Building the Tools to Work with Glucosepane Cross-Links

Good news from the SENS Research Foundation arrived today: the programs targeting harmful cross-links in human tissues are starting to make concrete progress. The occasion is marked by a publication in the prestigious journal Science that covers the establishment of one of the first basic tools needed to work with glucosepane, the most important constituent of age-related human cross-links.

Cross-links are sugary compounds known as advanced glycation end-products that form in the extracellular matrix as a natural byproduct of metabolic processes. They glue together proteins and alter the physical properties of the tissue as their numbers grow. Fortunately most are short-lived, but some hardy forms of glucosepane cross-link can linger for a lifetime, as our biochemistry hasn't evolved the mechanisms needed to remove them. These cross-links are a major cause of the reduced elasticity in skin and blood vessels that occurs with aging, among many other issues, but even blood vessel stiffening taken on its own is enough to kill people through hypertension, distortion of cardiovascular system tissues, and eventual catastrophic failure of the heart or blood vessel integrity.

The important thing to realize about glucosepane and research into cross-links is that next to no tools and methodologies exist to allow researchers to work with this compound in tissues and cell cultures. This is one of many small blind spots in the life sciences, places where the lack of basic development, documentation, and tooling has led to company after company, research group after research group deciding to do something else with their limited funds rather than be forced into building every last part of the basic toolkit they'd need to even get started. So while biotechnology has advanced by leaps and bounds on every side, every individual along the way made a rational short-term decision not to touch this area of research - and this despite the fact that it is a big, obvious target for the development of therapies that could help to extend healthy life and treat or prevent a wide range of age-related conditions that cause a great deal of suffering and death. Getting on with the thankless work of building the tools needed for glucosepane research was taken up some years ago by the SENS Research Foundation as a part of their efforts to unblock the road to rejuvenation therapies.

As for all such research programs coordinated by the SENS Research Foundation, this work was funded by philanthropic donations, including yours and mine made in past years. If you like what you see here, note that we're matching your donations to SENS rejuvenation research dollar for dollar for the rest of this year. Giving money to SENS research is a great way to help ensure that more progress occurs in the years ahead, moving down the road towards therapies capable of bringing aging under medical control, preventing age-related disease, and greatly extending healthy life.

As an aside, you'll see that the publicity materials quoted here talk about diabetes front and center. This is because the lifestyle disease of type 2 diabetes is where the funding is for cross-link research: yet another example of aging as the red-headed stepchild of medical science, locked in a closet and fed scraps, ignored in comparison to its potential for alleviating suffering and preventing death. In reality the real relevance is aging and the treatment of aging. Arguably the cross-link biochemistry of diabetic patients is somewhat removed from that of a healthy individual, as short-lived cross-links, including those that arrive in the diet, become much more important as a source of harm to organs in such a dysfunctional metabolism. It is a whole different picture, in which some facets overlap, but of course research establishments must ever follow the funding.

SRF-Funded Glucosepane Paper in Science

A new study funded by the SENS Research Foundation sheds greater light on diabetes and aging through a synthetic process. The new process will allow researchers to study glucosepane, a key molecule involved in diabetes, inflammation, and human aging. Glucosepane is considered to be a critical chemical link in both diabetes and aging. It is also an independent risk factor for long-term microvascular complications in diabetes. With access to synthetic glucosepane, scientists will now be able to generate tools to examine the role this molecule plays in human health and perhaps, develop molecules to inhibit or reverse its formation.

Glucosepane contains a rare isomer of imidazole, which has never before been observed in natural molecules, other than those in the glucosepane family. The researchers developed a new methodology for synthesizing this imidazole form that requires only eight steps.

"We are extremely proud to have supported this project and the developments leading to better insights on diabetes and aging. To have Science recognize the accomplishment of this team doesn't just demonstrate the value of our contribution to medical research; it helps raise awareness that the SENS Research Foundation approach can lead to better insights about aging and age related disease."

Concise total synthesis of glucosepane

Glucosepane is a structurally complex protein posttranslational modification that is believed to exist in all living organisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging, yet comprehensive biological investigations of this metabolite have been hindered by a scarcity of chemically homogeneous material available for study. Here we report the total synthesis of glucosepane, enabled by the development of a one-pot method for preparation of the nonaromatic 4H-imidazole tautomer in the core. Our synthesis is concise (eight steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. We expect that these results will prove useful in the art and practice of heterocyclic chemistry and beneficial for the study of glucosepane and its role in human health and disease.

Isn't there a freely available version?

Posted by: Antonio at October 16th, 2015 4:21 PM

"It is a whole different picture, in which some facets overlap, but of course research establishments must ever follow the funding."

Doesn't the funding come from our community?

Posted by: Antonio at October 16th, 2015 5:13 PM

@Antonio: For this work, yes, but not for the future expansion and commercialization of therapies, based on clearing glucosepane cross-links. The model for philanthropy is not to produce success directly, but to draw in the much larger support and funding from established sources that will then in turn produce success at a much faster pace and with more resources that are generally available to a non-profit. Philanthropy is only about funding the start to finish creation of discrete products where there seems to be no other alternative.

Posted by: Reason at October 16th, 2015 5:31 PM

I wish them well on developing (1) an antibody to detect and image glucosepane in animals (2) a small molecule drug or enzyme (catabody) to remove the glucosepane (3) luck in finding a development partner for this hypothetical glucosepane breaker.

Posted by: Jim at October 18th, 2015 5:30 AM

Excellent news! This blind spot in aging research could benefit from more funding, could this not be a suitable project for once the MitoSENS project ends?

Posted by: Steve H at October 19th, 2015 5:26 AM

Hi all !

This is great news and congratulate SENS. AGEs advanced glycation end-products are a direct consequence of glucose exposure cell glycation/glycoxidation and other inflammatory oxidative stressors. Glucosepane, which its name is related to Glucose*(-pane), is great AGE to study crosslinking from now on. If they can build a AGEs breaker for Glucosepane just like other lesser ones (carnosine beta-alanyl-histidine dipeptide, benfothiamine, v.B1 thiamine, v.B6 pyridoxine) it would be really great but let's not delude ourselves, just like metformin glucose reducer, the actual strength for true biorejuvenation is low. Not saying a genetic therapy can't do anything, just that AGEs supplements are not magic in a bottle (..of supplements). But if they can build a breaker of Glucosepane, CML (N-epsilon-CarboxyMethylLysine), Furosine, Pentosidine and Methylglyoxals, than nearly all AGEs will be covered and that would be incredible since ECM collagen AGEs level are in direct correlation and causation to biological age. It is ironic that an AGE breaker like Carnosine activates telomerase. Me thinks it is not Carnosine but the result of Carnosine extension of Hayflick limt because alanine+histidine is a strong antioxidant and is helped by telomerase - thus a reducer of oxidative stress and an improver of cell redox state. The reduction in inflammatory glycoxidative stress by Glucosepane from glucose is the ultimate reason. Telomerase is thus increased upon AGEs load reduction. Still, like metformin, it's playing catchup of trying to repair damage (remove crosslinks), so far these strategies of biorejuvenation have yielded slowing aging a little and failed on the point of really biorejuvenating - because Redox failure one study after another. Repairing damage is far worse than never accumulating inflammation damage in the first place. Redox is the master regulator of cell survival to oxidative stress (that damage we must avoid rather than spend precious energy/resources on repairing. I cross fingers gene therapy is the big one though cautiously optimistic(lackluster fail target results study after study) by way of telomere gene control. Oxidative stress being the ultimate reason of genome instability and thus aging.

Posted by: CANanonymity at October 19th, 2015 11:59 PM

Hey there,

This huge new study (there are over 50 researchers !) came out two days ago this october and show that gene therapy for biorejuvenation hits a brick wall in terms of result potency (although this is is a yeast C.elegans aging model, it is still highly relevant). In a short living animal like that you would think gene tinkering would allow it to live dramatically longer (it lives barely 20 days average, 40 max), because supposedly gene tinkering potency effect weakens as the longevity of the animal rises due to the fact that extremely long lived animals - are already genetically optimized to maximal function by evolution's longevity-gene selection pressure optimization to obtain extreme lifespan. Thus, any further gene tinkering is futile attempt and yields minimal longevity gains in long-lived species. Inversely, in short-lived species who profit and gain big life boost from gene editing therapy. Well, this study was able to delete certain lifespan-shortening calorie and inflammatory genes (creating a state of caloric restriction) with at best, a 60% lifespan extension (living to 60-90 days, very good ! Not asking for a miracle but this indeed no miracle, very good but still underwhelming weak effect)...Why ? Because this old study results blows the new study's results.
Indeed, the old study was able to obtain a near miraculous 300-500% lifespan increase (albeit the yeasts were retarded in development with some fragility, but were viable), the yeasts reached
250 days lifespan (nearly a full year !!! Going from 20 days to 250 days is a pretty good deal; that is some serious dramatic true biorejuvenation lifespan extension there !). But more importantly this old study (by mitochondrial membrande phospholipid fatty acids composition remodeling towards a low perodizable index PI and double bond unsaturation index DBI by genetically reduced desaturase (essentially switching perodizable polyunsaturates with monounsaturates/saturates, rendering membranes lipid peroxidation resistant/blocking hydroperoxide formation by DHA n-3 and lowering mitochondrial DNA lesions formation by membrane lipid peroxidation chain propagation), It's true though that these effects are due to transcriptional lipid genes regulation (so the genes are the reason of this dramatic effect and this is also a gene therapy, that hit the key points) this old study showed

1- that mitochondrial DNA preservation is crucial to extreme lifespan extension, because mitochondria's ETCs Complex I-IV produce the critical cell's energy ATP (Adenosine TriPhosphate),

2-that Avoiding Damage Altogether is exponentially more powerful than trying to repair it or just slow it. In this case, membrane lipid remodeling abrogated lipid peroxidation damage Cause of aging vs perodizable short lifespan of original yeast C.elegans.

3-Gene tinkering is a crapshoot (complexity), and more than often gene editing therapy does not reach such results (only by lucky rare 'accident' while playing around in them)

4-The Redox is at the heart of it all, as lipid peroxidation load drops redox balance is greatly affected, meaning a cell redox state of little oxidative stress and inflammatory gene activation (by absence of lipid peroxidation after lipid remodeling). Gene therapies are very important but should refocus on oxidative stress resistance via redox homeostasis.


Posted by: CANanonymity at October 20th, 2015 8:57 PM

So what does this mean for all the companies looking to develop aging therapies this way then? Will HLI's efforts be futile?

Posted by: Han at October 21st, 2015 4:16 AM

How do long lived species such as Whales avoid dying from heart disease resulting from glucosepane cross linking in the walls of their blood vessels?

Posted by: Jim at October 23rd, 2015 4:52 PM


Hi Ham !

There efforts won't be futile, just that many studies, by the lack of extension of maximum lifespan in long-lived mammals all seem to point towards a " Lowering return/yield with increasing lifespan " of the mammal species, including us; because evolution adapted and optimized these long-lived mammal species genes - to give them their long lifespan, as longevity increased, it selected certain genes to continue optimizing: it saw that longevity was a survival benefit that has a long and very quantitatively low birth offspring output/long sexual maturation period before offspring output. Meaning a risk of rapid death early age of long-lived specie is detrimental to specie survival, when theiy make so little offspring and so late in life. Meaning they - must live longer to reach that sexual maturity and readiness to have whatever precious offspring they will have - critical to that long lived specie's survival. And that is in the form of gene adaptation/optimization by evolution's gene selection pressure (evolution and natural selection, see Charles Darwin father inventor). With that said, seeing they already got the best end, long-lived species will, in theory, benefit less than short-lives species (who in them evolution favorizes (inverse) strategy of massive sexual reproduction offspring output (quick sexual maturity) to offset loss from specie's short lifespan and gene dysfunction/unoptimization/inflammation as the survival strategy). That is also why you see dramatic results in yeast, fly, rodent models but there is rarely a much longer lived specie (albeit the reason being it takes many years to follow the results, scientists can't wait an entire life to know if their intervention lengthens the lifespan of a long-lived specie or not. Hence they only study rapid aging short-lived species because time to reach results is conveniently quick). Like for example, calorie restriction did increase maximal lifespan of large long-lived apes, only average and health span, thus this is as close to us in terms of similarity of long-lived specie (humans descend as an isolated co-evolving branch offshoot from old world primate apes taxia).

Posted by: CANanonymity at October 23rd, 2015 7:41 PM


Small typo that makes a big difference :

" ... calorie restriction did *not* increase lifespan of large long-lived apes... "

Posted by: CANanonymity at October 23rd, 2015 7:47 PM


Let me reiterate clearly :

" calorie restriction did increase not increase Maximum Lifespan Potential MLSP of large long-lived apes - only improved Health Span (Healthy Quality span) and thus improved median Average Lifespan. "

Posted by: CANanonymity at October 23rd, 2015 7:53 PM


Oops, another typo, I apologize.

" calorie restriction did *not* increase Maximum Lifespan of large long-lived apes ... "

(I use a word memorizer/automator that sometimes repeats the word by accident, hence typos)

Posted by: CANanonymity at October 23rd, 2015 8:00 PM


Hi Jim !

The longest lived and mammal is the bowhead whale, it can live 200 years.
A transcriptome research of its organs revealed its gene signature is highly evolved and adapted for extreme longevity (slow metabolism, improved insulin gene signaling and glucose homeostasis, thus reduced blood glucose, improved cancer genes, improved endothelial function by eNOS (endothelial Nitric Oxide Synthase) meaning improved vascular coronary blood flow, improved microvasculature arterial and heart endothelium function) but more importantly, to answer your question, some whales display low blood glucose hypoglycemia, this affects the quantity and period of proteins/DNA/cell exposure to glucose glycation, glycosylation and glycoxydation reactions. Glucose accelerates Glucosepane formation by glycation process, as it falls in the AGE (Advanced Glycation End producr/crosslink). These long-lived whales heart have low exposure to glucose (glucose homeostasis and hypoglycemia) and low inflammation from that, thus low oxidative stress from blood AGEs circulation. Hba1c (glycated hemoglobin) is directly caused by hyperglucose concentration exposure, same as diabetes hyperglycemia, and is major contributor to " damaged blood/red blood cells " that circulate to the heart and have then difficulty carrying O2 to the heart, putting strain on it, creating inflammation on heart muscle tissue (by cardiac ischemia tissue lesion formation) and that is how heart attack deaths happen. Glucosepane AGE crosslink contributes to that greatly as it crosslinks ECM collagen and cartilage tissue in entire body. Bowhead whales evade that through superior cardiovasculature, low functioning hypoglycemia, low AGEs exposure and production, improved insulin longevity signaling (this is also seen in human centenarians who preserve glucose homeostasis, have no diabetes, have low adequate insulin production, have low glycation AGEs, high Redox potential and very low oxidative stress. Basically, the same conserved mechanisms in centenarians vs bowhead whale).

Posted by: CANanonymity at October 23rd, 2015 8:43 PM

@Ham @Jim

I wish to point that Bowhead whales are mammals, if they are mammals and live to 200 years, this means they are even better Evolved than us - longevity gene selection wise, meaning there is still hope to get to that mammals lifespan with which we share mammalian origin, it's not futile yet, albeit our environment and morphology are different, our gene mechanisms are conserved or homologuous/analoguous.

Posted by: CANanonymity at October 23rd, 2015 8:59 PM

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