Scores of Labs Should be Gearing Up to Work on Glucosepane Cross-Link Breakers, But Are They?

As we age skin and blood vessels lose their elasticity. People care too much about the skin and too little about the blood vessels, but that is always the way of it. Appearance first and substance later, if at all. Yet you can live inside an aged skin; beyond the raised risk of skin cancer its damaged state arguably only makes life less pleasant, and the present state of medical science can ensure that the numerous age-related dermatological dysfunctions can be kept to a state of minor inconvenience. Loss of blood vessel elasticity, on the other hand, will steadily destroy your health and then kill you. Arterial stiffening causes remodeling of the cardiovascular system and hypertension. The biological systems that regulate blood pressure become dysfunctional as blood vessels depart from ideal youthful behavior, creating a downward spiral of increasing blood pressure and reactions to that increase. Small blood vessels fail under the strain in ever larger numbers, damaging surrounding tissue. In the brain this damage contributes to age-related cognitive decline by creating countless tiny, unnoticed strokes. Ultimately this process leads to dementia. More important parts of the cardiovascular system are likely to fail first, however, perhaps causing a stroke, or a heart attack, or the slower decline of congestive heart failure.

From what is known today, it is reasonable to propose that the two main culprits driving loss of tissue elasticity are sugary cross-links generated as a byproduct of the normal operation of cellular metabolism and growing numbers of senescent cells. Elasticity is a property of the extracellular matrix, an intricate structure of collagens and other proteins created by cells. Different arrangements of these molecules produce very different structures, ranging from load-bearing tissues such as bone and cartilage to elastic tissues such as skin and blood vessel walls. Disrupting the arrangement and interaction of molecules in the extracellular matrix also disrupts its properties. Persistent cross-links achieve this by linking proteins together and restricting their normal range of motion. Senescent cells, on the other hand, secrete a range of proteins capable of breaking down or remodeling portions of the surrounding extracellular matrix, and altering the behavior of nearby cells for the worse.

The most important cross-linking compound in humans is glucosepane. Our biochemistry cannot break down glucosepane cross-links, and as a result it accounts for more than 99% of cross-links in our tissues. This isn't a big secret. Given this you might expect to find researchers working flat out in scores of laboratories to find a viable way to break it down. After all here we have one single target molecule, and any drug candidate capable of clearing even half of existing cross-links would provide a treatment that can both reverse skin aging and vascular aging to a much greater degree than any presently available therapy. The size of the resulting market is every human being, the potential for profit staggering. Yet search on PubMed, and this is all of relevance that you will see published on the topic in the past few years:

This is a tiny output of work. The research and development world is not beating a path here as it should. The thesis is that this lack of enthusiasm exists because the state of tools and processes needed to work with glucosepane has long been somewhere between underdeveloped and nonexistent. No group will choose to work in an area in which they have to build the tools first when there are so many other choices available. This sort of chicken and egg situation exists in numerous places in every field of science and technology, small fields where a great deal might be achieved, but no-one does anything because the short-term rational choice is to do something else in an area where the tooling already exists. This is why we need advocacy and philanthropy, to fix problems of this nature. In recent years the SENS Research Foundation has been funding development of the tools needed for research groups to work with glucosepane in living tissues, and just this year we have seen the first published results: a simple, cheap, efficient method of creating as much glucosepane as needed for ongoing cell and tissue studies. There is now no roadblock standing in the way of any researcher wanting to run up batches of glucosepane, create small sections of engineered skin and blood vessel tissue, generate cross-links in that tissue, and then carry out assessments of drug candidates for clearing those cross-links.

The tools are a big deal, I think. Glucosepane clearance is a very narrow, very small pharmacological problem with a huge pot of gold on the other side. Pharmaceutical companies and established laboratories should be packed with staff running, not walking, to work on this. It is crazy that anyone has to be out there banging the drum to draw attention.

Comments

Um, there still aren't any validated antibodies to act as markers of glucosepane removal in vivo. Surely that is a missing significant tool?

Posted by: Jim at December 8th, 2015 8:25 PM

Even though this is off topic I figured this glucosepane post would be a relevant place to ask about this...does anyone listen to the Joe Rogan Experience podcast? Aubrey de Grey was of course a guest earlier this year, and very recently Joe had UFC president Dana White on the show. In the middle of the podcast they began discussing fighter injuries, doctors, etc. and German doctor Peter Wehling came up. Dana mentions that Dr. Wehling has a new procedure that rejuvenates (my words) skin collagen and it's due to launch in about a year. Does anybody know anything about this? Here's a link to the beginning of the discussion, which is not safe for work:

https://youtu.be/b_LL_H7L_Tg?t=1h23m24s

Posted by: Robert at December 8th, 2015 10:16 PM

Glucosepane increases TGF-beta levels significantly too which has big implications for stem cell mobility/repair and the associated telomere - P53 - PCG-1a - Mitochondrial axis.

The Conboy work has demonstrated the benefits of inhibiting TGF-beta and what would likely happen if the source of the rising TGF was removed. So for me cleaving AGE is a no brainer.

The project I am working on cannot cleave AGE so we plan to do the next best thing and demonstrate the Conboy method and apply it to a lifespan study. It is my personal hope in doing this and IF we achieve good lifespan increase we can help point funding in the direction of AGE breakers.

I am friends with someone who worked on the original YALE glucosepane work and chatted to them about AGE, it appears that Metformin acts as a sacrificial agent too that slows glycation down. Its not the solution but it can help while one is found.

Posted by: Steve H at December 9th, 2015 2:12 AM

@Reason I have shared this on my networks to boost the signal. The situation is absolutely insane considering there are papers identifying Glucosephane as a main culprit in vascular aging going back to 2005!

What can we do to help this situation? Is there anything the MMTP can do beyond demonstrating the Alk-5 inhibition effect on lifespan to highlight the importance of glucosephane cleaving?

Posted by: Steve H at December 9th, 2015 3:09 AM

@Steve

Hi Steve,

I agree that stopping glucosepane effects and AGEs is a great way to mitigate its damage and inflammation on the body.
But, I have a feeling that is just wrong ECM signaling or remodeling. I spoke earlier about cellular reorganization (or also called cellular remodeling or plasticity) as something needed for a long lifespan. Glucosepane most likely changes (by crosslinkin) ECM plasticity and stiffens it; which is bad in itself. But TGF Transformation Growth Factor is a two-timing two-faced bad -and good- growth factor, it increases inflammation (as in glucosepane increasing TGF) and thus mutational unstable 'transformation' to neoplastic plasticity tissue from chronic oxidative stress inflammation exposure (cancer formation, TGF is involved in neoplasticization to an inflammed and damaged 'transformed' cancer neoplastic tissue).

But at the same time, TGF is also important for cell reorganization (so is every other growth factor (GF) involved and communicating with it) and Plasticity. With age we lose our plasticity. Mouse accumulate glucosepane, AGEs and others dramatically faster than naked mole rats in their ECM skin, brain and entire body. What is funny is that Naked Mole Rats have much higher plasticity in their brains and they also avoid all cancers (barely no cancer, yet to Have Plasticity/Cell Organization you need GF, such TGF), this means naked mole rats are Full of TGF and IGF and what not other GFs, just like us humans, they need this growth and they have special cancer blocking mechanisms that block TGF transformation (such as high molecular hyaluronic acid overproduction, meaning they tricked their own ECM with new tricks from it being transformed upon excessive glucosepane and AGEs ECM collagen crosslinking/damage) to mutant cancerous cells upon inflammatory oxidative damage to cells telomeres. They had to because they live in a low oxygen environment buried under the ground, in their tunnel labyrinths they build themselves gnawing with their huge 2 front rat-like teeth (living in low oxygen promotes dramatic cancer formation! by activation of HIF-1 Hypoxia Inducible Factor-1 and of course, TGF). When you think about it for a second, it means that TGF (and other GFs) is not So bad after all, when kept in check and has benefits (perhaps activation of TGF is a compensatory signal rather than an insult, but ends up overtransforming towards cancerous formation after oxidative challenges), how long does the mouse live (2,3 years), how long does the naked mole rat live (35 years), how much tumors do mouse get vs naked mole rat (so much more), how much glucosepane mouse gets vs naked mole rat (about 20 times more), who is getting more GFs to maintain plasticity/cellular reorganization/remodelling...naked mole rat. Humans same thing, without our constant brain and other organ tissue replasticity, by our GFs that are Created and Secreted by our own body (such as brain and other organs who secrete GFs), we would be dead and accumulate glucosepane Much faster; as in mouse. GFs have a reason for being they are our own creation in our body (part of our makeup) and are thus needed*. I think this is again a balancing act where we say growth factors = cancer/oxidation/inflammation = bad...

what we don't realize is that it is not always bad depending onthe type of species and context, and its cancer protection mechanisms, and that it's a *very fine balancing act between too little (no growth/death), too much (transformation/cancer); but just right (cell reorganization and good tissue replasticity). We will have to see how we can remove AGEs and break crosslinks while keeping our GFs function intact; our organs and tissues depend on them to reorganize themselves and thus allow our very long lived lives (as naked mole rat show, and centenarians how are not demented/no AZ',s have much higher brain plasticity retention and IGF-1/TGF-1 crosstalk for neurogenesis).
Plasticity has a capability to alter AGEs and glucosepane ECM somehow (plasticity is obviously linked to ECM scaffolds) so that it remains low and allows our long lives. If we are capable of breaking glucosepane and AGEs that's a good thing, but blocking IGF- TGF and other GFs is a risky pathway as shows in dementia and other demented people suffering brain involution, (when you have dementia your death rate increases dramatically and you could be (brain) dead in 10 years from ultra-brain pruning), (also even if GF themselves are risky). Balancing act indeed. It's more complicated than we thought (it's the famous :
F...if you do, F... if you don't). We'll have to find workarounds these continuous fun dillemas and paradoxs.
Or is just me who's blinded by my new found love in plastic (ity) (lol). : D

1.http://www.ncbi.nlm.nih.gov/pubmed/8830994
2.http://www.ncbi.nlm.nih.gov/pubmed/16297654
3 http:/www.ncbi.nlm.nih.gov/pubmed/9682785
4.http://www.ncbi.nlm.nih.gov/pubmed/1572403

Posted by: CANanonymity at December 9th, 2015 8:20 AM

ps: as for studies that continuously say IGF is bad IGF equals cancer, and then go on to show that IGF is higher in short-lived species vs long-lived species (like to say mouse have more IGF than naked mole rat), don't realize that some amount of it is needed otherwise there is no growth possible (in certain large specie as least such as us whom our Neoteny phase Needs growth to attain our adult size), so again I say depending on specie context and depending on the organ/tissue type, IGF and othe GFs can have wild different results so we cannot lump it all into 'Bad' category. Plasticity shows that. In our specie (humans), not naked mole rat, not mouse or other insect specie they study...but Human, IGF has Good Benefits (on brain especially, bone, sexual hormones and skeletal muscle formation). I'm betting TGF has Some too depsite getting a bad wrap for cancer contribution since it is a transformation growth factor and cancers all about Growth growing transformation/morphing mutating cells. There are obviously shades of gray we are missing, it's too black or white still. But everyone knew aging was going to be complex; now we know it's Way Way Wayyyy more complex than thought. Back to the drawing board/square 1.

Posted by: CANanonymity at December 9th, 2015 8:46 AM

One last thing paradoxal, dwarf mouse (Snell/Ames), growth hormone KO mouse and dwarf centenarians are the exception to this rule, and they have low IGF and GF, GHs (although mice live nothing like a human life, so mice are not really a good comparable example). but Dwarf Centenarians such as some Ashekenazi Jewish or small South American Centenarian Native Quechuan dwarf-like people who become centenarians and have low GF/IGF in their blood and are small stature are a proof that the insulin pathway-to-glycemia is a conserved growth pathway that must be kept 'adequatelly Low' (not hyperactivated); but that Even Dwarf Human Centenarians Need Some Igf Gf for their brain to function cause otherwise they *Too would be gone soon from a tiny receding brain from plasticity absence. Brain is central to lifespan and brain volume loss is causal to MLSP (brain pruning can be a sign of regional connection efficiency/rewiring/perhaps replasticizing after a TBI brain traumatic injury, but overall if it continues to lose volume and tissue mass, that's Normal Aging loss of brain tissue volume; and it's death that awaits soon).

Posted by: CANanonymity at December 9th, 2015 9:11 AM

Indeed some TGF-beta is good and needed its just when it reaches that tipping point it becomes a pro-aging factor not pro-youthful, similar to P53. The conboys are attempting to dial the levels back and "calibrate" the TGF to youthful levels. When they have done this in their tests rejuvenation of stem cells was observed in very short order.

The MMTP is proposing to test this on lifespan as part of a a number of mouse cohorts on already old (18 month) mice. It is unlikely we would dose at the same frequency the Conboys did which was daily for 12 days. Speaking to Mike Conboy he believes it would not be needed so often on a long term basis, we are trying to establish a suitable dosage that would balance TGF-beta levels to youthful norms without shutting it off completely.

Again as I mentioned previously we are testing this not to encourage development of Alk-5 inhibition as a therapy but to showcase what happens if AGE is cleaved and TGF levels are reduced (TGF increases significantly with AGE increase). It is the hope that we can prove a positive increase of healthy lifespan and importantly we can encourage more focus on cleaving AGE to gain these benefits and more.

We also want to explore the potential of other interventions including senolytics and Oxytocin and will test this too if we raise enough for an additional mouse cohort. We are testing 20 mice per group to ensure good data (40 would be ideal).

Phase 2 will see us explore combinations of the above and other compounds that may fit in with SENS strategy. We have a world leader in stem cells on our team so stem cell therapies are also potentially possible in later phases.

We will be launching a kickstarter on indiegogo in the new year and hope to work with Longecity to test this.

Posted by: Steve H at December 9th, 2015 11:08 AM

Why are you launching the kickstarter on Indiegogo and not lifespan.io?

Posted by: Slicer at December 9th, 2015 11:59 AM

@slicer a couple of reasons. Firstly Indiegogo has wider coverage and includes those interested in science generally not specifically longevity like lifespan.io focuses on. Secondly we are hoping to fund match via Longecity in addition to our kickstarter and the group feels that lifespan.io and Longecity cover too much of the same ground.

We will be doing a second lab project on Lifespan.io for our US based researcher and a third lab in France will be doing more tests funded directly by the International Longevity Alliance (ILA).

So in total we will have three labs testing with the first lab in Germany testing as described above.

Posted by: Steve H at December 9th, 2015 1:06 PM

Jason Hope donated half a million dollars a few years ago to set up a SENS lab at Cambridge headed by Dr William Bains. I don't know if this money has now run out, or if they are still getting some research done out of it (probably by working largely for free).

I saw mention somewhere (that I can't remember) that they tested a series of supposed marker antibodies against glucosepane and found that none of them were very specific and useful.

Could the SENS Foundation run another kickstarter campaign on Lifepan.io in the new year to raise money for the Cambridge Lab to generate antibodies to glucosepane and then validate them? How much would this cost? Would $45k be enough, or is this a more expensive undertaking?

Posted by: Jim at December 10th, 2015 10:10 PM

@Jim: you're quite correct that anti-glucosepane antibodies are a critical tool, and you're remembering rightly that the Cambridge SENS Lab found that none of the commercially- or academically-available putative anti-AGE antibodies were any good at this job. In fact, it's worse than that: none of the putative anti-AGE antibodies are really any good for detecting any AGE at all, and barely serviceable against related adducts like CML! We shut down the Cambridge lab (indeed, Dr. Bains fell on his sword) largely because without this basic tool, they had no way to carry their research forward.

Happily, the successful and convenient synthesis of glucosepane by our Yale researchers has enabled them to start working on developing this tool. They are now working to incorporate glucosepane into synthetic, chemically-uniform crosslinked peptides, which can then be used as antigens with which to vaccinate rabbits. Once vaccinated with these antigens, the animals are expected to generate antibodies targeting glucosepane-containing peptides. The B-cells that generate the antibodies in such animals can then be isolated and immortalized, generating monoclonal glucosepane-targeting antibodies on an industrial scale.

@Steve H: I appreciate your reasons for wanting to go with IGG. Consider, however, the longer-term advantages to the entire biomedical gerontology community of using the Lifespan.io platform: by helping to build up a roster of projects and a track record of success, they can attract more projects and eventually begin digging more aging research studies out of the woodwork, raising the profile of the entire sector and eventually allowing Lifespan.io to use their royalties for their advocacy activities for the advancement of anti-aging research.

Posted by: Michael at December 10th, 2015 11:09 PM

@Michael I agree with you about lifespan.io and I have asked the question to see if we can change for this first lab.

Our primary candidates are Alk 5 inhibitors and Dasatinib/Quercetin so I assume you approve of this choice? We want to combine them at a later phase too.

Also would SENS endorse our work? I am not talking about funding at this point as we want to apply to run stem cell lifespan work with you later once phase one is completed, as you know our team includes two world class stem cell researchers. Perhaps can support our work by allowing us to display the SENS name on our site and some supportive comments we can display? We could do likewise with SENS.

Posted by: Steve H at December 11th, 2015 2:02 AM

Thanks for the reply Michael. That sucks that the Cambridge Lab had to shut down due to such a simple road block. I guess it highlights the importance of the SENS Research Foundation, without you guys none of this research would have happened due to a few missing basic tools (as Reason has pointed out).

Hopefully the Cambridge Lab will be back once this tool and some more funding is available.

Given that David Speigel's Yale group are creating anti glucosepane antibodies... surely they should also be looking to create some of their 'faster cheaper' ARM (antibody recruiting molecules) to glucosepane as well?

Posted by: Jim at December 11th, 2015 10:35 PM

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