuins are the family of histone deacetylase proteins that have been heralded as keys to longevity. This is based on a number of studies in yeast, flies, worms, fish, rodents, and now (see page 4) in humans.

However, back in September, new data called the findings on worms and flies into question—but not the human finding, which had not yet been published. In the Nature paper, David Gems et al at University College London, U.K. reported that what the original overexpressed Sir2 in C. elegans and Drosophila lines reported regarding lifespan was due to confounding effects from genetic background and transgene insertion. In other words, it was the genetic code and not Sir2 that caused lifespan extension, and therefore the results were invalid.

How did they know this? By repeating the initial experiments with new controls, Gems and colleagues found no effect from Sir2 on lifespan. However, fast to respond was Leonard Guarente and colleagues at Massachusetts Institute of Technology, the researchers who did some of the initial Sir2 experiments. They contend that they were aware of these limitations, which were unavoidable at the time, and after they found out they redid the studies finding that although initial lifespan claims were an overestimate, Sir2 still produced a modest extension. In their original research, Guarente et al found that Sir2 overexpression lengthened worm lifespan by as much as 50 percent.2 Also, while the issue of sirtuins remains contentious, the body of research is quite large and the debate doesn’t significantly alter the findings that sirtuins affect mammalian health and metabolism.

On the other hand, Gems et al found that upon de-confounding the genetic predisposition, they overruled impartiality and the longevity effects for C. elegans vanished. Similarly, the Gems group found no Sir2 lifespan effect in transgenic Drosophilia flies compared to appropriate controls. Therefore, they conclude, Sir2 has nothing to do with the longevity effects of dietary restriction in flies. Gems noted that several independent research groups have replicated these findings, and wrote in an email, “The findings in our paper imply that increased Sir2 levels do not slow aging in worms and flies.”3

In a Nature Brief Communication, Guarente and Mohan Viswanathan of MIT agreed that the gene mutation contributed much of the lifespan extension seen in the original worm study. However, they report that even after extensive backcrossing, Sir2 stills lengthened life by 10 to 15 percent. Similar to Gems’ claim that independent research has replicated his finding, so says Guarente about the role of Sir2 in worm longevity.

But the real question that remains is not whether Sir2 has been demoted in its influence on lifespan—but what other genes of the more than 100 currently known to increase worm and fly lifespan to some degree actually do, and which others have larger effects. One thing not in dispute is the impact of “sirtuins” promoters, such as resveratrol, on caloric restriction effects. Witness the new finding of resveratrol in humans (see page 4), along with mouse studies, showing major healthful effects.

Based on the body of evidence, sirtuins have crucial roles in metabolic homeostasis. In mammals, they have been reported to prevent metabolic disorders, reduce phosphorylated tau, and play roles in learning and memory, among other things. As Cantó and Auwerx suggest in the same issue of Nature, “the metabolic adaptations that SIRT1 induces might indirectly influence mammalian lifespan,” and conclude, “SIRT1 activation remains a promising approach to delaying general age-related physiological decline.”4

References

  1. Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvári M, Piper MD, Hoddinott M, Sutphin GL, Leko V, McElwee JJ, Vazquez-Manrique RP, Orfila AM, Ackerman D, Au C, Vinti G, Riesen M, Howard K, Neri C, Bedalov A, Kaeberlein M, Soti C, Partridge L, Gems D. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 2011 Sep 21;477(7365):482-5. doi: 10.1038/nature10296.
  2. Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001 Mar 8;410(6825):227-30.
  3. Rogers MB. Alzheimer’s Research Forum. Sirtuins’ status less certain as study questions longevity effect. http://www.alzforum.org/new/detail.asp?id=2908. Updated September 26, 2011. Accessed November 19, 2011.
  4. Cantó C, Auwerx J. Don’t write sirtuins off. Nature 2011 Sep 22;477(7365):411.

Also after resveratrol supplementation, systolic blood pressure dropped as did the homeostatic model assessment (HOMA) index, indicating improved insulin sensitivity. Pancreas beta-cell insulin-releasing function was also enhanced.

Finally, following a test meal, resveratrol increased fat mobilization thereby improving metabolic flexibility. Together, these data demonstrate that 30 days of resveratrol supplementation induces positive healthful metabolic changes in obese humans, mimicking the effects of calorie restriction.

If You Are Obese … but Even If You Aren’t

A core part of the ancient Hippocratic Oath is alleged to be “First, do no harm” (primum non nocere in Latin). However, the Latin words are not found in the Hippocratic canon. Instead in the Hippocratic Corpus, something similar yet different is expressed as follows: “To help or at least not harm.” (Iuvare aut ad minus non nocere). So, “First do no harm” is unlikely to be the first concern of Hippocratic medicine practitioners. Consider that the “help and not harm” phrase begins with a positive rather than a negative, and joins two considerations, rather than one, thereby avoiding the precautionary trap. Thus this provides an excellent starting point for thinking about your diet, what you eat, and the dietary supplements that you ingest. Just as you want to eat the most nutritious and safest foods, so should it be the case with dietary supplements. And make no mistake, you are a practitioner of self-medication when you research and select anything that you ingest.

Resveratrol, at the levels given in the recent Dutch study, is safe. No adverse effects were reported. But it is not the reason why so many studies are currently under way. The reason is that resveratrol helps without producing harm. By the way, you do not have to be obese to make the choice to supplement with resveratrol. With an upside that is very great, resveratrol may really help—and at least not harm—your health. That’s a bargain to buy into.

References

  1. ClinicalTrials.gov. A service of the National Institutes of Health. http://clinicaltrials.gov/ct2/results?term=resveratrol&pg=1. Updated November 15, 2001. Accessed November 16, 2011.
  2. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MK, Kunz I, Schrauwen-Hinderling VB, Blaak EE, Auwerx J, Schrauwen P. Calorie Restriction-like Effects of 30 Days of Resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011 Nov 2;14(5):612-22.
  3. Centers for Disease Control and Prevention. Overweight and obesity: U.S. obesity trends. http://www.cdc.gov/obesity/data/trends.html. Updated July 21, 2011. Accessed November 13, 2011.
  4. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J.Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006 Dec 15;127(6):1109-22
  5. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006 Nov 16;444.


Will Block is the publisher and editorial director of Life Enhancement magazine.

Featured Product

  • Learn more about Resveratrol benefits and implementation strategies.

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator