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

Zeng-Yang Wang, Xin-Jie Zhao, Shuo Gao, Yuan-Xin Liao, Hao-Cheng Chen, Meng-Ge Zhang, Cheng-Cheng Li, Zhi-Jie Sun, De-Li Dong

State Key Laboratory of Natural Medicines, Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.State Key Laboratory of Natural Medicines, Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China. · pubmed

Paper

Abstract

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.

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Research summary

PDE4 inhibitors extend C. elegans lifespan and attenuate cellular senescence in MEFs via PKA-mediated improvement of mitochondrial function and reduction of oxidative stress. This paper provides mechanistic evidence for the anti-aging potential of a clinically approved drug class, linking cAMP signaling to mitochondrial health, which is a core driver of aging, though the findings are largely incremental given the known effects of PDE4 inhibitors on metabolic pathways.

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