Simon Melov, Ph.D.
Buck Institute for Age Research

Critically Testing the Free Radical Theory of Aging, and Development of a Practical Intervention.

The theory known as the "free radical theory of aging" has achieved prominence as one of the most compelling explanation for many of the degenerative changes of aging. Ongoing researches in the study of free radical biochemistry and in the genetics of aging have been at the forefront of this work. First, transgenic approaches in invertebrate models with candidate genes such as superoxide dismutase (SOD) involved in reactive oxygen species (ROS) detoxification have shown that the endogenous production of ROS due to normal physiological processes is a major limiter of life. Genes involved in ROS detoxification are highly conserved between eukaryotes; hence the physiological processes that limit life span in invertebrates are likely to be similar in higher eukaryotes. Secondly, the studies of transgenic mice deficient in the mitochondrial antioxidant enzyme superoxide dismutase (SOD) have shown the importance of endogenous free radicals in maintaining organismal homeostasis.

We have shown that mice lacking the mitochondrial form of SOD (Sod2) results in a neonatal lethality, due to damage from oxygen free radicals generated in mitochondria in the course of normal metabolism. We then demonstrated that treatment of Sod2 mutant mice with daily injections of synthetic SOD mimics can increase the lifespan dramatically in a dose dependent fashion, and rescue many of the phenotypes present in the untreated Sod2 mutant mice (Melov et al. 2001, J.Neuroscience, In Press).

Further, transgenic studies using Drosophila melanogaster with SOD illustrate that free radical production from either the mitochondria or cytosol within the fly limits lifespan. We have treated Caenorhabditis elegans with the same SOD mimics that rescue mammalian mitochondrial oxidative stress, and can dramatically extend the lifespan of wild-type worms. Together, the data from studies using invertebrates, and those using Sod2 mutant mice, demonstrate that modulation of metabolic ROS can have a profound effect on life span. These observations support the hypothesis that the endogenous production of free radicals from the mitochondria is a major limiter of lifespan. Hence the broad long-term goals of this study are to determine if chronic treatment of mammals with demonstrably efficacious synthetic antioxidants significantly prolongs both mean and maximal lifespan. Importantly, these studies are to be carried out on middle aged to old animals, as this is the most practical model for intervention of age related changes with regard to potential human studies.

The specific aims are:

A.Test the hypothesis that mitochondrial oxidative stress is a major limiter of lifespan in the mouse.

B.Investigate the relationship between genomic and proteomic profiles of aging, and oxidative stress in the mouse.

C.Identify effective catalytic antioxidants that will be useful in retarding age-related changes in mammals.

Contact Dr. Melov.