14 replies to this topic

[Nate-2004]

I decided to make a separate thread on GlycoSENS because in a search of the forums there's specific questions asked around AGEs but no general discussion threads on the topic as a whole. I think it's one of the most important areas of anti-aging research and it's just not getting the attention it deserves right now.

 

I was re-reading his and Aubrey De Grey's section on AGE blocking and breaking in the 2008 book Ending Aging and I'm realizing that I wasn't paying enough attention the first time through. It does seem that blocking AGEs is impossible, since there are multiple chemical pathways in the metabolic process to forge those crosslinks. If you try blocking free radicals it uses transition metals, remove transition metals you risk creating a kind of traffic jam where an accelerated buildup happens via other types of crosslink formation such as oxoaldehydes or myleoperoxidase, and apparently there's nothing that can specifically target oxoaldehydes as of yet without cleaving other essential carbon bond molecules. Inhibiting myleoperoxidase just makes you vulnerable to infection. 

 

I also wasn't entirely sure till now that pentosidine is the tough to break AGE involved in skin. There's no info on how this particular type of AGE forms though, through one of the above mechanisms or something else. If anything, just trying to block that particular type of AGE may help with aging skin if anything else, if we know how pentosidine forms.

 

The effects of ALT-711 on humans is unknown as nobody published the results of what happened. The theory about what happened was that it didn't target the major type of human AGE, glucosepane. I'm guessing because either our diet is different than monkeys and dogs, or something else is different. There's not enough info that I'm aware of on what other types it breaks and as far as I know, the effect is temporary, it only breaks the crosslink, leaving it there to reforge itself once you stop taking the drug. 

 

I'm surprised this drug didn't go to the veterinarian market.

 

My questions are these:

 

1. How much funding would it take to get some research started in synthesizing various AGE types and testing candidates? $100K? $250K? What would $1 million do?

2. Does autophagy affect the AGEs found in the ECM in any way?

3. How does pentosidine form? 

4. How does glucosepane form?

5. Is it true that the type of AGE is dependant on how it's crosslinked or created? i.e. if it's created via free radicals you get one type or if it's created by transition metals you get another... etc

 

Before anyone answers I'll attempt to answer some of the questions myself, 3 and possibly 5 in particular. Pentosidine is what supposedly causes wrinkles and crosslinks itself with lysine and arginine in collagen, though I cannot find any reference to this for proof, only that it is in skin collagen. It is formed via the Maillard reaction which is a non-enzymatic form of browning. A lot of foods have this sort of browning, cooked meats, roasted coffee and peanuts, pretzels, chocolate, cooked foods in general, but oddly enough, there's very little pentosidine in these foods. Yet, in this study, pentosidine was reduced on a diet free of these things. Wikipedia says it's derived from ribose, and a pentose.

 

 

Edited by Nate-2004, 24 July 2017 - 05:56 PM.

[YOLF]

Well, pentosidine correlates with diabetes complications which can include heart problems. Alagebrium is effective at improving the condition of patient's with related conditions. I imagine it could be effective against pentosidine, though I'm not sure where exactly looking at the pictures. They did do trials of alagebrium on skin conditions, which would suggest to me that it could have been known to have been of benefit. The only way to find out would be to order some and see if it improves your appearance.

[Nate-2004]

As of the original post, glucosepane has since been synthesized by Spiegel labs. They also already have a few crosslink breaking candidate drugs.

 

I was under the impression that rosmarinic acid breaks pentosidine crosslinks?

 

Assuming what I get from Dynveo is in fact a 30% extract of RA, and that it's not too soluble in DMSO, only 25mg/ml, this means any 30 ml bottle of solution is going to be weak.

 

So 750mg of plant and RA material max mixed in (225mg RA), that's only going to end up being 0.75% RA. Right? Not terrible but not strong either. Not sure how strong it'd need to be.

 

This is all only worthwhile assuming that in vivo RA works as a pentosidine crosslink breaker. In my experience of using this it isn't very potent. Next month I'll try again though with a different formulation of DMSO, Urea and Vit C. It'll end up being weaker (0.5%) but we shall see.

Edited by Nate-2004, 17 January 2018 - 03:44 PM.

[H2enthusiast]

crosslinking is necessary however just like ROS or inflammation out of control crosslinking is the issue. 

 

drug candidates such as ALT711 haven't been very effective with potential side effects.

 

Inhibition during the amadori rearrangement is likely key. By maintaining proper concentrations in blood of glucose:glutathione and also up regulation of SOD to deal with superoxide which largely contributes to the formations would be a good strategy. Lowering blood sugar as well, and cleaving crosslinks formed by fructose rather than glucose(high dose taurine may be promising), as fructose crosslinking may have a large role in advanced disease states like diabetes. 

 

Over all far too little study on this topic. 1m wouldn't be nearly enough to develop a product to break glucosepane and make it to market... even if it is a nutraceutical which is highly unlikely. 

[Nate-2004]

Interesting. Why only out of control crosslinking? Don't AGE's just build up over time and the only way to remove them is to break crosslinks? I know sulforaphane helps to upregulate glutathione (I'll find references when I get time but it's referenced in that Rhonda Patrick video on sulforaphane). Where did you hear about high dose taurine?

[H2enthusiast]

crosslinks are necessary for proper function, excess crosslinks that accumulate over time are the issue.

 

pretty sparse but this study suggests taurine for fructose based crosslinking

 

http://icmr.nic.in/i...august/0911.pdf at 2% in water solution the rats are consuming about 400mg per day. Multiply their weight by 350 for humans, and divide by 6 to find proper dosage and it's about 23g a day.. not really practical. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/

 

not really practical but well below the toxic limit.

 

Interesting. Why only out of control crosslinking? Don't AGE's just build up over time and the only way to remove them is to break crosslinks? I know sulforaphane helps to upregulate glutathione (I'll find references when I get time but it's referenced in that Rhonda Patrick video on sulforaphane). Where did you hear about high dose taurine?

 

[sthira]

Backing up a bit before proceeding:

I decided to make a separate thread on GlycoSENS...

My understanding is that once upon a time, one protein was one protein; then it attached to another protein and formed a bond. Suddenly, due to no fault of your own, you're handcuffed to a cop -- clink.

But these crosslinked protein molecules aren't always bad, are they, they're not the enemy, we do not want to completely raze and destroy all of them because they're literally how our bodies are built. Our tissues are protein crosslinks upon crosslinks, these comprise our very being. Links formed and reformed, shape shifted and grew and collected into patterns during the miracle of life, inside of mom, and these little basic constituents must last us a lifetime. Damaged proteins may be "repaired" or structurally put back together again -- Humpty Dumpty style -- but they don't seem to get entirely replaced.

And they do so much. With every heartbeat they allow the body to be flexible, for example, and for our organs to stay elastic in good functioning health. But over time pieces get hardened by chemistry, or they distorted, or they frayed by wear and tear: they age. They body reacts against them -- it might signal inflammation that then becomes chronic inflammation, and these little bastard deviant crosslinks might bend into weird tissue collections, or clogs, or inappropriate scars, or they become like horrible balloon animals, all bleak color and twist.

But because we have bad links doesn't mean we want to eliminate all links -- we'd melt and die -- we want sever the links that are obstructing healthy organ function. Rid them, render them harmless. Normal function means good health. So how do we keep the "good" protein links while destroying or immobilizing or rendering harmless the "bad" protein links?

GlycoSENS is about discovering the process, and then investigating which (if any) candidate enzymes or drugs or MGMT (not the band) or smart little nanobots designed to cleave only one identified detrimental protein crosslink -- just one, then gtfo.

Ok, SENS probably doesn't care about AI programmed nanobot protein cleavers, but they're a mind fuck anyway.

Growing lab glucosepane makes it easier for researchers to at least see what might be happening down there in the world of protein formations and dissolutions. Is it even possible to separate lysine-arginine bonds, or is that bond forever (without damaging healthy tissue)? Anyway, that's my fragile GlycoSENS understanding, which is here totally simplistic because I think the crosslinks develop very slowly and might not be noticeable until they've done big damage.

But I think the overall biology is so wildly complex and not yet understood well enough that we can't make actionable supplement guesses like -- what will 225mg of rosemeric acid, or DMSO, vitamin C or urea do to break specific crosslinks without damaging important crosslinks? I mean, I'm not discouraging self-experimentation because that's what this adventure of life is all about -- but don't hurt healthy tissue with possibly toxic compounds.

[H2enthusiast]

someone hit the needs citations link. Here are a few, I expanded on one part in my next reply with citations
 

[1] Mikhail D. Linetsky, Ekaterina V. Shipova, Roy D. Legrand, Ognyan O. Argirov, Glucose-derived Amadori compounds of glutathione, In Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1724, Issues 1–2, 2005, Pages 181-193, ISSN 0304-4165, https://doi.org/10.1...gen.2005.04.003.

(http://www.sciencedi...304416505001017)

Keywords: Non-enzymatic glycation; Glutathione; Glucose; Amadori compounds

[1] Azevedo M¹, Falcão J, Raposo J, Manso C. Superoxide radical generation by Amadori compounds. Free Radic Res Commun. 1988;4(5):331-5.

 

[1] Rodríguez-Mañas, L., Angulo, J., Vallejo, S. et al. Diabetologia (2003) 46: 556. https://doi.org/10.1...0125-003-1056-1

crosslinking is necessary however just like ROS or inflammation out of control crosslinking is the issue. 

 

drug candidates such as ALT711 haven't been very effective with potential side effects.

 

Inhibition during the amadori rearrangement is likely key. By maintaining proper concentrations in blood of glucose:glutathione and also up regulation of SOD to deal with superoxide which largely contributes to the formations would be a good strategy. Lowering blood sugar as well, and cleaving crosslinks formed by fructose rather than glucose(high dose taurine may be promising), as fructose crosslinking may have a large role in advanced disease states like diabetes. 

 

Over all far too little study on this topic. 1m wouldn't be nearly enough to develop a product to break glucosepane and make it to market... even if it is a nutraceutical which is highly unlikely. 

 

[Nate-2004]

 

crosslinks are necessary for proper function, excess crosslinks that accumulate over time are the issue.

 

pretty sparse but this study suggests taurine for fructose based crosslinking

 

http://icmr.nic.in/i...august/0911.pdf at 2% in water solution the rats are consuming about 400mg per day. Multiply their weight by 350 for humans, and divide by 6 to find proper dosage and it's about 23g a day.. not really practical. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804402/

 

not really practical but well below the toxic limit.

 

Interesting. Why only out of control crosslinking? Don't AGE's just build up over time and the only way to remove them is to break crosslinks? I know sulforaphane helps to upregulate glutathione (I'll find references when I get time but it's referenced in that Rhonda Patrick video on sulforaphane). Where did you hear about high dose taurine?

 

 

It sounds like just from that rat study that taurine merely prevents bad fructose crosslinks but doesn't break them. This is really all new to me since having read Aubrey De Grey's book and his section on glycation that any and all glycation crosslinks (AGEs) are bad and a cause of aging and that crosslink breakers were an important target for rejuvenation therapies.

Edited by Nate-2004, 18 January 2018 - 03:45 AM.

[H2enthusiast]

They are, but inhibitors may be more important and practical, for younger people anyways. I didn't re read the study it has been a while. It is possible it inhibits and not breaks, and more likely.

 

 

[YOLF]

Well if we can destroy enough crosslinks, won't our bodies just repair themselves minus most of the pathologies of unwanted the crosslinking over time? Aren't there other options? Can we simply survive w/o them and be a little more flexible? What benefits does it provide to have these molecules?

 

Are we just talking about bone growth fusion?

 

What about serrapetidase? It comes from a graveyard bacteria, or a bacteria that eats rotten stuff in the ground which has a propensity for causing opportunistic infection in humans that might have a positive, although quirky benefit against some cancers. I was wondering if it's arrival as a new supplement had something to do with SENS. 

 

Personally, I get pains when taking serrapeptidase, particularly in my spine, and perhaps previously in my knees, though one squirt of metacurcumin is sufficient to relieve it and it does go away slowly on it's own after discontinuation, even with a synergistic approach to it's possible benefits.

[sthira]

As of the original post, glucosepane has since been synthesized by Spiegel labs. They also already have a few crosslink breaking candidate drugs.

From two years ago (19 February 2016) when Longecity's very own "Mind" interviewed Spiegel:

"Justin Loew: Now that you made the molecule, and are looking at breaking the molecule, do you have any estimate of how long it might be before there is an effective therapy that addresses glucosepane?

"David Spiegel: That's a good question. I think that from the standpoint of basic research, we've already made some progress in identifying some potential strategies for breaking glucosepane. As you know, there is a significant regulatory challenge associated with bringing new therapeutics to market, and so if I had to estimate - well, this is a very high bar in terms of ... well it is an extraordinary challenge, just the idea of making therapeutics that can break a molecule is kind of an untested concept. But the progress we are making, and the surge of interest right now in protein and enzyme-based therapeutics in pharma, makes me speculate that it is possible we could have something that is therapeutically viable on the order of 10-20 years from now. That may not seem like a short time, but from a therapeutics perspective, I think it is within our kind of vision."

https://www.fightagi...-link-breakers/

[Nate-2004]

Now that they've been able to synthesize it, it'll be sooner than everyone thinks. I think people always greatly overestimate the time it takes to achieve something big. They forget that progress tends to be exponential in the collective knowledge base.  They have no problem estimating this when it comes to AI, knowing full well that once a rudimentary general artificial intelligence is achieved, it will be just a year before it doubles in magnitude and power and another before it's superintelligent. The *only* thing slowing them down in the field of biogerontology is government.

Edited by Nate-2004, 18 January 2018 - 10:37 PM.

[sthira]

The *only* thing slowing them down in the field of biogerontology is government.

When the barriers come down, as they will, inevitably, then what? What is it that we will wish to become?

Our current answer -- we seek to stop aging, to end diseases, to extend lifespans, to recapture youth, to gain supernatural powers.

Once gained, then what will we want to want?

Once we've broken the nasty crosslinks and rid the senescent cells and replaced all damaged organs anew -- with carbon or non carbon materials we may become cyborg beings -- then what?

While no one can accurately predict the future today, I say we'll explore the universe, search out new life forms, quest for "something else..." It sounds so Star Trek.

Be here now seems unsatisfactory, that's a curious quirk in our evolution, yet it's what makes us human. But humanity is on its way out, I think, and we'll do it fleshy crosslink by crosslink.

[Nate-2004]

That should be left entirely up to the individual. I'd like to get away from collectivist ideology. What will "we" become? I don't know who "we" is. What do I want to become? More than I am today, and I need at least a few hundred years more to do all the things I want to do with my life and explore or experience all the things I want to explore or experience. Entirely off topic though.

 

In the present moment I just want to get rid of the massive build up of crosslinks that's encroaching on my youthful vitality. I want to stop feeling lower back pain and having to do some ridiculously convoluted stretch routine every single day just to manage the stiffness that is building up in my joints and muscles. That's AGEs. I want to get all my skin elasticity back and firm up malar fat pads, etc, that's AGEs.  While some of this is inflammation possibly from senescent cells, it's quite likely mostly AGEs. Call me vain, I am vain, and I don't care, but I wanna look as good as I did in my 20's.

 

I want narrow minded, over hesitant and reputation worried scientists to get out of the way of our efforts. I want the FDA to just shut down and let other market based controls do the work of what the FDA fronts the pretense of doing.

Edited by Nate-2004, 19 January 2018 - 02:54 PM.