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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). 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.
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