Treatments are lacking for sarcopenia, a debilitating age-related skeletal muscle wasting syndrome. We identifed increased amounts of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the prostaglandin E-2 (PGE(2))-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The consequent reduction in PGE(2) signaling contributed to musde atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells, such as macrophages, within muscle. Overexpression of 15-PGDH in young muscles induced atrophy. Inhibition of 15-PGDH, by targeted genetic depletion or a small-molecule inhibitor, increased aged muscle mass, strength, and exercise performance. These benefits arise from a physiological increase in PGE(2) concentrations, which augmented mitochondrial function and autophagy and decreased transforming growth factor-beta signaling and activity of ubiquitinproteasome pathways. Thus, PGE(2) signaling ameliorates muscle atrophy and rejuvenates muscle function, and 15-PGDH may be a suitable therapeutic target for countering sarcopenia.