Can Life Span Be Extended in Mammals?

Abstract & Commentary

By M. Flint Beal, MD, Professor and Chairman of the Department of Neurology at Cornell Medical College, Editor, Neurology Alert. Dr. Beal reports no consultant, stockholder, speaker’s bureau, research, or other relationships related to this field of study.

Synopsis: Overexpression of the antioxidant enzyme catalase, which converts H2O2 to H2O, results in lifespan extension in long-lived mice.

Source: Schriner SE, Linford NJ, Martin GM, et al. Extension of murine lifespan by overexpression of catalase targeted to mitochondria. Science Express. 2005 May 5; [Epub ahead of print: www.sciencemag.org/sciencexpress/recent.shtml]. Accessed June 23, 2005.

The only consistent intervention which appears to extend lifespan in mammals has been caloric restriction. This has been shown in a number of species, and there are ongoing studies in primates. Patients who voluntarily undergo caloric restriction show improvement in some of the biomarkers which improve in calorically restricted mammals. Other interventions, however, have been largely unsuccessful in extending lifespan.

The oxidative stress theory of aging postulates that age-associated reductions in physiological functions are caused by slow steady accumulation of oxidative damage to macromolecules, which increase with age, and which are associated with reduced life expectancy. This hypothesis was subsequently refined, and it was suggested that mitochondria are the major target of free radical attack associated with aging. Reactive oxygen species are generated in large part from single electrons escaping from the electron transport chain. In strong support of the theory, is new evidence that overexpression of the antioxidant enzyme catalase in mitochondria extends lifespan in mice.

Prior studies had shown that oxidative damage and mitochondrial DNA point mutations accumulate with human aging. We found a 3-fold increase, which correlated with reductions in cytochrome oxidase activity. Other studies in which mitochondrial point mutations are engineered to occur in the mitochondrial genome, reduce lifespan in mice by 50%. Although some studies in both fruit flies and in mice have suggested that it may be possible to extend lifespan by overexpression of antioxidant enzymes, these studies have been criticized, since they generally have shown efficacy in short-lived strains.

In the study cited above, Shriner and colleagues show that overexpression of the antioxidant enzyme, catalase, which converts H2O2 to H2O, results in lifespan extension in long-lived mice. Shriner et al produced transgenic mice that overexpressed human catalase localized to the peroxisome, the nucleus, and the mitochondria. Only the mice with catalase targeted to the mitochondria showed a significant increase in lifespan. This was approximately a 20% or a 5-month increase in lifespan in 2 founders. There was a similar increase in both median and maximum lifespan. The mice overexpressing catalase showed reduced cardiac pathology, such as sub-endocardial interstitial fibrosis and arteriosclerosis, which occur with normal aging. In addition, there was a reduction in the severity of cataracts at 17 months. The mitochondrial-targeted catalase decreased the mean level of H2O2 production from heart mitochondria by 25%, and it prevented the inactivation of aconitase, which is a well-described marker of oxidative damage. It also protected against age-related increases in oxidative damage to DNA in skeletal muscles.

Commentary

These findings are of great interest. They are the first to directly show that overexpression of a free radical scavenging enzyme extends both median and maximum lifespan in mammals. It is of interest that these effects occurred only when the antioxidant enzymes were targeted to mitochondria. The results provide strong evidence that both mitochondrial dysfunction and oxidative damage play a critical role in normal aging and may contribute to pathological processes associated with aging including arteriosclerosis, neoplasia, cataracts, and neurodegenerative diseases. As such, development of safe effective antioxidants may be beneficial in preventing some of these age-related pathologies.