By Benjamin V. Treadwell, Ph.D.

Many find this time of year very stressful, even to the point of deep depressive states. So it seems appropriate in this month's Journal, particularly in light of recent findings, to examine why exercise may help.

Most of us believe that regular exercise is, for the most part, good for us physically, maintaining cardiovascular health and preventing age-associated diseases such as type II diabetes, osteoporosis and muscle atrophy. Research (See May 2006 Juvenon Health Journal Moderate Exercise: The Elixir of Mental Health.) has also suggested that exercise can function as an antidepressant. In fact, investigators have recently demonstrated that aerobic exercise may activate biochemical pathways within the brain, physically altering its chemistry to prevent depression.

Antidepressant Delay

Antidepressant medications have been prescribed for decades, based on the hypothesis that, by increasing the levels of specific neurotransmitters, they counteract one of the underlying reasons for the depressed state. The problem with this hypothesis is the unusually long time (weeks to months) it takes for an antidepressant to elicit a positive response in the patient.

Observing that the medication almost immediately (within days) elevates the neurotransmitter levels, scientists questioned whether there are additional factors involved. They found a correlation between patients reporting a response and the appearance of specific brain proteins, neurotrophic (nourishing to nervous tissue) factors, in the antidepressant treated brain. But what stimulates these proteins to appear?

Antidepressant Alternative

In a very recent study with mice (See this month’s "Research Update."), exercise activated a gene in specialized areas of the brain to produce a protein known as VGF. VGF has previously been described as a neurotrophic protein present in tiny vesicles within brain cells. (Interestingly, this protein is also involved in energy metabolism, strengthening neural circuits and transmitting nerve impulses.)

Non-exercised, sedentary mice were lethargic and scored poorly in activities associated with a sharp, active mental state. In other words, they were "depressed." When a group of these mice was placed in a cage with running wheels for a period of four weeks, then tested for “depression” again, there was a remarkable improvement in their mental sharpness and they were no longer lethargic.

Hyper-sensitive Hippocampus

Comparing the brains of the sedentary mice to the exercised mice, researchers found a sharp increase in the amount of VGF present in the hippocampus. In mammals, this area of the brain is involved in processing memory and states of behavior, including happiness/depression.

The hippocampus is ultra-sensitive to emotional stress. Its cells can be permanently damaged if the stress is chronic, resulting in deep depression. Electric shock therapy, often used with patients who don’t respond to medication, is one of the most effective treatments. Interestingly, this treatment has recently been shown to stimulate the synthesis of VGF protein, supporting the findings that VGF protein is a key player in inhibiting depression.

There are additional neurotrophic proteins, known as brain-derived neurotrophic factors (BDNF), which appear to be involved in maintaining hippocampus health and preventing depression. Researchers have also demonstrated that levels of these proteins increase in the brains of physically active animals as compared to sedentary control animals.

V.I.P. VGF

Identifying the precise role VGF protein plays in reducing/preventing depression is a work in progress. However, the investigators strongly suggest that the known activities ascribed to VGF, including, energy production, neuroprotection and synaptic plasticity (the capacity of a neuron to increase its firing strength), are most likely critical components. In fact, psychological stress, the precursor to depression, counters these activities, presumably by depleting the brain of VGF.

Improving Your Odds

Estimations are that 16 out of 100 individuals in the United States experience depression on a regular basis. Exercise could have a significant effect on improving this number. Recent studies, particularly the very recent work discussed here, suggest that exercise significantly improves the health of at least one important brain center, the hippocampus, involved in processing memory, behavior and happiness.

Even though the exact mechanisms have yet to be identified, the many other known benefits of exercise — maintaining cardiovascular health, preventing age-associated diseases, reducing stress — already make it a good bet. Take home message: put daily aerobic exercise at the top of your New Year’s resolutions.

In an advance online publication by "Nature Medicine," researchers, from the Yale University Department of Psychiatry and New York’s Mount Sinai School of Medicine Department of Neuroscience, discuss their study of the mechanisms underlying the antidepressant effects of exercise.

Specifically, the group examined the relationship between aerobic exercise and the activation of an antidepressant gene in the brains of mice. This seminal investigation identified a new role for the exercise-stimulated synthesis of the neurotrophic peptide VGF. The results strongly imply that VGF functions as an antidepressant in the hippocampus, the area of the brain associated with emotional states.

This work is provocative for two important reasons. First, it demonstrates that regular exercise promotes mental health in animals, implying the same for humans. Second, it presents a new potential therapeutic target for the development of more effective antidepressant drugs.

Engineering these drugs to increase the levels of the neurotrophic peptide VGF could decrease the time required for antidepressants to take effect. Additionally, VGF-targeted drugs may be far more potent in attenuating the depressed condition than the antidepressants on the market today.

Click here to read the full abstract.

"Antidepressant actions of the exercise-regulated gene VGF"

Nature Medicine 13, 1476 - 1482 (2007)

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.

QUESTION:  Does Juvenon contain time-released alpha lipoic acid? I have heard that the half-life of lipoic acid is on the order of two hours. — S.G.

ANSWER: Although the alpha lipoic acid in Juvenon is not time-released, we believe it functions to improve the cellular redox status (oxidized versus reduced state of the cell), which in turn helps promote cellular health for many hours even after it has been metabolized and excreted. Time-release may not be as good as immediate release in the sense that it may not result in a large enough concentration of ALA to trigger this event. However, this is speculation and remains to be experimentally determined.

Send your questions to AskBen@juvenon.com.

For more questions and answers, go to juvenon.com/product/qa.htm.

Benjamin V. Treadwell, Ph.D., is a former Harvard Medical School associate professor and member of Juvenon's Scientific Advisory Board.

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.

By Benjamin V. Treadwell, Ph.D.

Remember the day after an all night party? Probably not very well as your mind and body weren’t functioning at anywhere near full capacity. From experience, most of us are aware that we need a certain number of hours of sleep to maintain a sharp mind and sound body. What may not be so obvious is the quality of sleep we require for optimum physical and mental health.

Do Not Disturb

Continuous, undisturbed sleep. It's what we require for consolidation of memory — the transfer of short-term memory (all we experienced in a day) to meaningful, long-term memory. There is also a plethora of information from scientific studies that demonstrates, or at least suggests, an association between disturbed sleep patterns and an increase in numerous diseases, including diabetes, cardiovascular disease, and overall mortality. Certain negative indicators of health, such as blood levels of cortisol and lipids as well as blood pressure, all increase.

New experimental information, from studies on the common fruit fly (see this month's "Research Update"), links aging to interrupted or fragmented sleep as well. Unfortunately, as we age, continuous sleep is gradually replaced by fragmented sleep. Again, this type of sleep is not healthy and may be at least partly responsible for age-related issues, such as increased cardiovascular disease, diabetes and impaired memory. In fact, many experts believe that fragmented sleep can be used as a measure of frailty in humans.

Nap Time Again

The lack of continuous sleep is commonly associated with increased periods of wakefulness and symptoms like the need for frequent naps, even dosing off during the daytime hours. This is necessary because the previous night’s interrupted sleep pattern did not satisfy the body’s requirement for the rejuvenating properties of continuous sleep. But catnaps aren’t as effective as continuous sleep. Consequently our mental and physical health suffers.

Fruit Flies and Us

The fruit fly (Drosophila) studies mentioned earlier, and conducted recently at the University of Pennsylvania, produced exciting data that may help explain some of the factors or mechanisms involved in age-associated fragmented sleep.