Blocking Inflammation From PUFA Reverses Brain Aging

haidut

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This study is important on several levels. First, it shows that it is possible to fully reverse brain aging. Second, it suggests that one of the main mechanisms for brain aging is inflammation induced by the primary metabolites of PUFA - the leukotrienes. I talked about them in my first show with Danny Roddy. So, how can PUFA be good for us if its metabolites cause inflammation and brain aging, and bloking their effect or inhibiting their synthesis reverses brain aging?!?! Show this to your doctor the next time he tries to tell you about "essential" fatty acids.
Finally, the study suggests that there are drugs that can block some of the negative effects of already stored PUFA. Scroll to the end for more on that.

https://www.newscientist.com/article/dn ... AL-twitter

"...A drug called montelukast (Singulair), regularly prescribed for asthma and allergic rhinitis, blocks these receptors, so Aigner and his colleagues tried it on young and old rats. The team used oral doses equivalent to those taken by people with asthma. The older animals were 20 months old – roughly equivalent to between 65 and 75 in human years. The younger rats were 4 months old – about 17 in human years. The animals were fed the drug daily for six weeks, while another set of young and old rats were left untreated. There were 20 young and 14 old rats in total....By the end of their six-week drug regime, though, old animals performed as well as their younger companions. “We’ve restored learning and memory 100 per cent, to a level comparable with youth,” says Aigner. He presented his findings last week at the Society for Neuroscience meeting in Chicago."

The drug used to reverse brain aging is called montelukast and it acts as a leukotriene antagonist. I guess in Peat-world you can also call it a partial PUFA antagonist, with aspirin being another.

https://en.wikipedia.org/wiki/Montelukast

Another related drug that has the same effect is called zafirlukast. The second drug acts by inhibiting the enzyme 5-lipoxygenase (5-LO), which prevents leukotrienes from even getting synthesized. So, montelukast is to zafirlukast what cyproheptadine is to fenclonine, so to speak. According to the FDA database, both montelukast and zafirlukast have nearly identical effects. Why am I bringing this up? Because another very potent 5-LO inhibitor is good ole' minocycline.
https://en.wikipedia.org/wiki/Arachidon ... inhibitors

And since this would not be a haidut post without an honorable mention of cyproheptadine, this study shows that cyproheptadine is also a leukotriene antagonist, albeit weaker than montelukast:
http://www.ncbi.nlm.nih.gov/pubmed/9098782

So there you have it - restricting PUFA intake, or taking minocycline reverses brain aging. This is really not that surprising, minocycline has been shown in animal models to inhibit pretty much every neurodegenerative condition (MS, ALS, AD, PD, etc). Guess what they all have in common? Inflammation.

Btw, this study raises the interesting possibility of using minocycline (or other tetracyclines) or cyproheptadine to block some of the effects of already ingested PUFA. Taking aspirin as well should block the remaining.
 

charlie

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Incredible.

:hattip
 
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jaa

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Great work as always providing context for this news item haidut!

I just wanted to reiterate a point you made in one of your previous posts that it's not a good idea to take cypro with aspirin since the serotonin reducing drugs can cause bleeding.
 

peatra

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I've acquired some montelukast to experiment with its effect. It looks similar to ibudiblast in its MOA and therefore potential effects on brain inflammation - unfortunately that was too cost-prohibitive for me, but montelukast is relatively cheap. Could you explain more of what you mean with zafirlukast? Do you mean it is superior? I'm not as familiar with cypro.
 
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haidut

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peatra said:
post 108701 I've acquired some montelukast to experiment with its effect. It looks similar to ibudiblast in its MOA and therefore potential effects on brain inflammation - unfortunately that was too cost-prohibitive for me, but montelukast is relatively cheap. Could you explain more of what you mean with zafirlukast? Do you mean it is superior? I'm not as familiar with cypro.

I just meant that montelikast and zafirlukast are similar drugs. Montelukast acts like an antagonist of the leukotrienes that are already formed, while zafirlukast inhibits the very synthesis of leukotrienes. Both should have similar effects, with zafirlukast being preferable but as expected it is much more expensive. Cyproheptadine seems to act like montelukast and you can do a search on the forum for it as there are quite a few posts about cyproheptadine and its many benefits. Minocycline seems to act like zafirlukast and you can search the forum for it as well since just like cyproheptadine there are quite a few posts about it as well.
 
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peatra

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haidut said:
post 108758
peatra said:
post 108701 I've acquired some montelukast to experiment with its effect. It looks similar to ibudiblast in its MOA and therefore potential effects on brain inflammation - unfortunately that was too cost-prohibitive for me, but montelukast is relatively cheap. Could you explain more of what you mean with zafirlukast? Do you mean it is superior? I'm not as familiar with cypro.

I just meant that montelikast and zafirlukast are similar drugs. Montelukast acts like an antagonist of the leukotrienes that are already formed, while zafirlukast inhibits the very synthesis of leukotrienes. Both should have similar effects, with zafirlukast being preferable but as expected it is much more expensive. Cyproheptadine seems to act like montelukast and you can do a search on the forum for it as there are quite a few posts about cyproheptadine and its many benefits. Minocycline seems to act like zafirlukast and you can search the forum for it as well since just like cyproheptadine there are quite a few posts about it as well.

Thanks haidut! Zafirlukast does sound even better. Something to keep in mind for the long term when a generic becomes available.
 
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Peata

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haidut said:
post 106025 This study is important on several levels. First, it shows that it is possible to fully reverse brain aging. Second, it suggests that one of the main mechanisms for brain aging is inflammation induced by the primary metabolites of PUFA - the leukotrienes. I talked about them in my first show with Danny Roddy. So, how can PUFA be good for us if its metabolites cause inflammation and brain aging, and bloking their effect or inhibiting their synthesis reverses brain aging?!?! Show this to your doctor the next time he tries to tell you about "essential" fatty acids.
Finally, the study suggests that there are drugs that can block some of the negative effects of already stored PUFA. Scroll to the end for more on that.

https://www.newscientist.com/article/dn ... AL-twitter

"...A drug called montelukast (Singulair), regularly prescribed for asthma and allergic rhinitis, blocks these receptors, so Aigner and his colleagues tried it on young and old rats. The team used oral doses equivalent to those taken by people with asthma. The older animals were 20 months old – roughly equivalent to between 65 and 75 in human years. The younger rats were 4 months old – about 17 in human years. The animals were fed the drug daily for six weeks, while another set of young and old rats were left untreated. There were 20 young and 14 old rats in total....By the end of their six-week drug regime, though, old animals performed as well as their younger companions. “We’ve restored learning and memory 100 per cent, to a level comparable with youth,” says Aigner. He presented his findings last week at the Society for Neuroscience meeting in Chicago."

The drug used to reverse brain aging is called montelukast and it acts as a leukotriene antagonist. I guess in Peat-world you can also call it a partial PUFA antagonist, with aspirin being another.

https://en.wikipedia.org/wiki/Montelukast

You inspired me to get my Singulair Rx re-filled today.

I have used it off and on over the years short-term during my worst asthma/allergy times, such as this time of year. I don't know what it really does for me as I've always taken it along with a lot of other meds such Advair (on a schedule) and albuterol (as needed), along with other meds, but this year I'm not doing nearly as bad and have not needed Advair but only used theanine daily... however in the last few days the cough was getting worse at certain times (like a.m. or at night) and I felt like I needed the albuterol, so I added that back as needed.
 
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haidut

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I just wanted to add this study, showing that vitamin E, and especially gamma tocopherol are also potent inhibitors of the 5-LOX enzyme AND a delta tocopherol metabolite (13-COOH) acts like leukotriene antagonists comparable in strength to a pharma drug AND the same metabolite is an COX1/COX-2 inhibitor as well. The doses for reaching the effective concentrations are about 200mg for gamma tocopherol and 400mg for alpha tocopherol.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050064/

"...Leukotriene antagonists and 5-LOX inhibitors have been used to treat asthma and inflammatory diseases (2). Here we have demonstrated that γT, δT, and γTE, at physiologically relevant concentrations, suppressed neutrophil-mediated LTB4 production much more potently than αT by blocking intracellular calcium increase, which consequently led to inhibition of ERK phosphorylation and 5-LOX translocation, a key step for activation of 5-LOX. Unlike the unmetabolized vitamins, 13′-COOH, a long-chain metabolite of vitamin E, decreased leukotriene formation by direct inhibition of the 5-LOX activity."

"...We have previously demonstrated that 13′-COOH derived from δT strongly inhibits COX-1 and COX-2 by competing with AA for the binding to the substrate site of COXs (17). In this study, we found that 13′-COOH inhibits 5-LOX activity at a potency comparable with that of zileuton, a competitive inhibitor of 5-LOX. "
 
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haidut

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lexis said:
post 111192 http://www.medicalnewstoday.com/articles/299637.php

Hypertension drug reduces inflammation from traumatic brain injury

Telmisartan is an interesting drug since endurance athletes use it as a doping agent.
https://en.wikipedia.org/wiki/Telmisart ... _of_action

The *sartan drugs seem to be able to dramatically increase mitochondrial biogenesis, and reverse aging in some animal models. The related drug losartan has been to shown to reverse mitochondrial aging in rats.
http://www.natap.org/2011/newsUpdates/081811_13.htm

Btw, taurine has the same angiotensin II blocking effects as all the *sartan drugs an unsurprisingly taurine has also been found to reverse mitochondrial aging.
 
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narouz

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Noticed this article,
Chapter 16: Leukotriene Blocking Drugs One Year Later
http://www.asthma.partners.org/NewFiles/BoFAChapter16.html

Here's an excerpt.
Mentions a third drug, zileuton (Zuflo)...


"Several years ago scientists discovered that one group of chemicals causing these asthmatic effects in the bronchial tubes are the leukotrienes. They are very powerful in their effects; very small amounts cause asthmatic-type reactions that are relatively long lasting. Compared to the better known chemical involved in allergic reactions, histamine, one one-thousandth the amount of leukotrienes brings about the same response in the bronchial tubes. Until last year no medication was available to block the action of these leukotrienes.Then, scientists working at pharmaceutical companies discovered two types of medication that block these leukotrienes. One drug, zileuton (Zyflo®) reduces the amount of leukotriene that the body produces. Another, zafirlukast (Accolate®) [and now montelukast (Singulair®)], blocks the action of leukotrienes before they exert their effects (as antihistamines block the action of histamine). Other leukotriene-blocking medications of these two types will likely become available in the near future."
 

Peata

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I just wanted to add this study, showing that vitamin E, and especially gamma tocopherol are also potent inhibitors of the 5-LOX enzyme AND a delta tocopherol metabolite (13-COOH) acts like leukotriene antagonists comparable in strength to a pharma drug AND the same metabolite is an COX1/COX-2 inhibitor as well. The doses for reaching the effective concentrations are about 200mg for gamma tocopherol and 400mg for alpha tocopherol.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050064/

"...Leukotriene antagonists and 5-LOX inhibitors have been used to treat asthma and inflammatory diseases (2). Here we have demonstrated that γT, δT, and γTE, at physiologically relevant concentrations, suppressed neutrophil-mediated LTB4 production much more potently than αT by blocking intracellular calcium increase, which consequently led to inhibition of ERK phosphorylation and 5-LOX translocation, a key step for activation of 5-LOX. Unlike the unmetabolized vitamins, 13′-COOH, a long-chain metabolite of vitamin E, decreased leukotriene formation by direct inhibition of the 5-LOX activity."

"...We have previously demonstrated that 13′-COOH derived from δT strongly inhibits COX-1 and COX-2 by competing with AA for the binding to the substrate site of COXs (17). In this study, we found that 13′-COOH inhibits 5-LOX activity at a potency comparable with that of zileuton, a competitive inhibitor of 5-LOX. "


If I don't take Singulair for even one night, the next morning I am already experiencing the chronic cough again. I am trying to find other things to take care of the cough. Mainly because I do not want to be dependent on my doctor for the prescription. He only lets me get one month at a time and now wants me to come back in. When I go in, he pushes Metformin and Mammograms. I don't want to go through the process of getting another doctor right now, I'd much rather just not go to one at all if I don't have to. So I'm trying other things to manage it. Back to the chronic cough (it comes on in late Sept and lasts to Spring if I'm to go by what happened last year as it's also happening this year).

Obviously, Singulair works great but I must stay on it, not even missing one dose.

Theanine worked, but only in large doses and the effect seemed to last only a couple hours.

Cyproheptadine does not seem to help.

I'd try Aspirin but I'm already on Cypro and Vitamin E, and don't wish to mess with platelets in a way that could be dangerous.

So I'm increasing the Swanson Ultra Max Gamma Tocopherols back to 2 gelcaps instead of 1 even though that's probably a really high dose.

Open to other suggestions.

The other things I take: B1 250 mg- 500 mg, Niacinamide 500 mg 2 x day, D2000&K1000 every other day, 15 mg Biotin 2 x day, and a little B complex. Cypro, dose varies. I'll probably taper off this eventually, I don't like to stay on it continuously. Also 1 g. Taurine.
 
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If I don't take Singulair for even one night, the next morning I am already experiencing the chronic cough again. I am trying to find other things to take care of the cough. Mainly because I do not want to be dependent on my doctor for the prescription. He only lets me get one month at a time and now wants me to come back in. When I go in, he pushes Metformin and Mammograms. I don't want to go through the process of getting another doctor right now, I'd much rather just not go to one at all if I don't have to. So I'm trying other things to manage it. Back to the chronic cough (it comes on in late Sept and lasts to Spring if I'm to go by what happened last year as it's also happening this year).

Obviously, Singulair works great but I must stay on it, not even missing one dose.

Theanine worked, but only in large doses and the effect seemed to last only a couple hours.

Cyproheptadine does not seem to help.

I'd try Aspirin but I'm already on Cypro and Vitamin E, and don't wish to mess with platelets in a way that could be dangerous.

So I'm increasing the Swanson Ultra Max Gamma Tocopherols back to 2 gelcaps instead of 1 even though that's probably a really high dose.

Open to other suggestions.

The other things I take: B1 250 mg- 500 mg, Niacinamide 500 mg 2 x day, D2000&K1000 every other day, 15 mg Biotin 2 x day, and a little B complex. Cypro, dose varies. I'll probably taper off this eventually, I don't like to stay on it continuously. Also 1 g. Taurine.

some people find that B12 quells their cough. have you tried it?

Have you tried reduced breathing aka Buteyko method or bag breathing? In my experience a cough is due to a very low CO2 level in the body and this can be fixed (and fix a lot of other things) with this type of training.
 

Peata

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some people find that B12 quells their cough. have you tried it?

Have you tried reduced breathing aka Buteyko method or bag breathing? In my experience a cough is due to a very low CO2 level in the body and this can be fixed (and fix a lot of other things) with this type of training.

I have not tried extra B12. I do use methods to increase CO2, such as breathing with mouth shut, tenting blanket over face at night, and B7 increasing CO2. I do not think my problem is dominantly a CO2 issue as this seems to come on in a seasonal way and has responded to inhalers and leukotriene inhibitor more than anything.
 

Peata

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I thought the Niacinamide I was taking was helping my cough at first, but my cough was bad yesterday, then in the night I used two pillows to elevate my head so I could breathe better. I felt like I was suffocating from fluid or something in my lungs. This morning my lungs were sore and filled with something - fluid, mucous, or just swollen airways making it seem like they were filled. When I inhaled and exhaled there was wheezing, slight rattling both in and out. The cough was bad until about noon. Now I'm pretty settled. I've been mindful of breathing less to help things. I also took that extra gelcap of Vitamin E. Other than that, supps have been the same.

In case anyone wonders, I have had my lungs tested just last year, and lung function is fine. In fact, was better than average for my age. In past have been Dxd with copd, chronic bronchitis. This is allergic related. Allergies to things like tree pollen, dust, mold, some weeds, cat. But then things get bad in the Fall/Winter with my lungs. Last year I was on Antibiotics, inhalers and all that. I went to doctor twice over it all just for the lung issues last winter. After the pollen comes in the spring, I'm pretty much OK until Fall again.

I have thought about using Benadryl again because unlike Cypro, Benadryl really knocks down my allergy symptoms. I always take as small amount as I can to control symptoms so I won't have much sedation and so I can hopefully not raise serotonin (still not sure what dose raises it).

I tried Nasalcrom, it didn't help.
 

Blossom

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You might be able to get singulair through an online pharmacy. Here's some information on benadryl dosage and serotonin.
benadryl question | Ray Peat Forum
It's haidut answering a similar question I had awhile back. I hope you are able to get the allergy related breathing issues resolved @Peata. It sounds like you have thought through all of this thoroughly and are on the right track.
 

Peata

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You might be able to get singulair through an online pharmacy. Here's some information on benadryl dosage and serotonin.
benadryl question | Ray Peat Forum
It's haidut answering a similar question I had awhile back. I hope you are able to get the allergy related breathing issues resolved @Peata. It sounds like you have thought through all of this thoroughly and are on the right track.
Thank you, Blossom. I missed that one somehow. That's very helpful. I never took enough to raise serotonin either.

This morning my lungs felt like they had one small area that needed cleared out (with a cough) and then I've been pretty much fine. Huge difference between yesterday and today. It's possible the horrible symptoms the last few days was from a sort of rebound effect from going off Singulair. Or maybe the extra tocopherols is helping. Or.. I don't know.

I also notice I can cough after eating, as though I also have a reflux issue, and sometimes I cough under stress. But that is different than the allergic cough.

Anyway I just brought this up here since the topic has to do with Singulair and also brain inflammation - I do not want to go back to brain fog because I'm off the med or the cough signals inflammation building up all over. I want to keep my thinking as clear as it's been lately. It's probably from a combination of things. I just thought I'd look for more suggestions to get that inflammation under control.
 

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