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Low Doses of Insulin-Like Growth Factor-I Induce Mitochondrial Protection in Aging Rats

Department of Medical Physiology (J.E.P., I.C.C.), School of Medicine, University Universidad San Pablo-CEU, 28668 Madrid, Spain; Department of Medical Physiology (J.E.P., M.G.-F., J.R., S.G.-B., I.C.C.), School of Medicine, University of Málaga, 29071 Málaga, Spain; and Department of Internal Medicine (J.M.), Liver Unit, University of Córdoba, 14080 Córdoba, Spain

Address all correspondence and requests for reprints to: Inma Castilla Cortazar, M.D., Department of Medical Physiology, School of Medicine, University CEU-Universidad San Pablo, Boadilla del Monte, 28668, Madrid, Spain. E-mail: iccortazar{at}uma.es.

Serum IGF-I levels decline with age. We have recently reported that in aging rats the exogenous administration of IGF-I restores IGF-I circulating levels and age related-changes, improving glucose and lipid metabolisms, increasing testosterone levels and serum total antioxidant capability, and reducing oxidative damage in the brain and liver associated with a normalization of antioxidant enzyme activities. Understanding that mitochondria are one of the most important cellular targets of IGF-I, the aims of this study were to characterize mitochondrial dysfunction and study the effect of IGF-I therapy on mitochondria, leading to cellular protection in the following experimental groups: young controls, untreated old rats, and aging rats treated with IGF-I. Compared with young controls, untreated aging rats showed an increase of oxidative damage in isolated mitochondria with a mitochondrial dysfunction characterized by: depletion of membrane potential with increased proton leak rates and intramitochondrial free radical production, and a significant reduction of ATPase and complex IV activities. In addition, mitochondrial respiration from untreated aging rats was atractyloside insensitive, suggesting that the adenine nucleotide translocator was uncoupled. The adenine nucleotide translocator has been shown to be one of the most sensitive locations for pore opening. Accordingly, untreated aging rats showed a significant overexpression of the active fragment of caspases 3 and 9. IGF-I therapy corrected these parameters of mitochondrial dysfunction and reduced caspase activation. In conclusion, these results show that the cytoprotective effect of IGF-I is closely related to a mitochondrial protection, leading to reduce free radical production, oxidative damage, and apoptosis, and to increased ATP production.