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The present disclosure provides compositions and methods based on the use of 15-PGDH as a therapeutic target in rejuvenation of aging non-skeletal muscle tissues and/or organs. The 15-PGDH inhibitor SW033291 administered intraperitoneally for 4 weeks resulted in restoration of follicular structure and re-establishment of the marginal zone in spleens of 25 month old mice. Treatment of 25 month old mice with SW033291 also reduced the levels of IL10, IL6, BTC, GM-CSF, IL 13 back to levels similar 0 to 4 month old mice.