Cells are continuously exposed to toxic oxidants (Reactive Oxygen Species - ROS). Oxidative stress occurs when ROS levels exceed the cell’s capacity to maintain redox homeostasis – balance between oxidized and reduced states. At this point the cell either re-establishes redox balance or embarks towards cell death. Recent research shows that the transcription factor Nrf2 plays a pivotal role in the extraordinarily complex biochemical processes that determine which path is taken. For technical details on this research, click here. "Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid " PNAS | March 9, 2004 | vol. 101 | no. 10 | 3381-3386 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.

By Benjamin V. Treadwell, Ph.D.

Last month's Juvenon Health Journal reported on the importance of metabolic balance in maintaining health and preventing disease (See Vol.5 No.6 Metabolic Balance For Maximum Health). The article briefly described how one built-in system, the phase II enzyme system, helps maintain cellular metabolic balance. This month we continue this theme with emphasis on age-associated loss of metabolic balance.

The government considers the aging process to be a normal physiological event and not a disease. This opinion may soon change. Recent scientific information indicates the negative events associated with aging can be attenuated, and the aging process may be slowed down. See how you feel about the government's opinion after reading today's article.

Redox Balance

A key factor in maintaining a healthy cell is redox balance. This simply means that our cells must have a certain ratio between the oxidized and reduced forms of specific molecules comprising key redox circuits in our cells and tissues. The ratio of the reduced to the oxidized state of these key molecules, usually given in millivolts, is known as the redox state. So what does that mean? First, I will discuss the three key molecules produced by our cells, and involved in maintaining redox balance.

Glutathione, Cysteine, and Thioredoxin

Each of these three amino acid-containing molecules contains at least one sulfur atom which, because of its unique electronic structure, can donate electrons when in the reduced state (saturated with electrons) or take-up electrons when in the oxidized state. There are specific enzymes unique to each of the three sulfur-containing molecules, which function as catalysts in donating electrons (oxidases) and accepting electrons (reductases). Each of the three molecules, therefore, can be thought of as existing in pairs, reduced and oxidized forms. The healthy cell has a specific ratio of the reduced to the oxidized form (redox pairs). It turns out this ratio can vary somewhat during certain cellular events, such as when the cell divides or is involved in a battle with an infectious agent, a chemical carcinogen (smoking) or chemotherapy. Under normal healthy conditions, the ratio of the reduced to the oxidized is highly in favor of the former, which, as discussed below, gradually changes with age promoting the development of age-associated disease.

Why is the reduced:oxidized ratio so important to our health?

It turns out that each of the three sets of redox pairs appears to sense different conditions in the cell. For example, the glutathione pair responds to certain toxic substances in an effort to reduce or detoxify them, whereas the thioredoxin pair responds to different toxic agents. You might ask why aren't all three redox pairs in the reduced state, since reducing toxic oxidants seems to be the major function of the redox pair. While it is normally true that the healthy cell contains these redox pairs in favor of the reduced state, it also requires a certain amount of oxidized molecules. For example, under certain conditions, such as when a cell becomes cancerous, the relative quantities of oxidized molecules increase. This functions as a signal to activate a pathway that eliminates the diseased cell.

Aging impairs the re-establishment of redox-balance

Toxic attacks, whether from carcinogens in our environment (smoking, pesticides, toxic metals, etc.) or chronic diseases (diabetes, atherosclerosis) and infectious agents (cold virus, bacterial infection), have the effect of pushing the redox balance toward the oxidized state. In our youth, this is normally corrected after the toxic event is neutralized, and the redox state returns to a healthy resting ratio. Finally, I have reached the most interesting part of this story. As we age, especially when we reach our forties, this redox state becomes progressively slanted toward an increase in the oxidized form of the redox pair; re-establishment of the healthy redox balance no longer occurs and in fact worsens with age. Why?

The Phase II Enzyme System and Redox Balance

In our youth the redox state is brought to the proper balance almost immediately after the resolution of a redox-upsetting episode (such as smoking). The credit for this re-establishing event largely goes to the Phase II detoxification system. Let's look at how one redox pair, glutathione reduced/glutathione oxidized, responds when placed under oxidant stress. First, the oxidant acts on the reduced form of the redox pair, and converts it to the oxidized form, thus creating a redox imbalance. The oxidant is neutralized, but now the cell must quickly re-establish redox balance to be ready for the next assault. It must reduce the oxidized glutathione back to its reduced state.

The cell has a built-in oxidant sensor to detect the imbalance. When a redox imbalance occurs, the sensor activates a specific molecule (Nrf2), which in turn travels to the nucleus and transmits a signal to switch on a gene coding for a Phase II enzyme, in this case an enzyme that makes glutathione. This enzyme in turn re-establishes redox balance by producing more of the reduced glutathione.

Recent research indicates that as we age, the cellular levels of Nrf2 decrease. This impedes the replenishment of reduced glutathione. Unfortunately, if the redox state reaches a critical imbalance, it results in the activation of another enzyme, SMase. SMase in turn acts on membrane components to produce a different set of signaling molecules, resulting in molecular signals to place the cell into a death pathway. The cell follows instructions that have been altered by an age-associated event (less available Nrf2). The consequence is an inability to correct a redox imbalance that eventually progresses to disease and death.

Interestingly, the above situation is not hopeless. Recent work indicates that with the proper tweaking of the old cell, using specific therapeutic agents, it may be possible to re-establish the healthy redox state. This research is very recent and numerous agents capable of reversing this age-associated condition may be available in the future. The results should be exciting with respect to aging, and age-associated diseases.