Mitophagy in mammalian aging and longevity

线粒体自噬在哺乳动物衰老和长寿中的作用

• 批准号: RGPIN-2021-03724
• 负责人: Gouspillou, Gilles
• 金额: $ 3.42万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=765326
• 关键词: Mitophagy; mammalian; aging; longevity

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.

线粒体是细胞内的细胞器，调节许多基本的细胞过程。因此，保持线粒体的最佳含量和功能，或者换句话说，保持线粒体的适合性，对哺乳动物的大多数细胞和所有器官都是至关重要的。压倒性的证据表明，线粒体的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，有丝分裂，即负责移除功能失调的线粒体的过程，在几个器官中随着年龄的增长而下降。因此，吞丝分裂的全身性损伤代表了一种诱人的机制，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衰老中发挥重要作用。然而，目前还缺乏关于吞丝分裂在哺乳动物机体衰老中所起作用的直接、全面和机械性的调查。我们最近的工作表明，过度表达Parkin-吞噬作用的关键调节因子-足以防止肌肉衰老。基于最近的这一发现，我的研究计划的长期目标是调查有丝分裂在哺乳动物生物体老化中所起的作用。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有丝分裂的影响。到目前为止，还缺乏关于线粒体控制质量过程如何在许多重要器官随年龄增长而演变的全面调查。为了填补这一主要的知识空白，将在年轻(3mo)、成年(6mo)、中年(12mo)、中晚期(18mo)、老年(24mo)和衰老(27mo)MitoQC小鼠的多个重要器官(心、肝、胰腺、肾、肠、骨骼肌和脑)中量化有丝分裂--这是一种转基因模型，可以在体内准确地测定有丝分裂的数量。目的：明确刺激有丝分裂是否能影响哺乳动物多种重要组织的衰老过程，延长寿命。为了实现这一目标，我们将建立两个新的转基因小鼠模型，在骨骼肌中普遍或特异地过度表达Parkin。我们预计，Parkin的过度表达，无论是普遍存在的，还是专门在骨骼肌中表达的，都将减弱多种重要组织中衰老的特征，并将延长寿命。目的3：明确卡路里限制(CR)是否需要有丝分裂才能发挥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(有丝分裂缺陷)小鼠衰老和寿命的影响。我们预计，在Parkin基因敲除的小鼠中，CR的抗衰老作用将减弱。拟议的研究计划应该会填补我们对关键哺乳动物器官在衰老过程中如何进化的理解上的根本空白，并应该为调节衰老和长寿的过程提供新的机械见解。