#21

Here is a bit more news on this topic.

Known drug restarts flow of brain cleaning fluids

The team then set out to see if they could revive the lymphangions and identified a drug called prostaglandin F2α, a hormone-like compound commonly used medically to induce labor and known to aid smooth muscle contraction.

The lymphangions are lined with smooth muscle cells, and when the researchers applied the drug to the cervical lymph vessels in older mice, the frequency of contractions and the flow of dirty CSF from the brain both increased, returning to a level of efficiency found in younger mice.

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Common drug (prostaglandin F2α) restores youthful function to clean up aging brains - Rochester Medical Center
#22

The reason I don’t like Aspirin is that it inhibits Cox1 and limits the creation of prostaglandins

https://www.gastrojournal.org/article/0016-5085(90)90277-8/fulltext

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Devices that Reverse Alzheimer's Cognitive Decline and Increase Human Longevity
#23

This is interesting. I wonder if oxytocin might have a similar effect as it increases labor contractions also. In addition, since the effect of clearance utilized cervical lymphatic pathways, why not go to a lymphedema therapist regularly to perform treatment.

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#24

At least for mice, it’s a topical cream. We’ll see if it works the same in humans.
“Sure enough, administering the drug to the elderly mice with a topical cream got the pumps working again to the point that the team saw the flow of dirty CSF out of the brain return to the same level of efficiency seen in younger mice.”
See this thread:
https://spotify.localizer.co/t/common-drug-restores-youthful-function-to-clean-up-aging-brains/15669/2?u=ng0rge

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#25

a formulation comprising an erectile dysfunction treating amount of a prostaglandin, namely prostaglandin E1, prostaglandin E2, or pharmaceutically acceptable salts or derivatives thereof, wherein the prostaglandin is formulated with a small amount of prostaglandin F.sub.α2 together with a pharmaceutically acceptable delivery medium and/or a lubricant.

It seems it has other beneficial effects. I plan on acquiring some and rubbing it in vigorously.

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#26

The article says: “It would be of interest in future studies
to assess the effects of smaller aspirin doses on mu-
cosal PGE2, and PGF2a content and injury in light of the
widespread use of low-dose aspirin in the prophylaxis
of cardiovascular diseases” … so maybe the ship hasn’t
sailed quite yet. In this study, subjects received 2.6g not 81mg.

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#27

Perhaps it’s the vigorous rubbing that produces the effects…:joy:

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#28

It is very clear that aspirin acts by inhibiting cox-1 and cox-1 is needed to create prostaglandins. Whether you seen an effect at 81mg of aspirin on AD I don’t know.

Personally I have tried some low levels of aspirin and seen how aspirin appears to reduce melatonin production the next night and a little bit the night afterwards. (it tends to fade away over 48 hours on a linear model).

AIUI it also reduces cortisol and the CAR (Cortisol Awakening Response)

Aspirin has been shown to attenuate the adrenocorticotropic hormone (ACTH) and cortisol response to physiological challenge suggesting its potential to act as an augmenting agent in depression.

What is interesting about taking aspirin during the night is that potentially it can help sleep during the night that it is taken, but disrupt it the next night.

However, in the round I avoid aspirin.

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#29

Do you measure melatonin, or is the this some indirect triangulation somehow?

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#30

I monitor it by how it affects sleep. With less melatonin it is harder to get to sleep and sleep does not last as long.

You can experiment with Aspirin and see the effects. When it reacts with Cox-1 that lasts for about 48 hours as cox-1 is replaced. There is somewhere a paper which shows a straight line reduction in inhibitory effect.

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#31

Brief searching for “prostaglandin aging” and similar terms finds many reports that PG levels rise with age, and are causal for some forms of impairment. I don’t know how to reconcile these claims, other than that the effects are likely tissue specific. The alleged improvement in overall (mouse) health with 15-PDGH inhibition is something that could bear further investigation.

#32

Prostaglandins are on the pathway to all sorts of things. I don’t think you can take a simplistic view that more is good or less is good. My personal concern is to enable the body to produce prostaglandins when it decides they are needed.

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#33

Epirium Bio Presented Late-Breaking Preclinical Data of MF-300 (15-PGDH Enzyme Inhibitor) at the Gerontological Society of America Annual Scientific Meeting 2024

MF-300 is a first-in-class, orally administered, 15-PGDH enzyme inhibitor shown to restore muscle quality and strength in aged mice

November 13, 2024 10:15 PM Eastern Standard Time

SAN DIEGO–(BUSINESS WIRE)–Epirium Bio, Inc. (Epirium), a biopharmaceutical company advancing medicines for neuromuscular and fibrotic diseases, presented preclinical data for its lead candidate, MF-300, at the Gerontological Society of America’s (GSA) annual meeting being held November 13-16, 2024, in Seattle, WA.

MF-300 is a first-in-class, orally administered, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme inhibitor in development for the treatment of age-induced muscle weakness, or sarcopenia. According to the U.S. Food and Drug Administration’s (FDA) Patient-Focused Drug Development Initiative report on sarcopenia, up to a third of Americans over the age of 60 are affected by sarcopenia, which increases their risk for falls, fractures and mortality. There are no FDA-approved therapies for sarcopenia, a disease that disproportionately affects fast-twitch muscle fibers, and is characterized by decreased muscle quality and muscle mass.

Epirium’s study, presented at GSA, tested whether MF-300 could improve muscle force in aged mice. After 12 weeks of oral administration at its target dose, MF-300 significantly increased absolute and specific force (i.e., force per unit of muscle) of isometric plantar flexion in aged animals compared to vehicle. The study also demonstrated that MF-300 significantly increased specific force and contraction rate in clinically relevant fast-twitch muscle. Together, these data show that MF-300 has the potential to reverse the decline in muscle quality (i.e., the loss of specific muscle force) that occurs with aging.

“The capacity of muscle to generate force is a better indicator of muscle quality, health, overall functional capacity, and survival than the quantity of muscle mass. MF-300’s novel mechanism of action on intrinsic muscle properties has the potential to improve functional outcomes and allow people to live physically independent lives longer,” said Dr. Scott Delp, Professor of Bioengineering, Stanford University Schools of Medicine and Engineering.

Details of the poster presentation include:

Title: MF-300 (15-PGDH Enzyme Inhibitor) Reverses Age-Related Muscle Weakness in Mice by Restoring Muscle Quality
Presenter: Micah Webster, Ph.D.
Poster Number: 1914819

The presentation is available in the “Posters and Publications” section of Epirium’s website, www.epirium.com

About MF-300

MF-300 is an orally bioavailable small molecule that reversibly binds to the Prostaglandin E2 (PGE2)-binding site of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that converts PGE2 to an inactive metabolite. MF-300 target engagement inhibits 15-PGDH activity, stabilizing and increasing levels of PGE2 in a cell-based assay and in vivo in skeletal muscle in preclinical studies.

In humans and rodents, 15-PGDH gene expression is elevated in muscle coincident with the onset of age-induced muscle weakness. PGE2, a lipid signaling molecule with multiple beneficial effects on the motor unit, including enhanced muscle quality and improved function of the neuromuscular junction, is reduced in skeletal muscle of aged mice due to increased activity of 15-PGDH. Inhibiting 15-PGDH in aged muscle may be a strategy to increase physiologic levels of PGE2 to improve muscle quality and function.

GSA2024_Poster_Epirium_final.pdf (855.5 KB)

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#34

Sort of the opposite to Aspirin and NSAIDs which inhibit prostaglandin creation.

#35

Excellent news. Do we have any other candidate interventions against muscle aging?

#36

Absolutely - two come to mind right now:

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#37

Its initial focus was on inflammatory bowel disease and the promotion of blood cell reconstitution after bone marrow transplant. The company’s pipeline targets prostaglandin, a family of signaling molecules associated with tissue repair and regeneration. Their lead product blocks 15-prostaglandin dehydrogenase (15-PDGH), an enzyme that breaks down prostaglandin. In preclinical studies the drug appears to protect against colitis and idiopathic pulmonary fibrosis, a rare and fatal disease that involves scarring of the lungs. It also seems to promote liver degeneration.

“The enzyme 15-PGDH plays a key role in many disease-relevant processes such as stem cell self-renewal and epithelial barrier repair,” said Raymond Deshais, senior vice president of Global Research at Amgen. “Given the encouraging preclinical data to date, we are excited about the opportunity to develop a novel therapy with potential in a range of important inflammatory disease indications.”

https://www.businesswire.com/news/home/20200831005502/en/Rodeo-Therapeutics-Nominates-First-in-Class-Oral-Development-Candidate-for-Inflammatory-Bowel-Disease

#38

Since you take such large doses of melatonin daily, I don’t see how low-dose aspirin would negatively affect you.

Low-dose aspirin has so many positive studies showing its influence in the prevention of everything from bowel cancer to the prevention of cardiovascular events, it boggles my mind that you wouldn’t take it, especially considering your age, unless you are one of those that have stomach or intestinal bleeding as a side effect.

#39

I have not tried it with under 100mg melatonin during the night, but unless i am drinking i only take melatonin at night