Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila.
Autophagy is involved with the turnover of intracellular components and the management of stress responses. Genetic studies in mice have shown that suppression of neuronal autophagy can lead to the accumulation of protein aggregates and neurodegeneration. However, no study has shown that increasing autophagic gene expression can be beneficial to an aging nervous system. Here we demonstrate that expression of several autophagy genes is reduced in Drosophila neural tissues as a normal part of aging. The age-dependent suppression of autophagy occurs concomitantly with the accumulation of insoluble ubiquitinated proteins (IUP), a marker of neuronal aging and degeneration. Mutations in the Atg8a gene (autophagy-related 8a) result in reduced lifespan, IUP accumulation and increased sensitivity to oxidative stress. In contrast, enhanced Atg8a expression in older fly brains extends the average adult lifespan by 56% and promotes resistance to oxidative stress and the accumulation of ubiquitinated and oxidized proteins. These data indicate that genetic or age-dependent suppression of autophagy is closely associated with the buildup of cellular damage in neurons and a reduced lifespan, while maintaining the expression of a rate-limiting autophagy gene prevents the age-dependent accumulation of damage in neurons and promotes longevity.
Simonsen
Anne
A
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Cumming
Robert C
RC
Brech
Andreas
A
Isakson
Pauline
P
Schubert
David R
DR
Finley
Kim D
KD
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D004330:Drosophila / Q000235:genetics / Q000502:physiology*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009424:Nervous System Physiological Phenomena; D016877:Oxidants / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D025801:Ubiquitin / Q000378:metabolism
C066839:Appl protein, Drosophila; C527373:Atg8a protein, Drosophila; D029721:Drosophila Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016877:Oxidants; D017382:Reactive Oxygen Species; D025801:Ubiquitin