The hypothesis that caloric restriction (CR) increases longevity is widely accepted, but the mechanisms by which it works are bewilderingly complex. A recent study shed new light on these mechanisms. This work demonstrated a proliferation in the number of mitochondria per cell (mitochondrial biogenesis) which was triggered by a CR-diet induced expression of the enzyme endothelial nitric oxide synthase (eNOS). To read the highly technical, peer-reviewed article that presents the results, click here. "Calorie Restriction Promotes Mitochondrial Biogenesis by Inducing the Expression of eNOS" Science 14 October 2005: 314-317. This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

By Benjamin V. Treadwell, Ph.D.

Wouldn't it be nice to know the formula for maximum health and longevity? Perhaps you are expecting the same old sermon: eat right, exercise, and maybe have a glass of red wine on occasion, and that is all one can do for maximum health. Many of us just don't have enough faith in this formula to initiate a program that, at least initially, demands discipline, sacrifice, and hard work. Furthermore, why should we believe such a program will actually improve our health?

Some recent research pulls together the three elements of this formula and gives us more reason to believe. Numerous studies have demonstrated the positive health effects of exercise, calorie restricted diet, and a compound in red wine. All three components appear to exert at least some of their health-promoting effects through a common biochemical pathway. For example, a calorie restricted diet activates the production of a messenger molecule, nitric oxide (NO). NO, in turn, activates the synthesis of an additional cellular messenger, cyclic GMP (cGMP). This messenger activates a number of biochemical pathways that culminate in various effects, including increased synthesis of mitochondria, those cellular organelles involved in the production of virtually all cellular energy. An increase in the number and size of the mitochondria present in the cell has been shown to improve the efficiency of the conversion of food to energy.

The Calorie Restricted Diet Connection

Research has shown that a calorie restricted diet significantly extends the life of virtually all living creatures. Although a calorie restricted (CR) diet has not yet been shown to increase lifespan in humans, it clearly improves markers of health in humans, such as cholesterol, blood pressure and several other indicators of health, suggesting it eventually will prove to be a life-extender in humans, too (see our article on Caloric Restriction, for additional information on this diet).

		Intermittent Fasting Works, Too Caloric restriction can be achieved with an every-day low-cal diet, or intermittent fasting. Think of our hunter-gatherer ancestors, who might have killed wild game, eaten well for a few days, and then had to fast when food was scarce. Today, we can eat a normal diet one day, then the next day eat very lightly (but enough to stave off light-headedness).

The recent research also helps explain the paradox of the calorie restricted diet. This diet increases the utilization of oxygen by the cells of the body. This in turn should produce more toxic oxidants or free radicals, since we know that free radical production is associated with increased oxygen consumption. According to the free radical theory of aging, an increase in free radicals promotes cellular aging, yet the calorie restricted diet inhibits cellular aging.

How is this possible? It turns out that the greater the number and size of the mitochondria, the more efficient the cell is at converting food to energy. This means that although more oxygen is consumed per cell, fewer free radicals are generated due to improved energy efficiency. In a way, this is analogous to the energy-efficient hybrid car, which has two engines. In the cell, multiple engines working to convert food to energy emit fewer toxic fumes than a single energy-producing engine.

Another important consideration is that multiple engines located in numerous energy-consuming cellular compartments provide an immediate source of energy where it is most needed. This too can help decrease the level of toxic products, as it takes an immediate source of energy to produce the antioxidants required to clean up any toxic spills.

Additional evidence indicates that the caloric restricted diet promotes health by stimulating the burning of fat for energy, which is believed to be the consequence of the diet-promoted synthesis of another cell-regulator described below.

The Red Wine Connection

The CR-stimulated synthesis of NO and cGMP also promotes the synthesis of another factor, SIRT1, an enzyme involved in the regulation of genes that promote longer life. SIRT1 may be associated with a metabolic switch telling the cell to burn fat rather than carbohydrates for energy. (The analogy here is the hybrid car switching from gasoline to electricity.)

This is where the red-wine connection enters the story. The active ingredient in red wine is the polyphenolic compound, resveratrol, which has previously been demonstrated to stimulate the synthesis of this longevity factor, SIRT1. The recent research mentioned above indicates that the mechanism by which resveratrol activates the cell to produce this longevity gene product is via the production of NO and cGMP. This makes a lot of sense, since moderate consumption of red wine has been associated with improved cardiovascular health, which in turn is at least partially the consequence of a resveratrol-induced increase in cGMP and NO. cGMP also has the property of lowering blood pressure, which is important for cardiovascular health.

The Exercise Connection

Physical exercise has also been shown to increase NO-cGMP production by muscle cells. This too fits into the scheme laid out in this review. It is an established fact that exercise stimulates the synthesis of mitochondria. The mechanism is likely to be the exercise-induced activation of the NO-cGMP biochemical pathway. This is at least one of the mechanisms involved in promoting the well-known positive effects of exercise on health, especially cardiovascular health.

Interestingly, earlier research demonstrated in animal studies that the number of mitochondria per cell decreases with age. An increase of the production of free radicals accompanies the age-associated decrease in mitochondrial number. This all fits into the overall picture described above, namely that energy efficiency improves with greater numbers of mitochondria per cell, and the number per cell is inversely proportional to the age of the animal, including humans.

In summary, exercise, diet and red wine all improve health at the cellular level by activating the synthesis of the messengers, nitric oxide and cyclic GMP. These messengers activate additional cellular events that culminate in increased mitochondrial number, lower blood pressure and numerous additional markers of good health. They also ultimately increase the synthesis of longevity factor, SIRT1, which, in turn, increases the burning of fat for energy, thus decreasing fat stores, and improving cellular health.