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.) 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, supporting the findings that VGF 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 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.

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