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.
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."
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.