Original Contribution AGE-DEPENDENT INCREASES IN OXIDATIVE DAMAGE TO DNA, LIPIDS, AND PROTEINS IN HUMAN SKELETAL MUSCLE PATRIZIA MECOCCI,* GIORGIO FAN ´ O, ² STEFANIA FULLE, ‡ USHA MACGARVEY, ¶ LESLIE SHINOBU, ¶ M. CRISTINA POLIDORI,* ANTONIO CHERUBINI,* JACOPO VECCHIET, § UMBERTO SENIN,* and M. FLINT BEAL ¶ *Istituto di Gerontologia e Geriatria, Universita ´ di Perugia, Perugia, Italy, ² Dipartimento di Scienze Biomediche, Universita ´ G. D’Annunzio, Chieti, Italy, ‡ Dipartimento di Biologia Cellulare e Molecolare, Universita ´ di Perugia, Perugia, Italy, § Istituto di Malattie Infettive, Universita ´ G. D’Annunzio, Chieti, Italy, and ¶ Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA (Received 3 June 1998; Revised 10 July 1998; Accepted 10 July 1998) Abstract—A role for oxidative damage in normal aging is supported by studies in experimental animals, but there is limited evidence in man. We examined markers of oxidative damage to DNA, lipids, and proteins in 66 muscle biopsy specimens from humans aged 25 to 93 years. There were age-dependent increases in 8-hydroxy-2-deoxyguanosine (OH 8 dG), a marker of oxidative damage to DNA, in malondialdehyde (MDA), a marker of lipid peroxidation, and to a lesser extent in protein carbonyl groups, a marker of protein oxidation. The increases in OH 8 dG were significantly correlated with increases in MDA. These results provide evidence for a role of oxidative damage in human aging which may contribute to age-dependent losses of muscle strength and stamina. © 1998 Elsevier Science Inc. Keywords—Aging, Muscle oxidative damage, 8-Hydroxy-2-deoxyguanosine, Malondialdehyde, Protein carbonyls, Free radicals INTRODUCTION An age-dependent attrition of muscle strength and stam- ina for sustained physical effort is a well-established feature of aging in humans and other species [1]. One hypothesis of aging proposes that the physiological changes of aging are a consequence of the accumulation of random oxidative damage to DNA, lipids, and pro- teins. The free radical theory of aging was first proposed by Harman [2], and has, subsequently, been focused on mitochondria as the major site of free radical generation and damage [3–5]. Evidence in support of this contention has accumulated in concert with advances in methodol- ogies for measuring oxidative damage. To date, however, most of the evidence comes from studies in species other than humans [6]. Two tissues that may be particularly prone to oxida- tive damage are muscle and the central nervous system. Both tissues contain postmitotic cells, which are liable to accumulate oxidative damage over time, and both ac- count for a large share of the body’s total oxygen con- sumption at rest. We previously showed an age-depen- dent accumulation of oxidative damage to both nuclear and mitochondrial DNA in human cerebral cortex [7]. The increase was 10-fold greater in mitochondrial DNA as compared with nuclear DNA, consistent with prior work in aging rat liver. [8] Similarly, an age-dependent increase in protein carbonyls was found in brain in hu- man and animal models [9,10]. Other studies in humans showed age-dependent de- creases in state 3 and state 4 respiration in liver mito- chondria [11]. There are age-dependent increases in numbers of cytochrome oxidase deficient myocytes in skeletal and cardiac muscle, and reduced activities of several electron transport chain complexes in skeletal muscle mitochondria [12–15] Age-dependent increases in mitochondrial deletions and rearrangements are also found in human skeletal muscle [14,16]. A correlation between content of mitochondrial DNA deletions and declines in respiratory chain enzyme activities in human skeletal muscle was reported [17]. The accumulation of mitochondrial deletions overall is low but high levels are Address correspondence to: M. Flint Beal, M.D., Neurology Service/ WRN 408, Massachusetts General Hospital, 32 Fruit St., Boston, MA 02114, USA; Tel: 617-726-8463; Fax: 617-724-1480; E-Mail: beal@helix.mgh.harvard.edu. Free Radical Biology & Medicine, Vol. 26, Nos. 3/4, pp. 303–308, 1999 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0891-5849/99/$–see front matter PII S0891-5849(98)00208-1 303