167 replies to this topic

[Guest]

Just a thought on some recent papers:

 

 

the facilitation of autophagy (ap) seems to be a - or even the - major pathway by which rapamycin exert its health and life extending action. The are roughly 2 kinds of ap:

 

a) non-selective ap targets all kinds of cellular components for recycling, to access building blocks for cellular metabolism in case of cellular starvation (in practice resulting from organismal starvation - think of caloric restriction)

 

This recycling can include damaged as well as undamaged components of the cell.

 

 

b) selective ap specifically targets damaged components of the cell.

 

This process is thought to be largely independent of starvation signaling, i.e. non reliant on mTOR signaling

 

https://www.ncbi.nlm...les/PMC4871809/

"Mechanisms of Selective Autophagy"

 

 

Imagine you have a bunch of damaged mitochondria. What kind of ap is better? In case of non-specific ap the cell targets damaged as well as undamaged mitochondria for recycling. At some point the remaining mitochondria are going to multiply to make up for increased energy demand or just to replace recycled mitochondria. As of current knowledge there is no preferential muliplication of undamaged ones. So statistically you end up facing the same composition in term of the ratio of damaged and undamaged mitos.

 

While the mechanisms of mTOR acitvated ap are not greatly understood, it is currently believed that mTOR signaling - and hence rapamycin - favours non-specifiv ap (there are at least 10 papers on that, e.g. https://www.ncbi.nlm...s/PMC4792600/).

 

 

Glucosamine seems to be a different game. While in vitro is has been demonstrated to affect mTOR/AMPK signaling just as rapamycin, there is an additional channel of non-mTOR ap (in other words: potentially selective ap):

 

https://www.research...phagy_induction (2018)

https://www.research...pendent_pathway (2009)

 

Also in the one and only mice study for glucosamine, the life extending effect in 23 month old mice is proven to be independend of the hexosamine channel:

https://www.ncbi.nlm...les/PMC3988823/

 

 

This is quite curios, as jontly with mTOR the hexosamine channel is the nutrient sensing mechanism of the cell, given a plausible narrative to non-starvation/non-mTOR driven ap caused by Glucosamine:

"Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling" (2018)

https://www.ncbi.nlm...les/PMC6136272/

 

 

In 3 observational studies low dose glucosamine (about 1500 mg a day - I mean low dose, because the dose at which side effects occur is more than 10 times; in contrast to metformin and rapamycin) appeared to exert stupifyingly large tumor supressor effects of about 50% reduction in cancer death for long term consumers of frequent (i.e. daily) glucosamine. This is another plausible point for the narrative: in recent years there is emerging consensus, that many cancers are actually driven by mutant mitochondria. If glucosamine indeed preferably targets damaged mitochondria (as opposed to rapamycin) this could explain the results.

 

 

Glucosamine seems to manifest its benefits via different channels than mTOR. Should people start taking glucosamine in addition to their regular rapamycin/metformin supplements?

 

 

I know there is a lot of evidence for metformin(?), that's why most people in this forum are supplementing it and many take rapamycin. Nobody takes glucosamine for life extension like they do for metformin/rapa. I guess it's because the risk-reward ratio is not as good as metformin/rapamycin?

[Kimer Med]

I recently added Glucosamine to my stack. During my research, I found support for the following:

• Extends average lifespan in mice by 6%
• Anti-cancer effects in humans
• Activates AMPK (like Metformin and Resveratrol)
• Inhibits mTOR (like Rapamycin)
• Anti-inflammatory
• Increases mitochondrial mass
• Mimics low-carb diet
• Free from serious side-effects

You want the sulfate form, not the HCl, and I suggest one that's not made from shellfish, to minimize risk of contaminants.

 

More info at the link:

 

https://examine.com/...ts/glucosamine/

 

It's also worth noting that bone broth is high in Glucosamine. The GAPS Diet wins again!

[smithx]

I've been taking about 12g / day of n-acetyl glucosamine (from shellfish) since 2010. Have you come across anything about that with respect to these results?

 

I take it to correct an auto-immune condition (which it did/does almost entirely) and because it's an immediate precursor of hyaloronic acid and therefore good for joints (even in the absence of auto-immune conditions).

 

 

[QuestforLife]

I'll say it before and I'll say it again: IMO glucosamine is a keto mimetic drug: it impedes glycolysis therefore placing more emphasis on mitochondria to stay healthy. It stands to reason this would make it rather difficult for cancer.

[Guest]

Glucosamine recreating a ketogenic diet might well be the case. On the outset this sound improbable:

 

Glucosamine is a competitve inhibitor of glucose metabolising enzymes - it doesn't disable the enzymes permanently (that would be uncompetitive inhibition). This means, if the substrate (in this case glucose) is much more abundant, it still is going to "win" most of the time for access to the enzyme.

 

Average people eat anywhere from 80 to 300 grams of carbs (so eventually glucose) a day. The typical amount of Glucosamine - if taken daily - is 1,5 gram. The variation of day-to-day glucose intake is probably much larger than 1,5 gram. So how can that little glucosamine cause a pronounced change in cell metabolism (oversimplistically speaking: if it can only outcompete 1,5 gram of carbs)?

 

 

The solution:

 

you don't have 300 gram of circulating glucose 24/7. You eat a meal. Insuline goes up. Glucose is quickly cleared into cells and by the liver into fat. If you sleep you're not eating at all (hopefully!). During times of not-eating-carbs the liver is producing minuscule amounts of glucose every minute to keep the body functioning.

 

Enter glucosamine.

 

Glucosamine has a half time of 15 hours: https://www.oarsijou...0193-7/fulltext

 

Glucose got a half time of minutes.

 

 

So while you are sleeping, you still got most of the Glucosamine circulating in your system, slowly entering the cells and inhibiting glucose metabolism. During one night the liver produces more glucose than tere is circulating glucosamine. Sure. But at any given moment the circulating amount of glucosamine is larger than the circulating amount of glucose. So more often than not it outcompetes glucose for access to the enzymes. If you increase the amount of glucosamine in your body, the more often it is able to outcompete even higher amounts of circulating glucose. That's why there is a dose dependend effect in the observational studies.

 

 

So is there is maximum safe threshold to glucosamine intake? For example the mice study used the human equivalent of 5-7 grams of glucosamine. Luckily that question is answered: 

A comprehensive review of oral glucosamine use and effects on glucose metabolism in normal and diabetic individuals.

https://pdfs.semanti...a9c0518c902.pdf

 

even giving truly enormous amounts of glucosamine to animals did not kill or visibly harm any of the various species (they could only conclude, that the LD50 is above the range of tested concentrations). As for humans I'm gonna quote from the paper:

 

"When they subsequently intravenously infused 30.5 g of glucosamine—achieving plasma levels >20-fold higher than would be expected with usual doses of oral glucosamine—into five healthy volunteers, this dose was well tolerated by four subjects and only one had symptoms—he developed a headache."

 

 

In total humans taking glucosamine developed LESS side effects of any kind than those taking placebos. That's not the case for metformin - and glucosamine got better life extension effects in mice AND large scale observational studies in non-sick humans.

 

 

 

@smithx: n-acetyl glucosamine unfortunately does not compete with glucose for metabolism - so it's unlikely to recreate the same effects as glucosamine. Glucosamine is used to create n-acetyl glucosamine in the hexosamine channel - but as outlined before that is unlikely to be the main cause of it's beneficial effects.

Edited by Guest, 20 February 2019 - 07:19 PM.

[Mind]

Let me bring a little skeptical thinking to the conversation.

 

I personally know A LOT of older people who take the glucosamine/chondroitin combination for joint problems. Some report some relief in their joints, others not. Subjectively, I am unable to detect any other health benefits in these subjects. If glucosamine upregulates autophagy to a great extent, don't you think that we would have noticed it by now - with the millions of people who take it daily? Maybe I am missing something.

[GABAergic]

i always thought NAG, acetyl form of glucosamine is more brain bioavailable so it must have some benefit on the brain? also i read its better absorbed in general in comparison to plain cheap glucosamine. i mean thats why its not found everywhere, its more expensive. i would be so happy if someone is willing to help me gather enough information on NAG vs plain glucosamine since there isnt much reliable comparison out there

[QuestforLife]

Let me bring a little skeptical thinking to the conversation.

I personally know A LOT of older people who take the glucosamine/chondroitin combination for joint problems. Some report some relief in their joints, others not. Subjectively, I am unable to detect any other health benefits in these subjects. If glucosamine upregulates autophagy to a great extent, don't you think that we would have noticed it by now - with the millions of people who take it daily? Maybe I am missing something.

This is a wider point - in any less than AMAZINGLY effective aging therapy - where the rate of deterioration is only slowed, or perhaps reversed and maintained to some small degree, would we even notice?

If I gave you an elixir than slowly rejuvenated you, perhaps with no obvious effects for say 4 years - and you were skeptical of my claims it was an elixir, would you even keep taking it long enough to see effects? And this elixir is better than anything we know about now.

As a case in point, did you ever notice people who take salbutamol don't tend to get Parkinson's? I didn't.

https://www.sciencem...inson-s-disease

[Daniel Cooper]

Let me bring a little skeptical thinking to the conversation.
 
I personally know A LOT of older people who take the glucosamine/chondroitin combination for joint problems. Some report some relief in their joints, others not. Subjectively, I am unable to detect any other health benefits in these subjects. If glucosamine upregulates autophagy to a great extent, don't you think that we would have noticed it by now - with the millions of people who take it daily? Maybe I am missing something.

Makes me want to suspect that you can probably rule out any profound effects.  Perhaps there is a subtle effect that's not been noticed.  After all, who would know when these people should have died had they not taken it.  

 

Also, I've seen a lot of people that say "Oh yeah, I take X for Y condition" but when you start quizzing them you'll find that they take it very sporadically for a relatively short period of time.  I've personally never seen any huge benefit taking glucosamine for joint pain, so in my mind this tends to be just the sort of supplement that people with take off and on for awhile, then just drop it altogether.  If this stuff has what's likely the best case effect due to autophagy you'd probably have to take it consistently for years to get what .... maybe a 5% longevity increase?

 

 

[GABAergic]

This is a wider point - in any less than AMAZINGLY effective aging therapy - where the rate of deterioration is only slowed, or perhaps reversed and maintained to some small degree, would we even notice?

If I gave you an elixir than slowly rejuvenated you, perhaps with no obvious effects for say 4 years - and you were skeptical of my claims it was an elixir, would you even keep taking it long enough to see effects? And this elixir is better than anything we know about now.

As a case in point, did you ever notice people who take salbutamol don't tend to get Parkinson's? I didn't.

https://www.sciencem...inson-s-disease

 

yeah thats why those anti aging drugs and formulas are going to be making someone a lot of money with the proper technique of promoting and distributing them. basically on the simple true idea, you wont know until years after. i cannot get into this because of simply this, since as a guy who uses drugs and alcohol and other things that act within seconds to minutes of using, believing in an idea of something might benefit long term over years and years of use spending thousands of dollars doesnt float for me, yes, anything that can act so quick is not the best, but i can also feel benefits from simply eating an orange with vitamin c or other fruits and vegetables, compared to spending thousands of dollars over years believing that MIGHT BE helping. how do you convince someone to do something that though, can you explain? because this is where huge marketing and money making business can come in effect. if i had the ability i might as well try to go for it and sell some bulk powder labeled as whatever anti aging substance that takes many years to take effect and put it in capsules and sell it for more money per mg. of course i wont cheat, but first i wouldnt even know if the lab itself didnt cheat me first and second, as stated it might take years to work. so how the hell such thing even works for customer or even business owner long term?? i suppose it works in a simple manner. have enough gullible customers willing to invest and risk over years time and hope your business grow. thats not cool in my book though. im a simpleton, something works NOW or never!

Edited by GABAergic, 21 February 2019 - 06:25 AM.

[QuestforLife]

Makes me want to suspect that you can probably rule out any profound effects.  Perhaps there is a subtle effect that's not been noticed.  After all, who would know when these people should have died had they not taken it.  

 

 

Exactly my point - effects can be both subtle and profound.

 

Look at something like calorie restriction or keto - you'd hardly say that adopting that lifestyle suddenly makes you young again. But look at people that have followed those interventions for years and compare them to those who haven't, and it's obvious it's had a profound effect.

 

For all we know, the right combination of supplements or currently available drugs might be able to slowly rejuvenate a person, but it would be hard to see the effect. If something takes month to show an effect in mice, that's YEARS in humans.

 

That is why we badly need some decent aging biomarkers.

[Mind]

That is probably the case. It probably is beneficial, but not too huge of an effect. Most supplements only have small effects, but many are still worth taking.

[GABAergic]

not sure anyone understood my reply. thanks for the reply and lots of downvoting though, always appreciated

[Harkijn]

Glucosamine has purportedly lowered human mortality, but human mortality goes down any way. Probably by many other factors, such as eating less transfats or better health care. So it would be hard to tell which is which.

I first heard about Glucosamine in 2008 and have taken it ever since, though perhaps not often or frequent enough. I take it mostly after eating fast carbs which I avoid eating anyway.

My primary source gathered a lot of evidence in 2014 and I believe he is still taking glucosamine:

http://www.anti-agin...-for-longevity/

[Phoebus]

Question 

 

Glucosamine sulfate vs Glucosamine HCL? 

 

same? one is better? 

[William Sterog]

Question

Glucosamine sulfate vs Glucosamine HCL?

same? one is better?

I have read that HCL is ineffective.

[zorba990]

I have read that HCL is ineffective.

I don't see any sulfate requirement here:
https://www.ncbi.nlm...23/#!po=31.3953
d-Glucosamine supplementation extends life span of nematodes and of ageing mice


Also from https://www.ncbi.nlm...les/PMC3042150/

"Typical use of GlcN and oral bioavailability
GlcN is mainly sold in one of two commercial forms as a salt of GlcN hydrochloride (GlcN·HCl) or GlcN sulfate (GlcN·SO4). When ingested, both salts dissociate fully yielding free GlcN, and the bioavailability of GlcN derived from either source is expected to be the same. "

Edited by zorba990, 24 February 2019 - 06:20 PM.

[brosci]

How does NAG compare to Glucosamine Sulfate for these benefits? (Is there any reason to pick up NAG instead?)

 

Would it be better to take glucosamine with a meal in the evening, or in the morning fasted?

Edited by brosci, 06 March 2019 - 11:47 PM.

[GABAergic]

from what i assume is that NAG has better blood brain barrier penetration, correct me if im wrong. its supposedly because of its acetyl- addon as most supps with acetyl group have better bioavailability in the brain. i did purchase NAG before but nothing memorable. i got it for stomach issues. it seems glucosamine might help with stomach inflammation at least in one study i read.

[William Sterog]

In preclinical testing, glucosamine readily penetrated the blood-brain-barrier? and had a positive effect on ability to complete a cognitive task [2]. Glucosamine treatment also improved spatial memory in a test using small mammals [3]. There are several potential ways glucosamine may protect the brain. In small mammals and invertebrates, glucosamine promotes generation of mitochondria?, which power our cells [7]. Cell culture studies also suggest that glucosamine inhibits inflammation? [4-6].

https://www.alzdisco...ngs/glucosamine

[Turnbuckle]

Let me bring a little skeptical thinking to the conversation.

 

I personally know A LOT of older people who take the glucosamine/chondroitin combination for joint problems. Some report some relief in their joints, others not. Subjectively, I am unable to detect any other health benefits in these subjects. If glucosamine upregulates autophagy to a great extent, don't you think that we would have noticed it by now - with the millions of people who take it daily? Maybe I am missing something.

 

 

Perhaps because little mitophagy occurs without mito fission. Fission is required to get mitochondria small enough to be engulfed by lysosomes, and it's generally required to detect defective mtDNA loops, as more than one loop in a mitochondrion can cover for each other. They can do this even if all are defective, so long as they have working genes among them to make all necessary enzymes for the Krebs cycle. Mito fission is easily obtained by creating a high NAD+/NAD ratio. 

[GABAergic]

it doesnt seem that serious or a big deal but i think i should mention the french are warning people about adverse effects with consuming glucosamine; https://www.nutraing...lth-supplements

[APBT]

See this thread for furthur discussion:  http://www.longecity...-low-carb-diet/

[GABAergic]

why mimic low carb diet when you can actually just lower your carbs. 1) save money on heavy carb foods 2) save money not buying glucosamine or other mimicry of low carb diet

[manofsan]

You want the sulfate form, not the HCl, and I suggest one that's not made from shellfish, to minimize risk of contaminants.

 

More info at the link:

 

https://examine.com/...ts/glucosamine/

 

It's also worth noting that bone broth is high in Glucosamine. The GAPS Diet wins again!

 

I've been taking Glucosamine for years - I've tried both the sulfate and the HCl, and I find HCl has better effects on me by far. Sulfate form does nothing for me (maybe I'm unique? My mother did have an allergy to Sulfa drugs, but I don't know if that's relevant)

 

I never knew Glucosamine was useful for autophagy, much less that it was good for selective autophagy. How can this selective autophagy from Glucosamine be maximized? Could I take the Glucosamine just before vigorous cardio exercise perhaps? Usually, vigorous exercise will increase mitophagy, but can also put stress on your joints - and Glucosamine affects the joints in particular, making them a little more tender.

 

I'll tell you that I also suffer from a ruptured blood vessel inside my head which had subsequently sealed. It's caused me huge discomfort for many years - but I found early on that Glucosamine gives me some relief. If you were to give me 100 placebo doses and only 1 was Glucosamine, I'd be able to identify it without fail. Likewise, this problem that I have also gives me acute sensitivity to Blueberries, Red Grapes, Folic Acid, Vitamin E (they immediately give me relief from the discomfort), as well as strong sensitivity to greasy/fatty foods like bacon, salami, etc (they increase the feeling of discomfort).

 

So I can "sense" Glucosamine very directly  (like "Spidey Sense") 

Edited by manofsan, 10 April 2019 - 02:53 AM.

[Guest]

To emphasize the point of this topic: I found a study that I explain in a little detail in the glucosamine-and-cancer-thread:

 

https://www.longecit...hread/?p=874170

 

In that study, rate were infused 40 hours with glucosamine to successfully treat cancer. One change they noted is:

 

"[...]many large, swollen mitochondria and numerous, large, autophagic vacuoles" 

 

That is in-vivo evidence in mammals, that glucosamine drives autophagy.

[Guest]

why mimic low carb diet when you can actually just lower your carbs. 1) save money on heavy carb foods 2) save money not buying glucosamine or other mimicry of low carb diet

 

There is probably more to glucosamine than suppressing the glucose metabolism - given that in one study in rats high dose of glucosamine completely killed off transplanted cancers within 5 days. I doubt that 5 days of zero-carb-diet would kill off tumors in rats (but I would be glad to be wrong about that).

 

Also this in-vivo study in mice:

https://www.ncbi.nlm...les/PMC3772083/

 

indicates, that autophagy induced by glucosamine is stronger than autophagy induced by caloric restriction (unfortunately they don't indicate the degree of food restriction) - the dose used in this study for mice is by allometric scaling about 3 grams of glucosamine per day in humans; that's just 2x the commonly used 1,5 gram dosis.

 

Also in the lifespan study in mice, glucosamine performs clearly better than metformin in the metformin lifespan studies. It's started later in life than in the metformin studies and still gets better life-extension (with a human equivalent dosis of about 6 grams per day). Metformin downregulates glucose release in the liver - effectively starving the body of glucose more than glucosamine is able to. Still glucosamine performs better.

[GABAergic]

interesting. if thats really true, then it makes glucosamine a super ingredient to take. i doubt such simple dirt cheap chemical can so important. we have been disappointed many times with studies done on rats translating to humans before. also it has many side effects, including a nasty deadly side effect https://naturalmedic...r-problems.aspx there was also recent article showing this problem.

btw do you know which type of glucosamine is the one able to insert the positive effects? maybe its not the really widely available cheap form. anyway regardless of this, at doses of 3 grams its too much and is able to cause many side effects probably including liver damage.

[William Sterog]

interesting. if thats really true, then it makes glucosamine a super ingredient to take. i doubt such simple dirt cheap chemical can so important. we have been disappointed many times with studies done on rats translating to humans before. also it has many side effects, including a nasty deadly side effect https://naturalmedic...r-problems.aspx there was also recent article showing this problem.
btw do you know which type of glucosamine is the one able to insert the positive effects? maybe its not the really widely available cheap form. anyway regardless of this, at doses of 3 grams its too much and is able to cause many side effects probably including liver damage.

The problems are only seen, as far as I can tell, in people who already have liver disease. In my opinion, at this moment at least, it is like saying that Potassium is dangerous because it can kill people with advanced renal disease.

[Harkijn]

interesting. if thats really true, then it makes glucosamine a super ingredient to take. i doubt such simple dirt cheap chemical can so important. 

A (mildly) exasperating trait of us in the longevity crowd is the tendency to overthink, to overtinker, and to bend us over backwards from fusion to fission and back... . If  something is simple, actionable and not expensive we don't believe it works and move on to the next hype..

 

Glucosamine is in long-term human studies correlated with longevity. Better 'proof' than that will probably never be available (and there may be many other useful longevity supplements). In 2014 Vincent Giuliano neatly summarized glucosamine's characteristics. He also  discussed the various types of Glucosamine. His article will still be very useful to those who want to read up on Glcn.

 

http://www.anti-agin...-for-longevity/

Edited by Harkijn, 22 May 2019 - 09:46 AM.