Juvenon Health Journal volume 9 number 12 december 2010
By Benjamin V. Treadwell, Ph.D.
Remember the stamina and physical strength of our youth? Nothing, it seemed, could slow us down. What’s happened to our bodies, over time, to produce, comparatively, much less strength and endurance? (Not to mention a significant amount of fat instead of muscle?) More importantly, is there anything we can do to slow the rate at which this occurs and, perhaps, even reverse some of the decline?
The answer may be as simple as more exercise. A number of animal and human studies have already shown the positive effects of aerobic exercise on many parameters of health, including pulmonary function (breathing and CO2/O2 exchange), markers of vascular/cardiovascular health (lipid profile, HDL, LDL, triglycerides, total cholesterol) and bone density.
Researchers have observed improvements in strength and endurance, too. But, until recent experiments with mice, the biochemical mechanisms behind these changes had not been explored. The results of this new study are the subject of this issue of the Health Journal, along with their implications for the aging human population.
Life, whether it’s plant or animal, seems to be remarkably resilient. The evolutionist would attribute this to a billion or more years of adjustments to allow for survival and propagation in variable environments.
Research has shown that in times of food scarcity, for example, many organisms probably survived by activating specific biochemical pathways (survival pathways) for more efficient conversion of food to energy. This phenomenon, although first demonstrated in lower forms of life, appears to apply to mammals, primates and even man.
Recent studies have also revealed that caloric/dietary restriction (CR/DR), which essentially mimics those spartan environmental conditions (See Juvenon Health Journals, Volume 9, Number 2, “Dietary Restriction: Getting More From Your Mitochondria” and Volume 8, Number 8, “Anti-aging Solution: Less Food or More Nutrients?”.), actually supports better health, as well as survival. In other words, it appears the body’s machinery has evolved to respond positively to periods of nutritional deprivation.
Interestingly, it seems the body’s musculature also requires periods of “nutrient” deprivation for best performance.
Exercise, Genes and Proteins
For hundreds of years, we’ve observed that physical exercise, aerobic and resistant, improves muscle strength as well as endurance. (Atlas reportedly carried a calf on his shoulders to make him strong.) But little information has been available as to how this occurs…until recently.
Similar to a Calorie Restricted diet, which depletes stored food metabolites, exercise consumes another nutrient from muscle tissue: oxygen. Just as caloric restriction triggers biochemical mechanisms with positive health effects, there also seems to be a biochemical explanation for an exercise-induced increase in muscle mass and endurance.
In experiments with mice, Harvard Medical School researchers demonstrated that the depletion of oxygen coincides with the activation of two regulatory agents within the muscle cells, peroxisome proliferator-activated receptor-gamma co-activator 1 alpha (PGC1 alpha) and sirtuin protein (SIRT1). (Interestingly, these same agents are activated under conditions of caloric restriction.) SIRT1 is believed to be involved in amplifying the activation of PGC1 alpha, a transcriptional factor previously implicated in muscle’s response to exercise.
Through in vitro work, the team showed that PGC1 alpha, in turn, triggers another agent, hypoxia inducible factor 2 alpha (HIF-2 alpha). HIF-2 alpha then activates a number of genes to produce protein products that are directed at resolving the oxygen-deprived state of the exercised muscle.
One of these proteins prompts the construction of new blood vessels to deliver more oxygen and more oxygen-carrying red blood cells to the muscle (greater muscle mass). Since the exercising muscle requires additional energy, another activated gene produces proteins to increase the output of the energy-generating cellular dynamos, the mitochondria (more endurance).
Exercise also increases the production of toxic oxidants. The Harvard group identified one more exercise-activated gene that produces superoxide dismutase (SOD2), a protein that neutralizes the oxidants and prevents tissue damage, maintaining muscle mass. One additional and intriguing finding in exercised muscle was a switch from a less active muscle type, fast twitch, to a slow twitch muscle, promoting muscular endurance.
This description of muscle’s response to exercise is the result of experiments with mice and mouse skeletal tissue. Preliminary results suggest similar mechanisms in humans, but further studies are needed.
Biochemical Pathway Parallels
The research on muscle response to exercise is remarkably reminiscent of the studies on caloric/dietary restriction (CR/DR). In fact, some of the same gene-stimulating factors have been linked with the activation of biochemical pathways in response to the stress of either food or oxygen deprivation. These responses evolved over a billion-year period as humankind was periodically confronted with challenges like low food supplies (CR/DR) and the need to out-run predators (oxygen depleting exercise).
Getting back to the question at the beginning of this issue: Is there anything we can do to slow, maybe even reverse, the age-associated decline in muscle strength and endurance? Now that we are beginning to understand the process, it stands to reason that the answer may be regularly activating the exercise biochemical pathways, developed for our species health/survival.
Substitutes for Exercise?
What if strenuous exercise, with the potential benefits of oxygen deprivation, isn’t possible, as in cases of extreme sarcopenia (loss of muscle mass and strength)? Research, currently in progress, is examining the potential of developing compounds, both natural and synthetic, capable of substituting for exercise (also caloric restriction) at the biochemical level. Of course, companion research, not only to verify that mice and humans have similar, exercise-activated biochemical pathways, but also to fully identify the human sequence, is needed.
In a recent issue of PNAS (Proceedings of the National Academy of Sciences), a group of investigators, from the Dana-Farber Cancer Institute and the Department of Cell biology at Harvard Medical School, reported on their experiments to determine how muscle responds to exercise at the biochemical level.
The team demonstrated in vivo, with mice exercised overnight on a wheel, that a number of genes were activated in the mouse skeletal muscle. PGC1 alpha (peroxisome proliferator-activated receptor-gamma co-activator 1 alpha), previously implicated in muscle’s response to exercise, was one of the earliest transcriptional factors triggered. This factor has been connected to the increase in mitochondrial biogenesis associated with muscle exercise.
Through in vitro work, the Harvard group discovered that PGC1 alpha, in exercised muscle, also forms a complex with another protein, ERR alpha (estrogen-related receptor alpha). This complex, PGC1alpha-ERR alpha, binds to and stimulates specific genes, culminating in the production of HIF2 alpha (hypoxia inducible factor 2 alpha).
HIF2 alpha, in turn, activates numerous other genes, such as those necessary for developing blood vessels (angiogenesis), producing red blood cells (erythpoietin EPO), and increasing the defense system (super oxide dismutase, SOD2) to combat the additional oxidant stress of exercise.
Further experiments yielded, perhaps, the most interesting finding: that the HIF2 alpha transcriptional factor acts as a key regulator of a muscle fiber-type program and the adaptive response to exercise. With strenuous exercise, there is a switch from synthesizing the less active, low endurance type IIb muscle fiber (more common in the elderly) to the more oxidative, high-endurance type IIa.
Because type IIa muscle fiber is believed to be less susceptible to muscle atrophy (sarcopenia), the researchers believe this knowledge, in particular, could lead to new methods to stop or slow-down the sarcopenia associated with some muscle tissue conditions, as well as aging.
Read abstract here.
Dr.Treadwell answers your questions.
question: I keep reading about the benefits of DHEA, yet I seem to recall that some danger exists in this item. I would appreciate your views. Thank you — A
answer: Although DHEA (dehydroepiandrosterone) is readily available as an over-the-counter dietary supplement, in a 2004 review, the American Journal of Sports Medicine concluded, “The marketing of this supplement’s effectiveness far exceeds its science.”
Claims that this hormone, secreted by the adrenal gland, fights the effects of aging are unproven. In fact, after a two-year experiment, researchers from the Mayo Clinic saw no measurable improvement in their male and female subjects, age 60 and older. Studies on the longer-term effects of DHEA are very limited. Theoretically, this naturally occurring steroid may increase the risk of hormone-sensitive cancers.
So, I would not recommend taking DHEA, except to treat specific conditions (Preliminary findings indicate it may help with middle-age-onset mild-to-moderate depression.), and then only under the supervision of a licensed health professional who feels you would benefit.
Benjamin V. Treadwell, Ph.D., is a former Harvard Medical School associate professor.