The time has come for great goals - an interview with Aubrey de Gray - chapter one
What is aging? We can define it as the process of accumulation of molecular and cellular damage resulting from normal metabolism. While researchers still poorly understand how metabolic processes cause damage accumulation, and how accumulated damage causes pathology, the damage itself — the structural differences between old and young tissue — is classified and studied very well. Correcting the damage and restoring the old - intact - young state of the body, we really rejuvenate it! It sounds very promising, and so it is. And for some types of damage (for example, for senescent cells) it is shown that it works!
Today in our virtual studio somewhere between cold rainy St. Petersburg and warm sunny Mountain View we meet a famous person. I hope everyone knows Aubrey de Gray - the man who fell to Earth to change our understanding of aging, fight him, and finally save us from him! For those of you who are not familiar with it, below is a brief information.
Dr. Aubrey de Gray is a biomedical gerontologist who explores the idea of ​​negligible aging in humans and founded the SENS Research Foundation . He received a bachelor's degree in computer science and a Ph.D. in biology from the University of Cambridge in 1985 and 2000. Dr. de Gray is the chief editor of the journal Rejuvenation Research , a member of the Gerontological Society of America and the American Association for Aging, and is on editorial and scientific advisory boards of numerous journals and organizations. In 2011, de Gray inherited approximately $ 16.5 million from his mother. Of these, he allocated $ 13 million to finance SENS.
I will not ask Aubrey de Gray all these stupid questions that journalists usually bother him about his appearance, overpopulation and so on. Instead, we will talk about science and engineering, which will rejuvenate our bodies, allow us to be healthy and live longer (I mean really much longer). Thanks to recent breakthroughs in many areas, from bionics and applied physics to molecular biology and regenerative medicine, this can (and I am sure will be) sooner than you think.
Interview
Fineman : Good afternoon, Dr. de Gray!
de Gray : Good afternoon - thanks for inviting me to the interview.
Feinerman : In 2012, I read an article by David Sinclair in which he wrote how he restored mitochondrial functions in old mouse cells using NAD +. I felt something change. The past five years have been awesome! Every day I read new articles and news about the reversal of aging. In three years, several dozens of new bioengineering companies have been created, whose main goal is the reversal of aging. Billions of dollars are invested in this area. I believe that we will remember the years 2016-2017 as the most important. Do you share my feeling?
Note: The first phase of the human aging treatment test (GDF, Myostatin) will be in a year or two, and George Church talks about the rejuvenation of the whole organism! The first version of the human CRISPR / Cas9 was created in 2013 and is now ready for use. In 2015, eGenesis began working on xenotransplantation pigs, and now they said they created the right pigs! In 2016, Juan Carlos Belmonte reprogrammed the cells using special factors and “moved” the biological clock back to the living mice. And this is only a small part of the news!
de Gray : Yes and no. Yes, in the sense that there are indeed more and more exciting scientific breakthroughs in the laboratory, and, of course, I am very proud that SENS is responsible for some of them. But no, in the sense that we still have a very long way ahead; we need to fix a lot of different things to get rid of aging, and in some of them we are still at a very early stage of research.
Feinerman : George Church said that his lab is already reversing aging in mice, and human trials can pass in just a couple of years. He said: “We have 65 gene therapies that are tested in mice and larger animals. If they go well, we will begin human trials. ” Church predicts that the reversal of aging will become a reality within 10 years as a result of new developments in genetic engineering. However, he warns that the reversal of aging at the molecular level does not necessarily mean that everything else is rejuvenated. No one knows what it will mean to people. Anyway, it all sounds very promising!
de Gray : George is absolutely right, both in his perseverance and optimism, and in cautioning about how little we still know.
Feinerman : You have changed the opinion of the world community, but now you are backstage. I regularly read about new scientific breakthroughs in the news, but I see little about your work, although research at SENS is more fundamental as a whole! When I went to the SENS website, I was fascinated by how much you do. Very unfair, and how can we help?
de Gray : Oh, I'm still very noticeable - I still speak a lot in public. If to some extent my contributions have now eclipsed the breakthroughs of other people, this is good! I have always said that my goal is to advance the crusade far enough so that I can go to glorious obscurity, for others do my work better than me.
Feinerman : For many people, their appearance is just as important as their health. When you say that the SENS 1.0 panel can rejuvenate people from 60 to 30, will they look like 30?
De Gray : Definitely yes. When we completely rejuvenate the inner part of the body, the outer is the easiest!
Fainerman : Is it possible to say that biomedical engineering and biotechnology have entered an exponential phase?
de Gray : I suppose we can say yes. This is quite exciting.
"Ending Aging"
Feinerman : Your famous book “ Ending Aging ” was published 10 years ago. Are you planning a new version?
de Gray : I probably should at some point, but this is not a priority, because the general approach described in the book has stood the test of time: we have made great progress and have not encountered any unforeseen obstacles that would cause us to change course in respect of any of the damage.
Note: If you haven’t read Ending Aging ( Russian version ) yet, I recommend that you do it as soon as possible, and to make you more comfortable with the ideas that we discuss below, I strongly recommend that you read a brief introduction to the SENS study . Also, if you are interested in the latest news and reviews in the study of aging and rejuvenation, the best place to look is Fight Aging! blog. Finally, if you are an investor or you are just wondering, I recommend that you take a look at Jim Mellon's Juvenescence .
Finerman : You are looking for bacteria that feed on dead organisms in order to find the enzymes that destroy glucosepan . Have you considered insects? They can eat almost anything - and much faster!
de Gray : Good idea, but we are looking for other species. Insects eat food and secrete what they cannot digest, as we do. Bacteria are much more versatile.
Finerman : Many insects do not have specific enzymes, instead they rely on bacteria that do all the work. In any case, they are a good place to look!
de Gray : Not really. Insects have commensal bacteria, like us. In general, however, bacteria that live freely in the environment are more diverse than those in the intestines of animals.
Feinerman : How are you looking for good bacteria?
de Gray : We use a “ metagenomic ” strategy for identifying enzymes that can destroy glucoseepan: we take standard E. coli bacteria, turn off one or two of their genes so that they cannot synthesize a particular substance (in our case, as a rule, arginine or lysine), so they need to take it from their surroundings, and then we add random DNA from the environment (which can come from any bacteria, even uncultivated) to an E. coli culture. Accidentally, a new DNA can encode an enzyme that breaks down glucoseepan, and if so, bacteria will grow even without arginine or lysine in the environment, if (but only if) we give them glucoseepane instead of them, and they destroy it to create arginine and lysine .
Finerman : In your book, you suggested the Whole-body Interdiction of Lengthening of Telomeres (WILT) - cutting telomerase from the cells of the whole organism to prevent cancer, and reseeding the stem cell population on a regular basis. Is there any success? And would it not be easier to use non-integrating telomerase therapy to safely lengthen telomeres? How are the approaches developed in Sierra and BioViva ?
de Gray : We have made progress, yes, for example, we have shown that reseeding stem cells without telomerase works for blood . However, the problem with non-integrating telomerase is that it will increase the cancerous telomeres, like the telomeres of normal cells. I support these studies, not least because there may be breakthroughs in the fight against cancer in other ways (especially the immune system), and in this case it would be much safer to stimulate telomerase systemically.
Finerman : Now we have a very accurate CRISPR , and removing genes is easier than inserting, because you can aim at the same cell more than once. When we solve the delivery problem, can we apply WILT?
de Gray : Yes, of course.
Finerman : Why can't we remove telomerase locally in diseased tissue?
de Gray : We tried, but it is very difficult to make the removal selective.
Fainerman : There is growing evidence that epigenetic changes are very organized and can be one of the causes of aging. They allowed some researchers to state that aging is a program. However, it does not matter how they see them - as a program or as damage. But by restoring the previous epigenetic profile with the help of special reprogramming factors , we can turn the old cell into a young one, and by dropping the profile we can turn an adult cell into a pluripotent stem. Experiments have shown that the restoration of the epigenetic profiles of many cells in vivo rejuvenates the entire body. What do you think? Maybe we should consider epigenetic changes as damage in the SENS model?
de Gray : We need to be more precise with the definitions in order to answer your question. Epigenetic changes can be divided into two main classes: shear and noise. Shift means changes that occur in a coordinated manner among all cells of a given type and tissue, whereas noise means changes that occur in different cells, increasing the variability of this type of cell. Shifts are caused by some kind of program (genetic changes in the cell environment), so yes, they can be changed by restoring the environment and running the program in the opposite direction. Noise, on the other hand, is not reversible. And for several years we have been working on determining whether it matters in our present life. We do not have a definitive answer, but it does not seem to, epigenetic noise accumulates too slowly to make a difference, except, perhaps, in cancer (which, of course, we decide otherwise).
Fainerman : Should we use reprogramming factors to reverse the epigenetic program?
de Gray : Probably not. There may be some advantages of them as a way to restore the number of certain types of stem cells, but we can always do it differently (especially direct stem cell transplantation), so I do not think that we will ever de-differentiate cells in vivo .
Finerman : One thing keeps me awake at night: the fear that accidental damage to nuclear DNA and mutations can play a big role in aging. Ten years ago, you assumed that most cells that have critical DNA mutations, a) perform apoptosis, b) become senescent or c) cancerous. But if the mutations are not critical, the cells will live, accumulate them - one wrong protein here, another there - and they will eventually lead to a malfunction of the organ.
de Gray : Do not worry. They do not accumulate quickly enough to harm us, because they are prevented by the same mechanism that prevents cancer during normal life, and cancer can kill us, since only one cell does the wrong thing. Noncritical mutations will have to capture a huge number of cells in order to affect the function of the tissue.
Fainerman : If it is shown that nuclear DNA damage and mutations play a role in aging, do you have something in stock? I bet you already thought about that. How do we fix the problem? Maybe global cell therapy (for example, induced cell exchange in the body)?
de Gray : That's right. But they do not play a role.
Note: The Whole-Body Induced Cell Turnover (WICT) induced cell exchange in the body replaces the entire set of endogenous patient cells with exogenous cells (of the same number and type as the endogenous cells they replace) derived from human pluripotent stem cells and directed differentiated in vitro prior to their administration. The idea of ​​WICT was first proposed in 2016 and improved in 2017 .
The goal of WICT is to remove from the body the accumulated cellular and intracellular debris present in the patient’s endogenous cells, including telomere reduction, nuclear DNA damage and mutations, mitochondrial DNA damage and mutations, replicative aging, functionally harmful age-related changes in gene expression, and accumulated cellular and intracellular aggregation.
Fainerman : What do you think about WICT? In combination with WILT, they look like an all-in-one solution for their implementation.
de Gray : The general idea of ​​speeding up cell shifts is certainly good. This is a bit like the idea of ​​replacing entire organs: if you replace the entire structure, you do not need to repair the damage that this structure contains. However, like the replacement of organs, it has potential drawbacks, because evolution has given us a certain rate of change of individual cells, and the function of each of our cell types is optimized for it. Thus, it can be difficult, with many pros and cons.
Feinerman : While other anti-aging therapies (with the possible exception of OncoSENS) are achievable in the near future and are not related to special genetic engineering, complete allotopic expression is a very long way. What do you think about, for example, NMN , which raises the level of NAD + and restores mitochondrial function in the cell?
de Gray : It may help a little to maintain health, but I think it is unlikely to extend life by more than a year or two on average (and maybe even less). But we are working hard to develop more efficient gene therapy methods that can make allotopic expression practical before people think.
Finerman : Oh, can you open the veil?
de Gray : We combine two technologies that are very safe (in the sense that they have a very low frequency of accidental DNA damage), but they have mutual limitations. One of them is CRISPR, which can make small changes very safely at a selected location in the genome, but cannot insert more than a very small amount of new DNA. The other is a very little used system called BXB1, which can insert large pieces of code, but only in a place that does not exist in the mammalian genome. Our idea is to use CRISPR to install the BXB1 “landing pad” in the right place, and then use BXB1 to insert our selected engineering genes into it. We develop our method at the Buck Institute in Brian Kennedy's lab .
Fainerman : Thank you for your explanation! However, there is a big problem with all genetic therapies. We need to change every cell in the body, and now it is impossible. Our best delivery systems, for example, adeno-associated viruses (AAV), available today, have an efficiency of only 10-50%. And the efficiency of gene insertion is even lower. We must honestly admit that we still do not have a universal tool for introducing new genes into the body of an adult. How do you solve this problem?
de Gray : We believe that the approach that I described in my previous answer will achieve much higher efficiency, since the absence of a non-target effect means that it can be used at a much higher titer.
Finerman : The main approach of SENS is to rejuvenate our own bodies, but there is also regenerative medicine, which includes tissue and organ engineering. Is it not easier to print or grow new organs instead of rejuvenating old ones? Of course, we cannot replace everything, but we can replace some critical parts: we can grow a new heart, liver, muscles and, of course, skin.
Note: Tissue and organ engineering is among the most rapidly developing areas of regenerative medicine. Engineers have already printed or grown almost all human organs in bioreactors. Now they are mainly used to test new therapies and drugs. The main problem, why they cannot be used in transplantation, is the problem of vascularization. Although engineers can print or grow arteries and large vessels, they are still unable to create a network of small vessels and capillaries within an organ. Companies like Organovo pursue this goal and promise to solve it over the next decade.
de Gray : That is absolutely correct. I expect that in the first days of the introduction of SENS some organs will be easier to replace than to repair. However, replacement of the organ requires invasive surgery, so we want to eventually develop rejuvenation.
Finerman : You emphasize that stem cell research is already a well-developed field, and SENS does not need to participate in it. As far as I know, many of them belong to very specific diseases, and not to rejuvenation. Or will we get it as a side effect?
de Gray : As you know, I do not think that “age-related diseases” should be called diseases at all - they are part of aging, therefore their treatment is certainly part of rejuvenation. A good example is Parkinson's now - several stem cell clinical trials or their preparation are currently underway.
Feinerman : You mean that they are part of aging, how does a runny nose and cough be part of the flu? Therefore, treating them individually is as stupid as treating cough without treating the cause — the flu virus.
de Gray : This is even worse. Treatment of rhinitis and coughing makes some sense, because the body will continue to attack the flu virus, and at this time it makes sense to be less unhappy. But in aging, we are simply talking about different parts of a phenomenon that the body does not know how to attack.
Faynerman : In what order, in your opinion, will anti-aging therapies appear?
de Gray : Well, many of the stem cell therapies are already in clinical trials, as is the removal of amyloid in the case of Alzheimer's disease. The next on the list is probably the removal of senescent cells, as reported by Unity , they will be at the clinic next year, and the removal of intracellular debris in the treatment of macular degeneration at our company Ichor . The other three are more difficult, but they all develop little by little!
Finerman : About twenty different types of amyloid are known, we see some success in the removal of transthyretin and beta-amyloid . What about others? Can we make progress in removing others using their progress?
de Gray : I am sure that the removal of other amyloids can be achieved using more or less the same methods that worked against these two. Next on my list will be islet amyloid, which contributes to diabetes.
Fainerman : As far as I know, the intracellular debris in the eyes is not lipofuscin per se , but A2E, an oxidized form of vitamin A. Is there any progress in eliminating true lipofuscin — a more common form of intracellular debris?
de Gray : We have financed some preliminary work on this issue, but only initial ones. The difficulty lies in the fact that lipofuscin is very heterogeneous, it consists of many different components. We plan to deal with it as with glucosepane in the intercellular matrix: instead of destroying it, we want to identify key stitches that protect it from splitting using the existing lysosomal mechanism.
Feinerman : Now everyone is obsessed with "biomarkers of aging" and "biological clock." Are they the right concepts? Is it possible to have a single “watch” for the whole body? Wouldn't it be better to use all types of damage as biomarkers and keep them below a certain threshold?
de Gray : I agree with you - we still need to repair the damage, so that no indirect markers will tell us more than the damage itself. These indirect markers are useful now, when we do not have anti-aging biotechnology, because they help us understand which interventions can (slightly) slow down the accumulation of damage.
The time has come for great goals - an interview with Aubrey de Gray - chapter two
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