E-Letter responses to:

reports: Samuel E. Schriner, Nancy J. Linford, George M. Martin, Piper Treuting, Charles E. Ogburn, Mary Emond, Pinar E. Coskun, Warren Ladiges, Norman Wolf, Holly Van Remmen, Douglas C. Wallace, and Peter S. Rabinovitch Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria Science 2005; 308: 1909-1911 [Abstract] [Full text] [PDF]

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Published E-Letter responses:

Role of Catalase in Life Span Extension

P. Hemachandra Reddy   (24 May 2005)

Catalase versus Glutathione Peroxidase

Ijaz S. Jamall   (24 May 2005)

Role of Catalase in Life Span Extension 24 May 2005
P. Hemachandra Reddy, Research Oregon Health & Science University Respond to this E-Letter: Re: Role of Catalase in Life Span Extension	The work by Schriner and colleagues is an important advance in understanding the free radical theory of aging and its implications for healthy aging and longevity (1). These investigators created transgenic mice that overexpress human catalase localized to peroxisomes, nucleus, and mitochondria, and studied the effects of aging from birth to death in these transgenic mouse lines. Interestingly, but not surprisingly, they found that mice that overexpress human catalase targeted to mitochondria exhibited increased life-span 5.5 months longer relative to control wild-type mice, suggesting that overexpressed catalase in mitochondria decreases reactive oxygen species (ROS) and boosts the mitochondrial function. These events ultimately lead to an extended life-span. This finding has tremendous implications for healthy aging, longevity, and age-related illnesses, particularly Alzheimer’s, Parkinson’s, and ALS. The free radical theory of aging, one of the prominent aging hypotheses, holds that during aging, an increase in ROS in mitochondria causes mutations in the mitochondrial DNA and damages mitochondrial components, resulting in senescence. Although tests of the free-radical theory of aging have provided conflicting interpretations, findings from recent gene expression studies (2, 3), mitochondrial DNA studies (4), and aging animal model studies (5, 6) support this hypothesis, suggesting that an age-dependent increase in ROS is a key factor in causing age-related problems and diseases (7-9). Schriner and colleagues’ exciting work suggests that early treatment with antioxidants may help reduce free radicals and mitochondrial DNA damage and may increase oxygen consumption in electron transport chain and ultimately their mitochondrial function. The use of antioxidant treatments, alone or in combination with calorie restriction, which has also been found to reduce ROS and to increase the life-span of rodents (10), may help reduce mitochondrial toxicity, increase life-span, and improve health during these increased years of aging. Schriner and colleagues’ research demonstrates increased mitochondrial function in skeletal muscle, heart, spleen, and other tissues in catalase transgenic mice relative to control wild-type littermates. It would be useful to examine changes in the brain in these transgenic mouse lines in terms of ROS and mitochondrial function/dysfunction. Further, a reasonable next step would be to study exact mechanism(s) of how overexpressed catalase can reduce ROS within mitochondria, and catalase interactions with mitochondrial proteins, if any, within mitochondria. Overall, this study is exciting, with implications for longevity, treatments for age-related diseases, and healthy aging. References 1. S. E. Schriner, N. J. Linford, G. M. Martin, P. Treuting, C. E. Ogburn, M. Emond, P.E. Oskun, W. Ladiges, N. Wolf, H. V. Remmen, D. C. Wallace, P. S. Rabinovitch, Sciencexpress Report (2005) 2. T. Lu, Y. Pan, S.Y. Kao, C. Li, I. Kohane, J. Chan, B.A. Yankner, Nature 429, 883 (2004). 3. P. H. Reddy, S. McWeeney, B. S. Park, M. Manczak, R.V. Gutala, D. Partovi, Y. Jung, V. Yau, R. Searles, M. Mori, J. Quinn, Hum, Mol, Genet. 13, 1225 (2004). 4. M. T. Lin, D. K. Simon, C. H. Ahn, L. M. Kim, M. F. Beal, Hum. Mol. Genet. 11, 133 (2002). 5. A. Trifunovic, A. Wredenberg, M. Falkenberg, J. N. Spelbrink, A..T. Rovio, C. E. Bruder, Y. M. Bohlooly, S. Gidlof, A. Oldfors, R. Wibom, J. Tornell, H. T. Jacobs, N. G. Larsson, Nature 429, 417 (2004). 6. M. Manczak, Y. Jung, B.S. Park, D. Partovi, P. H. Reddy, J, Neurochem. 292, 494 (2005). 7. R.,H. Swerdlow, S.,M. Khan, Med, Hypotheses 63, 8 (2004). 8. P. H. Reddy, M. F. Beal, Brain Res. Rev., in press. 9. R. W. Taylor, D. M. Turnbull, Nature Rev. Genet. 6, 389 (2005). 10. M. P. Mattson. Annu. Rev. Nutr. (2004), pub ahead electronic.
Catalase versus Glutathione Peroxidase 24 May 2005
Ijaz S. Jamall, Toxicologist Risk-Based Decisions, Inc. Respond to this E-Letter: Re: Catalase versus Glutathione Peroxidase	The paper by Schriner et al. adds considerable weight to the growing body of scientific evidence on the role of oxygen-derived free radicals in aging, notably in the cardiac mitochondrion. However, it is noteworthy that although the authors attribute the significantly increased life-span to the overexpression of catalase (CAT) in heart mitochondria in transgenic mice (MCAT) as compared with wild-type (WT) mice, they fail to address the role of the selenoenzyme, glutathione peroxidase (GPx), in these same cardiac mitochondria. We and others have previously shown the relative importance of GPx over CAT in the heart and liver of the rat (1-4). GPx has also been shown to be of greater importance than CAT in the house fly, Musca domestica (5). Both CAT and GPx have been shown to detoxify hydrogen peroxide in vivo in numerous models. Importantly, it has previously been shown that that GPx has a greater affinity (i.e., a lower Km in the micromolar range) for hydrogen peroxide as compared to CAT (Km in the millimolar range ) and this provided a plausible explanation for the primacy of GPx over CAT especially in cardiac mitochondria (6). Life- long reductions in manganese superoxide dismutase (MnSOD) activity in mice have been shown to result in increased DNA damage, but this damage was not accompanied by any acceleration in aging (7). The end result of the SOD reaction is still hydrogen peroxide, which can only be detoxified by either CAT or GPx. Without simultaneous measurements of both these enzymes in the MCAT transgenic mice used by the authors, it would seem difficult to attribute the extended life-span observed in the MCAT transgenic mice solely to CAT activity. References 1. I. S. Jamall, J. Sprowls, J.Tox. Appl. Pharmacol. 87, 102 (1987). 2. T. W. Simmons, I. S. Jamall, Cardiovasc. Res. 23, 774 (1989). 3. T. W. Simmons, I. S. Jamall, Biochem. J. 251, 913 (1988). 4. T. Li, P. W. Singal, Circulation 102, 2105 (2000). 5. T. W. Simmons et al., FEBS 218, 251 (1987). 6. F. Antunes et al., Free Radical Biol. Med. 33, 1260 (2002). 7. H. Van Remmen et al., Physiol. Genomics 16, 29 (2003).