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Free keywords:
Aging/genetics/*physiology
Animals
Animals, Genetically Modified
Autophagy/genetics/*physiology
Autophagy-Related Proteins/genetics/*metabolism
Caenorhabditis elegans/genetics/*physiology
Caenorhabditis elegans Proteins/genetics/*metabolism
Drosophila/genetics/physiology
Drosophila Proteins/genetics/*metabolism
Female
Gene Expression Regulation
Gene Knockdown Techniques
Intracellular Signaling Peptides and Proteins/genetics/*metabolism
Longevity
Male
Mice, Inbred C57BL
Abstract:
Autophagy, an evolutionarily conserved cytoplasmic degradation system, has been implicated as a convergent mechanism in various longevity pathways. Autophagic activity decreases with age in several organisms, but the underlying mechanism is unclear. Here, we show that the expression of Rubicon, a negative regulator of autophagy, increases in aged worm, fly and mouse tissues at transcript and/or protein levels, suggesting that an age-dependent increase in Rubicon impairs autophagy over time, and thereby curtails animal healthspan. Consistent with this idea, knockdown of Rubicon extends worm and fly lifespan and ameliorates several age-associated phenotypes. Tissue-specific experiments reveal that Rubicon knockdown in neurons has the greatest effect on lifespan. Rubicon knockout mice exhibits reductions in interstitial fibrosis in kidney and reduced alpha-synuclein accumulation in the brain. Rubicon is suppressed in several long-lived worms and calorie restricted mice. Taken together, our results suggest that suppression of autophagic activity by Rubicon is one of signatures of aging.
