By Benjamin V. Treadwell, Ph.D.

Mitochondria serve a number of functions vital to our cellular health, one of which is energy production. Most normal cells use an efficient production pathway referred to as the Krebs cycle. Many types of cancer cells function differently, however, as noted not only in recent studies (See this month's "Research Update."), but also as early as the 1920's.

Warburg Hypothesis
In 1924, biochemist and Nobel Laureate Otto Heinrich Warburg postulated that cancer cells differ from normal healthy cells in how they convert fuel (food, glucose) to energy. As already mentioned, most normal cells follow the Krebs cycle, which requires oxygen to convert glucose to energy and produces 36 ATP molecules per unit of fuel.

Warburg presented evidence that many cancer cells make energy through glycolysis, with a lactic acid byproduct that accounts for the acidic cellular environment common to cancerous tissue. Glycolysis is also a much less efficient energy production pathway, yielding just two ATP molecules per unit of fuel, only one-eighteenth of Krebs cycle production. Therefore, the cancer cell has to consume much more glucose to generate enough energy to thrive.

Although Otto was a brilliant biochemist, most of his peers did not take his hypothesis seriously (except for a few such as Nobelist and co-discoverer of vitamin C, Albert Szent-Gyorgyi). In fact, until recently, the Warburg Hypothesis had generally been forgotten.  

Warburg Revisited
One of the issues with the Warburg hypothesis was why cancer cells would use less efficient glycolysis to produce energy even when sufficient oxygen was present, a condition normally favoring the Krebs cycle. New information points to modification of an important regulator of energy metabolism — the hypoxia-inducible factor (HIF) — that senses how much oxygen is in the cellular environment, determining which energy-producing pathway is used.

The cell doesn't need this regulator under normal oxygen conditions, as HIF is destroyed as fast as it is synthesized via a specific cellular control mechanism. However, when oxygen is used up by the cell faster than the blood vessels can deliver it to the tissues, such as during intense exercise (running a marathon) or wound healing, HIF senses this condition and a mechanism is activated to stop its destruction.

The cellular quantities of HIF can now increase to a level that promotes the activation of a specific set of genes. The activated genes produce cellular substances that function to correct the low-oxygen condition, for example by stimulating the synthesis of blood vessels to deliver oxygen and other nutrients to the tissues demanding them (why exercise increases vascular supply).

High levels of HIF also mean larger quantities of specifically designed transporters that deliver high amounts of glucose in the blood. This is especially beneficial for "glucose-addicted" cancer cells, which need more fuel for less efficient energy production through glycolysis.

(Side note: The cancer cell's addiction to glucose led to the development of a sensitive method to detect and monitor cancer growth. A PET scan, short for fluorodeoxyglucose positron emission tomography, scans the body for tissues containing unusually high glucose levels).   

During the Krebs cycle process of converting food to energy, a certain amount of free radical oxidants are produced and manage to escape from normal mitochondria. Abnormal mitochondria produce even more free radical oxidants.

Antioxidants such as vitamin C and N-acetylcysteine (NAC) have been shown to inhibit cancer growth in cell culture and animal research. Previously, the theory was that the antioxidants neutralize the free radicals, preventing damage to the cell's genetic material, or in other words, protecting the DNA. However, new information not only supports a different mechanism for the role of antioxidants, but also Warburg's earlier hypotheses about cancer cells and energy metabolism.

The researchers present evidence that free radicals play a role in impairing the function of an iron-containing enzyme that normally activates the mechanism to eliminate HIF. In their studies, the high production of free radicals in cancer cells actually inactivated the mechanism. Consequently, HIF levels remained abnormally high. Introduction of the antioxidants vitamin C and NAC normalized the activity of the HIF-destroying enzyme, inhibiting cancer growth in an animal model.

Antioxidant = Anti-cancer?
There is considerable data showing anti-cancer activity in cell culture and animal studies of antioxidant compounds (vitamin C, NAC). The strongest evidence to date, in human health, is from epidemiological studies which indicate that a diet rich in antioxidants (fruits, vegetables, legumes, berries) is associated with a decreased incidence of a number of cancers. However, unequivocal evidence that antioxidants prevent cancer in humans is still lacking.

In a recent study, researchers from Johns Hopkins University and Stanford University Schools of Medicine identified key characteristics in the function of some cancer cells and demonstrated the potential of inhibiting cancer growth with antioxidants. However, the results of their study present a new paradigm for the mechanism of antioxidant protection.

Previous studies from other laboratories attributed the benefits of antioxidants to their capacity to neutralize DNA-damaging cellular oxidants and preserve DNA (genomic) structure and stability. According to the new research, the cancer-inhibitory effect is, instead, a result of antioxidant action on an oxygen-sensing regulator of metabolism, the hypoxia-inducible factor (HIF).

Cancer cells have an unusually high level of HIF, which is instrumental in supplying them with nutrition to grow. The authors of this study present evidence linking this high HIF level with oxidant-induced impairment of a specific enzyme involved in controlling its degradation. In support of this conclusion, their results also show that the antioxidants vitamin C and N-acetylcysteine (NAC) can normalize levels of HIF in cancer cells and inhibit cancer growth.

Read the full article here, including details and methodology.
"HIF-Dependent Antitumorigenic Effect of Antioxidants In Vivo"
Cancer Cell, Vol 12, 230-238, 11 September 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:  I am in my mid forties and practice what I call healthy aging. I have taken Juvenon for a while and I feel great. My question is about drinking alkaline water for reverse aging. As I understand it, the theory is that the waste products of cells create a very acidic environment in our body, resulting in a host of problems and disease processes. Alkaline water balances the acidity. I am not a scientist but would love to hear the opinion of one who is not trying to sell me a machine or other product to make water alkaline. — S.

ANSWER: I wish I could tell you more about this issue. The only possible association between keeping your blood alkaline and good health is that cancer seems to thrive in an acidic environment. But to date, I am unaware of any peer-reviewed, published scientific work demonstrating the health-promoting effects in humans of drinking alkaline fluids (water).

Send your questions to AskBen@juvenon.com.
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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.