Institute for Chemical and Bioengineering, ETH Zurich, Switzerland.
Department of Biochemistry, Centre for Life Sciences and Yale-NUS College, Science Division, National University of Singapore, Singapore.
J Gerontol A Biol Sci Med Sci. 2014 Jul;69(7):810-20. doi: 10.1093/gerona/glt210. Epub 2014 Jan 7.
Aging has been associated with the accumulation of damages in molecules and organelles in cells, particularly mitochondria. The rate of damage accumulation is closely tied to the turnover of the affected cellular components. Perturbing mitochondrial turnover has been shown to significantly affect the rate of deterioration of mitochondrial function with age and to alter lifespan of model organisms. In this study, we investigated the effects of upregulating autophagy using lithium in Caenorhabditis elegans. We found that lithium treatment increased both the lifespan and healthspan of C. elegans without any significant change in the mortality rate and oxidative damages to proteins. The increase in healthspan was accompanied by improved mitochondrial energetic function. In contrast, mitochondrial DNA copy number decreased faster with age under lithium. To better understand the interactions among mitochondrial turnover, damage, and function, we created a mathematical model that described the dynamics of functional and dysfunctional mitochondria population. The combined analysis of model and experimental observations showed how preferential (selective) autophagy of dysfunctional mitochondria could lead to better mitochondrial functionality with age, despite a lower population size. However, the results of model analysis suggest that the benefit of increasing autophagy for mitochondrial function is expected to diminish at higher levels of upregulation due to a shrinking mitochondrial population.
衰老是与细胞内分子和细胞器损伤的积累有关，尤其是线粒体。损伤积累的速度与受影响细胞成分的周转率密切相关。干扰线粒体的周转率已被证明会显著影响线粒体功能随年龄恶化的速度，并改变模式生物的寿命。在这项研究中，我们使用锂在秀丽隐杆线虫中研究了上调自噬的效果。我们发现，锂处理既延长了秀丽隐杆线虫的寿命又延长了健康寿命，而死亡率和蛋白质的氧化损伤没有任何显著变化。健康寿命的延长伴随着线粒体能量功能的改善。相比之下，在锂的作用下，线粒体 DNA 拷贝数随年龄的增长下降得更快。为了更好地理解线粒体周转率、损伤和功能之间的相互作用，我们创建了一个数学模型，描述了功能失调和功能正常的线粒体群体的动态。模型和实验观察的综合分析表明，尽管功能失调的线粒体数量较少，但选择性自噬功能失调的线粒体可以随着年龄的增长导致更好的线粒体功能。然而，模型分析的结果表明，由于线粒体数量的减少，增加自噬对线粒体功能的益处预计会随着调控水平的提高而降低。
