Reactivating young muscle regenerative pathways in ageing through inhibition of the 'gerozyme' 15-hydroxyprostaglandin dehydrogenase.

We are living longer, but the years lived free from chronic diseases and disabilities have not increased at the same rate. The loss of skeletal muscle function in late life constitutes a major barrier to achieving this goal. With age, muscle mass and strength progressively decline. When the loss of muscle function becomes pathological, it is clinically recognized as a syndrome, sarcopenia. The goal of our laboratory is to understand the cellular and molecular mechanisms that drive muscle ageing and sarcopenia and to identify therapeutic strategies that preserve or restore muscle function in older individuals. In this review, we discuss our discovery of the gerozyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a molecular driver of ageing that impedes muscle tissue growth, maintenance and regeneration. 15-PGDH abundance and enzymatic activity increase with age, leading to degradation of prostaglandin E2 (PGE2), a lipid mediator with key roles in skeletal muscle regeneration and tissue homeostasis. By limiting PGE2 bioavailability, elevated 15-PGDH contributes to the impaired regenerative and adaptive capacity of aged muscle. Pharmacological inhibition of 15-PGDH restores PGE2 signalling and improves muscle mass, strength and regenerative capacity in old mice and constitutes a promising therapeutic strategy to counter sarcopenia and promote late-life muscle function. This article is part of the theme issue 'Developmental circuits in ageing'.