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Inhibiting leukotrienes and aging
Posted: Saturday, September 17, 2022 6:02 AM
Joined: 2/26/2016
Posts: 287

I found a great well-researched article on leukotrienes written by a PhD holder in molecular biology that explains their functions without getting into a lot of difficult medical terminology. Leukotrienes appear to be envolved in the increased neuroinflammation present in Alzheimers and in other dementias related to aging.

Leukotrienes are lipid signaling molecules that elicits a immune response and are among the first responders in our innate immune system. There are two main types - leukotriene B4 and cysteinyl leukotrienes. Montelukast inhibits cysteinyl leukotrienes by blocking them at their receptor sites on immune cells.  

No drug has yet been developed that safely and effectively blocks leukotriene B4 at its receptor site. Astra Zeneca however has developed the drug AZD5718, which inhibits both leukotriene B4 and cysteineyl leukotrienes. AZD5718 inhibits 5-lipooxygenase activating protein (FLAP) which is necessary to convert arachidonic acid to leukotriene B4 and cysteinyl leukotrienes. AZD5718 is now in three separate FDA clinical trials to treat certain types of heart disease, kidney disease and asthma. Montelukast will still be the preferred leukotriene inhibiting drug for Alzheimers and dementia because, according to Astra Zeneca, AZD5718 can not cross the blood-brain barrier to any significant degree.

Inhibiting cysteinyl leukotrienes with montelukast and other leukotriene inhibitors could bring positive results.

1. Lowering the activity of white blood cells (eosinophils and mast cells) for a lower immune response and less inflammation. A immune response that is too high and off target, which is often the case in older people, can increase aging and cellular damage.

2. Reducing cytokine production which results in less damage to healthy cells.

3. Reducing brain microglial swelling and over-activation which drives neuro-inflammation present in Alzheimers and other dementias.

4. Reducing blood-brain barrier leakiness, which is a characteristic of Alzheimers and dementia. 

5. Reducing bone loss as we grow older.

AZD5718 inhibits both B4 and cysteinyl leukotrienes but does not cross the blood-brain barrier in a significant amount. However according the mentioned article, inhibiting B4 could possibly promote these positive outcomes:

1. Inhibiting production of plaques inside arteries and reducing the incidence of heart disease.

2. Helping to improve the condition of patients with Chronic Obstructive Pulmonary Disease (COPD).

3.Helping lower insulin resistance in diabetes.

4. Helping prevent and treat rheumatoid arthritis.

5. Being more effective than montelukast in treating asthma and allergies

We should get more information about inhibiting B4 and cysteinyl leukotrienes upon completion of the three ongoing AZD5718 trials, which is estimated to be completed for kidney disease (late 2022), for heart disease (2023) and for asthma (2024).

Leukotrienes are powerful signaling molecules that increase immune system activation when we are under attack by bacteria, viruses and other agents. They have allowed humans to survive for tens of thousands of years in a hostile environment. But with modern medicine and public sanitation, we may not need such a powerful activation of our immune system that can increase cell damage, especially as we are older. It appears that leukotriene inhibiting drugs like montelukast and AZD5718 and others simular drugs to come can slow down the over-activated immune system in older people and allow them to live longer and healthier lives. 

You can find scientific references in the above mentioned "selfhacked" article.