Fixing stiff collagens – damage to the extracellular matrix is the missing hallmark of aging

#1

What do people here think of this…

At Cambrian: we are. In our work creating translational drug development categories for the various hallmarks of aging, one of our 13 Drivers of Aging encompasses the changes to the ECM with age. For over three years now, we have been working to find new ways to restore or prevent ECMs from breaking down.

The ECM is a large, complex network of proteins and other molecules that surround, support, and give structure to cells and tissues throughout the body2. When you fall down and scrape your knee, you can watch over just a couple days as your cells produce tons of new ECM components and pour them into the gap in your skin created by that scrape – creating a scar.

Our ECM is constantly being damaged, in both big ways – like when we cut our finger with a knife, scrape our knee, or have a heart attack – and small ways – like through UV radiation, the inhalation of polluted air, or the death of cells throughout the body. On top of that, ECM proteins themselves ‘age’ – accumulating modifications that make them more and more brittle the longer they live in our body.

https://www.cambrianbio.com/news-and-publications/blog-post-fixing-stiff-collagens-damage-to-the-extracellular-matrix-is-the-missing-hallmark-of-aging

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#2

I agree that mechanical factors are underappreciated. Partly, I assume, because they’re harder to study in vitro. Regardless, I haven’t seen any good candidates for rejuvenating the ECM. In regards to the linked post
this is the most relevant result of a brief search. Doesn’t look too promising to me, but I could be wrong.

Poking at retinoid signalling is something I would like more info on re ECM. Dosed right it helps worms, but so does everything. Note that in human use retinoids require careful monitoring.

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#3

Some thoughts: how much is the decreased stiffening for these drugs? How long does it take to have full effect? Potentially, this could decrease heart attacks, strokes, other circulatory diseases, and cancer. Better circulation could alleviate many other conditions and general inflammation. Exercise could be easier and more effective.

Since they are only at the stage of identifying drug candidates, it sounds like we are 5-20 years away, but the potential is great.

A little background:

This post translational protein modification is associated with increased levels of glucose, affects protein structure and function through increased cross-linking, and results in the formation of “Amadori” and advanced glycation end products

age-related changes to the proteins of the ECM have far reaching consequences with the potential to disrupt many different aspects of homeostasis and healthy function

Collagen and elastin have a long half-life, as required by their structural role, which leaves them vulnerable to a range of post-translational modifications.

details on the target for their therapy, TG2:

TG2 promotes fibrotic disease through cell survival and profibrotic pathway activation

TG2 expression is highly correlated with cancer cell survival, malignancy, metastasis, and treatment resistance

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#4

The ECM topic is very interesting and I’ve been reading a great deal about it lately. It’s believed to be involved in the diastolic dysfunction which we often see in elderly women. There’s evidence that rapamycin can fix this issue through cardiac remodeling of the ECM.

https://grantome.com/grant/NIH/R00-AG051735-05

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#5

Although

https://grantome.com/grant/NIH/R00-AG051735-05

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.

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#6

As you say, there’s not much.

There’s this on glycine:

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#7

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:

CambrianIsterian
CambrianIsterian2496×1288 84.7 KB

Source: Pipeline

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#8

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.

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#9

Elsewhere in the forum, the action of DMSO in breaking down collagen is addressed. One member is injecting it. Any thoughts?

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#10

FWIW…

There is a posting on this forum with a link to a PDF copy of “the medical book” on DMSO.

Dimethyl Sulfoxide (DMSO) in Trauma and Disease by by SW Jacob

See;

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#11

Review older paper 1983

Dimethyl sulfoxide alteration of collagen

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#12

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?

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#13

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.

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#14

Thanks. Hope you post more as things progress in this area.

#15

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

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#16

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.

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#17

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

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#18

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.

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#19

This post is extremely important b/c this is one of the forms of damage that epigenetic reprogramming is least likely to reverse.

Exactly!

#20

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?

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