Mitoflash可以在线虫早期预测其寿命
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摘要
衰老是生物体的系统功能逐渐下降的过程,这个过程是从繁殖后代开始的。遗传、环境和随机因素都会影响生物体的衰老过程,并能够在一定程度上决定生物体的寿命。线粒体对于生物能学、自由基代谢和细胞死亡是非常重要的。毫不惊奇地是,线粒体在很多著名的衰老理论如生存速率理论、自由基理论和线粒体衰老理论等中占据着中心的位置。为了更好的理解线虫在衰老过程中的生理机能变化,希望找到一个能够在线虫青年期指示衰老速度的生物标志物,我们借助cpYFP荧光蛋白和使用荧光体内成像技术直接监测单个线粒体内自发的、爆发性的超氧阴离子自由基产生,即线粒体“超氧炫”(mitoflash)。研究表明“超氧炫”的活性与能量代谢、自由基产生、电子传递、基础活性氧水平等密切相关。
我们发现线粒体中的“超氧炫”频率可以预测线虫的寿命。我们从线虫成年第1天开始对线虫的“超氧炫”进行每天检测,发现线虫体内的“超氧炫”活性对代谢状态和氧化损伤高度敏感,并发现野生型线虫咽部肌肉细胞的“超氧炫”在第2-3天和第8.5-9.5天出现两个峰值,这两个峰值出现的时间恰好分别对应线虫的生育高峰和开始有个体死亡的阶段。在长寿或者短寿的突变体线虫中,这两个峰的位置和强度都有明显的特征性变化,暗示了线粒体的功能活性与衰老有着密切的关系。我们的实验结果表明遗传突变体线虫成年第3天的“超氧炫”活性可以在很大程度上反映其寿命,数据分析得知第3天的超氧炫频率与寿命呈负相关,而第9天的“超氧炫”频率与寿命没有相关性。生活在相同环境下具有相同遗传背景的线虫个体的寿命也是有长有短,一般来说,这些差异是由随机因素引起的。我们意外地发现野生型线虫独立个体成年第3天的“超氧炫”频率与单条线虫的寿命之间也存在负相关关系。另外我们用药物处理线虫使其寿命缩短,发现处理后的线虫成年第3天的“超氧炫”活性增强。以上结果表明线虫成年第3天的“超氧炫”频率可以预测线虫的寿命长短变化。这意味着虽然我们可以在线虫老年阶段改变它们的衰老过程,但是在生物机体最旺盛的时候衰老的速度很大程度上已经被决定了。
Aging is a gradual and systemic functional decline of an organism sometime after reproduction begins. Genetic, environmental, and stochastic factors all influence aging and determine how long animals eventually live. Mitochondria are pivotal to bioenergetics, free radical metabolism, and cell death. Not surprisingly, mitochondria take a central position in several prominent aging theories, e.g. the rate of living theory, the free radical theory, and the mitochondrial theory of aging. To better understand the physiology of mitochondria during the process of aging in C. elegans, and in the hope of identifying an early biomarker of aging, we used in vivo fluorescence imaging to characterize a physiological phenomenon directly related to superoxide production inside mitochondria. This phenomenon, called mitochondrial superoxide flash or mitoflash, is an intermittent, quantal mitochondrial activity that is linked to energy metabolism and free radical production. The mitoflash production requires the integrity of the mitochondrial electron transport chain (ETC), and the mitoflash frequency is highly sensitive to the metabolic status of the cell and a variety of insults including oxidative stress. Thus, mitoflash serves as a frequency-coded biological oscillator reflecting mitochondrial function in intact cells and even in live animals.
We have found that mitoflash can serve as a novel predictor of lifespan in C. elegans. By in vivo imaging of the pharyngeal-muscle mitoflash events during the lifetime of C. elegans, we found that the mitoflash activity in wild-type (WT) animals was highly sensitive to changes in metabolic states and oxidative stress, and displayed a robust early peak on adult day2-3and a later one on day8.5-9.5. Surprisingly, genetic mutations in diverse signaling pathways inversely modified lifespan and the mitoflash activity on adult day3. Furthermore, the day-3mitoflash activity also negatively correlated with the lifespan of individual WT worms whose lifespan variations are presumably due to epigenetic fluctuations. Drug treatment that shortened lifespan tended to enhance the day-3mitoflash. This is the first time that an early biomarker has been found that can predict the average lifespans of different mutants of the same species, and the lifespans of individual animals from an isogenic population in the same environment. That day-3mitoflash frequency is a predictor of C. elegans lifespan supports the notion that the rate of aging, although adjustable in later life, has been set to a considerable degree before reproduction ceases.
我们发现线粒体中的“超氧炫”频率可以预测线虫的寿命。我们从线虫成年第1天开始对线虫的“超氧炫”进行每天检测,发现线虫体内的“超氧炫”活性对代谢状态和氧化损伤高度敏感,并发现野生型线虫咽部肌肉细胞的“超氧炫”在第2-3天和第8.5-9.5天出现两个峰值,这两个峰值出现的时间恰好分别对应线虫的生育高峰和开始有个体死亡的阶段。在长寿或者短寿的突变体线虫中,这两个峰的位置和强度都有明显的特征性变化,暗示了线粒体的功能活性与衰老有着密切的关系。我们的实验结果表明遗传突变体线虫成年第3天的“超氧炫”活性可以在很大程度上反映其寿命,数据分析得知第3天的超氧炫频率与寿命呈负相关,而第9天的“超氧炫”频率与寿命没有相关性。生活在相同环境下具有相同遗传背景的线虫个体的寿命也是有长有短,一般来说,这些差异是由随机因素引起的。我们意外地发现野生型线虫独立个体成年第3天的“超氧炫”频率与单条线虫的寿命之间也存在负相关关系。另外我们用药物处理线虫使其寿命缩短,发现处理后的线虫成年第3天的“超氧炫”活性增强。以上结果表明线虫成年第3天的“超氧炫”频率可以预测线虫的寿命长短变化。这意味着虽然我们可以在线虫老年阶段改变它们的衰老过程,但是在生物机体最旺盛的时候衰老的速度很大程度上已经被决定了。
Aging is a gradual and systemic functional decline of an organism sometime after reproduction begins. Genetic, environmental, and stochastic factors all influence aging and determine how long animals eventually live. Mitochondria are pivotal to bioenergetics, free radical metabolism, and cell death. Not surprisingly, mitochondria take a central position in several prominent aging theories, e.g. the rate of living theory, the free radical theory, and the mitochondrial theory of aging. To better understand the physiology of mitochondria during the process of aging in C. elegans, and in the hope of identifying an early biomarker of aging, we used in vivo fluorescence imaging to characterize a physiological phenomenon directly related to superoxide production inside mitochondria. This phenomenon, called mitochondrial superoxide flash or mitoflash, is an intermittent, quantal mitochondrial activity that is linked to energy metabolism and free radical production. The mitoflash production requires the integrity of the mitochondrial electron transport chain (ETC), and the mitoflash frequency is highly sensitive to the metabolic status of the cell and a variety of insults including oxidative stress. Thus, mitoflash serves as a frequency-coded biological oscillator reflecting mitochondrial function in intact cells and even in live animals.
We have found that mitoflash can serve as a novel predictor of lifespan in C. elegans. By in vivo imaging of the pharyngeal-muscle mitoflash events during the lifetime of C. elegans, we found that the mitoflash activity in wild-type (WT) animals was highly sensitive to changes in metabolic states and oxidative stress, and displayed a robust early peak on adult day2-3and a later one on day8.5-9.5. Surprisingly, genetic mutations in diverse signaling pathways inversely modified lifespan and the mitoflash activity on adult day3. Furthermore, the day-3mitoflash activity also negatively correlated with the lifespan of individual WT worms whose lifespan variations are presumably due to epigenetic fluctuations. Drug treatment that shortened lifespan tended to enhance the day-3mitoflash. This is the first time that an early biomarker has been found that can predict the average lifespans of different mutants of the same species, and the lifespans of individual animals from an isogenic population in the same environment. That day-3mitoflash frequency is a predictor of C. elegans lifespan supports the notion that the rate of aging, although adjustable in later life, has been set to a considerable degree before reproduction ceases.
引文
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