Resveratrol Boosts Strength and Endurance in Mice

Resveratrol Keeps the Golden Age Going

Resveratrol Boosts Strength
and Endurance in Mice

New study shows that mice experience dramatic
improvement without exercise training!
By Will Block

Facts which at first seem improbable will, even on
scant explanation, drop the cloak which has hidden
them and stand forth in naked and simple beauty.

— Galileo Galilei

hen Bruce Jenner won Olympic gold in the decathlon in 1976, he was hailed as the world’s greatest athlete—and it didn’t hurt that he was also handsome and charming. His record-shattering victory filled American hearts with pride (and he probably set many a female heart aflutter). He was as close to perfection as one could imagine. Was there a man anywhere who didn’t secretly wish to have what Jenner had?

It’s in our genes to desire physical prowess and to admire, even revere (and sometimes fear), those who have it in abundance. How we wish we could run faster, jump higher and longer, and hurl objects farther than anyone else. It’s a legacy of our ancestors’ epic struggle for survival on the African savanna—hunting (and being hunted by) animals that could run like the wind or attack with terrifying ferocity.

Resveratrol, Anyone?

Our species may have outlived the need for great physical strength and endurance, but we still want it. The trouble is, it takes a lot of work just to stay in good shape, let alone be an Olympian. Why can’t we just pop a pill that will boost our strength and energy while we’re watching football on TV? Is instant gratification too much to ask for?

Of course it is . . . or is it? Enter resveratrol. You have probably heard—and you certainly know, if you read this magazine regularly—that resveratrol (pronounced rez·VEER·ah·troll) is the red-wine compound that greatly prolongs life in a variety of organisms, including mice (see “Revolutionary Antiaging Discovery with Resveratrol” in last month’s issue). And with mice, we’re getting pretty close to humans on the evolutionary tree of life. Whether it’s yeast or worms or flies or fish or mice, the study results are the same: give these creatures substantial amounts of resveratrol, and they live a lot longer. It’s as simple as that—and it’s spectacular.

Resveratrol Alone Increases Aerobic Capacity

By definition, of course, life extension is not instant gratification—it takes a long time (which is the whole idea). Now, however, comes a study suggesting that instant gratification of sorts is possible with resveratrol—at least in mice—and the discovery is every bit as remarkable as that of the life extension already documented.

A research team from France, Finland, and the United States, led by Dr. Johan Auwerx (pronounced OH·wer·ix) of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France, has found that healthy young mice fed large amounts of resveratrol for 15 weeks show greatly increased aerobic capacity and physical endurance during exercise, and a significant increase in grip strength as well.1 No training, no conditioning, no sweat—just supplemental resveratrol!

Resveratrol Almost Doubles Physical Endurance!

For the endurance tests, the researchers used a tiny treadmill enclosed in a Plexiglas chamber. As with treadmills for humans, this one’s speed and angle of incline could be increased at intervals, making the task more challenging as time progressed. There was one additional feature, however, that human treadmills don’t have: at the rear of the belt, there was a wire grid that delivered a mild electric shock if the mice slacked off and touched it. This motivated them to keep running until they could run no more, i.e., to the point of total exhaustion (about 1 km, or 0.6 mile, for your average mouse).

The researchers found that normal, healthy mice receiving resveratrol in addition to their standard diet of mouse chow ran 1.8 times as far on the treadmill as control mice that were on the same diet but without resveratrol. Nearly identical results (1.7 times as far) were obtained with mice that were being fed a high-fat diet instead of regular chow. Thus, in both cases, adding resveratrol almost doubled the distance the mice ran, i.e., it almost doubled their physical endurance! Contrast that with human athletes who train like demons to improve their performance by a mere 1%.

It must be mentioned that the amount of resveratrol used was enormous: 400 mg per kilogram of body weight, per day. This is 18 times greater than the largest amount used (22.4 mg/kg per day) in the longevity study with obese mice by David Sinclair and colleagues that we discussed last month.2 As in that study, the researchers in the new study found that resveratrol was well tolerated, with no toxic effects—nor have any been observed in humans taking supplemental resveratrol (albeit in much smaller amounts).*


*For a 75-kg (165-lb) human, 400 mg/kg per day would be 30,000 mg (30 g, or 1.1 oz) of resveratrol per day—a huge amount by the standards of nutritional supplements. As we reported last month, Dr. Sinclair has for several years been taking resveratrol in the amount of 5 mg/kg per day; if he weighed 75 kg, this would amount to 375 mg per day.


Researchers Focus on Cellular Energy Metabolism

The researchers did much more than give the mice exercise tests. Their objective was to investigate the biological effects of resveratrol on mitochondrial function and energy metabolism. Mitochondria are the tiny organelles within our cells where nutritional fuel molecules—glucose and fatty acids—are “burned” to generate the energy upon which all life processes depend. Called cellular respiration or cellular energy metabolism, this is a complex process involving many enzyme-catalyzed chemical reactions.

One element of the process is a chain of reactions called oxidative phosphorylation, which results in the production of ATP (adenosine triphosphate), the body’s master energy molecule. Most life processes are driven by the chemical energy released by ATP when it’s degraded, via enzymes, to ADP (adenosine diphosphate). ATP must then be reconstituted from ADP via combustion of more fuel, which keeps the oxidative phosphorylation—and life—going.

Resveratrol Enhances Mitochondrial Function and Number

The availability of ATP is thus a key determinant of our physical capabilities (mental too, because ATP powers our thought processes). Nowhere is this more evident than in muscle contraction, which expends a lot of energy. So if mitochondrial function is enhanced, or if the number of mitochondria is increased, there will be more ATP available for use in powering activities such as running on a treadmill. (Compromised mitochondrial function, by the way, is associated with age-related degenerative diseases and reduced longevity.)


The effect of resveratrol on the mitochondria in brown adipose tissue (BAT) and calf-muscle fibers from mice, measured as total visible mitochondrial surface area in electron micrographs. In the arbitrary scale on the left, 1.0 represents the total mitochondrial surface area with the high-fat diet, so the effect of resveratrol can be seen as a multiple of 1.0. (Adapted from Ref. 1)

Sure enough, the researchers found that mouse mitochondrial function was greatly enhanced by resveratrol, as evidenced by the much larger size—hence the greater energy-output capacity—of the mitochondria in brown adipose tissue (a type of fat that generates heat to regulate body temperature) and calf-muscle fibers. They also found evidence of mitochondrial biogenesis, an increased number of mitochondria, in muscle fibers.* These changes translated to increased energy expenditure, improved aerobic capacity, and enhanced motor function, including the strength increase mentioned above.


*Surprisingly to the researchers (and probably disappointingly), no enhancement of mitochondrial function or number was seen in the heart, whose function was unaffected by resveratrol.


Resveratrol Prevents Weight Gain and Protects Against Diabetes

An important consequence of the enhanced mitochondrial function was that the resveratrol-supplemented mice on the high-fat diet were burning off most of their excess calories rather than storing them as fat, so they were largely protected from weight gain. This is consistent with other research suggesting that resveratrol’s effects mimic those of caloric restriction, the extremely low-calorie regimen that prolongs lifespan in a wide variety of organisms. The antiobesity effect observed was in stark contrast, however, to the results seen in the Sinclair study, in which the resveratrol-supplemented mice on the high-fat diet became just as obese as the others (recall, though, that the resveratrol dosage there was much lower than in the Auwerx study).


“. . . it is rare that we identify orally
active molecules, especially
natural molecules, that have such a
broad-based, positive effect on a
problem as widespread in society
as metabolic disease.”


Most important, perhaps, is that in both studies, resveratrol protected the mice from developing insulin resistance, the precursor to type 2 diabetes. Thus it appears that resveratrol possesses intrinsic antidiabetic properties whether or not it prevents obesity. This is a tremendous benefit by any standard.

Resveratrol Provides “Training” without Exercise

How did the researchers explain all these improbable facts, causing the “cloak” that Galileo spoke of to be dropped? They did it through meticulous molecular biological studies carried out on tissues from the resveratrol-supplemented mice. In brief, their explanation goes like this: resveratrol stimulates the expression of the longevity gene SIRT1 (this had been known for several years), which codes for the protein SIRT1. The actions of SIRT1 are those of a deacetylase, meaning that it removes acetyl groups from proteins that have them in certain places in their molecular structure. SIRT1 performs this function on (among others) a protein called PGC-1α, which controls mitochondrial biogenesis and function; PGC-1α is thus a strong arbiter of cellular energy metabolism. When this protein is deacetylated, its biological activity increases, and so do mitochondrial number and function.

The result (as seen in the mice) is greatly enhanced physical capability in the absence of increased physical activity (i.e., exercise). This enhancement is induced in part by an increase in the proportion of “oxidative” muscle fibers, the type with the greatest capacity to carry oxygen and sustain aerobic activity (such a conversion of one type of muscle fiber to another type is called remodeling). Oxidative fibers are the type of muscle fiber that maximizes endurance and is found abundantly in trained athletes.

Resveratrol Holds Great Promise for Humans


© iStockphoto.com/Nancy Edmonds
A key finding of the numerous experiments in this study was that the SIRT1 protein plays the central role in resveratrol’s myriad effects, in part through its activation of PGC-1α (although the muscle remodeling alone also involved dozens of other resveratrol-activated genes that are associated with a variety of physiological functions).

To put this finding to the test, the researchers investigated the effects on human energy homeostasis (the balance between energy input and energy output) of five variant forms of the SIRT1 gene that are found in human populations from northern and western Europe. Their hypothesis was that if any of these five forms, called single-nucleotide polymorphisms (SNPs), significantly altered human energy homeostasis, this would support the idea that SIRT1 is indeed involved in that process, as was strongly suggested by the resveratrol experiments.

For the trial, conducted in Finland, the researchers recruited 123 healthy, normal-weight, nondiabetic offspring (average age 34) of type 2 diabetic patients. The metabolic tests revealed that three of the five SNPs were significantly associated with the subjects’ energy homeostasis, thus supporting the hypothesis. The authors stated,1

Although most of our conclusions are based on cellular studies and pharmacological interventions in mice, the novel association between genetic variations in the Sirt1 gene and energy homeostasis in man reveals a significant place for our work in the context of human pathophysiology.

Long Live the Golden Age

Toward the end of the nineteenth century, many physics professors advised their students that physics was a dead-end science. With Maxwell’s brilliant elucidations of the kinetic theory of gases and electromagnetism, the great discoveries had all been made, it seemed, and the Golden Age of physics was over. All that remained was to refine our knowledge through more precise measurements of things already known—a worthy but intellectually sterile endeavor. Physics, the professors said, was thus a poor career choice for bright young scientists who wanted to set the world on fire.

Wow—how wrong can one be? Even as they spoke, the electron was about to be discovered (Thomson, 1897), with the atomic nucleus soon to follow (Rutherford, 1911). And quantum theory (Planck, 1900) and relativity (Einstein, 1905) would take the scientific world by storm. These twin pillars of modern physics were destined to deluge the world with radical new knowledge and capabilities—not just in physics but also in the other natural sciences, because all are derived, ultimately, from physics.

Most notably, quantum mechanics revolutionized chemistry in the 1930s, transforming and vastly expanding the material world as we knew it—a process that continues to this day. And the new chemistry soon spawned the fruitful field of molecular biology, which, in turn, reshaped modern medicine, putting much of it on solid scientific ground for the first time.

The central figure in these developments was Linus Pauling, of whom Einstein once said, “Ah, there’s true genius.” As seminal as it was, Pauling’s work on vitamin C and other aspects of orthomolecular medicine toward the end of his career was but a footnote to his earlier, monumental achievements in physics, chemistry, biology, and medicine. Through his discoveries, it has been said, he illuminated more aspects of the natural world than anyone else who ever lived. He did not, however, pretend to be able to see the future.

Many scientists have had a penchant for predicting the future course of science and technology, but they have usually been wrong—their track record is terrible. (As Niels Bohr once said, “It is hard to predict—especially the future.”) This is due largely to the difficulty of imagining the almost unimaginable, i.e., those revolutionary discoveries that blindside us from time to time and injure or kill our sacred cows. Sometimes they show that something fundamentally important that we “knew” to be true was, in fact, false, or vice versa.

Such unforeseeable seismic shifts alter the scientific landscape in radical ways (as do unforeseeable social, economic, and political events). There is no good reason to doubt that many more surprising and exhilarating discoveries still lie ahead in the always messy and confusing march of scientific progress.

Even now, though (as always), some aging scientists harbor the notion that the Golden Age of science is over. They believe that everything of importance that can be discovered has been discovered, so it’s probably going to be all downhill from here. Pop psychology suggests that this foolish idea is rooted in a mixture of hubris (“I’m too smart to have overlooked anything really important”) and wishful thinking (“If all the important stuff has already been discovered, I won’t be missing out on anything after I’m gone”). Let us pity those who are thus deluded.

Meanwhile, let us marvel at the capabilities of resveratrol, the discoveries of which epitomize the kind of breakthroughs that can revitalize a stagnant scientific discipline and open up new avenues of research. Only a few years ago, most physiologists would probably have dismissed as absurd the idea that a single, simple chemical compound could dramatically increase longevity or physical strength and endurance. They must now be kicking themselves for having been so wrong.

Thanks in part to the amazing, unforeseen properties of resveratrol, the Golden Age seems to be aging gracefully indeed—or perhaps it’s not aging at all. May it live forever!

In an interview, Dr. Ronald Evans, a renowned authority on the hormonal control of metabolism at the Salk Institute for Biological Studies in San Diego, said that the study by Auwerx and his colleagues had “shown very convincingly that resveratrol improves mitochondrial function” and fends off metabolic disease, such as diabetes.3 He went on to describe the study as “very important, because it is rare that we identify orally active molecules, especially natural molecules, that have such a broad-based, positive effect on a problem as widespread in society as metabolic disease.”


© iStockphoto.com/Dan Van Oss
Resveratrol—Hottest Topic in Antiaging Medicine

The old saw about anything that seems too good to be true is starting to lose some of its validity, as our jaws drop in amazement at what resveratrol is capable of doing. This story of mice and men (and, of course, women) is just beginning, and many questions remain to be answered. Among the most important of these are: Will resveratrol have similar effects in humans? If so, how much will it take to produce these effects? And are those amounts safe? Based on current, still very meager knowledge, the answers to these questions are: Probably; Probably a lot; We don’t know.

We do know, however, that many studies on resveratrol thus far have pointed to a variety of remarkable health benefits in addition to those of increased longevity and endurance.* And now the studies by Sinclair and Auwerx and their colleagues have electrified the scientific world, triggering what will surely be an explosion of new research on resveratrol. It’s undoubtedly the hottest topic ever in antiaging medicine.


*See “Resveratrol and Ginkgo Battle the Scourge of Dementia” (February 2004), “Resveratrol and Quercetin—Puzzling Gifts of Nature” (July 2005), “Resveratrol Fights Brain Plaque” (November 2005), “Can Resveratrol Help Prevent Alzheimer’s?” (February 2006), “Resveratrol Prolongs Life in a Vertebrate!” (April 2006), “Resveratrol—Star Molecule Against Disease and Aging” (August 2006), “Resveratrol Instead of Aspirin for Heart Health” (November 2006), and “Revolutionary Antiaging Discovery with Resveratrol” (January 2007).


A word of caution: Exaggerated and fraudulent claims about resveratrol’s seemingly “miraculous” properties are being touted by many people whose understanding (or even caring) about the science behind their products leaves much to be desired. Caveat emptor. We, however, will continue to bring you news of resveratrol based exclusively on careful, sober analysis of the scientific literature. You deserve no less.

References

  1. 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-1α. Cell 2006 Dec 15;127(6):1109-22.
  2. 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(7117):337-42.
  3. Wade N. Drug doubles endurance, study says. New York Times, Nov. 16, 2006.


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

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