The Present State of Progress Towards Clearing Glucosepane Cross-Links, a Contributing Cause of Degenerative Aging

Cross-links are in essence a type of damage resulting from metabolic waste, a natural side-effect of the normal operation of our cellular biochemistry. Many different types of sugary molecules known as advanced glycation end-products (AGEs) end up in the spaces between cells and can react with and link together the intricate structures of the extracellular matrix. The arrangement and constituents of the matrix are what gives each tissue its particular set of properties: elasticity in skin and blood vessels, the ability to bear load without brittleness in cartilage and bone, and so forth. The presence of cross-links in significant numbers sabotages these properties, such as by preventing long, parallel molecular structures from sliding freely past one another. Further, there is evidence to suggest that AGEs produce raised levels of chronic inflammation by altering cellular behavior through the receptor for AGEs, RAGE. Inflammation contributes to the pathology of all of the common age-related diseases.

Most cross-links formed by AGEs are transient, and perhaps only significant in an abnormal metabolism, such as that produced by obesity or type 2 diabetes. The present consensus is that the real problem - leading to age-related loss of skin elasticity and stiffening of blood vessels, among other issues - is produced by a single type of hardy cross-link formed by one type of AGE called glucosepane. Studies suggest that glucosepane makes up the overwhelming majority of cross-links in old humans, and our natural biochemistry is not equipped with tools that can effectively remove these chains.

This is one compound, and to greatly reduce its contribution to aging all that is needed is one moderately effective drug candidate that can break it down. This drug candidate would have as its target market more than half of the human race - pretty much everyone over the age of 30. Yet the broader research community has shown no interest in this goal, an issue we might blame on the lack of tools for working with glucosepane. Any research group diving into this problem would have to build all of the tools from scratch, and that means that near everyone who did take the time to think about it has chosen, again and again, to work on other, more accessible problems instead. This sort of situation requires philanthropy to break the log jam, and thus the only significant funding for glucosepane research in the past few years has come from the SENS Research Foundation, via philanthropists such as Jason Hope, and of course the charitable support of this community.

Nonetheless, because this is a narrow domain problem, the search for one drug candidate for one target, I believe it is the most likely SENS technology to follow on from senescent cell clearance as next in line for commercial development. A method of senescent cell clearance is currently being developed by Oisin Biotechnology, and whatever happens next after that in the SENS space is probably a race between a viable glucosepane breaker drug and transthyretin amyloid clearance, with mitochondrial DNA repair just a few years behind those. However, my knowledge of the latest activity has been getting out of date, so I recently talked to some of the people involved; Aubrey de Grey of the SENS Research Foundation, David Spiegel who runs a lab at Yale, and William Bains who collaborates with an eclectic range of researchers in numerous fields, including this one. What follows is a rough summary of their thoughts on the matter.

A Way to Make Glucosepane is a Big Step Forward

The Spiegel lab developed a reliable way to make glucosepane last year. This is a big deal because people who could not previously collaborate with this type of research can now set up their own studies and investigations. It also ensures that, at least for the foreseeable future, everyone is working from the same definition of what exactly is meant by glucosepane and its particular molecular structure.

There are Still Doubts Over the Glucosepane Consensus

The consensus on glucosepane as the overwhelming majority of relevant cross-links in the process of aging is not airtight - there are growing doubts. It is perhaps reasonable to think that it should be the primary target based on the evidence to date, and Spiegel is optimistic that useful therapies will emerge, but de Grey is cautious, and Bains somewhat unhappy about the poor quality of some past research on this topic. If there was a way to break glucosepane, then doubts could be rapidly solidified or put to rest, but that still lies in the future. The SENS Research Foundation is presently funding research with Jonathan Clark at the Babraham Institute to attempt to ratify that glucosepane is the target, determine whether or not there are other targets, and establish that the present understanding of the structure of glucosepane is in fact the right thing to aim for. Remember that a molecule made of a given set of constituent parts might have a poorly understood shape when folded, these molecules are large and complicated, and shape determines function.

A Drug Candidate Doesn't Exist Yet

There is no drug candidate to clear glucosepane at this time, and not even a speculative idea of where to look for possibilities in the enormous back catalog of existing and explored pharmacology. This lack of direction is a consequence of the lack of exploration of this type of compound in the field. Finding the drug candidate is the big gap that lies between where things stand today and the point at which someone could launch a startup company to finalize a potential glucosepane breaker therapy. The labor required to verify that such a drug candidate works or does not work is modest in comparison to the work of finding such a candidate; this would involve building fairly standard forms of assay to determine levels of glucosepane before and after treatment. One standard approach to this sort of thing would be to equip the immune system with antibodies that react to glucosepane, and then measure the response.

A Drug Candidate Will Most Likely Emerge from Mining the Bacterial World

The Spiegel lab is following the same approach as the LysoSENS research program did over the past decade, which is to search for enzymes in bacteria capable of efficiently breaking down glucosepane. We know they exist because graveyards are not sticky sumps of metabolized sugar. This might actually be discouraging to hear at first, as LysoSENS ran for a decade before transferring the first drug candidates for commercial development by Human Rejuvenation Technologies. However, an enormous advance in the ability to culture bacterial species has taken place in just the past couple of years, an advance not available to the LysoSENS researchers. One of the open secrets of the life sciences used to be that 99% of all bacterial species couldn't be cultured in the lab - but all of a sudden and with a comparatively simple technological advance, that has changed. Everything that bacterial researchers achieved in the past was accomplished with the 1% of bacterial species that were suitable to work with, but now that all bacterial species are fair game, the search space for new molecules has multiplied a hundredfold.

The researchers at the Spiegel lab have already isolated and cultured bacterial species that they are reasonably confident are consuming glucosepane. David Spiegel believes that it might plausibly take two years at the present level of funding to characterize how the bacteria are doing this and whether it involves a simple, single enzyme or something more complicated. If it is a single enzyme, then that can move fairly rapidly to becoming a drug candidate. If not, well, it is probably faster just to look for more bacteria with better candidates. This is a research project that could move faster with more money, as the activities can be carried out in parallel were there more researchers on the staff - but of course raising funds for research in this field is ever a challenge.

Note that I'm glossing over the challenges inherent in picking out enzymes from bacteria and turning them into drugs. There are often unwanted effects, such as triggering of the immune system, that have to be designed out. Many of the options for working around this problem, such as encapsulating drug molecules in a protective sheath, are not practical for something that is intended to get into the tiny spaces of the extracellular matrix. And so on. But these are all challenges that can be addressed, extra work requiring technologies and approaches from elsewhere in the research community to be pulled in.

Two Models for Future Commercial Development

There are two models for commercial development from this point. The first is for an investor with two years of patience, $2 million, and an appetite for risk and uncertainty to come in and fund a company to finish the work started by David Spiegel, William Bains, and Jonathan Clark and their research teams. This sort of thing does happen in many industries, but it is very hard to arrange without deep pockets and good connections. That is why you see this sort of arrangement more often taking the form of a partnership with a pharmaceutical company, as happened for the development of the transthyretin amyloid clearance therapy based on CPHPC.

The other model is to cheer on the researchers, and support them as we can with our donations, for the perhaps few years needed to iron out the doubts about glucosepane, and find a candidate bacterial enzyme. Once they are within striking distance of a proof of concept in mice or rats, then a seed-funded startup could be founded and work proceed from that point. That is much easier to swing for this community - if Oisin managed to obtain seed funding from SENS supporters, then a glucosepane-breaker company could certainly do so to the same level a few years from now.