Fool Mother Nature with Resveratrol

Resveratrol Mimics
Caloric Restriction

Studies of caloric restriction in humans (finally) give
insight into how it improves health and prolongs life
By Will Block

Yond’ Cassius has a lean and hungry look;
He thinks too much: such men are dangerous.

— Shakespeare, Julius Caesar, Act I, Scene 2

o you want a sure-fire way to live a lot longer (barring some unexpected occurrence, such as death)? Then eat less—a lot less—in terms of calories. Start while you’re still young so that the life-extending effects of your Spartan (but nutritionally complete and balanced) diet will have maximum impact, i.e., so that you’ll live well beyond the historical limit of about 120 years.

Ideally, according to the experts, you should take in 30–40% fewer calories, every day for the rest of your life, than would be required to maintain what is currently considered to be a normal weight. (That’s “ideally” from the point of view of achieving longevity—not so much from the point of view of actually enjoying life, assuming that eating is one of your main enjoyments.)

This life-extending regimen is called caloric restriction (CR). It is believed to be effective, but it’s so unpopular that few humans have ever tried it (voluntarily) for any length of time. We don’t know for certain that CR will work in humans, but there is every reason to believe that it will, based on many studies proving that it works—often spectacularly—in maintaining robust health and extending maximum lifespan in a wide variety of lower organisms, such as yeast, worms, insects, fish, and rodents. (It was probably unpopular with them too, but they didn’t have much say in the matter.)

Studies on nonhuman primates have been underway for many years, and all indications are that CR makes them much healthier than their more generously fed brethren. Thus their maximum lifespans will likely be extended too.

Calling All Lean Rugged Individualists

Here and there, a few brave individuals of the human persuasion have been practicing CR in the hope of preventing the chronic degenerative diseases of aging, thereby achieving significant life extension, perhaps beyond the 120-year “limit.” A few years ago, researchers at the Washington University School of Medicine in St. Louis brought 18 of these “dangerous thinkers” together from various parts of the USA and Canada for testing.1

There were 15 men and 3 women, aged 35–82 years (average: 50), whose self-imposed, strict CR regimens had been underway for 3 to 15 years (average: 6). All were in good health, with no chronic diseases, and none were smokers. Not surprisingly, they were very lean (and probably hungry), with extremely low body fat; their average body mass index (BMI) was 19.6. By contrast, the control group of 18 normal, age-matched individuals, who were on a typical American diet, had an average BMI of 25.9 (slightly overweight).

Caloric Restriction Is Profoundly Beneficial

The researchers’ primary interest in the CR individuals was their risk factors for atherosclerosis. What they found was stunning. The subjects’ cholesterol, triglycerides (fats), and blood pressure were exceptionally low (or high, in the case of HDL-cholesterol, the “good cholesterol”) for their age; often they were in the range associated with healthy young adults or even children.

The same was true of their fasting plasma glucose and insulin levels, their levels of C-reactive protein (CRP, a valuable marker of inflammation and a predictor of cardiovascular risk), and their levels of platelet-derived growth factor-AB (PDGF-AB, a substance that promotes cell proliferation in vascular smooth muscle cells). None of the CR individuals showed signs of atherosclerotic plaque in their carotid arteries.

In other words, the risk of atherosclerosis in these individuals appeared to be essentially nil. Their diet was profoundly beneficial to their health—and, probably, to their life expectancy—and they were about as far from having the metabolic syndrome as it’s possible to get. (For a discussion of this extremely important and prevalent gateway to diabetes and cardiovascular disease, see the article “Cinnamon and Chromium Counteract the Metabolic Syndrome” on page 11 of this issue.)

Interestingly, the individuals’ medical records (where available) showed that most of the improvement in the factors cited above occurred during the first year of their CR regimen, while they were losing much of their body fat. Some further improvement occurred gradually during the ensuing years.

Here’s What They Ate, and Took

The CR individuals had designed their diets to be calorically meager, yet adequate to sustain life. They consumed a balance of foods that provided more than 100% of the Recommended Daily Intake (RDI) for all essential nutrients, while minimizing caloric intake, which ranged from 1112 to 1958 calories/day. (The caloric intake of the controls was 1976 to 3537 calories/day, or about 80% higher.) They ate a wide variety of fruits, vegetables, nuts, dairy products, egg whites, wheat and soy protein, and meat, and they avoided all processed foods containing trans fatty acids, as well as high-glycemic-index foods, such as refined carbohydrates, desserts, snacks, and soft drinks.

All but four of the CR individuals took supplements, in various combinations of the following items: a multivitamin, vitamin C, vitamin E, beta-carotene, folic acid, and selenium. In terms of serum lipid, lipoprotein, and CRP levels, as well as blood pressure and carotid artery intima-media thickness (a measure of arterial health), the individuals who took one or more supplements did not differ significantly from those who took none. (This should not be construed to mean that taking supplements has no benefit for people in good health. There are many aspects to health and aging besides those that pertain to the risk for atherosclerosis.)

Resveratrol May Prevent Fatty Liver

When you drink a glass of red wine, you’re ingesting a known amount of alcohol (about 20 ml, or 0.7 fl oz) and an unknown amount of resveratrol (it varies widely, but the average is probably about 0.2 mg, or 200 mcg, per glass). So what? What does the alcohol have to do with the resveratrol? For one thing, they’re both good for you. That, at least, is the view of many scientists, who believe that small amounts of alcohol (moderation!) from any source (not just wine) are beneficial to health. In fairness, though, other scientists do not believe this, and the jury is still out.

Once you exceed the moderation domain, there is no scientific disagreement: alcohol will harm you or kill you. One way is by causing fatty liver, a self-defining term whose medspeak counterpart is hepatic steatosis. This condition can also be caused by overeating of fatty foods. Either way, the intriguing questions are: What molecular mechanisms cause the degeneration of liver cells, allowing fat to accumulate in them? And how might this be prevented?

A group of researchers in Florida sought to answer these questions for alcohol-induced fatty liver, using cultured liver-cancer cells from rats and the whole livers of alcohol-fed mice.1 In their scenario, ethyl alcohol upregulates (stimulates the production or activity of) a protein called SREBP-1, which increases the synthesis of cholesterol and fats in the liver. The latter mechanism is regulated in part by the action of another protein, SIRT1, which happens to be upregulated by . . . resveratrol. Aha! There’s your other connection—an indirect one—between alcohol and resveratrol.

It turns out that chronic alcohol feeding in mice downregulates SIRT1, thereby facilitating alcohol’s upregulation of SREBP-1, which causes the liver to degenerate. If resveratrol were used prophylactically to upregulate SIRT1, it might counteract the effect of alcohol and help prevent fatty liver. Oddly, the researchers didn’t try that with the mice. Using the rat cell cultures, however, they verified that resveratrol does indeed have this effect at the molecular level. What a nice irony—red wine gives us alcohol and resveratrol (but not nearly enough of the latter), working at crossed purposes.

The authors stated, “Taken together, our findings for the first time suggest that SIRT1 may play a crucial role in regulating ethanol-mediated lipid accumulation in liver.”

And that, as we have seen, means that resveratrol might be beneficial in this regard. It would not be the first instance in which resveratrol’s health benefits are attributed to its upregulation of SIRT1. That remarkable protein is, in fact, the very one thought to be the principal mediator of the beneficial effects of caloric restriction, including its ability to extend maximum lifespan. For that reason, the gene that codes for SIRT1 is called a longevity gene.

More on this next month.

Reference

  1. You M, Liang X, Ajmo JM, Ness GC. Involvement of mammalian sirtuins 1 in the action of ethanol in the liver. Am J Physiol Gastrointest Liver Physiol 2008 [online preprint]. doi:10.1152/ajpgi.00575.2007.

Resveratrol Nullifies the Liabilities of Obesity

Interestingly, none of the CR individuals took resveratrol (rez·VEER·ah·troll), the fabled red-wine polyphenol to which scientists have attributed an amazing spectrum of health and longevity benefits in laboratory animals. If these individuals had not adopted their severe dietary regimen, they might have done well to consider taking resveratrol—as, indeed, might anyone who is interested in achieving the health and longevity benefits of caloric restriction without actually undergoing caloric restriction.

That sounds preposterous—but research in the past few years has demonstrated that the biological effects of resveratrol actually do mimic those of caloric restriction in fundamentally important ways. In the article “Revolutionary Antiaging Discovery with Resveratrol” (January 2007), we discussed a groundbreaking study showing that, in obese mice on a high-fat diet, resveratrol did the following:

  • Made them physically more robust in terms of balance and motor function.

  • Protected them from insulin resistance and diabetes.

  • Protected them from the liver damage and heart damage commonly caused by a high-fat diet.

  • Shifted their overall physiology toward that of the control mice on a standard diet, thereby counteracting the many pathologies associated with obesity.

  • Substantially prolonged their lives.

Basically, resveratrol nullified the major liabilities associated with obesity and made the fat mice equivalent in health and longevity to the normal, healthy controls, except for one thing: they remained fat. For all practical purposes, though, they had achieved the benefits of caloric restriction without caloric restriction! Amazing, but true.

A necessary caveat: the study was done with mice, and we don’t know what the results of a similar study with humans would be—we’ll have to wait and see. Meanwhile, though, it would be interesting to learn whatever else there is to know about the short-term effects of caloric restriction on humans, because there is good reason to believe that resveratrol might mimic those effects.

A Controlled CR Study with Human “Volunteers”

Let’s go to Louisiana, where, believe it or not, a group of adult human beings agreed to undergo caloric restriction for 6 months in a scientifically controlled study.2* The study was part of an ambitious research program called the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE), which is funded by the National Institute on Aging. Scientists at the Pennington Biomedical Research Center in Baton Rouge selected 48 healthy but sedentary men (aged less than 50) and women (aged less than 45) from among the 599 (!) who applied. The subjects’ body mass index (BMI) was in the range 25 to less than 30, i.e., they were overweight (obesity is a BMI of 30 or more).


*Were these folks masochistic or just so gung-ho for medical research that they voluntarily stepped up to an empty plate? Neither—they were paid to participate in the study! As the authors put it, the “significant monetary compensation” (doled out incrementally) provided the motivation to sign up, and it “likely facilitated the excellent retention rate.” If that’s what it takes . . . good!


The 48 subjects were randomized into 4 groups of 12:

  1. Caloric restriction (CR) – A 25% reduction in calories (from the individual’s measured baseline energy requirement), with no other change in lifestyle.

  2. Caloric restriction with exercise (CREX) – A 12.5% reduction in calories, plus a 12.5% increase in energy expenditure through monitored, structured exercise (walking, running, or cycling), i.e., the equivalent of a 25% calorie reduction.

  3. Very-low-calorie diet (VLCD) – A “crash” diet of only 890 calories/day until a 15% reduction in body weight was achieved (generally, this occurred by week 8 for the men and week 11 for the women), after which the diet was adjusted for maintenance of the new weight.

  4. Controls – These lucky ones were required only to maintain their normal weight.

Two Big Questions: Metabolic Adaptation and Oxidative Stress

The researchers expected, of course, that caloric restriction would produce significant weight loss, and with it, a proportionate reduction in the amount of energy (calories) required to maintain the new, lower body weight. They did not know, however, whether or not the body would adapt to its lower weight and higher muscle/fat ratio through metabolic changes that would require even less energy than predicted on the basis of weight. In other words, would the participants’ metabolism become more efficient in the use of available energy? This was an important question, because studies on rodents have yielded contradictory results.

Another important question pertained to oxidative stress, which is the cumulative, harmful effects of the body’s generation of reactive oxygen species, including free radicals, in the course of energy metabolism. Oxidative stress is believed to play a fundamental role in many degenerative diseases and in the aging process itself, in part by damaging our DNA. Hence a CR-induced reduction would be highly significant in terms of health and life expectancy. Here too, the results of animal studies (in this case, rhesus monkeys) have been contradictory.

The Facts: Weight Loss and Improved Metabolic Function

As expected, the calorically restricted individuals lost a great deal of weight, most of it as fat. After 6 months, the CR group had lost slightly more weight (10.4%) than the CREX group (10.0%), but the CREX group had lost slightly more body fat (25%) than the CR group (24%); the CREX group had, of course, been building some muscle mass. Meanwhile, the VLCD group had lost 13.9% of body weight and 32% of body fat.

There were no significant changes in fasting glucose levels after 6 months, but fasting insulin levels were significantly reduced—a very favorable result—in all three groups. The average 24-hour core body temperature in the CR and CREX groups was reduced—another favorable result—but not in the VLCD group. In all three groups, plasma thyroxine (thyroid hormone) levels were significantly reduced, indicating a reduced metabolic rate. There were no significant changes, however, in the levels of DHEAS (dehydroepiandrosterone sulfate), the DHEA metabolite to which almost all of our DHEA is converted in the liver.

Metabolic Adaptation? Yes
Reduced Oxidative Stress? Yes

Three of the above factors—insulin, temperature, and DHEAS—are particularly important because they had been proposed as biomarkers of aging in a study published in 2002.3 Those researchers found that non-CR men who, for whatever reasons, had below-median insulin levels, below-median temperatures, or above-median DHEAS levels lived longer than men on the other sides of those median values. These findings jibe with the fact that CR monkeys have reduced insulin levels and temperature, and higher DHEAS levels.

Overall, the most important findings of the Louisiana study were that 6-month caloric restriction in overweight humans caused:

  • A reduction in insulin levels and core body temperature, i.e., a positive change in two of the three previously reported biomarkers of aging.

  • A positive metabolic adaptation, i.e., a decrease in energy expenditure that was greater than expected on the basis of weight loss. This was associated with reduced thyroxine levels.

  • A reduction in cellular DNA damage. This was presumably due to a decrease in the production of reactive oxygen species, although in the one direct measure of oxidative stress used in this study (protein carbonylation), no CR-induced change was seen; other measures might tell a different story.

Making Resveratrol More Bioavailable

In the article “Resveratrol—Star Molecule Against Disease and Aging” (August 2006), we summarized the evidence for resveratrol’s benefits in protecting against cancer and heart disease, inhibiting inflammation and enhancing immunity, protecting against tissue damage in heart attack and stroke, and slowing the aging process. We also discussed the scientific rationale for the evidence-based belief that resveratrol can mimic the effects of caloric restriction. In next month’s issue, we will have more to say about that, and it will tie in with further exciting results from the human subjects studied in the CALERIE program.

In the August 2006 article, we also mentioned the vexing problem of resveratrol’s low bioavailability, which afflicts other supplements too, such as the turmeric curcuminoids. A new approach to this problem is to dissolve the compounds in question in solid-lipid nanospheres (SLNs)—tiny spheres in the nanometer size range, made from natural phospholipids and triglycerides—which form a sol (a solid-in-liquid colloidal dispersion). There is reason to believe that such sols may enhance the bioavailability of the compounds dissolved in them. For more on this technology and on the subject of bioavailability, see “Solid-Lipid Nanospheres for Delivering Curcuminoids” (February 2008) and “Getting Our Curcuminoids Is Difficult, but Worth It” (March 2008).

What’s for Dinner?

It’s fascinating to learn how caloric restriction can improve our health and, probably, prolong our lives, and it’s gratifying to learn that, through resveratrol, there may be a way to reap these benefits without the culinary deprivation that no one wants to have to endure even briefly, let alone for a lifetime. As Ring Lardner said, “I’ve known what it is to be hungry, but I always went right to a restaurant.” When you go, make sure they have resveratrol on the menu.

References

  1. Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci USA 2004;101(17):6659-63.
  2. Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J, Nguyen T, Martin CK, Volaufova J, Most MM, Greenway FL, Smith SR, Deutsch WA, Williamson DA, Ravussin E, for the Pennington CALERIE Team. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA 2006;295:1539–48.
  3. Roth GS, Lane MA, Ingram DK, Mattison JA, Elahi D, Tobin JD, Muller D, Metter EJ. Biomarkers of caloric restriction may predict longevity in humans. Science 2002;297:811.


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

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