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Trehalose autophagy mechanism discovered

trehalose autophagy nash

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#1 niner

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Posted 03 March 2016 - 10:10 PM


A new paper in Science Signaling reports that the disaccharide trehalose initiates autophagy by blocking a glucose transporter.  Cells are thus nutrient deprived, so it's something like a CR mimetic.   The paper further reports that trehalose treats fatty liver disease, at least in mice.


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#2 Logic

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Posted 04 March 2016 - 03:29 PM

Ok, but unlike mice, humans break down Trehalose to Glucose in the the gut and very little gets into circulation IIRC.
Weren't Trehalase blockers being discussed?

Now you seldom start a new thread Niner so either very little is needed to block the glucose transporter, or other glucose transporter blocking means came to your mind..? :)

I also wonder about the wisdom of stopping glucose uptake at the cell wall as that leaves it floating around in the ECM where Glucosepane is formed?



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#3 niner

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Posted 04 March 2016 - 06:23 PM

I just thought it was interesting to know the mechanism.  Too bad about the pharmacokinetics.  I don't have any trehalase inhibitors up my sleeve, but they exist.  Trehalose is a very common carbohydrate storage form in the animal world, and is particularly critical for insects.  Trehalase inhibitors have been looked at as insecticides, and work by inducing hypoglycemia in bugs.



#4 tunt01

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Posted 05 March 2016 - 08:32 PM

I've seen the suggestion in other forums that the trehalase enzyme is easily overwhelmed, such that humans do not breakdown all trehalose during digestion.  I'm not sure what the right dosage is or what data there exists to support that theory, but it might be worth exploring, if anyone has a thought.



#5 Mind

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Posted 05 March 2016 - 09:26 PM

The water bear uses trehalose to cryopreserve itself.


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#6 zorba990

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Posted 05 March 2016 - 10:30 PM

I've seen the suggestion in other forums that the trehalase enzyme is easily overwhelmed, such that humans do not breakdown all trehalose during digestion. I'm not sure what the right dosage is or what data there exists to support that theory, but it might be worth exploring, if anyone has a thought.


Methinks a glucose meter would give some indication of that....

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#7 Logic

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Posted 05 March 2016 - 10:49 PM

Novel autophagy inducers lentztrehaloses A, B and C

 

Trehalose has widespread use as a sweetener, humectant and stabilizer, and is now attracting attention as a promising candidate for the treatment of neurodegenerative diseases as it is an autophagy inducer and chemical chaperone. However, the bioavailability of trehalose is low because it is digested by the hydrolyzing enzyme trehalase, expressed in the intestine and kidney. Enzyme-stable analogs of trehalose would potentially solve this problem. We have previously reported an enzyme-stable analog of trehalose, lentztrehalose, and herein report two new analogs. The original lentztrehalose has been renamed lentztrehalose A and the analogs named lentztrehaloses B and C. Lentztrehalose B is a di-dehydroxylated analog and lentztrehalose C is a cyclized analog of lentztrehalose A. All the lentztrehaloses are only minimally hydrolyzed by mammalian trehalase. The production of the lentztrehaloses is high in rather dry conditions and low in wet conditions. Lentztrehalose B shows a moderate antioxidative activity. These facts suggest that the lentztrehaloses are produced as humectants or protectants for the producer microorganism under severe environmental conditions. All the lentztrehaloses induce autophagy in human cancer cells at a comparable level to trehalose. Considering the enzyme-stability, these lentztrehaloses can be regarded as promising new drug candidates for the treatment of neurodegenerative diseases and other autophagy-related diseases, such as diabetes, arteriosclerosis, cancer and heart disease.

http://www.nature.co.../ja201523a.html

 

Anybody got some actinomycete strain Lentzea sp. ML457-mF and some steamed germinated brown rice or flattened barley lying around!?  :)


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#8 stefan_001

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Posted 11 March 2016 - 02:54 PM

Another mechanism:

Trehalose supplementation In aorta of old mice supplemented with trehalose, the autophagy markers beclin 1, WIPI-1, LC3-II and LAMP-2a were restored to levels observed in young mice, and p62 levels were reduced (Fig. 2).

http://onlinelibrary...012.229690/full

 



#9 Logic

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Posted 11 March 2016 - 07:50 PM

Another mechanism:

Trehalose supplementation In aorta of old mice supplemented with trehalose, the autophagy markers beclin 1, WIPI-1, LC3-II and LAMP-2a were restored to levels observed in young mice, and p62 levels were reduced (Fig. 2).

http://onlinelibrary...012.229690/full

 

Mice do not metabolise Trehalose the same way humans do so end up with much higher levels in circulation than we humans do.
This has been discussed on the forum somewhere, before, so it would be a wast to rehash it all here again.

More interesting are Lentz-Trehaloses IMHO as they should overcome the above issue nicely?

http://www.nature.co.../ja201523a.html

 

I wouldn't be surprised if  a capsule full of dehydrated Water Bear, as mentioned by Mind earlier in the thread, were a cheap source of lentz trehalose?


Edited by Logic, 11 March 2016 - 07:59 PM.


#10 stefan_001

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Posted 11 March 2016 - 09:06 PM

 

Another mechanism:

Trehalose supplementation In aorta of old mice supplemented with trehalose, the autophagy markers beclin 1, WIPI-1, LC3-II and LAMP-2a were restored to levels observed in young mice, and p62 levels were reduced (Fig. 2).

http://onlinelibrary...012.229690/full

 

Mice do not metabolise Trehalose the same way humans do so end up with much higher levels in circulation than we humans do.
This has been discussed on the forum somewhere, before, so it would be a wast to rehash it all here again.

More interesting are Lentz-Trehaloses IMHO as they should overcome the above issue nicely?

http://www.nature.co.../ja201523a.html

 

I wouldn't be surprised if  a capsule full of dehydrated Water Bear, as mentioned by Mind earlier in the thread, were a cheap source of lentz trehalose?

 

 

No worries I posted because of the different autophagy mechanism. Didnt know about the bio availability, indeed the compound you post sounds interesting - that would become very interesting if Mind's suggestion works out.

 



#11 Skyguy2005

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Posted 12 March 2016 - 01:54 AM

I can't say I ever noticed anything from trehalose, seems those talking about low bioavailability are bang on. 


I can't say I ever noticed anything from trehalose, seems those talking about low bioavailability are bang on. 



#12 stefan_001

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Posted 12 March 2016 - 08:35 PM

Another mechanism:
Trehalose supplementation In aorta of old mice supplemented with trehalose, the autophagy markers beclin 1, WIPI-1, LC3-II and LAMP-2a were restored to levels observed in young mice, and p62 levels were reduced (Fig. 2).
http://onlinelibrary...012.229690/full


Mice do not metabolise Trehalose the same way humans do so end up with much higher levels in circulation than we humans do.
This has been discussed on the forum somewhere, before, so it would be a wast to rehash it all here again.

More interesting are Lentz-Trehaloses IMHO as they should overcome the above issue nicely?
http://www.nature.co.../ja201523a.html

I wouldn't be surprised if a capsule full of dehydrated Water Bear, as mentioned by Mind earlier in the thread, were a cheap source of lentz trehalose?

No worries I posted because of the different autophagy mechanism. Didnt know about the bio availability, indeed the compound you post sounds interesting - that would become very interesting if Mind's suggestion works out.


Mmmm perhaps it's not that promising.....seems nobody has yet created Water Bear supplements. I can find live ones for sale for the true experimenter:
http://www.carolina....60.pr?question=

#13 Logic

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Posted 12 March 2016 - 09:05 PM

 

 

 

Another mechanism:
Trehalose supplementation In aorta of old mice supplemented with trehalose, the autophagy markers beclin 1, WIPI-1, LC3-II and LAMP-2a were restored to levels observed in young mice, and p62 levels were reduced (Fig. 2).
http://onlinelibrary...012.229690/full


Mice do not metabolise Trehalose the same way humans do so end up with much higher levels in circulation than we humans do.
This has been discussed on the forum somewhere, before, so it would be a wast to rehash it all here again.

More interesting are Lentz-Trehaloses IMHO as they should overcome the above issue nicely?
http://www.nature.co.../ja201523a.html

I wouldn't be surprised if a capsule full of dehydrated Water Bear, as mentioned by Mind earlier in the thread, were a cheap source of lentz trehalose?

No worries I posted because of the different autophagy mechanism. Didnt know about the bio availability, indeed the compound you post sounds interesting - that would become very interesting if Mind's suggestion works out.
 

Mmmm perhaps it's not that promising.....seems nobody has yet created Water Bear supplements. I can find live ones for sale for the true experimenter:
http://www.carolina....60.pr?question=

 

 

:-D

No, you wont find Water Bear supps.  :)

What mind posted was that the cryopreserve themselves with trehalose.
ie: When the water dries up so do they and are inanimate with no biology going on...  until the next rains...

Now  "lentztrehaloses are produced as humectants or protectants for the producer microorganism under severe environmental conditions."

So its possible that the Water Bear also produces similar trehaloses, but that's just pure speculation on my part.

They are certainly hardy.



#14 normalizing

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Posted 15 March 2016 - 07:26 AM

so trehalose is of low bioavailability in humans? i havent seen a study done on humans to show this but it keeps being repeated its low available and its somehow unreliable for humans seriously someone guide me to this and explain why is that so

 

and btw we probably ingest water bears regularly anyway since they are impossible to see and happen to nest in everything especially soil, plants and things humans do consume. but would you really want one of the strongest organisms that cannot die inside you? those things can get clogged in your body in suspended animation and one day when its comfortable to relight itself, it will


Edited by normalizing, 15 March 2016 - 07:29 AM.

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#15 geo12the

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Posted 30 March 2016 - 12:22 AM

Trehalase deficiency has negative effects in humans:

 

https://rarediseases...ncy/resources/1

 

suggesting that too much trehalose can produce negative effects on the human digestive tract.

 

In people without this deficiency, digestion of anything in the human gut is unlikely to be 100%. It is possible that at the right dose, enough trehalose gets into the bloodstream and remains undigested to have a stimulatory effect on autophagy. 


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#16 niner

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Posted 30 March 2016 - 02:14 AM

Interesting.  If trehalase deficiency is common in Greenland, I wonder if you could find some Greenlanders with improved aging profiles due to trehalose consumption? People with this deficiency can develop diarrhea and vomiting if they consume too much trehalose, but a big enough dose to affect autophagy might be small enough to tolerate. If not, then that would suggest that a trehalase inhibitor would have some nasty side effects.
 


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#17 treonsverdery

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Posted 03 August 2016 - 05:31 PM

amazon has trehalose, ebay has enteric coated capsules

 

could enteric coated capsules, or possibly just (LOL) trehalose soaked corn release trehalose at the lower GI tract, avoiding turnng it to glucose?

 

 


Edited by treonsverdery, 03 August 2016 - 05:36 PM.


#18 nikolay

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Posted 04 August 2016 - 11:10 AM

@treonsverdery: I can't find enteric-coated trehalose on eBay. Can you post a link, please?



#19 treonsverdery

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Posted 13 August 2016 - 12:02 AM

actually there are enteric empty capsules, that a person could fill with trehalose.  the capsule link is http://www.ebay.com/...sd=252352632340

 



#20 normalizing

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Posted 02 October 2016 - 01:23 AM

ok the wacky japs found replacement for trehalose, just move on now please; http://pubs.acs.org/...cs.jafc.6b02782


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#21 Logic

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Posted 02 October 2016 - 11:36 AM

ok the wacky japs found replacement for trehalose, just move on now please; http://pubs.acs.org/...cs.jafc.6b02782

 

Did you miss post # 7?
Thx for the new link though.

The question now is where to get hold of lentztrehalose..?


Edited by Logic, 02 October 2016 - 11:41 AM.


#22 Nate-2004

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Posted 24 August 2017 - 05:30 PM

Interesting.  If trehalase deficiency is common in Greenland, I wonder if you could find some Greenlanders with improved aging profiles due to trehalose consumption? People with this deficiency can develop diarrhea and vomiting if they consume too much trehalose, but a big enough dose to affect autophagy might be small enough to tolerate. If not, then that would suggest that a trehalase inhibitor would have some nasty side effects.
 

 

If trehalose or lentztrehalose is a viable alternative to mTOR inhibition for autophagy then wouldn't it be wise to just use any kind of trehalase inhibitor or lentztrehalose for no longer than perhaps a week or two at a time? We are talking about CR or more accurately, fasting memetics here. Nobody's going to fast longer than a week or two really, and we don't know how long a fast is necessary to induce autophagy, but if it can be done to equivalent degrees without fasting then wouldn't we only want to do it for a week or two, perhaps seasonally?  I think that people assume you have to take something every day for it to be an option. Maybe for profit, yeah, but it doesn't seem like something you would have to use very often. Nobody should be undergoing autophagy for so long a period of time. At some point you gotta rebuild.

 

Another question, where can I get lentztrehalose?

 

Also has anyone tried applying this to skin in a DMSO solution?


Edited by Nate-2004, 24 August 2017 - 05:35 PM.

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#23 Nate-2004

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Posted 24 August 2017 - 05:42 PM

From one of the studies regarding their methods of making lentztrehalose and it looks like A is a lot easier to achieve without sequential chromatography. However does anyone know where to get or how to culture this 15 strain ML457-mF8 bacteria I'm assuming? According to some taxonomy txt file it's called Lentzsea. Also need an autoclave and to somehow gain access to DIAION HP20 I guess?

 

The previously reported methods for the production and isolation of lentztrehalose A were modified.15 Strain ML457-mF8 was cultured in a steamed germinated brown rice medium (IRits, Tokyo, Japan, rice grain:water=3:5, autoclaved at 121 °C for 20 min) for 3 weeks. The whole culture was extracted with twice the volume of MeOH and EtOH, sequentially. The extract was evaporated and separated with a DIAION HP20 (Mitsubishi Chemical, Tokyo, Japan) column in a batch process using water and 50% MeOH. Although lentztrehalose A was purified from the water fraction, B and C were isolated from the 50% MeOH fraction. Each fraction was separated by sequential chromatography with an octadecyl silica (Hydrosphere C18, YMC, Kyoto, Japan) and polyamine (YMC-Pack Polyamine II, YMC) HPLC, silica gel (Wakosil C-300, Wako Pure Chemical Industries, Ltd, Osaka, Japan), activated carbon (Wako) and Sephadex LH-20 (GE Healthcare Japan, Hino, Tokyo, Japan) open columns. The elution solvents used were water and MeOH for octadecyl silica HPLC, acetonitrile and water for polyamine HPLC, BuOH: MeOH:water=4:1:2 mixture for the silica column and MeOH for the activated carbon and LH-20 columns. For the purity or yield check, lentztrehaloses were separated by HPLC with a hydrophilic interaction chromatography column (XBridge Amide, Waters, Milford, MA, USA) by using a linear gradient of 90–50% acetonitrile and detected by an evaporative light scattering detector system (ELSD 2000ES, Alltech, Deerfield, IL, USA). The structure and physicochemical properties of lentztrehaloses B and C were determined by spectrometric analyses performed as previously described15,19 using the equipment as follows. Optical rotations were recorded on a P-1030 polarimeter (JASCO Inc., Tokyo, Japan). UV spectra were obtained on a U2800 spectrophotometer (Hitachi High-Technologies Corporation, Tokyo, Japan). 1H (600 MHz) and 13C (150 MHz) NMR spectra were measured in methanol-d4 with a JNM-ECA600 spectrometer (JEOL Resonance Inc., Tokyo, Japan) using tetramethylsilane as an internal reference. HRESI-MS spectra were obtained on a LTQ Orbitrap XL mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) or T-100LC TOF-MS (JEOL Ltd, Akishima, Tokyo, Japan). IR spectra were recorded on a FT/IR-4100 Fourier transform infrared spectrometer (JASCO). The novelty of the lentztrehaloses was confirmed with the databases Dictionary of Natural Products on DVD

Edited by Nate-2004, 24 August 2017 - 06:08 PM.


#24 eighthman

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Posted 07 November 2017 - 03:33 PM

https://healthunlock...-clinical-trial

 

There seems to be some evidence that trehalose can get thru if taken in a big enough dose.  Any body got a different method? Under the tongue? Enema? Enteric?  This stuff could be big league and safe if we can find a way into the blood stream that's not onerous.



#25 thedarkbobo

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Posted 07 November 2017 - 05:43 PM

I am eating trehalose 1-2 tbl spoons lately, average 2-3 times per week. Bought 1kg food grade, not too expensive. Not much to tell as I am healthy - have to watch calories.

Where does one even get Lentztrehaloses  and at what price? :)



#26 eighthman

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Posted 07 November 2017 - 06:22 PM

I take trehalose on an enteric capsule one a week before bed.  I often wake feeling a little weird afterwards, so I think something must be happening.



#27 PhaQ

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Posted 05 December 2017 - 08:33 AM

What about liposomal trehalose? Water lecithin and trehalose go into the blender. Blend the crap out of it and drink it up. Sonication optional. IIRC, trehalose is used to stabilize liposomes, so it should work just fine.


 


From one of the studies regarding their methods of making lentztrehalose and it looks like A is a lot easier to achieve without sequential chromatography. However does anyone know where to get or how to culture this 15 strain ML457-mF8 bacteria I'm assuming? According to some taxonomy txt file it's called Lentzsea. Also need an autoclave and to somehow gain access to DIAION HP20 I guess?
 

You can probably get it acceptably pure without HPLC. If the bacteria doesn't produce any kind of toxins you could probably just use the crude alcohol extract and be done with it.

#28 Daniel Cooper

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Posted 22 December 2017 - 03:45 PM

I think liposomal trehalose is exactly what you want.  I have serious doubts about enteric capsules preventing it from being broken down at the gut wall.

 

 

 

 



#29 eighthman

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Posted 22 December 2017 - 05:17 PM

Could you elaborate on why you believe liposomal trehalose would be effective?  This could benefit a lot of people particularly those with neurological conditions (maybe)



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#30 Daniel Cooper

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Posted 22 December 2017 - 06:56 PM

Well I have a high level of confidence that liposomally encapsulated trehalose will make it through the gut without being broken down into glucose as normally happens to almost all trehalose passing through the digestive tract.

 

The only question for me would be does that encapsulated trehalose translate into trehalose crossing the BBB, which would be of interest to you if you are trying to treat some neurodegenerative brain disorder (Parkinson's, Huntington's, Alzheimer's, etc).  Certainly I don't believe the liposomes will cross the BBB themselves, but I suspect that there are mechanisms where at least some of the trehalose released from the liposomes will make it across.

 

I however am more interested in the anti-atherosclerosis aspect of trehalose, and I don't think there's much of a question that we can deliver significant quantities of trehalose to the arterial wall through liposomal encapsulation.  I'm looking for a commercial source now and barring progress there will try to make some up myself.

 

Someone earlier suggested enteric capsules.  But enteric coating only gets a target compound through the stomach.  They are designed to release their delivery drug in the small intestines.  But, that's exactly where trehalose is broken down, it is not digested in the stomach, so I don't see that helping us much.

 

 


Edited by Daniel Cooper, 22 December 2017 - 07:00 PM.






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