By Benjamin V. Treadwell, Ph.D.

What immediately comes to mind when someone mentions exercise? Guilt? Rationalizing? (I’m still pretty healthy even though I don’t exercise. A lot of my friends don’t exercise and they seem healthy.) Of course, not everyone should run miles at a time or lift massive weights. But there is compelling evidence to support the significant health benefits, both physical and mental, from a daily regimen of exercise appropriate for you.

One form of exercise, endurance training, was the subject of a recent study at the Howard Hughes Medical Institute (HHMI) laboratory, located at Yale University School of medicine. For decades, scientists have known that physical activity like running and swimming, which increases heart rate and breathing, results in significant physiological changes or adaptations to improve muscle function. For the first time with living human subjects, this current research was able to demonstrate another beneficial effect of this type of exercise. 

Function Plus Production
With endurance training, changes in muscle tissue might include increased production of new blood vessels, greater capacity of cells to store energy and increased sensitivity to insulin so glucose, as fuel, can enter the cell more readily. All of these changes are directed toward improving the delivery of nutrients and fuel to satisfy the increased energy demands of the exercising muscle.

Beyond better fuel delivery, earlier animal and in vitro (cell culture) studies revealed an increased capacity of the cells that comprise the working muscles to burn fuel, especially fat, converting the fuel to energy. Moreover, the endurance-conditioned cells continued to burn fuel, including fat, even when at rest. But why?

Chain Reaction
Exercise initiates a series of complex biochemical events in the muscle cells. One of these, the production of a substance known as AMPK, activates a cellular tool called PGC-1 alpha. This tool, in turn, enters the control center of the cell, the nucleus, where it homes in on the on/off switches of specific genes to turn them on. The activated genes produce proteins required to construct new fuel-burning organelles, the mitochondria.

This explains why muscle cells isolated from an endurance-trained animal, in earlier research, had a greater capacity to produce energy than cells isolated from a sedentary counterpart. Simply put, more exercise produced more mitochondria/cell “furnaces” for more energy to make the exercise easier.

Animals to Humans
The early studies laid the groundwork for the team at the HHMI lab at Yale. They wanted to determine whether the same or similar changes occurred with humans, in particular, the effect endurance exercise has on the mitochondria in our skeletal muscle. Faced with difficulties in applying the same techniques used with animals and cultured cells, the investigators realized a newly developed, non-invasive tool could yield similar information if applied to humans.

MRS Technology
The technique involved using a magnetic resonance spectrometer (MRS). This technology can accurately measure the amount of a nutrient containing a tag (13C-acetate) that is metabolized in the energy-producing cycle (the Krebs cycle or TCA cycle).

Two groups of human subjects were chosen for the study. Seven healthy males of normal weight who exercised in running-based sports a minimum of four hours a week were in one group. The second group included eight males of similar age, weight and overall health, but who did not participate in endurance training.

Both groups were injected with the 13C-acetate nutrient. After a fixed period of time and under non-working (resting) conditions, the muscle of the right calf was scanned with the MRS instrument. Because the 13C-acetate is essentially converted to substances that are burned as fuel, the scans provided the investigators with information on the rate at which the tag was being metabolized (oxidized into other compounds during the production of energy) in the cell’s mitochondria.

More Fuel Burned Without More Work
The results showed 54% more fuel burned in the TCA cycle in the endurance-trained group as compared to the sedentary controls. Interestingly, this burned fuel did not represent an increase in the production of ATP, the cellular chemical utilized by the muscle to do work (contract muscle). The amount of measured ATP in both groups was virtually identical.

On the one hand, this is not too surprising as the measurements were taken at rest, when little muscle contraction is occurring and, therefore, little of the energy molecule, ATP, is necessary. But on the other hand, the normal coupled reaction between fuel-burning and ATP production seems to have been disrupted in the endurance-trained subjects. In other words, the muscle of the endurance-trained group was still burning more calories (released as heat and not converted to ATP), even while at rest.

Getting The Fat Out
Modern man/woman is exposed to excessive amounts of energy-rich foods. As a consequence, we are more likely to develop diabetes, heart disease and other age-related conditions. Previous animal and cell-culture studies have shown that exercise improves insulin sensitivity, guarding against insulin resistance, the precursor to diabetes.

The recent HHMI research gives us even more insight into the potential long-lasting effects and benefits of exercise, specifically in relation to the fat-laden cells, including muscle cells, that have been associated with many health concerns. Endurance exercise, as demonstrated by the Yale team, activates cellular tools. They, in turn, increase the production of the cellular fuel-burning machinery (mitochondria) necessary to remove excess fat from cells…even while we sleep.

A group of investigators, from the Howard Hughes Medical Institute (HHMI) laboratory at the Yale University School of Medicine, recently examined the effects of endurance exercise on the rate of conversion of food to energy in the skeletal muscle of humans. The team published “Increased substrate oxidation and mitochondrial uncoupling in skeletal muscle of endurance-trained individuals,” reporting their findings in Proceedings of the National Academy of Sciences (PNAS).

The study involved seven individuals, in good health, who exercised (running sports) at least four hours a week. They were compared to a group of eight subjects, similar with respect to physical health except that they did not participate in endurance sports. Using a magnetic resonance spectrometer (MRS), the rate of disappearance of a specific tag (13C isotope) from the calf muscle was measured in both groups. This rate corresponds to activity of the fuel-burning organelles, the mitochondria, in other words, the conversion of food to energy.

The results clearly demonstrated a much higher (54%) level of fuel-burning activity in the mitochondria of the endurance group. Interestingly, there was not a corresponding increase in ATP production compared to controls, implying a higher level of activity even with little or no muscle contraction.

The researchers speculated that, by removing excess fuel, such as fat, endurance training improves the health of skeletal muscle cells. They also theorized that this type of exercise, and the associated increase in fatty acid oxidation, may enhance muscle insulin sensitivity.


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: Why are some pills supposed to be taken with meals? I've got this idea that I should take C and B-complex in time-release form in the morning since C and some B have half-lives on the order of a few hours and were probably taken in by means of small meals throughout the day when we were hunter-gatherers. My subjective feeling, upon doing this, first with C only, is that it makes me feel more energetic. I've added B-complex time-release and noted no change. What do you think? Also, can you give me the scientific reasons for taking Juvenon on an empty stomach?  – B

answer: In response to your first question, a number of supplements, such as vitamin D, E, K and the vitamin-like cofactor, Coenzyme Q10, as well as certain prescription drugs, are soluble in fat. It activates the digestive system to secrete specific substances (emulsifiers) that improve fat absorption.

As to your idea about taking time-release C and B-complex, I think your comparison to our hunter-gatherer days is reasonable. However, in bad (low nutrient) conditions we often did go for periods of time without food. I also find it interesting that you feel the time-release C improves your energy. Thank you for that information as it is helpful to us and our research.

Finally, the reason for taking Juvenon on an empty stomach is the water-soluble nutrients in the supplement, which are absorbed best without food. Otherwise, some of the nutrient can be lost by adsorbing onto one or more of the food constituents and being excreted before being taken-up by the blood stream.*

*Editor’s note: Thanks to readers who brought to our attention an apparent contradiction between Dr. Treadwell’s response about taking Juvenon on an empty stomach and the “with food” instructions appearing elsewhere. Scientifically speaking, food interferes with maximum absorption of the water-soluble nutrients in Juvenon. However, some of our first customers reported an upset stomach when they took the supplement without food. So, the “with food” recommendation is intended to prevent discomfort. An effective amount of the nutrients will still be absorbed.

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.