Funded by the SENS Research Foundation and allied philanthropists, the researchers at the Spiegel Lab are working on the tools needed to build the means to remove glucosepane cross-links from aged tissue. Like clearance of senescent cells, this is one of the more promising near-term approaches to rejuvenation therapies because it is just the single, narrow problem, rather an enormous range of compounds and mechanisms grouped into a category, as is the case for amyloids, lipofusin, and other forms of damaging metabolic waste. It should be possible to develop and deploy working approaches to glucosepane cross-link breaking in a much shorter period of time, once the initial hurdles are overcome.
Persistent sugary cross-links form in the extracellular matrix as a side-effect of the normal operation of cellular metabolism. In humans the vast majority of lasting, problematic cross-links involve glucospane. These cross-links alter and corrode the structural properties of tissue, making bone and cartilage fragile, and producing loss of elasticity in skin and blood vessels. While all of these are bad, the loss of blood vessel elasticity is probably the most important of these consequences, as increased vascular stiffness with advancing age drives the progression of hypertension, cardiac hypertrophy, and fatal cardiovascular disease. The sooner the research community makes the leap to far greater funding and interest in cross-link breaking, the better. This requires better tools, such as those planned in this new research project.
SENS Research Foundation (SRF) has launched a new research program focused on developing monoclonal antibodies against glucosepane. David A. Spiegel will be running the project in his laboratory, which focuses on developing new methods and molecules that will facilitate our understanding and treatment of human disease.
Glucosepane is the most prevalent crosslink found in collagen in people over 65 years of age, and its presence has been correlated to age-related tissue damage through various mechanisms. Understanding of glucosepane has been hampered by the molecule's complex and sensitive chemical structure; it can only be isolated from human samples in minute quantities and in an impure form. To enable these advances in both basic and therapeutic science, the Spiegel laboratory has recently accomplished the first total synthesis of glucosepane.
The lab is now utilizing its novel synthetic glucosepane derivatives to generate the first monoclonal anti-glucosepane antibodies. Access to these antibodies would profoundly accelerate the goal of developing the first discrete, specific reagents for labeling, studying, and perhaps also cleaving glucosepane in vivo. Such tools have tremendous potential to help illuminate, and reverse, age-related damage as it occurs in human tissues.
This research has been made possible through the generous support of Michael Antonov and the Forever Healthy Foundation and its founder Michael Greve. The Forever Healthy Foundation is a private nonprofit initiative whose mission is to enable people to vastly extend their healthy lifespans and be part of the first generation to cure aging. In order to accelerate the development of therapies to bring aging under full medical control, the Forever Healthy Foundation directly supports cutting-edge research aimed at the molecular and cellular repair of damage caused by the aging process.