Blocking endotoxin may reverse cognitive decline of aging

haidut

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Another study implicating endotoxin (LPS) and its associated receptor (TLR4) in a phenotype of aging considered "normal" by mainstream medicine, though it almost universally progresses into dementia territory with advancing age, to the point where 90%+ of people over 85 have at least moderate levels of dementia, even if not officially diagnosed with Alzheimer's disease (AD). Well, the study below demonstrates that there may be nothing "natural" or "unavoidable" about this cognitive decline associated with (actually, due to) aging, and that a major component of it is chronic inflammation, driven by activation of TLR4. While the article never mentions endotoxin by name and tries to fearmonger about blocking TLR4, it does concede that in older people blocking TLR4 may be highly beneficial, at least when it comes to brain health. In fact, a "surprising" finding of the study was that remove TLR4 completely (genetic knockout model) did not have any detrimental effects on the animals. Thus, chemically blocking TLR4 would be even less risky as it comes nowhere near the effectiveness of deleting/removing the TLR4 receptor altogether. A number of OTC substances act as TLR4 blockers including progesterone, androgens, pregnenolone, emodin, vitamin D3, vitamin A, vitamin K, etc. In addition, mos of the old and well-tested tricyclic molecules used as antidepressants in the 1960s and 1970s are also quite potent. Ketotifen and cyproheptadine are two such chemicals, and even non-tricyclics such as diphenhydramine (Benadryl) are quite effective at blocking TLR4.

TLR4 Deletion Improves Cognitive Brain Function and Structure in Aged Mice - PubMed
Toll-like Receptor Deletion Improves Memory in Aged Mice

"...In a new study, genetic deletion of the TLR4 receptor ameliorated aspects of age-related cognitive decline in naturally aging mice, probably due to decreased inflammation [1]....The researchers do not report any deleterious effects of TLR4 knockout, which is intriguing since TLR4 is an important part of the immune system. The reason for that might be that lab animals live in a cleaner environment and encounter fewer pathogens."
"...Since TLR4 participates in the innate immune response, going after it might seem like a bad idea, but with age, due to its inflammatory nature, TLR4’s overall contribution likely becomes negative. Whichever is the case, lifelong TLR4 knockout is unavailable for humans, but chemically suppressing TLR4 later in life is an intriguing approach, though it demands a lot of further research."
 

Lonewolfx

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Interesting stuff... but wasn't there another study that connected Benadryl usage with increasing Alzheimers?
 
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haidut

haidut

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Interesting stuff... but wasn't there another study that connected Benadryl usage with increasing Alzheimers?

It was epidemiological and it said all anticholinergic drugs (Benadryl is one of them) were associated with increased risk. I suspect it was an attempt to salvage the "cholinergic hypothesis" on which virtually all Alzheimer drugs to date have been based on...and have all miserably failed.

So, if cholinergic drugs don't work and make matters worse, my bet would be that anticholinergic ones would help. And we have a confirmation of sorts, as the officially approved drug Alzheimer drug memantine is anticholinergic, just like Benadryl.
 

Lonewolfx

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Ok great, thank you. I was careful of my Benadryl usage because of that but I guess it's not a worry after all.
 

J.R.K

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It was epidemiological and it said all anticholinergic drugs (Benadryl is one of them) were associated with increased risk. I suspect it was an attempt to salvage the "cholinergic hypothesis" on which virtually all Alzheimer drugs to date have been based on...and have all miserably failed.

So, if cholinergic drugs don't work and make matters worse, my bet would be that anticholinergic ones would help. And we have a confirmation of sorts, as the officially approved drug Alzheimer drug memantine is anticholinergic, just like Benadryl.
An interesting study but not terribly surprising, blocking endotoxin ie preventing yourself from poisoning yourself makes common sense. Perhaps that is the problem.
I would wonder about including something as simplistic as carrot salad, well cooked mushrooms, or bamboo shoots with vinegar and coconut oil, as a mild antibiotic to reduce the bacterial load as a preventative measure. It would be interesting to see if this would have any effect on the percentage of the population afflicted with Alzheimer’s.
 

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