Zhao Lin, Zou Xuan, Feng Zhihui, Luo Cheng, Liu Jing, Li Hao, Chang Liao, Wang Hui, Li Yuan, Long Jiangang, Gao Feng, Liu Jiankang
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Center for Mitochondrial Biology and Medicine, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China; Center for Translational Medicine, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China.
Exp Gerontol. 2014 Aug;56:3-12. doi: 10.1016/j.exger.2014.02.001. Epub 2014 Feb 8.
Adipogenesis and lipid accumulation during aging have a great impact on the aging process and the pathogenesis of chronic, age-related diseases. However, little is known about the age-related molecular changes in lipid accumulation and the mechanisms underlying them. Here, using 5-month- and 25-month-old rats (young and old, respectively), we found that epididymal fat is the only tissue to accumulate during aging. By testing tissues rich with mitochondria in old and young animals, we found that the old animals had elevated levels of triglycerides in their muscle, heart and liver tissues but not in their kidneys, while, the mRNA level of fatty acid synthase remained unchanged among the four tissues. Regarding lipid catabolism, we determined that the activities of mitochondrial ETC. complexes changed in aged rats (muscle: decreased complex I and V activities; heart: decreased complex I activity; liver: increased complex I and III activities; kidney: decreased complex I and increased complex II activities), while changes in mitochondrial content were not observed in the muscle, heart nor in the liver tissue except increased complex IV and V subunits in aged kidneys. Furthermore, decreased mitochondrial fusion marker Mfn2 and decreased PGC-1α level were observed in the aged muscle, heart and liver but remained unchanged in the kidneys. Down-regulation of Mfn2 with siRNA in 293T cells induced significant mitochondrial dysfunction including decreased oxygen consumption, decreased ATP production, and increased ROS production, followed by increased triglyceride content suggesting a contributing role of decreased mitochondrial fusion to lipid deposit. Meanwhile, judging from autophagy marker p62/SQSTM1 and LC3-II, autophagy was suppressed in the aged muscle, heart and liver but remained unchanged in the kidneys. Taken together, these data suggest that reduction in PGC-1α expression and disruption of mitochondrial dynamics and autophagy might contribute to lipid accumulation during aging.
衰老过程中的脂肪生成和脂质积累对衰老进程以及慢性、与年龄相关疾病的发病机制有重大影响。然而，关于脂质积累中与年龄相关的分子变化及其潜在机制却知之甚少。在此，我们使用5月龄和25月龄大鼠（分别为年轻和年老大鼠），发现附睾脂肪是衰老过程中唯一会积累的组织。通过检测年轻和年老动物富含线粒体的组织，我们发现年老动物的肌肉、心脏和肝脏组织中甘油三酯水平升高，而肾脏中则没有，同时，脂肪酸合酶的mRNA水平在这四个组织中保持不变。关于脂质分解代谢，我们确定老年大鼠线粒体电子传递链（ETC）复合物的活性发生了变化（肌肉：复合物I和V活性降低；心脏：复合物I活性降低；肝脏：复合物I和III活性增加；肾脏：复合物I活性降低，复合物II活性增加），而除了老年肾脏中复合物IV和V亚基增加外，在肌肉、心脏和肝脏组织中未观察到线粒体含量的变化。此外，在老年肌肉、心脏和肝脏中观察到线粒体融合标记物Mfn2减少和PGC-1α水平降低，而在肾脏中保持不变。在293T细胞中用siRNA下调Mfn2会诱导明显的线粒体功能障碍，包括氧气消耗减少、ATP生成减少和活性氧生成增加，随后甘油三酯含量增加，这表明线粒体融合减少对脂质沉积有促进作用。同时，从自噬标记物p62/SQSTM1和LC3-II判断，老年肌肉、心脏和肝脏中的自噬受到抑制，而在肾脏中保持不变。综上所述，这些数据表明PGC-1α表达降低以及线粒体动力学和自噬的破坏可能导致衰老过程中的脂质积累。
