Mitophagy in mammalian aging and longevity

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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.