Project: Break Aging Arteries Free

Posted by Michael Rae on March 05, 2013 | GlycoSENS

In Ending Aging, SENS Research Foundation (SRF) Chief Science Officer Dr Aubrey de Grey and I described how chemical "crosslinking" of the structural proteins of our arteries slowly stiffens them with age, leading to more rigid blood vessels, rising  "systolic" blood pressure (the first or top number in a blood pressure reading), and eventually to the loss of the ability of the kidneys to filter toxins from our blood, and a rising risk of stroke with age.

Rejuvenation biotechnology can prevent these scourges at their source. New medicines that break apart these molecular "handcuffs" would allow the proteins of the arteries to move freely again, restoring the supple flexibility and cushioning capacity of aging arteries to youthful health and functionality. As a result, damage to the kidneys would be prevented, and strokes averted.

We also described the proof-of-concept research that validates this approach. Prototype drugs that break crosslinks had been shown to reverse the stiffening of the arteries and heart in aging and diabetic rats, dogs, and even monkeys, improving arterial health and preventing worse pathology. Unfortunately, as we described, these drugs proved of very little effect in humans, most likely because they targeted a particular form of crosslink that is very rare in humans.

To make a better crosslink-breaking therapy, then, we need to go after the main crosslink that actually builds up in human arteries: a complex chemical  shackle called glucosepane. But as we lamented in the Afterword to the updated 2008 edition of Ending Aging, this was nearly the only area of SENS research where there had been little sign of progress since the first edition of the book. Progress continued rapidly in mastering the new "induced pluripotent" stem cell technology; Dr. Marisol Corral-Debrinski had pioneered her revolutionary new technique for making mitochondrial mutations harmless; researchers working with SRF funding had identified and begun to characterize enzymes capable of degrading wastes inside our cells that cause age-related diseases like atherosclerosis and macular degeneration; vaccines to clear out the sticky beta-amyloid protein that contributes so much to the terrible pathology of Alzheimer's disease had advanced into late-stage clinical trials ... things were proceeding rapidly in nearly every field of rejuvenation research. And yet no one had risen to the challenge of designing a second-generation crosslink breaker.

We hereby announce the ignition of that stalled engine.

With a generous donation from software entrepreneur Jason Hope, SENS Research Foundation and the Cambridge University Institute of Biotechnology have established a new SENS Research Foundation Laboratory at Cambridge. The new center will be managed by Programme Manager Dr. William Bains, with research led by Principal Investigator Professor Chris Lowe of Cambridge. With no one else taking on this challenging, critical research, the scientists in the Cambridge SENS lab will initiate work on biomedical solutions to glucosepane crosslinks starting from the ground up — with research to develop reagents that can rapidly and specifically detect proteins that have been crosslinked by glucosepane. The development of such reagents is an indispensable enabling technology for the development and testing of candidate glucosepane-breaking drugs.

In parallel, SENS Research Foundation is also providing funding to Dr. David Spiegel’s group at Yale University, which has special expertise in making glycation crosslinks and which has recently been studying the mechanisms and chemical vulnerabilities of precursors of glucosepane. Dr. Spiegel's group has also recently published a report clarifying how the first generation crosslink-breaking drug worked. Once the Cambridge SRF lab has successfully established methods for identifying proteins that have been handcuffed together by glucosepane, Dr. Spiegel’s group will use them to begin developing potential glucosepane-cleaving agents. Completing the cycle, candidate agents can then be tested at the Cambridge center — initially in tissue culture, and eventually in vivo.

Let's be clear: we have no intention of restricting this foundational technology to researchers funded by the Foundation. Once developed, any glucosepane-labeling reagents that emerge from the first phase of this work will made available as openly as possible, to accelerate research into the role of crosslinks in disease and aging, and into ways to combat them. But we're blazing the path in biomedical glucosepane research, and when the time comes we're ready to help pour the concrete, too.

Glucosepane has for too long slowly stolen the flexibility from our arteries. We and our loved ones have for too long suffered needless strokes, the poisoning of our blood, dialysis, and the agony of awaiting a kidney transplant. With this new research, SENS Research Foundation marks the beginning of the end of these diseases and disabilities of the degenerative aging process, and another step toward reclaimed youthful health and vigor for all.