title: Autophagy in aging and Alzheimer's disease: pathologic or protective?
abstract: Some hypothesize that aging in humans is a cumulative process of macromolecular and mitochondrial damage starting years, even decades before any symptoms arise. Aging may begin when the rate of damage exceeds the rate of continual repair and turnover. Quality control for damaged mitochondria entails cellular digestion by mitophagy, a specialized kind of autophagy. Insufficient protective autophagy could cause damaged cellular components to accumulate over many years until they affect normal function in the cell. Alternatively, aging could be the result of overactive, pathologic autophagy. Current knowledge supports both hypotheses with conflicting data, depending on which stage of autophagy is examined. To distinguish these opposite hypotheses, two criteria need to be observed. First, is there a buildup of undigested waste that can be removed by stimulation of autophagy? Or second, if autophagy is overactive, does inhibition of autophagy rescue cell, organ and organism demise. Both of these are best determined by rate measures rather than measures at a single time point. Here, we review the generalized process of autophagy, with a focus on the limited information available for neuron mitophagy, aging, and Alzheimer's disease (AD). In two mouse models, treatment with rapamycin abolishes the AD pathology and reverses memory deficits. As a working model, we hypothesize that insufficient protective autophagy accelerates both aging and AD pathology, possibly caused by defects in autophagosome fusion with lysosomes.
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA. abarnett2@siumed.edu
authors.forename: Aaron
authors.initials: A
authors.lastname: Barnett
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Brewer
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology* / Q000517:prevention & control; D001343:Autophagy / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species