The Culprit of Aging - Helen Blau's work at Stanford / PGE2, 15-PDGH

Dr.Helen Blau of Stanford University is attempting something seemingly impossible: to treat aging as a disease; to lessen the devastation of old age; to recover strength, muscle mass, and endurance—for people already old.

According to Dr. Blau, a typical person past 50 will lose 10-15% of their strength every decade. But is this inevitable?

Not if a molecule called PGE2 turns out to be helpful.

When Dr. Blau gave PGE2 to old mice, it stimulated muscle stem cells and restored strength, muscle mass and endurance to their aged limbs. They ran faster and longer on the treadmill.

She also discovered a protein that breaks down PGE2, so it will not work. She called the negative protein a gerozyme, an aging associated enzyme, also known as15-PGDH,a prostaglandin degrading enzyme.

The gerozyme accumulates in muscle tissue as we age. Because the gerozyme is present in relatively higher amounts in the elderly, the availability of PGE2decreases, which is problematic for muscle regeneration.

So, the “hero” of aging could be PGE2 (prostaglandin), and the “villain” is the gerozyme 15-PDGH (hydroxyprostaglandin dehydrogenase).

PGE2could make muscles more powerful; 15 PDGH could wither the limbs.

Full article here:

More information:

For well over a decade now, scientists have been experimenting with “couch potato” drugs that could confer the benefits of exercise without having to flex a muscle. The latest candidate is a small molecule inhibitor impeding the degradation of prostaglandin E2 (PGE2), recently shown to act directly on mature muscle fibers to prevent deleterious molecular changes that arise with aging, according to Helen Blau, professor of microbiology and immunology and director of the Baxter Laboratory for Stem Cell Biology at Stanford University School of Medicine.

In gel form, PGE2 is already being used to induce labor and treat respiratory distress in newborns, says Blau. It now appears that restoring PGE2 later in life could be a way to rejuvenate aging muscles and possibly treat conditions such as age-related muscle atrophy (sarcopenia), Duchenne muscular dystrophy, and other myopathies.

The Stanford researchers previously discovered that PGE2 regulates muscle stem cells and enhances regeneration, and another group showed that knocking out the enzyme responsible for PGE2 synthesis has harmful effects on muscles, says Blau. Her team has now found that levels of PGE2 are lower in older than younger mice while levels of the prostaglandin-degrading enzyme 15-PGDH are elevated, and that partially blocking its activity can restore their strength and endurance.

The study is newly published in Science (DOI: 10.1126/science.abc8059). Overexpression of 15-PGDH in young mice induced muscle loss, and its short-term inhibition reversed muscle wasting associated with aging. Notably, inhibiting 15-PGDH restored PGE2 in aged muscles to physiological levels characteristic of young muscles. This restoration of PGE2 to youthful levels led to a pronounced increase in strength in elderly mice.

Blau notes that the 15-PGDH inhibitor had a notably robust effect on muscle strength—a roughly 15% gain in the aged mice after one month of treatment. “Humans after the age of 50 lose 10%-15% of their muscle strength and mass per decade, so if they could get that back with a short-term treatment… it would be really remarkable.”

A small molecule inhibitor of 15-PGDH was formerly used to promote tissue regeneration in mouse models of colon and liver injury by increasing level of PGE2, Blau says. Since PGE2 stimulates stem cells, the Stanford team reasoned that the same pathway might also be important in aging.

It came as a welcome surprise that elevating PEG2 by inhibiting 15-PGDH led to body-wide improvement in aged mice, she notes. PGE2 has a “very short” half-life, making it difficult to translate into a therapy. “You would have to inject it right into the muscles.”

Read full story:

More Research Reading:

Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength

Prostaglandin E2 (PGE2), an eicosanoid that mediates inflammatory responses, also supports the function of muscle stem cells. Palla et al. found that loss of PGE2 in aging mice contributes to loss of muscle and appears to be a consequence of increased activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that degrades PGE2 (see the Perspective by Becker and Rudolph). Restoring PGE2 concentrations by inhibiting 15-PGDH in older mice improved muscle function. Decreased activity of 15-PGDH in older animals had beneficial effects that included decreased proteolysis and transforming growth factor–β signaling and increased mitochondrial function and autophagy. The findings reveal a potential therapeutic strategy to help maintain muscle mass and function during aging.

To test if the disseminated muscle wasting seen in sarcopenia could be overcome by systemic delivery of a small-molecule inhibitor of 15-PGDH, we treated aged mice and young control mice daily intraperitoneally with SW033291 (SW) or vehicle (10) (Fig. 2A). SW is an inhibitor with specificity for 15-PGDH in vitro (k i of 0.1 nM) (10). In vivo, SW increases amounts of PGE2 twofold, and increases amounts of PGD2 to a lesser extent in bone marrow, colon, lung, and liver, which augments regeneration following injury of these tissues in young mice (10). After 1 month of daily intraperitoneal SW treatment, 15-PGDH specific activity was significantly reduced in aged muscles and amounts of PGE2 and PGD2 (detected by LC-MS/MS) were increased in young and aged muscles (Fig. 2, B and C, and fig. S7, A and B). Histological analysis revealed that myofiber cross-sectional area was significantly augmented in SW-treated aged mice, indicating muscle hypertrophy (Fig. 2, D to F). Fiber type analysis revealed that SW treatment promoted an increase in the cross-sectional area of both oxidative (type IIa) and glycolytic (type IIb) fast twitch fibers (Fig. 2. G to J). Young mice treated with SW exhibited a trend toward increased muscle mass and absolute strength, which reached statistical significance for plantar flexor force difference compared to baseline

Orally Bioavailable Quinoxaline Inhibitors of 15-Prostaglandin Dehydrogenase (15-PGDH) Promote Tissue Repair and Regeneration

15-Prostaglandin dehydrogenase (15-PGDH) regulates the concentration of prostaglandin E2 in vivo . Inhibitors of 15-PGDH elevate PGE2 levels and promote tissue repair and regeneration. Here, we describe a novel class of quinoxaline amides that show potent inhibition of 15-PGDH, good oral bioavailability, and protective activity in mouse models of ulcerative colitis and recovery from bone marrow transplantation.


Dinoprostone is available inexpensively from Indian sources as a tablet or gel ($15 to $34 US) per package (but it doesn’t seem that just taking the medication, or applying the gel would work)

Chemical / Drug Tested successfully in Blau research (via daily injections in mice)


Helen Blau’s Lab at Stanford


This is really interesting.

and this is the company that they’ve spun out of the research:

1 Like

As is common in the startup world, it seems its had some challenges / pivots / mergers, etc … but seems to have good funding now:

Exclusive: ARCH-backed exercise-in-a-pill startup quietly laid off half its staff, ‘fully pivoted’ in October

In December 2019, a tiny decade-old California startup known as Cardero Therapeutics announced a new name — Epirium Bio — a new direction and $85 million in cash from blue-chip VCs such as ARCH and Vertex Ventures.

The company’s investigational pill has been tested in 110 patients total during Epirium’s proof of concept trials. But it hasn’t yet entered full-scale human trials, which are slated to begin early this year.


It sounds as if it’s gone through a few iterations. I’m guessing this is fairly typical of early stage biotech. I noticed recently that it looks as though AgeX might be potentially be bought out in a reverse merger. I don’t know enough about the biotech space to speculate, but I assume it’s hard to cashflow early stage development long enough to raise the kind of money you need for trials.

Epirium sounds promising for sure. I hope that they can get it into clinical trails soon.

Hmmmm… The only clinical trial I can find for Epirium is this one:

Study Overview

Brief Summary:

This is a Phase 1, open-label, dose escalation study aimed at evaluating the safety, early efficacy and potential biomarkers of (+)-epicatechin in patients with Becker or Becker-like Muscular Dystrophy (BMD).

Detailed Description:

The safety and tolerability of three escalating doses of (+)-epicatechin will be assessed and early effectiveness measured by changes in plasma biomarkers, tissue biomarkers from muscle biopsies, cardiac imaging, and on clinical function assessments of participants’ muscle strength. All patients will receive oral (+)-epicatechin for a total duration of approximately 52 weeks. Three doses of (+)-epicatechin will be tested in sequential 2 month periods with total daily doses of 75, 150, and 225 mg/day (+)-epicatechin. Doses will be escalated every 2 months, if tolerated, for the first 6 months of the study. Participants will then continue to receive the highest does they tolerated for an additional 6 months.

Show more


A Phase 1, Open-label, Dose Escalation Study to Evaluate the Safety and Preliminary Efficacy of Orally Administered (+)-Epicatechin in Patients With Becker or Becker-like Muscular Dystrophy With Continued Ambulation Past 16 Years of Age

I assume MF-NCE1 is the Quinoxaline. Hard to know how long it will take to get it into trials.

I just found this post in our “Gray Hair reversal” thread and it made me wonder if the Dinoprostone Gel (that is available inexpensively from India) might be something that would be useful in reversing gray hair… as a similar drug has done it. It seems worth a try. Easy and cheap.


I kind of like my silver hair. When I run I can imagine that I am the Silver Flash.

1 Like

Yeah, really interesting. Might be worth a try.

I did a little digging and it looks as though Dinoprostone and Latanoprost work on different receptors. There are some other pharmaceuticals that affect PDFA2 like latanoprost. I haven’t heard of these drugs and I’m not sure how available they are: Sulprostone, Dinoprost Tromethamine and Carboprost Tromethamine all seem similar to Dinoprostone. FYI, I used Chat GPT to research this so it might not be accurate.

Seems reasonably accurate:

1 Like

I’m pretty sure PGE2 is increased by castor oil (I remember this from hair growth forums a few years back, castor oil was a big craze)


If this 15-PDGH inhibition can restore/improve the motor end plate, the nerve/muscle junction, that would be a gigantic step. You can always gain muscle mass, even in old age. But there’s nothing you can do anything against denervation. if the muscle can’t receive any order from your brain because the junction becomes deficient, you’re dead, no matter the intensity of training.

Fresh off the press


Interesting that bile acid inhibits 15-PGDH

Bile acids inhibit NAD±dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes

And then closing a possible loop is that either glycine or taurine (both increase longevity) are needed to produce bile acids:

Prior to their secretion into bile, bile acids are conjugated with the amino acids taurine or glycine (Hofmann et al. 2010). Conjugation substantially reduces the passive reabsorption of the molecule through biological membranes.

Bile Acids and longevity?

Intestinal microbes in people aged 100 or over produce unique bile acids that might help keep infections at bay . Researchers found that a compound made by intestinal microbes in centenarians strongly inhibits the growth of Clostridium difficile (colorized), which causes severe diarrhea and gut inflammation.


“Blau and her colleagues plan to investigate at a molecular level how neural growth is stimulated by blocking 15-PGDH activity. Blau has also co-founded a company, Epirium Bio, to develop similar drugs for use in humans. Although her lab is still conducting animal studies, the company hopes to launch a clinical trial within the next year or so.”

“Inhibition of 15-PGDH, a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. 15-PGDH acts in vivo as a negative regulator of prostaglandin levels and activity, provides a candidate target.”

Of course, she must think it is a good idea to block 15-PGDH, especially in old people trying to stave off sarcopenia.

But on the other hand, it might increase their risk of cancer.

“15-PGDH (15-Hydroxyprostaglandin dehydrogenase) is a tumor suppressor in breast, colon, liver, lung, and pancreas since decreased expression of this enzyme is associated with increased tumorigenesis. 15-PGDH metabolizes intracellular PGE2 so that this ligand is unable to bind EP receptors, which results in suppression of PGE2 signaling”.

The tumor suppressor 15-PGDH is the key enzyme in prostaglandin E2 catabolism and is down-regulated in colorectal cancer (CRC) tissue. Canonical Wnt signaling is frequently elevated in colon cancers and has been shown to down-regulate 15-PGDH expression.

The most readily available 15-PGDH inhibitor that I could find is licorice root extract which contains β-Glycyrrhetinic acid.

I don’t think I will be adding any 15-PGDH inhibitors to my supplement list at this time.


Here is a link to the Empium Bio website. There are no updates in the past 3 years in their “news” section of the website, so I think that company may be dead now.

DesertShores, You mentioned licorice root. Here is a PubMed study using Licorice Flavonoid Oil (LFO) to help increase muscle mass after rehabilitation treatment for osteoarthritis of the knee. I don’t see it readily available as a supplement, but I did find references in other articles to Licorice Flavonoid Oil (LFO: Kaneka Glavonoid Rich Oil ). Of course, licorice root extract is readily available, but I wonder how different it would be than the LFO? I will investigate this further.

The effects of licorice flavonoid oil with respect to increasing muscle mass: a randomized, double-blind, placebo-controlled trial - PubMed.

Fwiw castor oil is a very common substsnce that increases pge2