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Modulation of Longevity by

mTORC2 and SGK 


Activation of autophagy, the process by which cells clear defective organelles and molecules, is required in almost every genetic, dietary, and pharmacologic manipulation that extends lifespan. However, elevated levels of autophagy under certain circumstances can also have negative effects. Here we show that mitochondrial permeability, or "leakiness" in our cells' powerhouse, determines whether the effects of autophagy on health and longevity will be positive or negative. Remarkably, in every case tested, the longevity benefit of autophagy was reversed by triggering increased mitochondrial permeability ("leakiness"). Even in mammals, elevated autophagy causes greater tissue damage during ischemia-reperfusion injury when mitochondrial permeability is high. We put forth the idea that it is not autophagy levels per se rather the cellular context in which autophagy is activated that is the critical determinant of whether autophagy is beneficial versus detrimental.

This work was published in Cell in April 2019. You can link to the paper by clicking here.

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