Interview with researcher David Spiegel about therapy that destroys glucose-propane stitches

Longecity community guides conduct regular podcast series of conversations with well-known supporters and researchers in the scientific community to extend life. The latest podcast is a conversation with the researcher David Spiegel of Yale University about the destruction of glucosean crosslinks . His research team, partly funded by the SENS Foundation , is working on the destruction of glucose cross-links as one of the causes of aging. For example, a loss of tissue elasticity underlies the vascular stiffness, hypertension, and cardiovascular diseases , but this is only one of the many problems caused by the growing number of persistent interprotein cross-links in older tissues. Earlier, I described the current state of research in this area , so I will not consider it here, but I will immediately post the text of the podcast:

Interview

Justin Lew : Welcome to Longecity Now. Many of you have been following SENS for more than ten years, and you are probably wondering if there is any progress. The answer is yes, as we learned from the podcast with Aubrey de Gray at the end of last year. In this interview, Aubrey mentioned that artificial glucoseepane was recently obtained. This is important because glucosepane is the cause of tissue aging. In this issue we will hear from the head of the laboratory about artificial glucoseepane. If you can't wait to learn more about the technical details of aging, our interview with David Spiegel will satisfy your curiosity.



David Spiegel : Hi! Glad to be with you.



Justin Lew : As a background, how did you become interested in synthetic chemistry? Was it mainly scientific curiosity, or the desire to cure diseases?



David Spiegel : Very nice, I am often asked this question. I, probably, was six years old when I was asked in second grade what I think I would do in 2000, after 21 years. I still keep the document in which I wrote that I want to be a chemist in a pharmaceutical company. So, I stayed true to this vision of my life. I have always been fascinated by molecules, and the fact that simple chemicals have a huge impact on people. Thus, chemistry was the natural result of this interest, and in particular the idea that I could rationally develop drugs to do what no one expected from them. So this led to research in my laboratory, one of which is in the field of immunotherapy , new types of molecules that can manipulate the immune system , do interesting and necessary things in it. In addition, the idea that drugs, small molecules, can be helpful in reversing the aging process.



Justin Lew : Your synthetic chemical lab was on the front pages last year because of glucose synthesis. Many listeners are familiar with the theory that glucosapane is probably an important factor in the aging process, forming protein-protein cross-links that make tissue, but less familiar with the reasons why it is so difficult to do something with it. Why science was so defenseless against this molecule, although it has been known for several decades.



David Spiegel : Yes, good question. It is very difficult to synthesize. Well, two problems: firstly, it is very difficult to synthesize it, and secondly, it is very difficult to isolate it. Therefore, despite the fact that it is found in all of us, in our tissues, in our bones, it is incredibly difficult to isolate it in pure form from the human body. Only very small amounts are obtained, and the isolated compounds are actually mixtures of very similar stereoisomers , glucosepane varieties, which simply cannot be separated. Therefore, for my part, I thought that it would be very useful to undertake this task, and this is indeed one of the main areas of my laboratory, the creation of very complex molecules, using organic chemistry methods. Therefore, in my opinion, this is what was believed for a long time. For glucoseepan, this is the perfect combination of interesting chemistry and very interesting biology. Biology is complex here, and it was hard for people, as you said, to study glucoseepan, and, of course, it turned out to be an incredibly difficult task because of its complex chemical structure. Thus, we were very interested in its creation, and now we think what we can do with it, especially with the aim of destroying glucosepan or developing agents that destroy it, which, in our opinion, can really reverse the pathologies associated with aging.



Justin Lew : Do you have any idea how big the role of glucosean is in the aging process?



David Spiegel : You know, there is a lot of evidence that glucose levels correlate with damage to organs and diseases such as diabetes, and it is believed that one of the distinguishing features of diabetes is a kind of accelerated aging of tissues. In addition, people who are older, people over 65 years old, have much more glucosopan in collagen than enzymes catalyzed by protein- bound cross-links . It is the collagen containing tissue that is most susceptible to aging. Such collagen-containing tissues include blood vessels, bones, joints, and what do we see in old age? We see cardiovascular diseases , we see diseases of the joints, we often observe kidney disease . Thus, there is a lot of evidence supported by reasonable mechanistic assumptions about the causal role that glucoseepan can play, which, in my opinion, really implies it as a key factor in what we call pathophysiology , damage, disease, an element of old age, which is a disease .



Justin Lew : Now that you have created a molecule and are learning how to break it, do you have any assessment of how soon we will have effective therapy against glucosepan?



David Spiegel : This is a good question. I think from the point of view of basic research, we have already managed to identify some potential strategies for the destruction of glucosean. As you know, there is a significant regulatory problem related to the launch of new therapeutic drugs on the market, and therefore, if I had to evaluate - well, this is a very high bar from the point of view ... well, this is an unusual task, just an idea to make therapy that can to destroy a molecule is an unverified concept. But the progress we are making, and the current surge in interest in therapy based on proteins and enzymes in pharmacology, leads me to suggest that it is possible that we can receive comprehensive therapy for 10–20 years. This may seem like a long time, but from the point of view of current pharmacology, I think this is a real time.



Justin Lew : The destruction of glucoseepan is very important in the study of aging, and some people believe that the enzymes that destroy it will be too large to achieve crosslinks located in collagen fibrils and prefer small molecules. Other people think that small molecules will not be task specific, what do you think? What is your preferred strategy?



David Spiegel : Another great question. I think that, as a chemist working with small molecules, I would really like to create a small molecule that could destroy glucosepan crosslinks, and this is definitely what we have long thought about. I believe that in fact it is a very difficult task for a small molecule to destroy a stable cross-link, such as glucosepan. Mechanically, in terms of the underlying chemistry, it is not clear to me how the small molecule will function. Now, from the side of the enzyme, or, rather, from the protein side, I think that one can imagine low-molecular enzymes that will be permeable to the tissues to the necessary extent in order to achieve glucose-junction crosslinks. Thus, my preferred strategy is a protein agent, but, of course, I urge everyone, including people in my own laboratory, that small molecules should not be discarded. I think both strategies are viable, but the fastest way to success is likely to lead us to find the enzyme.



Justin Lew : Another job in your lab is to use synthetic molecules to detect cancer and target the immune system to it. Do you think antibodies can be used against glucosepan?



David Spiegel : Absolutely, and I must say that our laboratory is in the process, and we are making great strides in determining the first selective antibodies against glucosopan. One can imagine an antibody that binds to glucoseepan and a catalyst attached to it that would improve the breakdown of glucoseepan. You can also imagine an antibody that is useful for diagnosis, the detection of protein-protein cross-links in tissue, and therefore I believe that the positions of antibodies are very high.



Justin Lew : Many people who would like to help in this study, but have no experience, use crowdsourced calculations, such as folding @ home . Could such work help in finding the molecule that destroys glucosepan?



David Spiegel : Absolutely, and in fact we, of course, discussed these efforts. We have employees who have begun work in these areas for computer modeling of the role of glucose cophenol in interprotein collagen crosslinks, and having this information one could develop a kind of hypothetical mechanistic strategy. When I say mechanistic, I mean how the molecule will work, what chemistry will look like for an antibody, a small molecule, some other therapeutic method for breaking down glucoseepan. It has a very unique and surprisingly stable chemical structure. In fact, the destruction of glucosepane is more difficult than its degradation. It is necessary to cleave the molecule in such a way as to separate lysine and arginine, which are crosslinked with glucoseepane, for example, to restore mobility and flexibility in tissues.



Justin Lew : For those who are engaged in synthetic chemistry, or for laboratories, is the molecule that you synthesized patented? Does your university license the process or molecule?



David Spiegel : Yes, it's patented. We are discussing the issue of licensing the molecule. We also provide the molecule to the community mainly at cost price. We encourage all efforts aimed at finding the molecule that destroys glucoseepan, so we plan to make it commercially available and develop cooperation with other laboratories. For those who are interested in it, do not hesitate to contact me, and we will certainly agree on how our laboratory will provide glucosepan for research purposes.



Justin Lew : Can anyone view your Spiegel Research Group page at Yale and contact you or a member of your lab?



David Spiegel : Right.



Justin Lew : Great! And finally, what else research is being conducted now in your laboratory?



David Spiegel : We have a number of research programs on aging and age-related inter-protein linking. I should also note that we are very grateful to the SENS Foundation for financing our work - Aubrey de Gray, William Baines , Michael Cope and other members of the organization were visionaries financing us. This is a very risky study. We have antibodies, we develop reagents for detecting a wide range of end-products of glycation , all of which we consider to be involved in the aging process. We are also making serious efforts, as I mentioned earlier, in developing new immunotherapies. Therefore, we use small molecules developed by us to look for various types of disease-causing cells, organisms, proteins, for their detection by the immune system. We can make molecules that alert the immune system about the presence of disease factors that it could miss. Thus, there is a huge therapeutic potential, not only aging, but also cancer, infectious diseases, autoimmune diseases, and much more.



Justin Lew : Well, that sounds very promising. We look forward to future scientific publications from your lab. Dr. Spiegel, thank you for joining me.



David Spiegel : Thank you!



Justin Lew : Nice to hear about the collaboration between SENS and the Spiegel Research Group. It seems that SENS have achieved good results from their investments. The problem is that the money runs out. Dr. Spiegel told me that there was less and less funding at his University, and Aubrey de Gray mentioned the same thing at the end of last year regarding SENS. This means that your support for research on rejuvenation is very important this year as the global economy slows down. Being a non-profit organization that advocates life extension and provides funding for small research, Longecity has the right to help. Please consider joining us as a member, and follow the 2016 fundraising campaigns organized by Longecity. Until next time.

Conclusion

More than ever, the progress of research in the field of rejuvenation is limited much more by the lack of funding than by the complexity of the problems associated with it. The life of our movement is always a jump from one source of finance to another, fundraising to do the right things, and then use this progress to attract the next source of finance. In total, we have achieved great success over the past fifteen years, starting with a complete lack of finance from SENS and having received tens of millions now. This, of course, is only preparation for the next jumps in search of more funding sufficient to do the work that remains to be done. It's amazing how much you need to convince people to help save their lives in the future, but this is the world in which we live.