New research takes us a step close to finding ways to remove the advanced glycation end-product known as glucosepane, a likely reason why our arteries stiffen as we age.
A possible solution to the problem
Some years ago, Aubrey de Grey from the SENS Research Foundation proposed that a possible solution to dealing with AGEs would be to find ways to break down the crosslinks, thus freeing up the trapped proteins and restoring tissue elasticity.
Until recently, glucosepane was very difficult to isolate, which is needed to develop drugs and therapies. This changed in 2015, when, thanks to funding from the SENS Research Foundation, the Spiegel lab perfected a method to create glucosepane on demand [1].
While it is not totally clear that AGEs are a primary cause of aging, some researchers such as Alexander Fedintsev and Alexey Moskalev believe that it is and presented evidence in support of it being a tenth hallmark of aging earlier this year [2].
Today, we want to highlight a new paper that concerns the development of antibodies specific for glucosepane [3]. This paper was published by a team of researchers, including Jonathan Clark from the Babraham Institute and David Spiegel from Harvard, who may be familiar to our regular readers. Once again, this research has been funded by the SENS Research Foundation, which continues to support this line of scientific inquiry.
Although there is ample evidence that the advanced glycation end-product (AGE) glucosepane contributes to age-related morbidities and diabetic complications, the impact of glucosepane modifications on proteins has not been extensively explored due to the lack of sufficient analytical tools. Here, we report the development of the first polyclonal anti-glucosepane antibodies using a synthetic immunogen that contains the core bicyclic ring structure of glucosepane. We investigate the recognition properties of these antibodies through ELISAs involving an array of synthetic AGE derivatives and determine them to be both high-affinity and selective in binding glucosepane. We then employ these antibodies to image glucosepane in aging mouse retinae via immunohistochemistry. Our studies demonstrate for the first time accumulation of glucosepane within the retinal pigment epithelium, Bruch’s membrane, and choroid: all regions of the eye impacted by age-related macular degeneration. Co-localization studies further suggest that glucosepane colocalizes with lipofuscin, which has previously been associated with lysosomal dysfunction and has been implicated in the development of age-related macular degeneration, among other diseases. We believe that the anti-glucosepane antibodies described in this study will prove highly useful for examining the role of glycation in human health and disease.
Conclusion
Highly specific antibodies for glucosepane are vitally important in order to develop potential drugs that can break down the offending AGEs, and without them, it would be impossible to progress a therapy. This paper is another important step forward for the development of a glucosepane breaker.
Currently, only one company is working on glucosepane breakers, and that is Revel Pharmaceuticals, which includes David Spiegel, one of the authors of this paper. Hopefully, this latest advance in our knowledge will encourage other AGE-breaker companies to launch and spark a surge of interest in this area in the same way that interest in senolytics has grown in recent years.
Literature
[1] Draghici, C., Wang, T., & Spiegel, D. A. (2015). Concise total synthesis of glucosepane. Science, 350(6258), 294-298.
[2] Fedintsev, A., & Moskalev, A. (2020). Stochastic non-enzymatic modification of long-lived macromolecules-a missing hallmark of aging. Ageing Research Reviews, 101097.
[3] Streeter, M. D., Rowan, S., Ray, J., McDonald, D. M., Volkin, J., Clark, J., … & Spiegel, D. A. (2020). Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue. ACS Chemical Biology.
