Autophagy promotes longevity—except in the presence of ‘leaky’ mitochondria

Commentary on ‘Mitochondrial permeability uncouples elevated autophagy(definition) and lifespan extension’ by Zhou B. et al., Cell, 2019. Once humans abandoned their hunter ancestors’ roaming lifestyle and settled down in permanent dwellings, they realized the importance and significance of housekeeping. Ironically, our cells long preceded us to this realization as they developed their own miniature housekeeping mechanism, known as autophagy (Greek for ‘self-eating’). During this evolutionarily-conserved process, potentially toxic cellular waste, such as damaged, dysfunctional, or simply long-lived organelles and protein aggregates, are sequestrated and enzymatically degraded in order to maintain cellular homeostasis. Astonishingly, autophagy does not only serve as a detoxification tool but also supports cellular fitness by directing the resulting products from waste hydrolysis towards energy production and cellular recycling. By virtue of these fundamental respo-nsibilities, autophagy is considered a vital homeostatic process essential for life during both standard and stressful conditions alike.1 In fact, the reduction in autophagy observed in ageing is causally implicated in the age-associated functional decline of different organs. In support of this notion, boosting autophagy through transgenic, nutritional, or pharmacological means has been shown to robustly improve health, including within the cardiovascular system,2,3 and promote longevity in various organisms, including mammals.4 That being said, it is quite puzzling why in a particular subset of diseases, such as ischaemic heart disease and cancer, autophagy appears to be a double-edged sword that can, at times, cause more harm than good.5,6