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.
