Although
seems to only be a statement of intentions and prospective research, there is some evidence that the ECM construction is altered by rapamycin, particularly in wound healing, such as the intima of the vascular tissue:
I have found very little research on this, however.
As you say, there’s not much.
There’s this on glycine:
It appears that Cambian has a “lead” (not sure the exact definition of this, compared to “candidate”), for this issue. The group under Cambrian working on this appears to be Isterian. Details on their website here:
Source: Pipeline
I think extracellular matrix (ECM) damage is definitely an important part of aging that is often forgotten. I have been trying to get it noticed more as an important problem to work on. It is often dismissed by people that think cellular reprogramming is the holy grail and will solve aging. It’s pretty clear to me that that’s not the case. Cellular reprogramming has great potential to rejuvenate cells but I have seen no good evidence that it will fix everything that is not a cell, like the ECM. Rejuvenating cells won’t just automatically fix the ECM anymore than fixing your house will automatically fix your garden. Also the gene expression of cells and their function is somewhat controlled by signaling from their environment, one implication of that being that an old and stiff ECM can negatively influence the cells contained within it. This may even make it harder to epigenetically rejuvenate the cells in an old person compared to a young one.
The ECM slowly accumulates damage with aging, damage that is stochastic in nature and caused by random chemical reactions. Glycation of extracellular proteins, which can result in cross-link formation and advanced glycated endproduct formation, is a prime example yet only one of many such damages. The cross-links accumulate with time resulting in a stiffer matrix that results in stiffer tissues ultimately causing all kinds of age-related problems like less compliant vasculature system, stiffer joints, tendons and more.
There have been some attempts to develop treatments to break cross-links. In the 90’s a company called Alteon developed ALT-711 which is a cross-link breaker whose purpose was to break cross-links in the body. It reached clinical trials but was aborted when it didn’t have much effectiveness. It had potential to reduce vascular stiffening but a major problem was that it only breaks a particular type of cross-links which are a small minority of the cross-link types found in humans so most of the cross-links were not broken down by ALT-711. That’s probably why it failed in clinical trials even though it was found to be somewhat beneficial in rodents.
Since the failure of ALT-711 I have been waiting for new cross-link breakers to be discovered or developed but nothing has come up since then. I think it’s mainly because it’s hard to create them, but also because there were hardly any companies trying. We really need a cross-link breaker that breaks glucosepane, which is the major cross-link that accumulates in humans and contributes greatly to tissue stiffening in humans. Such a cross-link breaker would have much greater potential than ALT-711.
There is a relatively new company called Revel that is working on finding cross-link breakers. I hope more companies join in and something will be discovered.
Elsewhere in the forum, the action of DMSO in breaking down collagen is addressed. One member is injecting it. Any thoughts?
FWIW…
There is a posting on this forum with a link to a PDF copy of “the medical book” on DMSO.
See;
Joseph, your September posting in the skin thread was what got me thinking about it. It seems this has been on olafurpall’s radar for some time, so I was wondering where he thought DMSO might fit in with the enzyme studies. I’ll take a look at the 1983 study you linked.
Anybody have any idea how MAC is doing with his DMSO injections?
There were some posts here about DMSO being able to dissolve collagen but I don’t think it has much bearing on age-related cross-link damage. First of all, if it did dissolve collagen, then ingesting DMSO or applying it topically might cause more harm than good because dissolving it could disturb the balance in the collagen fiber organization. Even though theoretically dissolving collagen might break some age-related cross-links it’s not discriminative in breaking them so it would also be able to break the enzymatic cross-links that are supposed to be there. You can categorize extracellular cross-links into two types; enzymatic and non-enzymatic. The enzymatic ones are produced deliberately by the body and they serve a purpose. The non-enzymatic ones are the ones that are formed randomly by stochastic damages and contribute to aging.
Thanks. Hope you post more as things progress in this area.
Just to clarify, its not that DMSO exactly dissolves collagen… its that: dimethylsulfoxide (DMSO), by contrast, is relatively aggressive and induces significant structural perturbations such as keratin denaturation and the solubilization of membrane components
Full Post / and Reference Here: Rapamycin for Hair Growth and Hair Pigmentation - #320 by RapAdmin
Snake venom analogues.
This post is extremely important b/c this is one of the forms of damage that epigenetic reprogramming is least likely to reverse.
The other way to deal with the AGE (Advanced Glycation Endproducts) cross-link issue is the avoid them in the first place.
Perhaps this approach can help: I spoke with Pankaj at the Longevity Summit at the Buck in December, and he’s excited by his research, which is a promising area. Of course, you have to take the word of any founder (when talking about his company’s products) with at least some skepticism… but still, interesting.
Pankaj Kapahi is an experienced professor at the Buck Institute with three decades of experiences in the fields of aging, metabolism and fasting. In this video, he showcases the mechanism of glycation and glycolysis, together with the hazards of AGEs. Besides, he reveals how the glycation-lowering compounds inhibit appetite, improve insulin resistance and longevity
Yes, slowing it down is the main thing we can do today. I have been trying to slow down AGE formation for 15 years.
Regarding Pankaj, I am no fan of his GLYLO product for reasons I have explained elsewhere before. I don’t think the GLYLO product is novel at all and I think the marketing of it is downright misleading. Here are the reasons why I think so.
The GLYLO product contains five ingredients; Alpha-lipoic acid, nicotinamide, pyridoxine, thiamine and piperine. Only two of these, namely pyridoxine and thiamine, have some direct antiglycating effects. The others do not. Those two ingredients are not particularly powerful and the doses of them in GLYLO are not particularly high, certainly not more than a whole lot of people have already been getting for many years simply by taking multivitamins or vitamin B complex supplements.
GLYLO is claimed to result in weight loss and increase insulin sensitivity. That’s not at all unreasonable. Alpha-lipoic acid has been found to improve insulin sensitivity so it’s not unreasonable to claim that GLYLO can improve insulin sensitivity. Alpha-lipoic acid has also been found to help a little bit with weight loss, at least in overweight/obese adults. It’s possible that this is a result of less cravings so the claims of GLYLO helping with cravings are not entirely unfounded. However, to the degree that that’s true, that’s not novel nor can alpha-lipoic acid be particularly effective at inducing weight loss. It’s been on the market for well over a decade and taken by thousands of people and weight loss is not a common experience from taking it.
Regarding the Alpha-lipoic acid in GLYLO, nothing is stated on the label regarding whether this is racemic alpha-lipoic acid or R-alpha-lipoic acid. When this is not mentioned it almost always means it contains racemic alpha-lipoic-acid, which is less expensive and is inferior when it comes to health. The racemic alpha-lipoic acid is known to be less bioavailable than the natural R-alpha-lipoic acid and to have higher chances of causing potential harmful effects. This was already apparent more than a decade ago. The fact that GLYLO contains the cheaper racemic alpha-lipoic acid means that they either are unaware of the superiority of the R-form or are simply cutting corners in the product to make production cheaper. Either case is a red flag IMO.
Regarding the Vitamin B6 in GLYLO, I recall an article on the longevity.technology website about GLYLO, supposedly written after interviewing Pankaj. That article stated that GLYLO contains pyridoxamine. However that is incorrect. GLYLO does not contain pyridoxamine, instead it contains pyridoxine, which is a cheaper form of vitamin B6 that is not as effective as pyridoxamine at inhibiting glycation. Pyridoxine and pyridoxamine are two vitamers of B6 vitamin with different properties when it comes to glycation. Pyridoxine is the most common form found in all kinds of multivitamins and vitamin B formulas but it’s the least effective against glycation of the vitamin B6 vitamers. Pyridoxamine on the other hand is not found in such formulas and is hard to find and more expensive. However, it is pyridoxamine that is a stronger antiglycating agent than pyridoxine!
I know that probably the main reason they put pyridoxine in GLYLO rather than pyridoxamine is that the latter was categorized as a drug some 15 years ago ago because some drug company realized it’s benefits and wanted to patent it. So it’s understandable if they can’t put pyridoxamine in GLYLO and I can sympathize with that. But they should at least be honest about that and not claim that it contains pyridoxamine in interviews when it doesn’t. Note that this is important since the mouse studies they used as basis for the benefits of GLYLO used pyridoamine not pyridoxine! But fortunately for them, most people don’t know the two forms have different effects.
Pankaj claimed that his lab has discovered the combination of supplements in GLYLO but I think that is also misleading. The insulin sensitizing effect of alpha-lipoic acid has been known for almost two decades now and the slight antiglycating effects of thiamine and the B6 vitamers (particularly pyridoxamine) has been known for over 15 years and many people that I personally know that have been around the longevity industry for long have known this and taken all these ingredients for these purposes for many years. The antiglycative effect of this product will be very small at best for most people except perhaps in some individuals that happen to respond unusually favorably to the glucose lowering effect of alpha-lipoic acid, in which case the antiglycative effect is merely secondary to lowering of average glucose levels.
The truth is, inhibiting glycation in humans in vivo is very hard to do. There are some ingredients that can have very small effects but none that are available and can inhibit glycation strongly in humans in vivo. The most effective way to inhibit glycation is still simply to keep the average blood glucose as low as possible.
Also I’m pretty sure some, if not most, of the benefits of GLYLO seen in the animal studies are explained largely by inadvertent calorie restriction (the group of mice given GLYLO ate less than the controls), but calorie restriction has major health benefits and also generally reduces whole body glycation.
Having said all this, I still very much appreciate the work Pankaj and his team are doing. I commend them for trying to work on an overlooked area of aging. I just don’t like the misleading hype and marketing surrounding the GLYLO formula.
This post is extremely important b/c this is one of the forms of damage that epigenetic reprogramming is least likely to reverse.
Exactly!
Hi - you bring up a lot of good points. I’m not as well versed in the specific science related to the compounds in the Glylo supplement. Would you mind if I invited Pankaj to the site to discuss the issues you’ve brought up and defend his supplement and the science behind it?
There are at least 3 forms of vitamin B6 depending on your definition.
I can’t find pyridoxamine on Amazon, but they sell Pyridoxal 5-Phosphate form which is quite a bit more expensive than the common form Pyridoxine.
What are you thoughts on comparing pyridoxamine to the Pyridoxal 5-Phosphate form?
Sure I don’t mind if you invite him to discuss this. I should tell you though that we have already discussed this somewhat on some Facebook groups and he is probably as tired of trying of defend my points as I am of being the “bad guy” here when I point out the flaws behind the product and it’s marketing. I think he is a well meaning scientist but I don’t agree with his conclusions of his research (like him thinking glycation reduction results in weight loss) nor the marketing of GLYLO.
Good question.
To start with lets get one thing clear. Vitamin B6 exists in three forms, pyridoxine, pyridoxal and pyridoxamine. Then there are three additional variations which are these three forms each with a phosphate group attached, namely pyridoxine-5-phosphate (PNP), pyrixoxal-5-phosphate (PLP) and pyridoxamine-5-phosphate (PMP). So six forms in total.
Pyridoxine, pyridoxal and pyridoxamine are all converted into PLP, but PLP is the coenzymatically active form of vitamin B6 in the body that performs the vitamin functions of vitamin B6.
Now PLP is sometimes sold as a supplement and claimed to be superior to the other forms on the basis that it’s the coenzymatically active form and therefore it the most useful form. People are told it makes sense to take PLP directly and that it’s better than taking other forms because the other forms need to be converted into PLP. This is supposed to justify the higher price of PLP supplements. This is wrong! PLP cannot be taken up by cells without first being dephoshorrylated into pyridoxal, so taking PLP ends up being a waste of money since eventually it has to be converted into the cheaper pyridoxal before being absorbed. Once inside cells the pyridoxal is then converted back to PLP to be used by the cells.
So there you have it. Don’t waste money on PLP. Just stick with pyridoxine if you can’t find a source of pyridoxamine.
This talk by Collin Ewald brings up the idea that degradation of the ECM is an independant hallmark if aging. And he think that chondroitin sulphate and Hyaluronic acid might be used to slow down the aging of the ECM.
