Already, animal models have been developed in which nuclear genes coding for antioxidant enzymes active in mitochondria have been inactivated. In one instance, mice lacking superoxide dismutase have been developed. The animals show increased oxidant levels and a vulnerability to illnesses similar to human neurodegenerative diseases. In fact, this animal model was developed in order to study the relationship between oxidants and neurodegenerative diseases. The animals are likely to serve as living laboratories for the testing of new antioxidant and gene therapies that reverse or neutralize oxidant damage.

Deliberate, targeted mutations have been introduced into mitochondrial DNA for the purpose of observing the consequences. And nuclear DNA genes that govern energy production in mitochondria have been genetically inactivated. Furthermore, nuclear genes other than superoxide dismutase, which code for proteins involved antioxidant activity, have been inactivated. Already, some of these studies have yielded exciting results, since the mice so treated developed heart defects that mimic human conditions. In a manner similar to the models being developed for mitochondrial-associated neurodegenerative disorders, these animals will provide a research model for investigating the causes and potential remedies for certain diseases of aging, such as cardiomyopathy.

If under-production of proteins and factors that detoxify oxygen free radicals can have negative consequences, then it seems reasonable that over-production of those same elements might, in some situations, prove therapeutic. Evidence for this hypothesis has been developed by researchers at the University of Guelph, Ontario, Canada in work with insects. They have over-expressed a form of superoxide dismutase in nerve cells of the fruit fly, Drosophila melanogaster. The normal lifespan of the flies went up 40%. Moreover, a strain of flies from which SOD had been deleted, and which died early as a result, could be rescued by introducing SOD into their nuclear DNA.

If these results can be reproduced in higher animals, the day may come when "boosting" antioxidant enzyme levels by gene splicing will provide a means of neutralizing the increased oxidative stress that accompanies aging. Researchers are also likely to build on early success of a non-DNA approach to increasing antioxidants, in which such compounds are specifically targeted to mitochondria.

With regard to the effects of diet on mitochondrial dysfunction and aging, a study of rhesus monkeys on a restricted diet is ongoing. Results from this important study are only now starting to appear. An intriguing observation is that mitochondrial DNA from animals fed such a diet develop fewer problems, particularly deletions, while they age, compared to their more richly fed cousins. Scientists at the University of Wisconsin are planning to observe the animals on a reduced calorie diet over an 8-year span. They plan to take tissue samples periodically from these and control animals and use DNA amplification techniques to measure the rate of deletions in the animals as they age. Early data from the study have confirmed that caloric restriction lowers oxidative damage in skeletal muscle.

The study of mitochondrial dysfunction and its relationship to aging is still a relatively young area of investigation in biology. Mitochondria, walled off by their double membrane, present obstacles to genetic and other forms of manipulation. These problems are already being addressed, and it is likely that the DNA and internal machinery of mitochondria will one day be manipulated with ease. Mitochondrial decay is not likely to be stopped anytime soon, but scientists appear confident that the process can be slowed, and along with it, the process of aging and the development of a number of age-related diseases.