title: Rapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice.
abstract: Rapamycin consistently increases longevity in mice although the mechanism of action of this drug is unknown. In the present investigation we studied the effect of rapamycin on mitochondrial oxidative stress at the same dose that is known to increase longevity in mice (14mgofrapamycin/kg of diet). Middle aged mice (16months old) showed significant age-related increases in mitochondrial ROS production at complex I, accumulation of mtDNA fragments inside nuclear DNA, mitochondrial protein lipoxidation, and lipofuscin accumulation compared to young animals (4months old) in the liver. After 7weeks of dietary treatment all those increases were totally or partially (lipofuscin) abolished by rapamycin, middle aged rapamycin-treated animals showing similar levels in those parameters to young animals. The decrease in mitochondrial ROS production was due to qualitative instead of quantitative changes in complex I. The decrease in mitochondrial protein lipoxidation was not due to decreases in the amount of highly oxidizable unsaturated fatty acids. Rapamycin also decreased the amount of RAPTOR (of mTOR complex) and increased the amounts of the PGC1-α and ATG13 proteins. The results are consistent with the possibility that rapamycin increases longevity in mice at least in part by lowering mitochondrial ROS production and increasing autophagy, decreasing the derived final forms of damage accumulated with age which are responsible for increased longevity. The decrease in lipofuscin accumulation induced by rapamycin adds to previous information suggesting that the increase in longevity induced by this drug can be due to a decrease in the rate of aging.
authors: Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University of Madrid (UCM), E-28040, Spain. Electronic address: vmcisuelo@gmail.com.
authors: V
authors: V
authors: Martínez-Cisuelo
authors: Department of Basic Biomedical Science, Faculty of Biomedical Science, Universidad Europea, Madrid E-28670, Spain. Electronic address: jose.gomez@universidadeuropea.es.
authors: J
authors: J
authors: Gómez
authors: Department of Genetics, Faculty of Biological Sciences, Complutense University of Madrid (UCM), E-28040, Spain. Electronic address: soyisa@hotmail.com.
authors: I
authors: I
authors: García-Junceda
authors: Department of Experimental Medicine, Faculty of Medicine, University of Lleida-IRBLLEIDA, Lleida E-25198, Spain. Electronic address: alba.naudi@mex.udl.cat.
authors: A
authors: A
authors: Naudí
authors: Department of Experimental Medicine, Faculty of Medicine, University of Lleida-IRBLLEIDA, Lleida E-25198, Spain. Electronic address: rosanna.cabre@mex.udl.cat.
authors: R
authors: R
authors: Cabré
authors: Department of Experimental Medicine, Faculty of Medicine, University of Lleida-IRBLLEIDA, Lleida E-25198, Spain. Electronic address: natalia.mota@mex.udl.cat.
authors: N
authors: N
authors: Mota-Martorell
authors: Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University of Madrid (UCM), E-28040, Spain. Electronic address: mltorres@bio.ucm.es.
authors: M
authors: M
authors: López-Torres
authors: Department of Genetics, Faculty of Biological Sciences, Complutense University of Madrid (UCM), E-28040, Spain. Electronic address: mgs@bio.ucm.es.
authors: M
authors: M
authors: González-Sánchez
authors: Department of Experimental Medicine, Faculty of Medicine, University of Lleida-IRBLLEIDA, Lleida E-25198, Spain. Electronic address: reinald.pamplona@mex.udl.cat.
authors: R
authors: R
authors: Pamplona
authors: Department of Animal Physiology-II, Faculty of Biological Sciences, Complutense University of Madrid (UCM), E-28040, Spain. Electronic address: gbarja@bio.ucm.es.
authors: G
authors: G
authors: Barja
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D004272:DNA, Mitochondrial / Q000235:genetics; D008062:Lipofuscin / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: C000608442:ATG13 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D004272:DNA, Mitochondrial; D008062:Lipofuscin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D020123:Sirolimus
keywords: Aging; Free radicals; Lipofuscin; Mitochondria; Rapamycin; Tor