The Longecity community leadership runs a regular podcast series, interviewing notable advocates and researchers in the longevity science community. The latest podcast is a discussion with researcher David Spiegel at Yale on the topic of glucosepane cross-link breaking. His research group, funded in part by the SENS Research Foundation, is working towards the means to remove glucosepane cross-link accumulation as a contributing cause of aging. Loss of tissue elasticity lies at the root of arterial stiffening, hypertension, and cardiovascular disease, for example, but this is only one of many problems caused by the growing numbers of persistent cross-links in old tissues. You can look back in the Fight Aging! archives for a long post from earlier this year that outlines the present state of research in this field, so I won't cover the same ground here, but rather skip straight to the podcast transcript:

David Spiegel: Hello! Great to be here.

Justin Loew: As a little background, how did you come to be interested in synthetic chemistry? Was it mostly scientific curiosity, or was it a determination to cure human diseases?

David Spiegel: So, it's funny, I often get asked this question. I was probably a six-year-old kid, asked in second grade what I thought I would be doing in the year 2000, at the time still 21 years away. I still have the document in which I wrote that I wanted to be a chemist in a drug company. And so, I have stayed pretty true to that vision for my life. I have always been fascinated by molecules, and the fact that simple chemical matter has profound changes on human beings. So chemistry was a natural outgrowth of that interest, and in particular the idea that I could rationally design drugs to do things that nobody else had thought a drug could do. So that has led to research interests in my lab, one of which is in the area of immunotherapeutics, new kinds of molecules that can manipulate the immune system, to do interesting and cool things there. Also, the idea that drugs, small molecules, can be useful in reversal of the aging process.

Justin Loew: Your synthetic chemistry lab made headlines last year for synthesizing glucosepane. Many listeners are familiar with the theory that glucosepane is possibly a significant contributer to the aging process, being an extracellular cross-linking molecule that stiffens tissues, but most less familiar with the reasons why it is so difficult to do anything about it. Why has science been so stymied in regards to this molecule, even though it has been known for decades.

David Spiegel: Yes, it is a good question. So, it is a very difficult molecule to make. Well, two issues: first it is very difficult molecule to make, but also it is actually a difficult molecule to isolate. So even though it is found in all of us, it is found in our tissues, our bones, trying to isolate it in a pure form from the human body is incredibly difficult. Only very small quantities are obtained, and the compounds isolated are actually mixtures of very similar stereoisomers, a kind of different versions of glucosepane that simply can't be separated. So from my perspective I thought it would be quite valuable to take on this challenge, and that is really one of the main areas of focus for my laboratory, which is making very difficult molecules using techniques in organic chemistry. So in my mind, this is something that believed in for a long time. For glucosepane, it is a perfect marriage of interesting chemistry and incredibly interesting biology. The biology here is hard, and people have had a hard time, as you said, studying glucosepane, and of course making it has proven an incredibly difficult challenge because of its complex and intricate chemical structure. So we've been very interested in making it, and now we're in the phase of seeing what we can do with it, particularly with the goal of breaking glucosepane, or developing agents that can break glucosepane, that we think can actually reverse the pathology associated with aging.

Justin Loew: And on that, to add to the pathology aging, do you have any idea on how big of a role glucosepane plays in the aging process?

David Spiegel: You know, there is certainly a lot of evidence indicating that glucosepane levels correlate with organ damage and diseases like diabetes, and there is an argument that in diabetes one of the hallmark features is a kind of accelerated aging of the tissues. Also in people who are simply older, in people greater than 65 years of age, it turns out that there is more glucosepane found in collage than there are enzyme-catalyzed cross-links, the cross-links that are actually supposed to be there are outnumbered by glucosepane. It is these very tissues that are involved in the disease of old age. So collagen-containing tissues include blood vessels, bones, joints, and what do we see in old age? We see cardiovascular disease, we see joint disease, we see renal disease, often. So there is a lot of correlative evidence that is backed by with reasonable mechanistic speculation about a causative role that glucosepane can play, that I think really does implicate it as a key factor in what we term the pathophysiology, the damage, the disease, the element of old age that is a disease.

Justin Loew: Now that you made the molecule, and are looking at breaking the molecule, do you have any estimate of how long it might be before there is an effective therapy that addresses glucosepane?

David Spiegel: That's a good question. I think that from the standpoint of basic research, we've already made some progress in identifying some potential strategies for breaking glucosepane. As you know, there is a significant regulatory challenge associated with bringing new therapeutics to market, and so if I had to estimate - well, this is a very high bar in terms of ... well it is an extraordinary challenge, just the idea of making therapeutics that can break a molecule is kind of an untested concept. But the progress we are making, and the surge of interest right now in protein and enzyme-based therapeutics in pharma, makes me speculate that it is possible we could have something that is therapeutically viable on the order of 10-20 years from now. That may not seem like a short time, but from a therapeutics perspective, I think it is within our kind of vision.

Justin Loew: Staying on that kind of thought there, that the breaking of glucosepane cross-links could be very important for aging research, some people think that cross-link breaking enzymes would be too big to reach the links that must be cut in collagen fibrils, and prefer small molecules. Other people think that small molecules would not be specific enough for the task, what do you think? What is your prefered strategy?

David Spiegel: That's another excellent question. I think that as a small molecule chemist, I would love nothing more than to develop a small molecule that could break glucosepane cross-links, and it is certainly something we've been thinking about for quite some time. I think it is actually a very difficult challenge for a small molecule to break a stable cross-link like glucosepane. Mechanistically speaking, in terms of the underlying chemistry, I think it's not clear how a small molecule would function. Now, on the enzyme side, or I should say on the protein side, I think it's possible to imagine low molecular weight enzymes that could be tissue-permeable to the extent that they actually do reach glucosepane cross-links. So my preferred strategy is a protein agent, but by all means I encourage anyone out there listening, and I'm also encouraging people in my own lab group, that small molecule strategies should not be abandoned. I think that both strategies are viable, but the one I see succeeding on the shortest time frame is probably an enzyme.

Justin Loew: Other work in your lab has revolved around using synthetic molecules to detect cancer, and encourage the immune system to attack. Do you think antibodies could be brought to bear against glucosepane?

David Spiegel: Absolutely, and I should say our lab is in the process, and we're making great strides towards identifying the first selective anti-glucosepane antibodies with just that goal in mind. One can imagine an antibody that can bind to glucosepane, and have attached to it some kind of catalyst that would enhance the breakdown of glucosepane. One could also imagine an antibody that is useful for the diagnosis, the detection of glucosepane cross-links in tissue, and so I think that antibody strategies are really high on the list.

Justin Loew: A lot people who would like to help out in this type of research but don't have the expertise use crowdsourced computing efforts such as folding@home. Could the search for a glucosepane breaker be helped by this type of work?

David Spiegel: Absolutely, and in fact we've certainly discussed those efforts. We have collaborators who have started work along those lines for computationally modelling the role of glucosepane in collagen cross-links, and with that information in hand, it really could be possible to develop a kind of hypothetical mechanistic strategy. When I say mechanistic I mean how would a molecule work, what would the chemistry have to look like for an antibody, a small molecule, some other kind of therapeutic modality, to break down glucosepane. It does have a very unique and suprisingly stable chemical structure. In fact, breaking down glucosepane is more than just causing it to degrade. One would also need to cleave the molecule in such a way as to separate the lysine and arginine strands that are being cross-linked by glucosepane, such as to restore the mobility and flexibility in the tissues that are being cross-linked.

Justin Loew: Then for the do-it-yourselfers who might be into synthetic chemistry, or for the other labs who might be listening in, is the molecule you synthesized patented? Is your university licensing the process or the molecule?

David Spiegel: Yes, so it is patented. We are in discussions surrounding licensing the molecule. We are also providing the molecule to the community for basically the cost it takes for us to make it. We want to encourage efforts of all kinds to find glucosepane breakers, so making it commercially available and developing collaborations with other laboratories are all very high on our priority list. For the do-it-yourselfers out there who are interested, feel free to contact me, and we can certainly make an arrangement where our lab will provide glucosepane for research purposes.

Justin Loew: They should just look online for the Spiegel Research Group at Yale University, and they'll be able to contact you or a member of your lab?

David Spiegel: Correct.

Justin Loew: Great! And lastly here, what other research is underway in your lab currently, something people should be keeping an eye out for?

David Spiegel: We have a number of research programs devoted to aging and age-related cross-links. I should also point out that we have been very grateful to the SENS Research Foundation for funding our work - Aubrey de Grey, William Bains, Michael Kope, and others at the organization have just been incredible in terms of the vision for funding this. This is fairly high risk research. We have antibodies, we are developing reagents for detecting a wide variety of advanced glycation end-products, all of which we believe are involved in the aging process. We also have a major effort, and as I mentioned before, in the development of new immunotherapies. So we're using small molecules that we designed to seek out various kinds disease-causing cells, organisms, proteins, for detection by the immune system. So we can actually make molecules that can alert the immune system to the presence of disease-causing factors that the immune system might have missed. So there is obvious therapeutic potential there, not only in aging, but also in cancer, infectious disease, autoimmune disease, and a whole range of other conditions as well.

Justin Loew: Well, that does sound very promising. We'll all look forward to future research publications from your lab. Dr. Spiegel, thank you for joining me.

David Spiegel: Thank you! Great to be a guest.

Justin Loew: It is refreshing to hear of the collaboration between SENS and the Spiegel research group. It seems that SENS has achieved good results from this investment. The problem is that the money is running out. Dr. Spiegel informed me that funding at his university is drying up, and Aubrey de Grey mentioned the same thing late last year in regard to SENS. This means that your support for rejuvenation research is even more crucial this year, as the world economy slows down. As a non-profit that advocates for life extension and provides funding for small-scale research, Longecity has the power to help out. Please consider joining us as a member, and watch for Longecity-approved fundraisers through 2016. Until next time.