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Red Wine Constituent Gives Mice Radical Metabolic Makeovers
11/23/2006
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French findings send the anti-aging potential of a newly famous constituent of grape skins soaring into the stratosphere
by Craig Weatherby 


Most of the health complaints of middle age connect in some way with age-related declines in people’s metabolisms.

Starting around age 40, human bodies begin a slow downward slide in metabolic efficiency characterized by burgeoning waistlines, and reduced strength and endurance.

Key Points
  • New study adds to anti-aging benefits of resveratrol reported in recent Harvard investigation.
  • High-dose resveratrol gave mice fed high-calorie diets the metabolisms and muscle tissue of endurance athletes.
  • Doses used were too high for humans to achieve using current supplements.
Age-related metabolic declines also promote a raft of degenerative disorders ranging from diabetes, cataracts, and cancer to cardiovascular disease, Alzheimer’s, and arthritis.

These and other degenerative conditions flow from age-related declines in two key capacities:
  1. The efficiency and rate of cellular metabolism.
  2. The ability to neutralize the damaging free radicals generated in cells as byproducts of their metabolic processes.
The most important metabolic reactions in cells occur inside their mitochondria: the minuscule organelles that retain the genes and enzymes needed for metabolic reactions, including the conversion of food molecules to usable forms of energy.

Collectively, the age- and lifestyle-related declines associated with increased rates of diabetes and heart disease are grouped under the term “metabolic syndrome”.

Metabolic syndrome is defined as having any three or more of six factors associated with increased risk of diabetes and heart disease: 1) excess abdominal fat, 2) insulin-resistant cells, 3) unhealthful blood fat/cholesterol profiles, 4) high blood pressure, 5) “sticky”, clot-promoting blood chemistry, and 6) chronic low-level inflammation.

And new research results from France strengthen the prospect that resveratrol, an antioxidant, anti-cancer constituent of grapes and red wine, will join marine omega-3s as a nutritional ally in the struggle to avoid this undesirable family of risk factors.

This week’s Thanksgiving feast provides the perfect context in which to consider new findings regarding the effects of resveratrol on human metabolism: results that suggest that this antioxidant compound from grapes and red wine may help us to stop accumulating body fat as we age.

(In our next issue, we’ll examine new research that boosts the reputation of omega-3s as allies in the fight to prevent weight gain and other aspects of “metabolic syndrome”.)

To understand why new research puts omega-3s and resveratrol in such a good light, it is important to understand the meaning of “metabolism.”

Broadly speaking, this key biomedical term encompasses the millions of chemical reactions that make life possible for everything from bacteria to humans.

But for our purposes, “metabolism” means “cell metabolism”: the smaller set of chemical reactions human cells use to process nutrient molecules from foods and maintain their own structures and functions.

Harvard team found metabolic miracles flowing from red wine constituent

Resveratrol is the strongly anti-oxidant, anti-cancer polyphenol compound found in abundance only in grape skins, red wine, and the root of a Chinese plant called giant knotweed or hu zhang.

Three weeks ago, we summarized headline-making findings about resveratrol reported from Harvard University.

In that study, David Sinclair, Ph.D. and his colleagues gave mice a high-calorie diet that made the rodents obese. And they found that feeding a concentrated dose of resveratrol at the same time kept the heavily overweight mice as energetic and healthy as their lean counterparts (See “Antioxidant from grapes and wine might extend life- and health-spans”).

Coincidentally, a French team at the Institute of Genetics and Molecular and Cellular Biology, led by Johan Auwerx, Ph.D., just released a resveratrol study whose results seem even more exciting (Lagouge et al 2006).

Resveratrol transforms pudgy mice into little Lance Armstrongs
The new French findings show that, compared with mice fed a standard, resveratrol-free diet, mice given high oral doses of resveratrol as part of a high-fat, high-calorie diet displayed astounding health advantages:
  • Prevented weight gain and reduced the size of fat cells.
  • Protected the animals from developing metabolic syndrome.
  • Increased the number of energy-producing mitochondria in muscle cells.
  • Boosted thermogenesis (burning of body fat).
  • Increased their aerobic capacity (i.e., increased their endurance).
  • Maintained their cells’ sensitivity to insulin, thus moderating blood sugar levels.
  • Transformed muscle fibers into the “slow” type seen in trained athletes.
  • Enhanced muscle strength and reduced muscle fatigue.
  • Improved the animals’ coordination.
  • Did not activate PGC1-a in the animals’ heart muscles, which could be harmful.
  • Produced no adverse effects on the liver or other organs.
These findings mean that resveratrol is the first natural food constituent found to exert a fundamentally positive effect on metabolism-driven diseases, which constitute the most pressing health problems in developed and developing countries.

Resveratrol activates enzyme that triggers "scarcity response"
The benefits produced in the mice by dietary resveratrol stem from its effects on an enzyme called SIRT1, which belongs to a recently discovered family of enzymes called sirtuins. Prior studies showed that SIRT1 activates a substance called PGC1-a, yielding four highly desirable anti-aging effects:
  1. Stimulates cells to produce more mitochondria.
  2. Increase the antioxidant capacity (i.e., reducing power) needed to handle the free radicals generated by extra mitochondria.
  3. Switches the mix of fibers in muscle toward the “slow” type seen in endurance athletes.
  4. Causes “burning” of body fat by increasing thermogenesis in brown adipose tissue.
Critically, the new findings prove that resveratrol activates SIRT1 in living animals, with very real, highly desirable metabolic effects.

The available evidence indicates that SIRT1, the sirtuin-class enzyme activated by resveratrol, commands the body’s metabolic and hormonal settings to switch from reproduction to survival mode when levels of energy expenditure drop in our cells.

This appears to be an evolutionary adaptation that lets animals live through famines and postpone breeding to better times.

Ironically, while sirtuin enzymes evolved to increase our chances of surviving hard times, resveratrol may help people survive times that are a bit too soft.

This is because the metabolic shifts triggered when hunger or resveratrol activates sirtuins include changes that discourage the major degenerative diseases of aging like cancer, diabetes, heart disease and dementia.

Many years ago, it was discovered that when rodents were placed on near-starvation diets, it made them dramatically healthier and more long-lived. Unsurprisingly, it was recently discovered that sirtuins play a central role in the molecular mechanisms that produce the benefits of such extreme calorie restriction.

In fact, some of the key signs of aging may stem from age-related declines in the activity of sirtuin-class enzymes over time.

We can safely assume that millions will await the results of the inevitable human trials with eager anticipation.

The devil's in the dose details
But before we get too worked up about these truly remarkable results, we should note that the mice in the new French study ate enormous amounts of resveratrol.

While the mice in Dr. Sinclair’s obesity study were fed 22 milligrams of resveratrol per kilogram of body weight—already a very high dose—the French team fed their mice 18 times as much: a whopping 400 milligrams of resveratrol per kilogram of body weight.

For a 130-lb person, the lower dose level used in the Sinclair study translates to 295 mg, or about 20 average-strength resveratrol capsules per day: an extreme and expensive but not entirely impractical regimen.

But for a 130-lb person to get the much higher dose level used in the startling French study he or she would need to take an absurdly impractical 1,573 capsules, each containing 15 mg of resveratrol, to provide the 400 mg of resveratrol per kilogram of body weight that achieved such amazing results (130 lbs. = 59 kilograms x 400 mg = 23,600 mg / 15 = 1,573 capsules).

Still, the Harvard and French reports indicate that resveratrol may prove to be a uniquely beneficial boon to human health, especially if it proves to yield positive effects in smaller doses.

The promise of resveratrol rests on the answers to three key questions:
  1. Is there is a minimum intake level below which dietary resveratrol produces no metabolic benefits?
  2. Would smaller doses of resveratrol produce metabolic benefits to correspondingly smaller extents?
  3. Can scientists modify the molecule so that it is effective at much smaller doses? (Dr. Sinclair co-founded a company that’s trying to do just that.)
We'll admit to hoping that the answers come back in favor of making resveratrol a practical way to make over aging metabolisms.

Metabolic makeovers in a pill may never become reality. But if resveratrol is proven to work even half as well in humans, people will probably break down doors to get it, or anything else that comes within shouting distance of it effects in mice.


Source
  • Lagouge et al. Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1a. Cell (2006), doi:10.1016/j.cell.2006.11.013.

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