The authors of a recent study, discussed nearby, seemingly contradict one of the most accepted theories of aging, the Free Radical Theory of Aging, which states that damage from free radicals is the primary cause of aging. The challenge to this theory is implied in the authors’ observation that the mutant cells in their study have no detectable increase in free radical production or in damage from free radicals. While this statement may be true for the mutant strain of mice used in this study, it most emphatically cannot be extrapolated to animals with a normal proof-reading enzyme. To access the article, click here. "Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging." Science. 2005 Jul 15;309(5733):481-4. 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.

What determines how we age and how long we live? Scientists have long pointed to the mitochondria, those microscopic cellular structures known to be indispensable for life and, on the scary side, death. They are involved not just in the production of energy from food to keep our body and mind active and healthy; they also can decide when a cell should be eliminated.

Apoptosis: Programmed Cell Death

Cell death is not always a bad thing. In fact, it is critical for normal development of the fetus, since temporary cell-produced structures must be removed to produce the mature healthy newborn. The process is similar to constructing a new building, which initially requires temporary scaffolds that later are removed to reveal the final structure.

This type of cellular death follows a programmed series of events commonly referred to as apoptosis, or programmed cell death. The events that trigger apoptosis are diverse, and under intense investigation. Apoptosis is also important in eliminating potentially dangerous cells, such as cancer cells, from the body. So, it is clearly an important program both in early development and later to protect us from the potential ill-effects of abnormal cells.

A recently published article, described below, presents some fascinating experimental data suggesting that an accumulation of mutations in the mitochondrial DNA can trigger apoptosis. In fact, it presents evidence to suggest that this may be the key event that results in the appearance of all those unpleasant events that occur during the aging process: wrinkled skin, hearing loss, muscle loss, graying hair, hair loss, and curvature of spine. All of these characteristics of aging can be prematurely produced in an animal model as a consequence of an increased rate of DNA mutations.

How do mitochondrial mutations cause us to age?

To test their hypothesis that mitochondrial DNA mutations play a causal role in aging, the investigators chose a strain of mice containing a defective gene. This gene codes for an enzyme that normally functions to protect the animal by proof-reading and editing the DNA. When it comes across an error (mutation) in the genetic code, it removes it. Without this enzyme in full operational condition, mutations in the DNA accumulate in the mitochondria.

Interestingly, the animals with the defective enzyme appear normal (similar to control animals containing the normal proof-reading enzyme) up to the age of 3 months, even though their numbers of mitochondrial DNA mutations are about 6 times those of their normal counterparts. At 9 months of age, however, the animals begin to show dramatic changes, including a decrease in muscle mass, and all those age-associated characteristics mentioned above that commonly occur in humans. In other words, the animals were aging prematurely; they were old before their time.

The mechanism involved in DNA mutation-induced cell aging appears to be a consequence of an increased rate of apoptosis. It appears that once a certain level of DNA mutations is achieved, enzymes within the cell, activated by the numerous mutations, begin to dismantle it piece by piece until it is eliminated from the body. The effect is most dramatic in those tissue types containing cells that constantly divide throughout our lifetimes. These include cells of the skin, tendon, liver and intestine. This can help explain why wrinkled skin, digestive system disorders, and inflexible joints are early signs of aging.

Why does cell-death make us look and feel old?

A high rate of cell destruction can exceed the required pace of cell division to replace old worn-out cells (mutated cells) to maintain healthy tissue. As a consequence of this replacement deficiency, we gradually age. We simply don’t have enough of the machines (cells) to keep our tissues (skin, tendons etc.) healthy and vibrant. Incidentally, it is not always a bad thing for a cell to self-destruct if it contains an abundance of mutations, since cells containing mutations can, in turn, malfunction and increase production of toxic substances, such as free radicals. Even more serious, a mutation can lead to cancer. Therefore, to slow the aging process, it would be necessary to prevent DNA mutations, especially to the mitochondria, and thus avoid this "Catch-22" predicament.

The important contribution this work makes to the field of aging is the experimental data showing that mutations in the mitochondrial DNA may be a critical factor in determining how fast we age. How these mutations are produced in cells with normal proof-reading enzymes, and how they escape from being removed by this enzyme, are important questions the field of aging must address. While it may be true that free radicals do not seem to be involved in aging in this mutant line of mice, it clearly does not preclude their involvement in animals with normal enzymes. In fact, free radicals, which are known to be produced in significant quantities in mitochondria under normal conditions, may attack the proof-reading enzyme to convert it to an inactive form similar to what is found in this mutant strain of mice. Once the proof-reading enzyme is inactivated, death-producing mutations will accrue even in the absence of subsequent free radical attacks.

The bottom line is we must do all we can to keep our mitochondria healthy and free from damage to cellular components, especially our mitochondrial DNA. The techniques available to do this are familiar to readers of this column: exercise, eat right, control stress, and ensure adequate intake of vitamins and dietary supplements.