Juvenon Health Journal Vol. 5 No. 6, June 2006
In light of the obesity epidemic, scientists have redoubled their efforts to understand the signaling mechanisms in the brain that regulate appetite and monitor levels of stored food and circulating nutrients. The signaling protein mTOR, acting on the hypothalamus within a signaling complex, has been shown to modulate feeding and body weight. For further information on this research, click here.
“mTOR tells the brain that the body is hungry”
Nature Medicine 12, 615 – 617 (2006).
By Benjamin V. Treadwell, Ph.D.
We have all heard the words, “life is a balancing act.” The phrase usually applies to mixing work, play and other activities to achieve a healthy mental-physical state. It turns out that the health of our body at the biochemical level is also a balancing act that involves numerous metabolic pathways interacting and communicating with each other within the cells of our tissues and organs. As with the adage, “too much work makes Jack a dull boy,” it is also true that too much exposure to certain external factors, such as toxins, carcinogens (impacted by smoking, for example) or even food, can create a metabolic imbalance. This metabolic imbalance, if not corrected, will lead to some form of disease. So what is metabolic imbalance, and how does it occur?
WHAT CAUSES A METABOLIC IMBALANCE?
Let’s take a look at what happens when we eat. When food is metabolized, some of it is converted to the sugar-fuel glucose. Glucose is transported into the blood stream, and is detected by a sensor in the pancreas, which in turn secretes the hormone insulin. Insulin is transported through the blood stream to various tissues of the body including muscle, fat, and liver. The cells in these tissues also have sensors for insulin, which in turn latch onto the circulating insulin. The interaction between insulin and its receptor activates a switch embedded in the cell’s membrane that turns on numerous signaling mechanisms in the cell. The cell then takes up the nutrient glucose, and either converts it to energy, or stores it in the form of fat. This is an example of a metabolic pathway. (See Figure below.)
The above figures provide a vivid answer to the question, “What is metabolic imbalance?” As you can see, metabolic imbalance occurs when too much food is taken in for too long a period of time. Why? The metabolic pathways contained within our cells evolved over a period of millions of years. They developed in response to the external environment, most importantly the availability of nutrients. Because nutrients were sporadically available, our ancient ancestors often gorged themselves when a food source (a beached whale, a field of berries) was present. The pathway described above kicked in to deliver nutrients to the cells to be converted into energy. Any excess was converted to stored fuel (fat) for sustenance until the next food source became available, often several days later.
An imbalance develops when the gorging goes on ad infinitum. Thanks to the agricultural revolution, people have become very efficient at producing foods, especially high energy foods (fat, sugar). Consequently, the typical adult now overeats continuously, resulting in obesity. Obesity was not a factor in the formation of our metabolic pathways, and it has a disrupting effect on metabolism. For example, it is now known that fat cells, although necessary for storing energy to get us through those nutrient-deficient times, become toxic when bloated with fat. The toxins impair the metabolic pathway that removes glucose from the blood. This is known as insulin resistance, or the pre-diabetic state, and virtually always leads to full-blown diabetes. This is an example of metabolic imbalance that could be largely avoided by adopting healthier eating habits!
Another balancing act
Another metabolic balancing act is called the Phase II Enzyme System. This pathway evolved to protect us from toxins, both environmental (such as smoke) and those produced during normal metabolism (free radicals). This system helps to remove toxins from our tissues. It also promotes the production of potent antioxidants, such as glutathione, to prevent cellular damage from free radicals and other oxidants. It appears to be more effective in protecting our tissues than individual antioxidants such as vitamins C and E.
Evidence is accumulating to indicate that the metabolic activation of this system of enzymes is impaired in aged animals, making them much more susceptible to the damaging effects of toxins and oxidants. (Just remember how fast we recovered from abuse to our body in our youth.) Recent research has demonstrated an intricate network of signaling pathways that are switched on in tissues confronted with environmental stress, such as a free radical. These pathways (survival pathways) communicate with other pathways (death pathways) to determine whether the cell under stress is worthy of saving. In other words, is it best to rid the damaged cell from the tissue for the benefit of the remaining healthy cells? Or is the damage limited, making it possible to repair and save the cell? An imbalance in this metabolic system can cause pathology, cancer, or produce a lethargic organ (heart) due to a lack of sufficient cells.
Intense stress, as well as the aging process, can disrupt metabolic balance. Older animals have a less responsive phase II enzyme system and consequently are more susceptible to the damaging effects of toxins. However, a super dose of stress to the cells of our body, even a young body, can overwhelm even a robust phase II system, and throw it into a metabolic imbalance. One example is an overdose of the common analgesic acetaminophen (Tylenol®). The effect is to suddenly deplete the liver of the phase II-produced antioxidant glutathione, which creates a metabolic imbalance that favors the death pathway. If this is not corrected by treating the patient with a potent antioxidant, such as N-acetylcysteine (NAC), the patient will surely die, or at best require a liver transplant. The timely administration of the proper compound, such as NAC, therefore, can function as phase II metabolic balancer.
Why is there an age-associated metabolic imbalance?
One credible theory is that errors accumulate in the cellular membranes where many of the metabolic signaling events occur. A cellular membrane clogged with oxidized proteins and lipids produces age-associated structures known as lipofuscin. Lipofuscin in turn may interfere with the mobility of the machinery involved in the numerous membrane-associated signaling events required for regulation of the phase II enzyme system. Therefore, agents that protect membranes from toxic insults and accumulation of lipofuscin may help attenuate, or reduce the effects of, age-associated metabolic imbalance in phase II regulation. Protection of this structure, the membrane, may prove to be a primary factor in promoting health and longevity. Damage to other cellular components may be secondary to the interruption of membrane structure.
Can you tell me under what conditions lipoic acid can act as a pro-oxidant? Is it due to its involvement in glucose metabolism?— G.K
G.K., via email
Benjamin V. Treadwell, Ph.D. is a member of Juvenon’s Scientific Advisory Board and formerly an associate professor at Harvard Medical School.
Send your questions to [email protected].
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It is not certain whether lipoic acid can become a pro-oxidant under physiological conditions. But remember, an antioxidant, once it has done its job of neutralizing an oxidant, itself becomes oxidized and therefore is essentially a pro-oxidant. However, under normal conditions antioxidants such as lipoic acid and vitamins C and E have enzymatic pathways that quickly convert them back into antioxidant condition.