ATG13
Autophagy-related protein 13 [KIAA0652]
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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.
MeSH Terms
- Adaptor Proteins, Signal Transducing
- Animals
- Apoptosis Regulatory Proteins
- Autophagy
- DNA, Mitochondrial
- Lipofuscin
- Longevity
- Male
- Mice
- Mitochondria, Liver
- Oxidative Stress
- Oxygen Consumption
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Reactive Oxygen Species
- Regulatory-Associated Protein of mTOR
- Sirolimus
Keywords
- Aging
- Free radicals
- Lipofuscin
- Mitochondria
- Rapamycin
- Tor