Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center;
and Division of Molecular & Computational Biology,
Department of Biological Sciences of the College of Letters, Arts & Sciences:
The University of Southern California
Los Angeles, CA 90089-0191, U.S.A.
FREE RADICALS AND ADAPTIVE HOMEOSTASIS IN EXERCISE
Kelvin J. A. Davies
Leonard Davis School of Gerontology of the Ethel Percy Andrus Gerontology Center; and Division of Molecular & Computational Biology, Department of Biological Sciences of the College of Letters, Arts & Sciences: the University of Southern California, Los Angeles, CA 90089-0191, U.S.A.
Free radicals (particularly oxygen- and nitrogen-centered radicals), and related reactive oxygen and nitrogen species, are generated in cells and tissues during exercise. Mitochondria (actually, ‘leakage’ of electrons from Complex I, ubisemiquinone, and other electron transport chain components), xanthine oxidase, membrane NADPH oxidases, and phagocytes such as neutrophils may all contribute to free radical production in exercise. As originally suggested some 34 years ago (1), evidence published in multiple papers from many laboratories now strongly suggests that free radicals and related oxidants generated during mild to moderate endurance-type exercise actually form part of the mechanism of exercise adaptation that includes extensive biogenesis of muscle mitochondria, increased muscle blood supply, and altered fuel consumption patterns. In particular, oxidant-inducible proteins such the mitochondrial Lon protease and Regulator of Calcineurin 1-4 (RCAN1-4) are rapidly synthesized in endurance exercise, and exert measurable protective effects. The stress-responsive Nrf2, Nrf1, and SIRT1 signal transduction pathways are activated by exercise, as are transcription/translation of many of their downstream target genes. Finally, multiple mitochondrial biogenesis/proliferation related factors, including mitochondrial fission protein 1 (Fis1), mitochondrial fusion protein (Mfn1), peroxisome proliferator-activated receptor coactivator-1α (PGC-1α), and mitochondrial transcription factor A (TFAM) are all up-regulated by endurance exercise. It is quite clear that endurance training causes major shifts in adaptive homeostasis that underlie many of the beneficial effects we associate with exercise. A number of studies are now even reporting that oxidant-inducible adaptations to endurance exercise are at least partially protective against heart attacks, strokes, cancers, and neurodegeneration.
Kelvin J. A. Davies, Alexandre T. Quintanilha, George A. Brooks, and Lester Packer (1982) Free radicals and tissue damage produced by exercise. Biochem. Biophys. Res. Commun. 107, 1198 1205.
Abbreviated CV
Kelvin J. A. Davies, PhD, DSc, FRSC, is the James E. Birren Chair and Dean of Faculty at the University of Southern California’s, School of Gerontology. He is also Professor of Molecular and Computational Biology in USC’s College of Letters, Arts, and Sciences.
Davies was born and raised in London, England and is a dual citizen of Great Britain and the U.S.A. Educated at London and Liverpool Universities, the University of Wisconsin, Harvard University, and the University of California at Berkeley, he was previously a faculty member at Harvard University and Harvard Medical School. Before moving to USC in 1996, Davies was Chairman and John A. Muntz University Professor of the Department of Biochemistry & Molecular Biology at the Albany Medical College, where he was also Distinguished Professor of Molecular Medicine.
Davies is an award-winning member of both the Society for Free Radical Research (SFRR) and the Society for Redox Biology & Medicine (SFRBM), and past-President of both SFRBM and SFRR International. He has won both the Distinguished Service Award and the Lifetime Scientific Achievement Award from SFRBM. He is the winner of several other prizes and awards, including the Harwood S. Belding award of the American Physiological Society, the Sir Arthur Harden Trophy, the Bari Prize in Biochemistry & Molecular Biology, Carnegie-Mellon Mentoring Awards, and the Chester M. Southern Outstanding Career Achievement Award.
Davies has organized of over 20 major scientific meetings and conferences, including an SFRRI conference (1990 in Pasadena, CA), an SFRBM conference (1993 in Charleston, SC), the Oxygen Radicals in Biology Gordon Conference (1996 in Ventura, CA), and the Oxidative Stress & Disease Gordon Conference (2009 in Il Ciocco, Italy. In 1988, as Secretary General of the Oxygen Society, Davies negotiated the formation of SFRR International with then SFRR President Tom Dormandy. He founded the journal Free Radical Biology & Medicine in 1985 and remains its editor-in-Chief, and has served as editor-in-chief or editorial board member for many other journals.
Davies has been Distinguished Visiting Professor at Cambridge University, University of Rennes, University of Padova, and University of Pisa. He has been awarded 10 honorary doctoral degrees and professorships from European, American, and Asian Universities and he has been elected a Fellow of no less than 11 national/international scientific societies: He is a Fellow of the American Association for the Advancement of Science, a Fellow of the Society for Redox Biology & Medicine; a Fellow of the Gerontological Society of America; a Fellow of the Royal Societies of Biology, of Medicine, and of Chemistry; a Fellow of the Royal Institution; and a Fellow of the Academy of Europe (Academia Europaea). In 2012 he was knighted by France as a Chevalier de l’Ordre National du Mérite (Knight of the National Order of Merit) for “services to science, humanity and international cooperation.”
Professor Davies’ research centers on the role of free radicals and oxidative stress in biology for which he coined the term, “The Oxygen Paradox.” In particular he is interested in genes that repair oxidatively damaged proteins, lipids, RNA, and DNA, and his laboratory has made major contributions to our understanding of this subject over the past thirty years. Davies discovered key roles free radicals play in exercise, and in mitochondrial redox-cycling-dependent cardiotoxicity of the chemotherapy drug Adriamycin. He uncovered stress-protection by Proteasome and the Lon protease, discovered several stress-related genes, including RCAN1 which contributes to Alzheimer’s disease, Down’s syndrome, and Huntington’s disease. Davies demonstrated that impaired induction of proteasome and mitochondrial lon protease genes contributes to senescence and severely diminished stress-resistance in aging. He developed the concept of Adaptive Homeostasis and has demonstrated the significance of its decline in both ageing and chronic diseases. At the Leonard Davis School of Gerontology, Professor Davies is focusing his research on the regulation of oxidative stress repair genes during aging. His laboratory is involved in biochemical, molecular biology, and genetic studies of both normal aging processes, and age-related pathologies such as cardiovascular diseases, dementias, cataracts, metabolic disease, sarcopoenia, frailty, and senescence.
