Mitophagy in mammalian aging and longevity

线粒体是细胞内的细胞器，调节许多重要的细胞过程。因此，维持最佳的线粒体含量和功能，或者换句话说，线粒体健康，对哺乳动物的大多数细胞和所有器官至关重要。压倒性的证据表明，线粒体完整性随着衰老而下降，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，负责清除功能障碍的线粒体的过程，随着年龄的增长在几个器官中下降。因此，线粒体自噬的系统性损害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的积累，并因此在哺乳动物的生物体衰老中发挥重要作用。然而，一个直接的，全面的和机械的调查，线粒体自噬在哺乳动物的有机体衰老中发挥的作用，目前缺乏。我们最近的工作表明，过度表达Parkin-线粒体自噬的关键调节因子-足以防止肌肉老化。基于这一最新发现，我的研究计划的长期目标是研究线粒体自噬在哺乳动物机体衰老中的作用。为此，将追求以下短期目标：目标1：全面调查衰老对几个重要器官线粒体自噬的影响。到目前为止，缺乏对线粒体控制质量过程如何在衰老过程中在许多重要器官中演变的全面调查。为了填补这一主要知识空白，将在年轻（3个月）、成年（6个月）、中年（12个月）、中年晚期（18个月）、老年（24个月）和衰老（27个月）MitoQC小鼠的多个重要器官（心脏、肝脏、胰腺、肾脏、肠、骨骼肌和大脑）中定量线粒体自噬-一种允许体内线粒体自噬准确定量的转基因模型。目的2：确定刺激线粒体自噬是否可以影响多个重要组织的衰老过程并延长哺乳动物的寿命。为了实现这一目标，我们将产生两个新的转基因小鼠模型过度表达帕金无论是无处不在或专门在骨骼肌。我们预计，过度表达帕金蛋白，无论是普遍存在还是特异性存在于骨骼肌中，都将减弱多种重要组织中的衰老标志，并延长寿命。 目的3：明确限制热量摄入（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敲除（线粒体自噬缺陷）小鼠衰老和寿命标志的影响。我们预期CR的抗衰老作用将在Parkin基因敲除小鼠中减弱。拟议的研究计划应该填补我们对整个衰老过程中关键哺乳动物器官中线粒体自噬如何演变的理解的根本空白，并应该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.