Axin-mediated regulation of lifespan and muscle health in C. elegans involves AMPK-FOXO signaling

SUMMARY Aging is a significant risk factor for several diseases. Studies have uncovered multiple signaling pathways that modulate the process of aging including the Insulin/IGF-1 signaling (IIS). In C. elegans the key regulator of IIS is DAF-16/FOXO whose activity is regulated by phosphorylation. A major kinase involved in DAF-16-mediated lifespan extension is the AMPK catalytic subunit homolog, AAK-2. In this study, we demonstrate a novel role of PRY-1/Axin in AAK-2 activation to regulate DAF-16 function. The pry-1 transcriptome contains many genes associated with aging and muscle function. Consistent with this, pry-1 is strongly expressed in muscles and muscle-specific overexpression of pry-1 extends the lifespan, delays muscle aging, and improves mitochondrial morphology in DAF-16-dependent manner. Furthermore, PRY-1 is necessary for AAK-2 phosphorylation. Together, our data demonstrate a crucial role of PRY-1 in maintaining the lifespan and muscle health. Since muscle health declines with age, our study offers new possibilities to manipulate Axin function to delay muscle aging and improve lifespan.