🧬 Aging Wiki

15-pgdh

Properties1
aliasesHPGD, 15-hydroxyprostaglandin dehydrogenase, 15-PGDH, prostaglandin dehydrogenase, SDR36C1, PGDH1, gerozyme

13 min read

15-PGDH (HPGD)

The canonical gerozyme — an NAD+-dependent oxidoreductase that degrades prostaglandin E2 (PGE2) and other eicosanoids to inactive keto-metabolites. 15-PGDH protein levels rise with age in skeletal muscle, neuromuscular junctions, and articular cartilage; this accumulation suppresses local PGE2 to below-physiologic levels, blunting regenerative signaling. Small-molecule 15-PGDH inhibitors (collectively abbreviated PGDHi) restore tissue-PGE2 and produce multi-tissue rejuvenation phenotypes in aged mice — the first enzymatic “gerozyme” target with demonstrated cross-tissue efficacy. Epirium Bio (formerly Myoforte Therapeutics) holds IP around PGDHi for aging/muscle indications but no human PGDHi trials are registered as of 2026-05-23 (druggability tier 2 — high-quality probe; see Limitations and gaps).

Identity

FieldValue
UniProtP15428 (15PGD_HUMAN)
NCBI Gene3248
HGNCHGNC:5154
EnsemblENSG00000164120
Chromosomal locus4q34.1 (10 exons)
Mouse orthologHpgd (NCBI Gene 15446)
GenAgeNot curated (HPGD not in GenAge-human as of 2026-05-23)
Protein length266 amino acids
Isoforms5 isoforms (alternative splicing; NM_000860.5 / ENST00000296522.11 = canonical isoform 1 per UniProt MANE-Select)

Gene synonyms: PGDH1, SDR36C1. In the experimental literature the protein is universally called “15-PGDH” and inhibitors “PGDHi”; the gene is always HPGD.

Biochemistry and catalysis

15-PGDH is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. The protein has a single Rossmann-fold NAD(P)-binding domain — the defining feature of the SDR family — and forms homodimers in solution.

Primary reaction:

Prostaglandin E2 (PGE2) + NAD+  →  15-keto-PGE2 + NADH

The enzyme oxidizes the 15β-hydroxyl group on the prostanoid chain. The resulting 15-keto metabolites are biologically much less potent at EP receptors than the parent prostaglandins, and are rapidly further metabolized to dinor- and tetranor-forms for excretion.

Substrate breadth: 15-PGDH accepts a broad eicosanoid/docosanoid substrate range 1:

  • Prostaglandins: PGE2 (primary substrate), PGD2, PGF2α, PGA2
  • Lipoxins (LXA4, LXB4)
  • Resolvins (some, via the 15-hydroxyl)
  • Thromboxane B2

This substrate breadth has implications for the spm-pathway: PGDHi not only raises PGE2 but may simultaneously alter lipoxin/resolvin catabolism, which could shift the balance between pro-inflammatory and pro-resolving eicosanoid tone. This interaction has not been systematically characterized. no-mechanism

Aging context — the gerozyme concept

The term gerozyme was coined by the Blau laboratory to describe enzymes that accumulate with age and whose activity is pathogenic — the enzymatic analog of gene-expression aging drift 2. Unlike the classical “hallmarks of aging” framing (which emphasizes damage accumulation), the gerozyme concept posits that specific enzymes actively drive age-related decline and are individually pharmacologically reversible.

Evidence that 15-PGDH rises with age:

  • Skeletal muscle: 15-PGDH protein levels are significantly elevated in aged C57BL/6 mouse muscle (>24 mo) vs young (2–4 mo); macrophages within aged muscle are the primary cellular source of the elevation 3. The same trend is detectable in human aged muscle by microarray gene expression analysis (Raue 2012 vastus lateralis dataset; aged mean 78 ± 6 yr vs young 25 ± 3 yr) (#gap/needs-human-replication — protein-level confirmation in a large age-matched human biopsy cohort has not been published).
  • Neuromuscular junction: 15-PGDH protein aggregates co-localize with “target fibers” — NADH-bullseye pathological fibers of chronic neurogenic disease — in n=10 human neurogenic-myopathy biopsies (axonal neuropathies, myositis, motor neuron disease including ALS and SMA, lumbar radiculopathy, neurogenic amyloidosis); 9/10 cases positive 4. Verified 2026-05-23 against full PDF. This argues for a conserved role at the NMJ.
  • Articular cartilage: HPGD mRNA and protein are elevated in aged and OA-injured murine articular cartilage; scRNA-seq identified a 15-PGDH-high “hypertrophic-like” chondrocyte population that expands with age and OA 5.

Why elevated 15-PGDH is harmful: PGE2 at physiologic levels signals through the EP4 receptor on muscle satellite cells, chondrocytes, and hematopoietic stem cells to promote mitochondrial biogenesis, autophagy induction, and ECM synthesis. Age-associated 15-PGDH elevation degrades PGE2 below these physiologic signaling thresholds, silencing regenerative programs. PGDHi re-elevates local PGE2 without exceeding physiologic ranges, because the enzyme-saturation kinetics are balanced by ongoing COX-2 synthesis. This distinguishes PGDHi from exogenous PGE2 infusion, which produces supraphysiologic spikes and rapid receptor desensitization.

DimensionStatus
Pathway conserved in humans?yes — SDR family, EP receptor signaling are conserved
Phenotype (age-related HPGD elevation) conserved in humans?partial — NMJ evidence in human myopathies; muscle/cartilage quantification sparse
Rejuvenation upon PGDHi replicated in humans?no — preclinical only as of 2026-05-23

needs-human-replication — Cross-tissue elevation of 15-PGDH with age has not been systematically quantified in age-matched human cohort biopsy series.

Tissue distribution and cell types

  • Skeletal muscle: Expressed in myofibers and infiltrating macrophages; macrophage expression predominates in the aged context 3.
  • Articular cartilage: Expressed in chondrocytes; hypertrophic-like chondrocyte subset is the high-15-PGDH population 5.
  • Neuromuscular junction / denervated muscle: Concentrated in target-fiber aggregates 4.
  • Colon/gastrointestinal epithelium: High expression; relevant to tumor-suppressor function (see below).
  • Lung: Expressed; lost in lung adenocarcinoma.
  • Hematopoietic system: Expressed in bone marrow; inhibition expands hematopoietic stem and progenitor cell (HSPC) populations 6.
  • Heart: Expressed in cardiomyocytes; elevated with age; inhibition improves cardiac systolic/diastolic function in aged mice 7.

Mechanistic consequences of PGDHi

PGE2 → EP4 → mitochondrial and regenerative signaling

Based on Palla 2021, the primary downstream effector is EP4 (the high-affinity prostanoid receptor with the broadest expression in muscle and cartilage) 3:

  • EP4 signals via Gs → cAMP → PKA → CREB axis
  • Downstream: ↑mitochondrial biogenesis (PGC-1α stabilization), ↑autophagy (mTORC1 inhibition), ↑protein synthesis (via mTOR-independent routes)
  • In muscle: PGDHi reduced TGF-β signaling and ubiquitin-proteasome pathway activity — two canonical drivers of age-related muscle atrophy
  • In cartilage: Singla 2025 identified mechanism as “gene-expression reprogramming of preexisting chondrocytes” — specifically converting hypertrophic-like 15-PGDH+ chondrocytes to an ECM-synthesizing articular chondrocyte state 5. This is notable: it argues that the therapeutic effect is transcriptional reprogramming, not progenitor expansion.

Autophagy link: PGE2/EP4-mediated mTORC1 attenuation is expected to induce macroautophagy, connecting 15-PGDH to mitochondrial-dysfunction and loss-of-proteostasis hallmarks. This connection is inferred from pathway logic; a direct mechanistic test in aged tissue has not been published. no-mechanism

Cross-tissue rejuvenation phenotypes

TissueModelOutcomeCitation
Skeletal muscleAged C57BL/6 mice, SW033291 gavage or genetic Hpgd depletion↑muscle mass, ↑grip strength, ↑exercise performance; ↓atrophy markers3
Neuromuscular junctionAged mice + sciatic nerve crush / chronic denervation + SW033291NMJ regeneration restored; target-fiber pathology reduced4
Articular cartilageAged/OA-induced mice, SW033291 systemic or local injectionCartilage regeneration, ↓OA pain, ↑ECM synthesis; scRNA-seq: ↑articular chondrocyte gene expression5
Rotator cuff muscleAged mice + rotator cuff tear, SW033291↑PGE2, ↑mitochondrial function, ↓muscle atrophy8
HeartAged C57BL/6 mice, SW033291↑systolic and diastolic function, ↓oxidative stress, ↓chronic inflammation7
Hematopoietic systemAged mice, SW033291↑HSPC frequency and number, ↑HSC transplantation engraftment6

The breadth of this cross-tissue table is notable: 15-PGDH inhibition produces regenerative phenotypes in mesenchymal, neurological, cardiovascular, and hematopoietic compartments, consistent with PGE2/EP4 being a ubiquitous trophic signaling axis silenced by age-elevated 15-PGDH. All evidence is preclinical (mouse) as of 2026-05-23.

Tool compound: SW033291

The canonical small-molecule 15-PGDH inhibitor is SW033291, first identified by Zhang et al. 2015 9 in a screen for compounds enhancing hematopoietic stem cell expansion after bone marrow transplantation. SW033291 binds to the NAD+-binding pocket of 15-PGDH and competitively inhibits prostaglandin oxidation. It is selective for 15-PGDH over other SDR family members at 50–500 nM concentrations. SW033291 is an oral compound with demonstrated in-vivo efficacy in mice across all tissue models above; it is not in clinical use. A dedicated compound page is planned: sw033291. needs-pk-data — tissue PK and systemic PGE2 dose-response in aged vs young animals not systematically published.

Clinical translation — Epirium Bio

Epirium Bio Inc. (formerly Myoforte Therapeutics; rebranded after pivoting to 15-PGDH-related programs) holds intellectual property around PGDHi for muscle and aging indications. Their clinical candidate compound identity is proprietary. proprietary-chemistry

A search of ClinicalTrials.gov (queried 2026-05-23) did not identify any active or recruiting trials with Epirium Bio targeting 15-PGDH or PGDHi for sarcopenia or aging indications. The only completed Epirium trial found was NCT04386304 (Phase 1 epicatechin in Becker muscular dystrophy), a wholly different mechanistic program. No human PGDHi trials are registered as of 2026-05-23. This is why the druggability tier is 2 (high-quality probe) rather than 1 — see Limitations and gaps. long-term-unknown

Cancer-aging tradeoff: 15-PGDH as tumor suppressor

This is the central tension of 15-PGDH pharmacology. In a pre-aging-biology context, HPGD is a well-characterized tumor suppressor gene:

  • Colon cancer: 15-PGDH knockout mice show a 7.6-fold increase in colon tumors vs wildtype; universal loss of 15-PGDH expression in adenomas from FAP patients 10. The enzyme opposes COX-2 oncogenic activity by degrading the PGE2 that COX-2 produces.
  • Lung cancer: 15-PGDH is targeted by HNF-3β and is lost in lung adenocarcinoma 11.
  • Liver cancer: Decreased HPGD expression correlates with HCC development via the ENO1/YAP1 axis.
  • Radioresistance: miR-620 silences HPGD to promote cancer radioresistance.

The tension: Systemic 15-PGDH inhibition — the desired therapeutic strategy for aging — would pharmacologically reproduce the tumor-promoting state seen in cancers that have genetically lost HPGD. Whether pharmacological PGDHi carries meaningful cancer-promoting risk depends on (a) reversibility (drug washout restores enzyme), (b) tissue specificity (is the relevant tumor-microenvironment PGE2 affected?), and (c) immune PGE2 effects (elevated PGE2 is immunosuppressive in some tumor contexts). This tradeoff is discussed in cancer-aging-tradeoffs.

contradictory-evidence — The gerozyme/rejuvenation framing (inhibit 15-PGDH → restore PGE2 → regeneration) and the tumor-suppressor framing (inhibit 15-PGDH → raise PGE2 → promote tumor growth, impair immune surveillance) make opposite safety predictions for long-term systemic PGDHi. This is not resolved. Epirium Bio’s clinical strategy likely involves intermittent dosing or tissue-targeted delivery to mitigate this risk; without published preclinical cancer-safety data, this remains an open concern.

Pathway memberships

  • spm-pathway — 15-PGDH catabolizes lipoxins and resolvins in addition to PGE2; PGDHi may simultaneously alter SPM tone; flux competition for arachidonate-derived substrates
  • arachidonic-acid-pathway — PGE2 is an arachidonic acid-derived prostanoid; 15-PGDH is the first committed step of its catabolism
  • prostaglandin-metabolism — primary metabolic pathway membership (stub page needed)
  • nlrp3-inflammasome — PGE2 elevation modulates NLRP3 activation; indirect crosstalk via cAMP/EP4 3
  • chronic-inflammation — PGE2 is a canonical eicosanoid mediator of inflammation; elevated 15-PGDH restricts it

Key interactors

  • COX-2 (PTGS2) — the upstream prostaglandin synthase; 15-PGDH is the functional antagonist of COX-2-derived PGE2. The pair constitutes the main PGE2 rheostat.
  • EP4 receptor (PTGER4) — primary downstream PGE2 receptor in aged muscle/cartilage; mediates regenerative cAMP signaling
  • NAD+ — cofactor; elevated intracellular NAD+ increases 15-PGDH activity, providing a metabolic connection to sirt1 / NAD+ precursor biology
  • mTORC1 — inhibited downstream of EP4/cAMP; connects to deregulated-nutrient-sensing and disabled-macroautophagy

Recency note (R25 search — 2023–2026)

PubMed search conducted 2026-05-23 using terms “15-PGDH prostaglandin dehydrogenase aging” (mindate 2023, maxdate 2026) returned 8 hits. Key recent literature integrated above:

PMIDYearKey findingIntegrated?
413081242026 (in-print; online 2025)Singla 2026: cartilage regeneration via 15-PGDH inhibitionYes
409715732026Blau & Porpiglia review: gerozyme concept + cross-tissue summaryYes
40608981202515-PGDH inhibition enhances hematopoietic regeneration in aged miceYes
404795012025PGE2 ameliorates aging-aggravated rotator cuff muscle atrophy via PGDHiYes
399523092025SW033291 improves age-related heart failure in miceYes
389049072024Ahmad SS et al. — biocomputational screening of natural compounds targeting 15-PGDH for skeletal muscle aging (Molecular Diversity 2024)Confirmed; not fully integrated (drug-discovery context)
37942226202315-PGDH downregulation promotes MASH-HCC (cancer context)Yes — cited in tumor suppressor section
378200102023Bakooshli 2023: NMJ regenerationYes

No meta-analyses or RCTs were found for this target (0 hits in the meta-analysis/RCT filter, 2020–2026) — expected, as the program is preclinical.

Limitations and gaps

  • needs-human-replication — All cross-tissue rejuvenation phenotypes are in mice. No human PGDHi trial has been published or registered as of 2026-05-23.
  • long-term-unknown — Long-term safety of systemic PGDHi is unknown in any species. Cancer-promoting risk from chronic PGE2 elevation is uncharacterized.
  • contradictory-evidence — Tumor-suppressor framing vs gerozyme framing; see Cancer-aging tradeoff section above.
  • proprietary-chemistry — Epirium Bio clinical candidate structure is not public.
  • needs-pk-data — Tissue PK of SW033291 and systemic PGE2 dose-response in aged animals not systematically published. dose-response-unclear
  • no-mechanism — Whether PGE2/EP4 mechanistically induces autophagy in aged tissue (expected from cAMP/mTORC1 logic) has not been directly tested with autophagic flux assays.
  • needs-canonical-id — prostaglandin-metabolism pathway page does not exist; wikilink is a stub.
  • mr-causal-evidence: not-tested — No Mendelian randomization instruments for HPGD identified via IEU OpenGWAS; genetic variation at 4q34.1 has not been used as an MR instrument for muscle mass, cartilage health, or other aging phenotypes.
  • druggability-tier: 2 rationale — SW033291 (Zhang 2015) is a high-quality, highly selective tool compound (Ki = 0.1 nM) demonstrating in-vivo efficacy in five tissue contexts (muscle, NMJ, cartilage, heart, hematopoietic). However, no clinical trial for a 15-PGDH inhibitor is registered on ClinicalTrials.gov as of 2026-05-23 (verified via API query). Epirium Bio holds IP and has stated clinical ambitions, but their only registered trial (NCT04386304) is an unrelated epicatechin/Becker MD program; the PGDHi compound identity is proprietary (#gap/proprietary-chemistry). Per CLAUDE.md druggability-tier definitions, tier 1 requires “a clinical drug exists”; without an active IND or registered trial, tier 2 (high-quality probe) is the accurate designation. Upgrade to tier 1 when a registered PGDHi human trial is confirmed.

Footnotes

Footnotes

  1. UniProt P15428 (15PGD_HUMAN), accessed 2026-05-23 · manually reviewed (Swiss-Prot) · gene HPGD (syn: PGDH1, SDR36C1) · 266 aa · SDR family ↩

  2. doi:10.1146/annurev-pharmtox-071724-100856 · PMID 40971573 · review (Ann Rev Pharmacol Toxicol) · 2026 · Blau HM & Porpiglia E · “From Cell Reprogramming to Tissue Rejuvenation: Countering Aging by Targeting a Gerozyme” · archive: download pending ↩

  3. palla-2021-15pgdh-muscle-rejuvenation · doi:10.1126/science.abc8059 · PMID 33303683 · n=aged C57BL/6 mice (multiple cohorts) · in-vivo (mouse, SW033291 gavage + genetic Hpgd KO) · p<0.05 (muscle mass, grip strength) · model: aged C57BL/6 mice; archive: download failed; PMC7938328 (OA) ↩ ↩2 ↩3 ↩4 ↩5

  4. bakooshli-2023-15pgdh-nmj-regeneration · doi:10.1126/scitranslmed.adg1485 · PMID 37820010 · PMC10763629 · Bakooshli MA,…, Blau HM (last; Bhutani is NOT an author) · Sci Transl Med 15(717):eadg1485 (2023) · in-vivo: male C57BL/6 (2–4 mo young Jackson + 24–26 mo aged NIA); SW033291 5 mg/kg i.p. once daily, 14 d crush / 1 mo aged · Hpgd mRNA rises ~20× by d90 post-SNT (10× at d14); protein 4×; primary source is denervated myofibers (snRNA-seq) NOT Schwann cells; mechanism is EP4-cAMP-CREB in motor neurons · plantar flexor force +37.2 ± 4.9% at 14 dpi (crush); motor-axon counts 1.9× higher; aged motor-neuron apoptosis 11.6%→4.2% with PGDHi · n=10 human neurogenic-myopathy biopsies, 9/10 positive for 15-PGDH target-fiber co-localization · local PDF at · verified 2026-05-23 against full PDF ↩ ↩2 ↩3

  5. singla-2025-15pgdh-cartilage-regeneration · doi:10.1126/science.adx6649 · PMID 41308124 · PMC13127300 · in-vivo (aged n=9 + PTOA n=7 C57BL/6 mice) + ex-vivo human OA cartilage (n=11 FACS / n=5 treatment readouts; total-knee-replacement source, ages 55–75) · scRNA-seq (GEO GSE308009) + multiplexed IF · Singla M, Wang YX,… Blau HM, Bhutani N (last/corresponding) · Science 391(6789):1053–1062, in-print 2026-03-05 (online 2025-11-27); journal PDF closed-access; PMC release 2026-04-29 used for verification · verified 2026-05-23 ↩ ↩2 ↩3 ↩4

  6. doi:10.1093/stmcls/sxaf047 · PMID 40608981 · in-vivo (aged mice, SW033291) · Chaudhary R, Cordova BA, Hong M, Klein BR et al. · Stem Cells 43(10) · 2025 · 15-PGDH inhibition enhances HSPC frequency and transplant engraftment in aged mice · archive: download pending ↩ ↩2

  7. doi:10.1016/j.exger.2025.112710 · PMID 39952309 · in-vivo (aged mice, SW033291) · Zhang L, Wang Q, Guan W · Exp Gerontol 2025 · SW033291 improves systolic/diastolic function in aged mice; ↓oxidative stress, ↓chronic inflammation · archive: download pending ↩ ↩2

  8. doi:10.2106/JBJS.24.00866 · PMID 40479501 · in-vivo (aged mice, rotator cuff tear model, SW033291) · Shu L & Zhang Y et al. · J Bone Joint Surg 2025 · ↑PGE2, ↑mitochondrial function, ↓muscle atrophy ↩

  9. doi:10.1126/science.aaa2340 · PMID 26068857 · in-vivo (mouse, bone marrow transplant) · Zhang Y, Desai A, Yang SY, Bae KB et al. · Science 348(6240) · 2015 · first report of SW033291 as a 15-PGDH inhibitor enhancing hematopoietic regeneration across multiple tissues · archive: download pending ↩

  10. doi:10.1073/pnas.0603235103 · PMID 16880406 · in-vivo (mouse, Hpgd KO + Min model) + human FAP biopsy (IHC) · Myung SJ & Markowitz SD · PNAS 2006 · 7.6-fold ↑ colon tumors in Hpgd KO · archive: download pending ↩

  11. doi:10.1158/0008-5472.CAN-07-6575 · PMID 18593902 · Cancer Research 2008 · Huang G et al. · HPGD is a HNF-3β target and tumor suppressor in lung cancer ↩

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