Drake Joshua C, Bruns Danielle R, Peelor Frederick F, Biela Laurie M, Miller Richard A, Miller Benjamin F, Hamilton Karyn L
Health and Exercise Science Department, Colorado State University, 220 Moby B Complex, Fort Collins, CO, 80523-1582, USA.
Aging Cell. 2015 Jun;14(3):474-82. doi: 10.1111/acel.12329. Epub 2015 Feb 26.
Maintaining proteostasis is thought to be a key factor in slowed aging. In several growth-restricted models of long-life, we have shown evidence of increased proteostatic mechanisms, suggesting that proteostasis may be a shared characteristic of slowed aging. The Snell dwarf mouse is generated through the mutation of the Pit-1 locus causing reductions in multiple hormonal growth factors and mTORC1 signaling. Snell dwarfs are one of the longest lived rodent models of slowed aging. We hypothesized that proteostatic mechanisms would be increased in Snell compared to control (Con) as in other models of slowed aging. Using D2O, we simultaneously assessed protein synthesis in multiple subcellular fractions along with DNA synthesis in skeletal muscle, heart, and liver over 2 weeks in both sexes. We also assessed mTORC1-substrate phosphorylation. Skeletal muscle protein synthesis was decreased in all protein fractions of Snell compared to Con, varied by fraction in heart, and was not different between groups in liver. DNA synthesis was lower in Snell skeletal muscle and heart but not in liver when compared to Con. The new protein to new DNA synthesis ratio was increased threefold in Snell skeletal muscle and heart compared to Con. Snell mTORC1-substrate phosphorylation was decreased only in heart and liver. No effect of sex was seen in this study. Together with our previous investigations in long-lived models, we provide evidence further supporting proteostasis as a shared characteristic of slowed aging and show that increased proteostatic mechanisms may not necessarily require a decrease in mTORC1.
维持蛋白质稳态被认为是延缓衰老的关键因素。在几种寿命延长的生长受限模型中，我们已经证明了蛋白质稳态机制增强的证据，这表明蛋白质稳态可能是延缓衰老的一个共同特征。斯内尔侏儒小鼠是通过Pit-1位点突变产生的，导致多种激素生长因子和mTORC1信号传导减少。斯内尔侏儒小鼠是寿命最长的延缓衰老的啮齿动物模型之一。我们假设，与其他延缓衰老模型一样，斯内尔侏儒小鼠的蛋白质稳态机制会比对照组（Con）增强。我们使用重水，在两周内同时评估了雄性和雌性小鼠多个亚细胞组分中的蛋白质合成以及骨骼肌、心脏和肝脏中的DNA合成。我们还评估了mTORC1底物磷酸化情况。与Con组相比，斯内尔侏儒小鼠所有蛋白质组分中的骨骼肌蛋白质合成均减少，心脏中各组分有所不同，而肝脏中两组之间没有差异。与Con组相比，斯内尔侏儒小鼠骨骼肌和心脏中的DNA合成较低，但肝脏中没有差异。与Con组相比，斯内尔侏儒小鼠骨骼肌和心脏中新蛋白质与新DNA合成的比率增加了两倍。斯内尔侏儒小鼠的mTORC1底物磷酸化仅在心脏和肝脏中降低。本研究未观察到性别影响。结合我们之前对长寿模型的研究，我们提供了进一步支持蛋白质稳态是延缓衰老共同特征的证据，并表明增强的蛋白质稳态机制不一定需要mTORC1的减少。
