Phosphodiesterase 4 inhibitors extend lifespan of C. elegans and attenuate cellular senescence of mouse embryonic fibroblasts

PDE4 inhibitors roflumilast and rolipram extend lifespan and improve fitness in C. elegans ; roflumilast attenuates cellular senescence in mouse embryonic fibroblasts. • Roflumilast and rolipram enhance mitochondrial function and reduce ROS levels by activating PKA signaling. • PDE4/cAMP/PKA signaling pathway-mediated anti-aging effects are conserved. Aging is driven by multiple factors such as mitochondrial dysfunction and oxidative stress, leading to various age-related diseases. Phosphodiesterase-4 (PDE4) is a subfamily of phosphodiesterases and specifically hydrolyzes cAMP. PDE4 inhibitors have been approved for the treatment of several diseases and shown to improve aging-related conditions. However, the precise effects and underlying mechanisms of PDE4 inhibitors on lifespan and cellular senescence remain unclear. Here, we report that two PDE4 inhibitors (roflumilast and rolipram) extend C . elegans lifespan and that roflumilast attenuates passage-induced cellular senescence in mouse embryonic fibroblasts (MEFs). We further demonstrate that protein kinase A (PKA) activation mediates PDE4 inhibitors’ anti-aging effects by improving mitochondrial function and alleviating oxidative stress, and that the mechanism is conserved in C. elegans and MEFs. Our findings provide evidence that PDE4 inhibitors possess anti-aging potential. Download: Download high-res image (205KB) Download: Download full-size image