Mitophagy in mammalian aging and longevity

线粒体是调节许多基本细胞过程的细胞内细胞器。因此，维持最佳的线粒体含量和功能，或者换句话说，线粒体适应性，对哺乳动物的大多数细胞和所有器官都是至关重要的。大量证据表明，线粒体完整性随着年龄的增长而下降，使线粒体功能障碍的积累成为衰老的标志。新出现的证据表明，线粒体自噬（负责清除功能失调的线粒体的过程）在一些器官中随着年龄的增长而下降。因此，线粒体自噬的全身性损伤代表了一种有吸引力的机制，可能有助于与衰老相关的线粒体功能障碍积累，因此可能在哺乳动物的机体衰老中发挥重要作用。然而，目前缺乏对有丝分裂在哺乳动物机体衰老中所起作用的直接、全面和机制的研究。我们最近的研究表明，过度表达帕金蛋白——有丝分裂的关键调节因子——足以防止肌肉老化。基于这一最近的发现，我的研究计划的长期目标是调查有丝分裂在哺乳动物机体衰老中所起的作用。为此，我们将追求以下短期目标：目标1：全面研究衰老对几种重要器官有丝分裂的影响。迄今为止，缺乏对许多重要器官中线粒体控制质量过程在衰老过程中如何演变的全面研究。为了填补这一重大知识空白，我们将在年轻（3个月）、成年（6个月）、中年（12个月）、中老年（18个月）、老年（24个月）和老年（27个月）MitoQC小鼠的多个重要器官（心脏、肝脏、胰腺、肾脏、肠道、骨骼肌和大脑）中对线粒体自噬进行量化。MitoQC小鼠是一种能够准确定量体内线粒体自噬的转基因模型。目的2：确定刺激线粒体自噬是否会影响哺乳动物多个重要组织的衰老过程，从而延长寿命。为了实现这一目标，我们将在骨骼肌中产生两种新的过表达Parkin的转基因小鼠模型。我们预计，在骨骼肌中普遍或特异性地过度表达帕金蛋白，将减轻多个重要组织的衰老特征，并延长寿命。目的3：明确卡路里限制（CR）是否需要线粒体自噬来发挥其抗衰老和延长寿命的作用。我们将研究CR对野生型和Parkin基因敲除（线粒体自噬缺陷）小鼠衰老和寿命指标的影响。我们预计，CR在帕金森氏基因敲除小鼠中的抗衰老作用将会减弱。拟议的研究计划将填补我们对哺乳动物关键器官中线粒体自噬如何在衰老过程中进化的理解的基本空白，并为调节衰老和长寿的过程提供新的机制见解。

Mitochondria are intracellular organelles that regulate numerous essential cellular processes. Maintaining optimal mitochondrial content and function, or in other words, mitochondrial fitness, is therefore vital for most cells and all organs in mammals. Overwhelming evidence indicates that mitochondrial integrity declines with aging, making the accumulation of mitochondrial dysfunction a hallmark of aging. Emerging evidence suggests that mitophagy, the process in charge of the removal of dysfunctional mitochondria, declines in several organs with aging. Systemic impairment in mitophagy therefore represents an attractive mechanism that could contribute to the aging-related accumulation of mitochondrial dysfunction and could consequently play an important role in organismal aging in mammals. However, a direct, comprehensive and mechanistic investigation of the role that mitophagy plays in organismal aging in mammals is currently lacking. Our recent work showed that overexpressing Parkin - a key regulator of mitophagy - is sufficient to prevent muscle aging. Building from this recent discovery, the long-term goal of my research program is to investigate the role that mitophagy plays in organismal aging in mammals. To this end, the following short-term objectives will be pursued: Objective 1: To comprehensively investigate the impact of aging on mitophagy in several vital organs. To date, a comprehensive investigation of how mitochondrial control quality processes evolve in many vital organs throughout aging is lacking. To fill this major knowledge gap, mitophagy will be quantified in multiple vital organs (heart, liver, pancreas, kidney, intestine, skeletal muscles and the brain) in young (3mo), adult (6mo), middle-age (12mo), late-middle-age (18mo), old (24mo) and senescent (27mo) MitoQC mice - a transgenic model allowing for the accurate quantification of mitophagy in vivo. Objective 2: To define whether stimulating mitophagy can impact the aging process of multiple vital tissues and increase longevity in mammals. To achieve this objective, we will generate two novel transgenic mouse models overexpressing Parkin either ubiquitously or specifically in skeletal muscles. We anticipate that overexpressing Parkin, either ubiquitously or specifically in skeletal muscles, will attenuate hallmarks of aging in multiple vital tissues and will extend lifespan. Objective 3: To define whether mitophagy is required for calorie restriction (CR) to exert its anti-aging effects and extend lifespan. We will investigate the impact of CR on hallmarks of aging and lifespan in Wild type and Parkin knock out (mitophagy deficient) mice. We anticipate that the anti-aging effects of CR will be blunted in Parkin knock out mice. The proposed research program should fill fundamental gaps in our understanding of how mitophagy evolves in key mammalian organs throughout aging and should provide novel mechanistic insights into processes regulating aging and longevity.