Chronic Caloric Restriction Preserves Mitochondrial Function in Senescence Without Increasing Mitochondrial Biogenesis

Caloric restriction (CR) without malnutrition appears to mitigate many detrimental effects of aging, in particular the age-related decline in skeletal muscle mitochondrial function. Although the mechanisms responsible for this protective effect remain unclear, CR is commonly believed to increase mitochondrial biogenesis; a concept that is now demanding closer scrutiny. Here we show that lifelong CR in mice prevents age-related loss of mitochondrial function, measured in isolated mitochondria and permeabilized muscle fibers. We find that these beneficial effects of CR occur without increasing mitochondrial abundance. Furthermore, whole-genome expression profiling and large-scale proteomic surveys revealed expression patterns inconsistent with increased mitochondrial biogenesis. These observations, combined with lower protein synthesis rates support an alternative hypothesis that CR preserves mitochondrial function not by increasing mitochondrial biogenesis, but rather by decreasing mitochondrial oxidant emission, increasing antioxidant scavenging, thereby minimizing oxidative damage to cellular components. Cross-sectional comparison of skeletal muscle from young (8mo), old (24mo) and old caloric restricted mice, obtained from the colony maintained on behalf of the National Institute on Aging.无营养不良状态下的热量限制（Caloric Restriction, CR）似乎可减轻衰老带来的诸多不良影响，尤以骨骼肌线粒体功能的增龄性衰退为著。尽管其发挥保护作用的具体机制尚不明确，但学界普遍认为CR可促进线粒体生物发生，这一观点如今亟待更严谨的审视。本研究证实，小鼠终生实施CR可延缓增龄性线粒体功能丧失，该结论通过对分离线粒体与透化肌纤维的检测得到证实。我们发现，CR的这些有益效应并不依赖于线粒体数量的增加。此外，全基因组表达谱分析与大规模蛋白质组学研究结果显示，其基因表达模式与线粒体生物发生增强的假说并不相符。结合蛋白质合成速率降低这一观测结果，上述发现支持了另一项替代假说：CR并非通过促进线粒体生物发生来维持线粒体功能，而是通过减少线粒体氧化剂释放、增强抗氧化清除能力，从而将细胞组分所受的氧化损伤降至最低。本研究对取自美国国家衰老研究所（National Institute on Aging）所维护的实验种群的年轻小鼠（8月龄）、老年小鼠（24月龄）以及老年热量限制小鼠的骨骼肌进行了横断面比较。