’s blog post: Scores of Labs Should be Gearing Up to Work on Glucosepane Cross-Link Breakers, But Are They? – Michael Rae’s reply to my comment

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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:

– Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study.
– Glucosepane and oxidative markers in skin collagen correlate with intima media thickness and arterial stiffness in long-term type 1 diabetes.
– Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes.
– Glucosepane: a poorly understood advanced glycation end product of growing importance for diabetes and its complications.
– The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes.

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.

My Comment:

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

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 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?

Michael Rae’s reply to my comment:

@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 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 to use their royalties for their advocacy activities for the advancement of anti-aging research.