PT  - JOURNAL ARTICLE
AU  - Won Jin Ho
AU  - Julianne N.P. Smith
AU  - Young Soo Park
AU  - Matthew Hadiono
AU  - Kelsey Christo
AU  - Alvin Jogasuria
AU  - Yongyou Zhang
AU  - Alyssia V. Broncano
AU  - Lakshmi Kasturi
AU  - Dawn M. Dawson
AU  - Stanton L. Gerson
AU  - Sanford D. Markowitz
AU  - Amar B. Desai
TI  - 15-PGDH as a Negative Regulator of Age-Related Organ Fitness
AID  - 10.1101/2020.12.22.424017
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.22.424017
4099  - http://biorxiv.org/content/early/2020/12/22/2020.12.22.424017.short
4100  - http://biorxiv.org/content/early/2020/12/22/2020.12.22.424017.full
AB  - Emerging evidence implicates the eicosanoid molecule prostaglandin E2 (PGE2) in conferring a regenerative phenotype to multiple organ systems following tissue injury. As aging is in part characterized by loss of tissue stem cell regenerative capacity, we tested the hypothesis that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) contributes to the diminished organ fitness of aged mice. Here we demonstrate that genetic loss of 15-PGDH (Hpgd) confers a protective effect on aging of murine hematopoietic and gastrointestinal (GI) tissues. Aged mice lacking 15-PGDH display increased hematopoietic output as assessed by peripheral blood cell counts, bone marrow and splenic stem cell compartments, and accelerated post-transplantation recovery compared to their WT counterparts. Loss of Hpgd expression also resulted in enhanced GI fitness and reduced local inflammation in response to colitis. Together these results suggest that 15-PGDH negatively regulates aged tissue regeneration, and that 15-PGDH inhibition may be a viable therapeutic strategy to ameliorate age-associated loss of organ fitness.ARTICLE SUMMARY 15-PGDH as a Driver of Age-Related Tissue DysfunctionCompeting Interest StatementThe authors (A. Desai, S.L. Gerson, and S.D. Markowitz) hold patents relating to use of 15-PGDH inhibitors in bone marrow transplantation that have been licensed to Rodeo Therapeutics. Drs. Markowitz and Gerson are founders of Rodeo Therapeutics, and Drs. Markowitz, Gerson, and Desai are consultants to Rodeo Therapeutics. Conflicts of interest are managed according to institutional guidelines and oversight by Case Western Reserve University. No conflict of interest pertains to any of the remaining authors.