132 replies to this topic

[OP2040]

I'm still very much interested in Trehalose.  We have explored all kinds of ideas here for delivery, although I do think just oral will have some benefits.  I even tried the rectal route, and I still think it's not a terrible idea.  However, as you can imagine, it gets old really fast lol. 

 

Has anyone investigated Trehalase inhibitors?  I see there are some small molecules known to inhibit Trehalase, but they have an unfavorable toxicity. Usually, you can find a study that shows a good natural alternative, which has the added benefit of accessibility.  But I haven't found one yet.  Also, most of them are focused on agricultural needs since Trehalose is an insect thing.

Edited by OP2040, 14 May 2019 - 03:00 PM.

[Daniel Cooper]

Just fyi - a lot of the papers you will see on trehalase inhibitors are in insects.  Trehalase is pretty central to insect biology so the interest there is to disrupt it's breakdown as a means of pest control.

 

Humans on the other hand don't normally use trehalase, so one would think that trehalase inhibitors would be less problematic.

 

 

 

[OP2040]

Ladies and Gents,

I'm not sure how we missed this gem, other than the fact that it is relatively new:

 

https://www.ncbi.nlm...les/PMC6479548/

 

 

In our hands, in the experimental layout corresponding to a gentle model of atherosclerosis, i.e., in a CD-fed male apoE-- mice, trehalose caused a 40% reduction of atherosclerotic plaques. Interestingly, this was accompanied by an increased content of macrophages and decreased necrotic cores in atherosclerotic lesions of apoE-- mice.

 

 

Trehalose was mixed without heating with the same diet and administered to mice at a dose of 2.5 g per kg of body weight per day. The dose of trehalose (2.5 g/kg of body weight per day) was chosen according to the Food and Drug Administration (FDA) rules of animal-to-human equivalents and was relevant to the average daily intake of trehalose estimated for the human population.

 

Pretty much says it all, with the usual caveat that it is with mice. 

 

I assume they mean 2.5G/KG added to the drinking water.  Don't feel like doing the calculation, but that translates into a really big HED, does it not?  Oh and it's not in the quotes, but it was for 16 weeks, a fairly long term for the mouse lifespan.

 

Anyway, 40% is just as good as the other Trehalose and Cyclodextrin studies we all got excited about, and it was all done orally.   Oh, and that's not to mention the other aspect of the study, which is it's positive affect on fatty liver disease.

Edited by OP2040, 14 May 2019 - 03:33 PM.

[OP2040]

Just to scale back the enthusiasm a bit.  The mice in the study that were fed a HFD as well as being APOE--, did not see the main benefit. 

 

IMO, the best part about Trehalose is that it can just replace the sugar that already exists in the cupboards of many homes.  Apparently it is a widely used, mainstream sugar in Japan.  One thing I've learned from all this intervention stuff is that convenience really does matter for things that require longer-term upkeep.

[Daniel Cooper]

My understanding is that mice do not efficiently break down trehalose in their digestive system via trehalase.  They do break it down in their liver but that is a slower mechanism after it has made it to the blood stream.

 

I don't have my reference at hand, I'll try to look them up perhaps this evening.

 

 

[OP2040]

Oh thanks Daniel.  I knew mice have Trehalase, but wasn't aware that it was possibly less effective at breaking down Trehalose.  Having said that, there are human studies with oral supplementation that show some positive effects on endothelial function for example.  None that show atherosclerosis regression though, for obvious reasons.   It may not be nearly as effective in humans, but still worth taking orally until we can find better delivery mechanisms. 

[Daniel Cooper]

I actually had an email conversation with the university research group that did the study you're alluding to.  They were underwhelmed with the effect, blamed it on so little trehalose getting from the gut into the bloodstream, and had considered liposomal encapsulation as a second attempt, but had gotten some grant money for another project and never gotten back to it.

 

It does seem that you can get some effect through straight oral consumption.  Not all trehalose is broken down in the gut or the first pass through the liver.  I substituted trehalose in my diet for a while but didn't keep up with it.  One thing to keep in mind - gram for gram trehalose is half as sweet as regular table sugar, however it has the same number of calories on a gram for gram basis.  So, if you substitute trehalose for regular sugar and maintain the same level of sweetness, you're going to get about 2x the calories as you were getting from sugar.

 

 

[OP2040]

True on the sweetness, and it is also more expensive than table sugar, but then almost everything is more expensive than table sugar.  The sweetness doesn't bother me because I don't really eat much sugar to begin with.  So when I put it in my coffee or anywhere, it tastes sweet enough for me, and I don't use all that much.  Also, I really don't care about raw calories in the slightest.  I sometimes do intermittent fasting, but most of the time I eat ad libitum and don't feel any special desire to overeat on most occasions.

[OP2040]

All I know is, things like Trehalose are the perfect example of a stopgap.  The only reason to be taking things like this is to live in a better state long enough to get to real rejuvenation therapies.   That's why I'm so annoyingly impatient in these threads.  If it can't work now, or in a couple years, then it's completely pointless.

 

The thing about atherosclerosis is that there are now half a dozen things shown to reverse it mice, including Trehalose, Cyclodextrin, PTP1B inhibitors, NAD+ precursors....  I'm not even sure I have atherosclerosis more than an average person my age.  But it is still the biggest killer so I still want to target it. 

 

Having said all that, the best overall bet includes things that you can get your hands on and deliver right now, not in 5 years, regardless of how marginal the effect may be.  I take Trehalose, I have but do not take Cyclodextrin, Magnolia for the PTP1B pathway and NMN for NAD+.

 

As long as they are relatively safe, which is why I skip the Cyclodextrin for now, then a bunch of smaller effects should necessarily lead to a larger effect.  The only drawback is that it will be more expensive until we have more powerful and targeted therapies.  I can't say any of this is helping, but no one can say for sure just yet. 

 

It would be great to have a powerful, targeted and measurable therapy.  But lets look at the rectal admin.  That was, in theory, a nice solution to the delivery problem.  In reality though, keeping it up day to day, not knowing if it's working, just wasn't going to fly.  We need cheap and easy measurements just as much as we need delivery.  Sorry for the rant guys.

[docmaas]

nimbidiol from neem bark is a strong trehalase inhibitor:

 

https://www.tandfonl...366.2012.694877

 

How might we combine it with trehalose?

[Daniel Cooper]

nimbidiol from neem bark is a strong trehalase inhibitor:

 

https://www.tandfonl...366.2012.694877

 

How might we combine it with trehalose?

 

I don't think you have to combine it, I would just take it before consuming the trehalose.  You'd probably like to figure out the pharmacodynamics - how long does it take before it effectively blocks trehalase?  Do I need to take it 30 minutes before consuming the trehalose or can I take it at the same time.  How much do I need to take to effectively shut down trehalase production. That sort of thing.

 

Oral isn't the only route that we have to work with.  We have oral, intravenous, and .... dare I say it .... rectal.  Oral is the only route that has the issue with trehalase breaking it down before it makes it into the bloodstream.

 

Rectal probably works too.  There is no trehalase produced in the lower end of the colon. You could make yourself some trehalose suppositories.  Either mix it up in some cacao butter and pour into into molds or simply cap it up in some 000 size gelatin capsules which should hold about a gram. I think you'd want to get about 3 grams a day. The studies for IV dosing were done around 20 grams once a week.

 

There is the "ick" factor for suppositories, but I think it would work and you won't have to wonder if you successfully shut down trehalase production.

[docmaas]

I did try rectal and lower gut via acid resistant capsules and both gave me diarrhea just as does oral.  Not sure whether it is a shortage of trehalase or an excess.  I recall seeing an Japanese study where they trialed it with some T2D subjects and found it to be well tolerated by a minority.  Where did you find that trehalase is absent from the colon? 

 

A prevalent theme in the thread is the lack of a safe trehalase inhibitor.  The Neem bark looks like the best candidate offered up to now. 

 

By the way Bio Blast sold their trehalose work to another company who have launched a trial for ALS so it is still in play for neurodegenerative diseases.

 

 

I've still got my trehalose

I don't think you have to combine it, I would just take it before consuming the trehalose.  You'd probably like to figure out the pharmacodynamics - how long does it take before it effectively blocks trehalase?  Do I need to take it 30 minutes before consuming the trehalose or can I take it at the same time.  How much do I need to take to effectively shut down trehalase production. That sort of thing.

 

Oral isn't the only route that we have to work with.  We have oral, intravenous, and .... dare I say it .... rectal.  Oral is the only route that has the issue with trehalase breaking it down before it makes it into the bloodstream.

 

Rectal probably works too.  There is no trehalase produced in the lower end of the colon. You could make yourself some trehalose suppositories.  Either mix it up in some cacao butter and pour into into molds or simply cap it up in some 000 size gelatin capsules which should hold about a gram. I think you'd want to get about 3 grams a day. The studies for IV dosing were done around 20 grams once a week.

 

There is the "ick" factor for suppositories, but I think it would work and you won't have to wonder if you successfully shut down trehalase production.

 

[Daniel Cooper]

I'm hopeful that BioBlast's treatment (don't recall who they sold it to) will eventually pop out as a treatment for a number of neurodegenerative diseases.  If it does, I suspect you're be able to get if off label for cardiovascular disease, but it's probably going to be stupid expensive.  Which is crazy - what's in that IV bag is sugar water.  An atypical disaccharide sugar, but sugar water none the less.  It shouldn't take an arduous years long process to approve something that is on the FDA's GRAS list.  It's unlikely to cause any harm.  Get to a large phase III trial as fast as possible, and it either works or it doesn't.  If it works, approve it and get it on the market. If it doesn't work, forget about it and move on.  Apparently we've all gotten used to the idea that it should take 10 years and a billion or two dollars to get a drug to market.  Nonsense.

 

It's strange that it is giving you diarrhea when taken orally.  If you think about it, without your trehalase inhibitor once you consume it orally it's getting almost instantly metabolized into glucose.  Which shouldn't have that effect unless you're consuming enough at one time that your blood sugar is doing something strange.