BECN1F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner

Macroautophagy/autophagy is necessary for lifespan extension in multiple model organisms and autophagy dysfunction impacts age-related phenotypes and diseases. Introduction of an F121A mutation into the essential autophagy protein BECN1 constitutively increases basal autophagy in young mice and reduces cardiac and renal age-related changes in longer lived Becn1(F121A) mutant mice. However, both autophagic and lysosomal activities decline with age. Thus, whether autophagic flux is maintained during aging and whether it is enhanced in Becn1(F121A) mice is unknown. Here, we demonstrate that old wild-type mice maintained functional autophagic flux in heart, kidney and skeletal muscle but not liver, and old Becn1(F121A) mice had increased autophagic flux in those same organs compared to wild type. In parallel, Becn1(F121A) mice were not protected against age-associated hepatic phenotypes but demonstrated reduced skeletal muscle fiber atrophy. These findings identify an organ-specific role for the ability of autophagy to impact organ aging phenotypes.

Automated summary

Macroautophagy/autophagy is essential for lifespan extension in various model organisms, and dysfunction in autophagy can affect age-related phenotypes and diseases. Aging wild-type mice maintain functional autophagic flux in heart, kidney, and skeletal muscle, but not in the liver, whereas old Becn1(F121A) mice exhibit increased autophagic flux in these organs compared with wild type, indicating an organ-specific role for autophagy in impacting organ aging phenotypes.