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A lifespan-extending form of autophagy employs the vacuole-vacuole fusion machinery

While autophagy is believed to be beneficial for lifespan extension, it is controversial which forms or aspects of autophagy are the responsible ones. We addressed this by analyzing the lifespan of yeast autophagy mutants under caloric restriction, a longevity manipulation. Surprisingly, we discovered that the majority of proteins involved in macro-autophagy and several forms of micro-autophagy were dispensable for lifespan extension. The only autophagy protein that is critical for lifespan extension was Atg15p, a lipase that is located in the endoplasmic reticulum (ER) and transported to vacuoles for disintegrating membranes of autophagic bodies. We further found that vacuole-vacuole fusion was required for lifespan extension, which was indicated by the shortened lifespan of mutants missing proteins (ypt7Δ, nyv1Δ, vac8Δ) or lipids (erg6Δ) involved in fusion. Since a known function of vacuole-vacuole fusion is the maintenance of the vacuole membrane integrity, we analyzed aged vacuoles and discovered that aged cells had altered vacuolar morphology and accumulated autophagic bodies, suggesting that certain forms of autophagy do contribute to longevity. Like aged cells, erg6Δ accumulated autophagic bodies, which is likely caused by a defect in lipase instead of proteases due to the existence of multiple vacuolar proteases. Since macro-autophagy is not blocked by erg6Δ, we propose that a new form of autophagy transports Atg15p via the fusion of vacuoles with vesicles derived from ER, and we designate this putative form of autophagy as secretophagy. Pending future biochemical studies, the concept of secretophagy may provide a mechanism for autophagy in lifespan extension.