I thought I would do a quick chatGPT on Aspirin and PGE2
The reason I don’t take Aspirin and have not for a few years is its inhibition of the cyclooxygenase enzyme which creates prostaglandins.
Here is a chatGPT link which superficially reads OK
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This research just gets more and more compelling…
Essentially, a single injection of PGE2 brokers the exchange in muscle stem cells of a lifetime’s worth of genetic bookmarks and dog-eared pages for a crisp new set of instructions that not only enhances the function of individual muscle stem cells but is also passed down to their descendants.
A single dose of a molecule that dwindles in aging restores long-term strength to old mice
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Yes it does have a similar effect and Oxytocin support the function of the aging glymphatic system. I take 30iu just before bed.
This had fallen off my radar. It looks incredibly promising. It looks as Empirium are moving ahead with human trials. Crossing fingers it’s successful.
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Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength
Highlights
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EP4 expression and phosphorylated CREB are decreased in aged MuSCs
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PGE2 reverses epigenetic and transcriptional changes in aged MuSCs
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AI identification of AP1 and grammar responsible for epigenetic rejuvenation
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PGE2 treatment increases aged MuSC function and strength after injury and with exercise
Summary
Repair of muscle damage declines with age due to the accumulation of dysfunctional muscle stem cells (MuSCs). Here, we uncover that aged MuSCs have blunted prostaglandin E2 (PGE2)-EP4 receptor signaling, which causes precocious commitment and mitotic catastrophe. Treatment with PGE2 alters chromatin accessibility and overcomes the dysfunctional aged MuSC fate trajectory, increasing viability and triggering cell cycle re-entry. We employ neural network models to learn the complex logic of transcription factors driving the change in accessibility. After PGE2 treatment, we detect increased transcription factor binding at sites with CRE and E-box motifs and reduced binding at sites with AP1 motifs, overcoming the changes that occur with age. We find that short-term exposure of aged MuSCs to PGE2 augments their long-term regenerative capacity upon transplantation. Strikingly, PGE2 injections following myotoxin- or exercise-induced injury overcome the aged niche, leading to enhanced regenerative function of endogenous tissue-resident MuSCs and an increase in strength.
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I wonder if Prostaglandin E1 has a similar effect?
AI Overview
PGE1 and PGE2 are both types of prostaglandins, which are hormone-like substances that play various roles in the body. They differ in their chemical structure and have distinct, though sometimes overlapping, biological effects. PGE1 is known to have anti-inflammatory properties, while PGE2 is often associated with inflammation.
Here’s a more detailed breakdown:
PGE1 (Prostaglandin E1):
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Anti-inflammatory: PGE1 is known to inhibit certain inflammatory processes.
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Platelet inhibition: It can inhibit platelet aggregation, meaning it can help prevent blood clots from forming.
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Muscle relaxation: PGE1 can relax smooth muscle in various tissues, including the gut and the lower esophageal sphincter.
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Gastric protection: It can reduce gastric secretion, which may help prevent ulcers.
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Examples in medicine: PGE1, in the form of misoprostol, is used for cervical ripening and labor induction.
PGE2 (Prostaglandin E2):
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Pro-inflammatory: PGE2 is often involved in inflammatory responses.
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Pain and fever: It can contribute to pain and fever sensations.
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Blood vessel constriction/dilation: PGE2 can affect blood vessel diameter, impacting blood pressure.
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Bone metabolism: PGE2 can influence bone formation and resorption.
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Examples in medicine: PGE2, in the form of dinoprostone, is also used for cervical ripening and labor induction.
Key Differences and Similarities:
- Receptors:
Both PGE1 and PGE2 bind to different subtypes of prostaglandin E receptors (EP receptors), which are linked to various cellular responses.
- Platelet function:
While both affect platelet function, PGE1 is generally a stronger inhibitor than PGE2, which can have both stimulatory and inhibitory effects depending on the concentration and conditions.
- Anti-inflammatory vs. pro-inflammatory:
PGE1 is generally considered anti-inflammatory, while PGE2 is often associated with inflammation. However, both can have roles in both processes depending on the specific context.
- Clinical applications:
Both PGE1 and PGE2 have clinical uses, including labor induction and cervical ripening, though they may be used in different formulations and routes of administration
There is an approved drug, “Iloprost”, that allegedly has beneficial effects on circulation long after a treatment (IV infusion of 4 sequential days). It acts on various prostanoid receptors but is alleged less active at EP4 than PGE2 is.
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Epirium Bio Presented Positive Phase 1 Safety, Pharmacokinetics and Pharmacodynamics Data for MF-300, Supporting its Role in Muscle Health
MF-300 is a first-in-class, orally administered 15-PGDH inhibitor advancing into Phase 2 for the treatment of sarcopenia in older adults
SAN DIEGO–(BUSINESS WIRE)–Epirium Bio Inc. (Epirium), a clinical-stage biopharmaceutical company advancing medicines for neuromuscular and fibrotic diseases, presented Phase 1 data for its lead candidate, MF-300, at the Gerontological Society of America’s (GSA) annual meeting held November 12-15, 2025, in Boston, MA.
MF-300 is an investigational, first-in-class, orally administered, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme inhibitor in development for the treatment of sarcopenia. Inhibition of 15-PGDH enhances endogenous prostaglandin E2 (PGE2) signaling, a pathway associated with the beneficial adaptive response to exercise. Preclinical studies have demonstrated that MF-300 increases muscle force and improves muscle quality in aged mice and in other preclinical models of neurogenic atrophy.
Phase 1 Results
The Phase 1 study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MF-300 in a total of 82 healthy adults, including 54 participants across single-ascending-dose (75–800 mg) and multiple-ascending-dose (75–200 mg daily × 5 days) cohorts. All endpoints of safety and tolerability were met. Key findings included:
- In multiple-dose cohorts (once-daily for 5 days), MF-300 showed rapid absorption and dose-dependent increases in exposure with a half-life that supports once-daily dosing.
- Observed MF-300 exposure levels were consistent with preclinical efficacy thresholds, supporting its potential to translate preclinical activity into clinical benefit.
- There were no unexpected or dose-limiting safety findings, no serious adverse events, and no early discontinuations.
- PD analyses demonstrated clear target engagement with increases in urinary PGE2, accompanied by decreases in urinary PGE-MUM – its primary metabolite – consistent with 15-PGDH inhibition. Importantly, the magnitude of PGE-MUM reduction matched levels previously associated with improved muscle quality, including gains in force, in aged mice.
- Collectively, the study met all predefined success criteria across safety, PK, and PD, providing a solid foundation for moving MF-300 forward in clinical development.
“The Phase 1 results demonstrated a favorable safety profile and predictable pharmacokinetics, supporting convenient once-daily oral dosing,” said Alex Casdin, Chief Executive Officer of Epirium.
Mr. Casdin added, “As the first 15-PGDH inhibitor tested in humans to date, MF-300 also produced biomarker changes confirming target engagement and clear proof of mechanism. Together these findings support continued clinical development of MF-300 as a first-in-class potential treatment for sarcopenia, addressing a significant unmet need and targeting a pathway directly linked to improving muscle strength.”
The presentation is available in the “Posters and Publications” section of Epirium’s website, www.epirium.com.
September_2025-Epirium_Bio-Non-Confidential_Deck.pdf (1.6 MB)
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An injection that blocks the activity of a protein involved in aging reverses naturally occurring cartilage loss in the knee joints of old mice, a Stanford Medicine-led study has found. The treatment also prevented the development of arthritis after knee injuries mirroring the ACL tears often experienced by athletes or recreational exercisers. An oral version of the treatment is already in clinical trials with the goal of treating age-related muscle weakness.
Samples of human tissue from knee replacement surgeries—which include both the extracellular scaffolding, or matrix, in the joint as well as cartilage-generating chondrocyte cells—also responded to the treatment by making new, functional cartilage.
The study results suggest it may be possible to regenerate cartilage lost to aging or arthritis with an oral drug or local injection, rendering knee and hip replacement unnecessary.
The treatment directly targets the cause of osteoarthritis, a degenerative joint disease that affects 1 of every 5 adults in the United States and is estimated to cost about $65 billion in direct health care costs each year. No drug can slow down or reverse the disease; the primary treatments for osteoarthritis are pain control and surgical replacement of the affected joints.
The protein, 15-PGDH—termed a gerozyme due to its increase in prevalence as the body ages—is a master regulator of aging. Gerozymes, identified by the same researchers in 2023, also drive the loss of tissue function. They are a major force behind age-related loss of muscle strength in mice.
Blocking the function of 15-PGDH with a small molecule results in an increase in old animals’ muscle mass and endurance. Conversely, expressing15-PGDH in young mice causes their muscles to shrink and weaken. The gerozyme has also been implicated in the regeneration of bone, nerve and blood cells.
https://medicalxpress.com/news/2025-11-inhibiting-master-aging-regenerates-joint.html
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Empirium Bio estimates MF-300 will be available in 2033. That’s a long wait for some of us. Maybe purchase a VIP pass? Bribe a lab assistant? Steal the secret formula?
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Here is a response from Gemini on my hypothesis relating to Sarcopenia:
Recent research supports the premise that sarcopenia is driven in part by aberrant RNA splicing and that this process is mechanistically linked to reduced protein acetylation. Consequently, increasing acetylation (primarily through HDAC inhibitors) has emerged as a promising therapeutic strategy to prevent or reverse muscle loss.
Short Answer
To a significant extent, sarcopenia is linked to aberrant RNA splicing caused by “epigenetic drift,” specifically a reduction in histone and non-histone protein acetylation. In aging muscle, the enzymes that remove acetyl groups (Histone Deacetylases, or HDACs) often become overactive or dysregulated. This leads to:
- Hypoacetylation of Histones: Causing chromatin to “close,” which represses regenerative genes and alters the splicing of key muscle transcripts.
- Hypoacetylation of Splicing Factors: Disrupting the machinery (spliceosome) responsible for processing RNA, leading to defective muscle proteins.
Evidence indicates that increasing acetylation (e.g., via HDAC inhibitors or metabolic interventions like ketone bodies/butyrate) can restore normal splicing patterns, reactivate regenerative pathways, and reduce muscle atrophy.
Detailed Mechanistic Breakdown
1. The Link Between Acetylation and RNA Splicing
While acetylation is traditionally known for regulating gene transcription (turning genes “on” or “off”), recent studies have revealed it is also a critical regulator of RNA splicing (how gene instructions are edited).
- The Mechanism: Splicing factors (proteins that edit RNA) and the spliceosome itself are regulated by acetylation. When these factors are acetylated, they function correctly. When they lose acetylation (due to aging or high HDAC activity), they mis-splice RNA.
- In Sarcopenia: Aging muscle shows a decline in the precision of these splicing events. For example, crucial muscle proteins like Titin (responsible for elasticity) and Ryanodine Receptors (calcium handling) undergo aberrant splicing in sarcopenic muscle, leading to weaker, dysfunctional fibers.
2. How Reduced Acetylation Drives Sarcopenia
The user’s premise that “reductions in acetylation” drive this process is supported by the “HDAC Barrier” hypothesis in muscle aging:
- Histone Deacetylase (HDAC) Overactivity: As we age, specific HDACs (enzymes that remove acetyl groups) can become upregulated or dysregulated in muscle tissue.
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Consequences:
- Repression of Regenerative Genes: Reduced histone acetylation compacts the DNA, making it harder for muscle stem cells (satellite cells) to access the genes needed for repair.
- Production of “Atrogenes”: The altered acetylation landscape can inadvertently activate atrophy-related genes (atrogenes) like MuRF1 and Atrogin-1, which actively break down muscle protein.
3. Can Increases in Acetylation Prevent or Cure Sarcopenia?
Yes, increasing acetylation is a validated therapeutic target.
Current research focuses on using HDAC inhibitors (HDACi)—compounds that block the removal of acetyl groups, thereby sustaining high acetylation levels.
| Intervention | Mechanism of Action | Effect on Sarcopenia/Muscle |
|---|---|---|
| HDAC Inhibitors (e.g., Givinostat, Trichostatin A) | Inhibits the enzymes that strip acetyl groups, causing hyperacetylation of histones and splicing factors. | • Restores “youthful” gene expression profiles. • Promotes compensatory regeneration (hypertrophy) to network deficits. • Currently in trials for muscular dystrophies and showing promise for age-related atrophy. |
| Butyrate (SCFA) | A natural HDAC inhibitor produced by gut bacteria. | • Increases histone acetylation in muscle. • Prevents muscle loss in aging mice by reducing atrogene expression. |
| Ketone Bodies (Beta-hydroxybutyrate) | Acts as an endogenous HDAC inhibitor. | • Links metabolism to epigenetics; maintains acetylation during calorie restriction or fasting, potentially preserving muscle mass. |
Limitations & Nuance
- Not Just “More is Better”: While general hypoacetylation is a driver of atrophy, the acetylation of mitochondrial proteins is different. In some cases, hyperacetylation of mitochondrial enzymes (due to low NAD+ and reduced Sirtuin activity) decreases their efficiency. Therefore, the goal is targeted acetylation (nuclear/histone) rather than global, non-specific acetylation.
- Splicing Complexity: While acetylation fixes many splicing defects, sarcopenic splicing is also driven by the loss of specific splicing factors (like TDP-43 or SRSF proteins) which may not be fully recoverable solely by increasing acetylation.
Next Step
Would you like me to find specific dietary protocols (such as ketogenic or high-fiber diets) that naturally act as HDAC inhibitors to potentially support muscle maintenance?
However,
I would generally go down the broader acetylation interventions
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The paywalled paper:
Inhibition of 15-hydroxy prostaglandin dehydrogenase promotes cartilage regeneration
Aging or injury to the joints can lead to cartilage degeneration and osteoarthritis (OA), for which there are limited effective treatments. We found that expression of 15-hydroxy prostaglandin dehydrogenase (15-PGDH) is increased in the articular cartilage of aged or injured mice. Both systemic and local inhibition of 15-PGDH with a small molecule inhibitor (PGDHi) led to regeneration of articular cartilage and reduction in OA-associated pain. Using single cell RNA-sequencing and multiplexed immunofluorescence imaging of cartilage, we identified the major chondrocyte subpopulations. Inhibition of 15-PGDH decreased hypertrophic-like chondrocytes expressing 15-PGDH and increased extracellular matrix-synthesizing articular chondrocytes. Cartilage regeneration appears to occur through gene expression changes in pre-existing chondrocytes, rather than stem or progenitor cell proliferation. 15-PGDH inhibition could be a potential disease-modifying and regenerative approach for osteoarthritis.
Very interesting:
Paywalled so preprint: 15-PGDH inhibition promotes hematopoietic recovery and enhances HSC function during aging
So potentially 15-PGDHi can rejuvenate blood (expansion of bone marrow stem and progenitor cells, niche rejuvenation, suppression of myeloid skewing), in addition to muscle and now cartilage.
If you’re making a list of the most promising longevity therapies currently, this is near the very top.
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A short summary of the pre-print paper:
PGDH Inhibition as a Hematopoietic Rejuvenation Strategy in Aging: A Longevity-Focused Analysis
This study identifies inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH)—the enzyme that degrades PGE₂—as a mechanism to rejuvenate aging hematopoiesis. In aged mice, chronic administration of the PGDH inhibitor SW033291 expands functional HSC pools, restores balanced lineage output, suppresses myeloid bias, and dramatically accelerates post-transplant recovery—all without disturbing steady-state blood production, a major translational advantage.
Mechanistically, PGDHi increases local PGE₂ signaling, a known regulator of HSC self-renewal and survival. This shifts the marrow niche toward an anti-inflammatory, pro-regenerative phenotype, marked by reduced IL-3/IL-12/MIP-2 and increased LIF, Arg1, Mrc1, Kitl, and Angpt1. The immune landscape transitions toward M2-like macrophage polarization, consistent with mitochondrial and stromal remodeling that supports HSC quiescence and metabolic fitness. Although the work doesn’t directly assay mTOR/AMPK or autophagy, elevated PGE₂ signaling generally favors survival pathways, niche adhesion, and improved mitoregulation, offering a plausible mechanistic bridge to improved stem-cell function.
The novelty lies in demonstrating that:
- 15-PGDH expression persists with age, making it a viable therapeutic target;
- PGDHi expands aged HSCs over months without exhausting them;
- PGDHi-conditioned donor marrow yields faster neutrophil and multilineage recovery after HSCT ; and
- PGDHi reduces age-associated myeloid skew in secondary transplants, indicating partial restoration of youthful lineage balance.
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On the trail of natural inhibitors of 15-pgdh I ended up ordering some dried leaves that are normally put into fish tanks. Im currently wondering how to consume them…
Wondering where the big money biohackers are relative to this topic. Certainly not liking the wait to 2033 for anything available for us bottom feeders.
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