Neuronal inhibition of the autophagy nucleation complex extends lifespan in post-reproductiveC. elegans

Autophagy is a ubiquitous catabolic process, which causes cellular bulk degradation of cytoplasmic components and thereby regulates cellular homeostasis. Inactivation of autophagy has been linked with detrimental effects to cells and organisms. The antagonistic pleiotropy theory postulates that fitness promoting genes during youth are harmful during aging (Williams 1957). On this basis we examined genes mediating post-reproductive longevity using an RNA interference screen. From this screen we identified 30 novel regulators of post-reproductive longevity including pha-4 . Through downstream analysis of pha-4 we identify that genes governing the early stages of autophagy up until the stage of vesicle nucleation, such as bec-1 , strongly extend both lifespan and healthspan. Further, our data demonstrates that the improvements in health and longevity are mediated through the neurons - resulting in reduced neurodegeneration and sarcopenia. We propose that autophagy switches from advantageous to harmful in the context of an age-associated dysfunction.