Elena Milova is at the Interventions to extend healthspan and lifespan 2018 conference in Kazan this week. This is an important conference in the aging research field, and it includes a variety of leading experts giving talks about their research. One of these experts is Dr. Andrei Gudkov, and Elena had the opportunity to talk with him about his research.
Dr. Andrei V. Gudkov, Ph.D., D.Sci, is a Scientific Co-Founder of Cleveland Biolabs, Inc. and has been its Chief Scientific Officer since June 2003. Dr. Gudkov serves as Chief Scientific Officer and Founder at Everon Biosciences, Inc. He co-founded Mega Biotech & Electronics Co., Ltd. and serves as its Chief Scientific Officer. Dr. Gudkov serves as Senior Vice President of Basic Science at Roswell Park Cancer Institute. He has over 25 years of experience in biomedical research. Prior to 1990, he worked with the National Cancer Research Center in Moscow (USSR), where he led a broad research program focused on virology and cancer drug resistance.
In 1990, he re-established his lab at the University of Illinois at Chicago, where he became a tenured faculty member in the Department of Molecular Genetics. In 1999, he defined p53 as a major determinant of cancer treatment side effects and suggested this protein as a target for therapeutic suppression. In 2001, Dr. Gudkov moved his laboratory to the Lerner Research Institute at the Cleveland Clinic Foundation, where he served as Chairman of the Department of Molecular Biology and Professor of Biochemistry at Case Western Reserve University. He has served as a Director of Cleveland Biolabs, Inc. since June 2003.
You have talked about the presence of dormant viruses that may act like a lifespan clock. Microbial burden is known to contribute to the aging process by contributing to inflammaging and immune system decline. How can we destroy persistent viruses like CMV, and other viruses that lie dormant in the body for years but replicate greatly during aging and cause chronic inflammation?
This is indeed a very serious question, and, honestly, I don’t have a good answer to that. The concept I am dealing with is actually our endogenous viruses, which are an integral part of our genome and have been there for millions of years. They are not actually viruses in all aspects of this definition; for example, they do not have an extracellular life, they only multiply by expanding inside the genome of a given cell. The cell solved the problem of having them inside by keeping them silent, basically asleep, which tells me that our evolution could not solve the problem of getting rid of these viruses. For dozens of millions of years of existence, the best we could do as their host was to keep them silent.
There is no mechanism of excision or eradication, so to me, it means one very depressing thing if we think about the viruses that are not endogenous but exogenous. The herpes virus is a great example; there are plenty of others as well, but herpes viruses are the most harmful right now, including CMV and Epstein-Barr. They are not endogenous, they are not encoded in our genes, but they live inside the cells which we cannot afford to kill, for example, the neurons. Killing every infected neuron will cause some deficiency in neuronal function, and we do not have a mechanism of eradication to keep the cell clean of them.
Since during these millions of years of evolution, our own organism could not solve this problem, my prediction is very depressing; most likely, we will not be able to do it. Nature is usually quite sophisticated in finding solutions for these types of things, which means that we need to follow nature and try to keep them under control rather than getting rid of them. I don’t think you can make a clean, virus-free environment; I think you can make an environment where viruses are controlled and kept harmless.
Research suggests that “inflammaging” plays a key role in aging; many publications also suggest that of the various sources of this chronic age-related inflammation, senescent cell accumulation and the SASP it produces is the primary culprit. Would you agree that this is the case, and what might we expect to see if therapies to remove these problem cells are used in people?
I have a different view from the majority. I was one of the big fans of senescent cells, and I was 100% inspired by the idea of finding them, eradicating them, and using that for rejuvenation. However, after we spent several years very focused on an extensive study of senescent cells in vivo, we realized that for a major portion of the mouse lifespan, we simply cannot find these cells. This is not because they don’t exist; I think they appear pretty frequently during our lives and mice’s lives, but they are being very efficiently eradicated by the immune system. Actually, we made the prediction that senescent cells are sources of SASP, this famous secretion that we don’t like, but I would say that it was never really proven. The fact that they secrete it is proven; there is no question. Whether the changes in inflammation in vivo with age are due to the activity of senescent cells is a big question, because when we tried to find these cells in, for example, an irradiated organism, most of the cells that people thought were senescent before the existence of conventional biomarkers appeared to be just parts of the immune system, which is malfunctioning in aging and created the appearance of senescent cells. Macrophages frequently become positive for biomarkers of senescent cells, and people using these biomarkers without looking carefully call them senescent. You might say that does not matter because the whole concept did not change that much; who cares what you name these cells? If certain cells with certain properties accumulate with life and if they secrete something bad, the concept is still intact, and I agree with that.
However, knowing the nature of these cells, we can choose the right weapon against them, and as long as we try to kill the cells that we can make senescent in culture and think we are killing the same cells in vivo, I think that we are on the wrong path. This is my first problem; my second problem is that the accumulation of senescent cells means a malfunction of the immune system because the normal immune system gets rid of them very efficiently. If you kill a cell that cannot be removed by the immune system, you are not getting rid of this potential garbage; you turn it into a different type of garbage. Because to eradicate a senescent cell, something needs to find it and eat it, swallow it, such as a macrophage. If this function is not working very well and you simply help the immune system by killing these cells, they still remain in the same place where they were; they’re just dead. Maybe this is good or not; maybe this will indeed help another branch of the immune system to clean up. I think, in general, that this is not obvious; first, it’s not obvious to me that senescent cells are unique in creating the “smell” of garbage that leads to inflammation or if it’s only one of many types of cells that become damaged and accumulate with age. I’m not sure that killing them physically really helps to improve the situation, because you are creating a wave of remains that has to be taken care of, too.
I personally chose an approach to invest in the immune system and repair its function so that it can do its job better, instead of us thinking that we can substitute it. So far, in medicine, substitution of lost function has only worked well in orthopedics but not in other areas. Therefore, I think that we need to either invest in a mechanism that blocks the appearance of senescent cells or invest into the mechanism of natural eradication to make the immune system work better. For example, if the part of the immune system that is responsible for clearing senescent cells gets exhausted, you can always try to redirect adaptive immunity against them by vaccination; I would see that as a more appealing thing. I want to make a disclaimer that everything I’m saying is my personal opinion which may be completely wrong, and I’m not going to be surprised or unhappy if it appears to be wrong; it is a normal process of people having different opinions, and I am only giving my personal view.
Your work also shows the role of senescence-associated macrophages (SAMs), and the data suggests they could be a target for potential anti-aging therapies. Do you think targeting these cells, in particular, is more important than other types of senescent cells, and why?
Honestly, I don’t know; the fact that we see an accumulation of cells of certain types with age doesn’t necessarily mean that they are the cause of frailty and the cause of the problem. I can easily imagine they could because macrophages are secreting cells, and the job of macrophages is to secrete proinflammatory cytokines. If they accumulate in these unusual macrophages, I would say that it’s a reasonable hypothesis that they may be contributors to this general change of environment. The problem is that A: we need to do more to prove if it’s right or wrong, B: we believe that one of the ways to deal with them is not necessarily killing them but reprogramming them, because macrophages are parts of the immune system that are known to have many faces, and they usually change their phenotype depending on the specific request from the organism for a specific function, and since they have many faces, I think there is a potential approach to convince them to turn into something better. However, this territory was just found, it’s unexplored, and everything I am saying is just a pipe dream at the moment. Another thing is that killing macrophages is a technically extremely difficult task; this is why I am talking about reprogramming, because macrophages are among the most resistant, to everything, cells in the body. The reason for that is based on common sense; they are made by nature to eat and digest garbage, poisons basically. It is hard to kill them because they are resistant to what they usually eat.
Are these SAMs fully senescent, or could they potentially be rescued by manipulating their polarization rather than destroyed, and returned to work?
It’s a good question, and I think I answered that; I can only tell you that we published another paper showing that their properties are reversible and inducible, so you can either mimic their appearance with certain environmental conditions or reprogram them into something else. We know that technically we can do this in vitro, but whether it’s applicable in vivo and whether that would change the environment, I have no idea yet.
It is generally considered that the main reason senescent cells accumulate in the first place is due to dysfunction of the immune system. If the SAMs can be removed, might we expect that senescent cell clearance via the immune system would be significantly improved?
Again, this is something we do not know; we can do bone marrow transplantation and start the blood and immune systems from scratch; however, when you look deep into that, you find that not every aspect of immunity or hematopoiesis is substitutable by donor bone marrow. There are certain types of cells that are only given to us once and forever. Tissue-resident macrophages, which sit in our bodies, under our skin for example, and form a shield against any damage that comes from outside, are actually poorly recycled. That is why tattoos are possible; tattoos are live cells that swallow the dye; these macrophages stay in the same places where they have always been. The fact that tattoos remain for the majority of lifespan means that these cells that swallow them stay alive and in the same place for as long as we can see the tattoo.
Assuming that immune system clearance of senescent cells could be restored to youthful levels again, would we even need senolytics that target non-SAMs?
As I explained earlier, senescent cells played an enormously important and positive role in gerontology, even if eventually it appears that they are not the main players; they have played the role of navigators, brought us to the right questions, and brought us to observations we would not have otherwise made. So as frequently happens in science, those who are behind the initial concept of senescence may not be exactly right, but they moved science in the right direction. I believe that the role of senescent cells is an exaggeration, I think that they are one of many types of garbage that accumulates with age; they simply brought us to the problem of a malfunctioning immune system whose normal function is to deal with this garbage.
Would you please share your thoughts on identifying senescent cells?
I am not personally working on that, because I think there are higher priorities. I find these cells very peculiar, but I still think that they only exist as long as we keep them away from the environment of the organism and leave them in culture; the moment you put them in the organism, they get eaten up and disappear. Since we know how this happens, and in part the mechanism, I am not that interested in finding out how to kill them better for the reasons mentioned earlier. Having their biomarkers would be very good and important, and it would be nice to have it. I am not sure if it is possible. We should not think that biomarkers of everything exist; it might be that we already know everything about them, the best biomarkers are already found, and they are not that great, but they are what we are left with.
Do you take any personal health and longevity measures yourself?
There is a legend that people whose brains are always working have less chance of developing Alzheimer’s; it’s probably the only precaution I am taking. I tell myself that I am working on solutions that will allow me to stay young regardless of maintaining bad habits and an unhealthy lifestyle. (laughs) We may be able to find pharmacological approaches to neutralize this problem, and when we have them, I will certainly be using them. I will say that I am very close to using the first things we are developing when they enter clinical trials; the moment I have the legal right to inject myself without jeopardizing the program, I will certainly do that.
What therapies do you think are the most promising at the moment, the ones that we might see in 5-10 years?
I think there are several. Being able to have rapamycin broadly used is a very real prospect, it will not change everything and will not overturn the problem, but it may improve our general health. Then, a lot will go towards immunization; we will be treating and training our immune system to be more responsive to accumulating types of things, so the adaptive immune system will help the innate immune system to do the job. I personally think that the cardinal improvement will come from inhibition of the endogenous DNA damage, which is ongoing in us every second of our lives. The big role, if not the biggest role, is played by the constant activity of retrotransposons. These get sporadically activated in a small proportion of cells for short periods of time, which is sufficient to create an overall increase in the number of retrotransposons and mutations in somatic cells, leading to an accumulation of damaged cells by exhausting the immune system, which has to deal with them, and putting even more pressure on it. If I had to make a prediction, I would say that ten years down the road, just as every bottle of water today has fluoride to prevent caries, it will have reverse transcriptase inhibitors to prevent cancer and aging. We are working towards that, and when we have a safe inhibitor, I will not be surprised if it is given to everybody.
What is the biggest bottleneck to progress in aging research, in your view?
There are no bottlenecks today. I think that development is in great shape; it is an excellent area that has quickly evolved thanks to the attention of the community and the attention of high-caliber scientists who are migrating to this field in large numbers. It’s very democratic; it’s open to new ideas, it’s very dynamic, and it currently allows us to follow multiple major directions without restriction.
We would like to thank Dr. Gudkov for taking the time to do this interview with us, and we look forward to seeing his future progress.
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