Dr. Mikhail Blagosklonny is a professor of oncology who now studies aging, and is the originator of the hyperfunction theory of aging. He has written numerous scientific articles on aging and, in particular, on the extension of lifespan with rapamycin.
Here, he and Dennis Mangan discuss how Dr. Blagosklonny‘s cancer research led him to the study of aging, whether rapamycin is the most important anti-aging intervention currently available, his skepticism about metformin as an anti-aging drug, and more.
Correspondence to: Mikhail V. Blagosklonny, email: [email protected], [email protected]
Keywords: rapamycin, mTOR, aging, longevity, oncology
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Below is a transcript of this interview between Dennis Mangan and Mikhail Blagosklonny, M.D., Ph.D.:
Dennis Mangan:
Hi. I’m here talking today to Dr. Mikhail Blagosklonny. He is a scientist who studies aging, a professor of oncology, and advocate of rapamycin. I’ve spoken to him before, and we’re going to continue our conversation here again today. Thanks for coming on, Mikhail. It’s good to have you on again.
Mikhail Blagosklonny, M.D., Ph.D.:
Thank you, Dennis. It’s my pleasure talking to you, always.
Dennis Mangan:
Thanks a lot. Let’s jump right in. You began your scientific career studying cancer. You are a professor of oncology. How did that lead to your studying aging, and in particular, how did that lead to studying rapamycin in connection with aging?
Mikhail Blagosklonny, M.D., Ph.D.:
I was studying senescence of cancer cells, induction of senescence by anticancer drugs, because I was working on anticancer therapy. And surprisingly, rapamycin prevented senescence, instead of inducing it, but it was not by chance observation. I had a hypothesis that cell senescence developed when cell cycle is blocked, so cells cannot divide, but growth-promoting pathways like, mTOR, ERK/MAPK are still active, driving, I would say, futile growth, pathological growth, which I call geroconversion, which leads from reversible arrest to irreversible senescence.
Then, we were looking for, testing this hypothesis, which pathways are involved. We used several inhibitors of MEK/MAP pathway, PI3 kinase mTOR pathway. The best drug that inhibited geroconversion to senescence was rapamycin. I also focused on rapamycin because it was a clinical available drug, in contrast to MEK inhibitors that were not available at the time. With this, by measuring reversibility of cell cycle arrest, which was golden marker.
Then, I realized that this is not only in vitro phenomena, but also organismal phenomena that mTOR may be involved in organism aging. It was like analogy. In cell culture, when proliferation is blocked, then mTOR drives senescence. In organism, when developmental growth is completed, then the same pathways drive organismal aging and age-related diseases.
I moved from cancer research to aging research. Fortunately, I was not indoctrinated by aging research before. I was free to think that aging is not caused by accumulation of molecular damage, which accumulates of course and would kill organism, but it’s not life limiting. Organism dies from hyperfunctional mTOR-driven aging as an example. mTOR is not the only pathway that involved, of course.
Pathways that drive cellular senescence are actually identical to pathways that make cell cancer, but in cancer cells, these pathways like mTOR activated by mutations, for example, PI3 kinase. In senescence … I sometimes pronounce senescence, sometimes senescence. How would you pronounce?
Dennis Mangan:
I would say senescence.
Mikhail Blagosklonny, M.D., Ph.D.:
I will say senescence too. In senescence, the same pathways activated by some feedback loops, and so on, not by mutations. Basically, I answered this question.
Dennis Mangan:
Okay. Let me ask you a follow-up if this doesn’t take us too far afield, because it’s not necessarily concerned with aging. Your insight into cancer and its analogy with senescence, does that relate at all to the idea of cancer as a metabolic disease, rather than something that’s mostly driven by genetic mutations?
Mikhail Blagosklonny, M.D., Ph.D.:
Well, actually, one doesn’t exclude another, because these genetic mutations happen in metabolic pathways. Of course, cell organism metabolism also affected. For example, in mice, fasting delays cancer. Calorie restriction delays cancer. The same, rapamycin, which also change metabolic pathways, and it delays cancer in mice. Some scientists even think that it’s not that rapamycin suppresses aging of the organism, but just delays cancer, so mice live longer. But, there are many arguments against this. I named one of my articles, Prevention of cancer by inhibiting aging. Cancer is age-related disease. If we inhibit aging of the organism, I use the word aging for organism and senescence for cells, then we delay cancer, age-related diseases and all other diseases.
Dennis Mangan:
Okay. All right. Very good. All right. Thanks for that. You’ve made some discoveries earlier that were more or less recently rediscovered. Could you talk about some of those?
Mikhail Blagosklonny, M.D., Ph.D.:
Yes. I would say that my work was not probably well understood by aging researchers, because I moved to this field from oncology. Something that was obvious for me was not probably obvious for aging researchers. Recently, rapamycin was announced senomorphic because it’s inhibit hyper secretory phenotype of senescent cells and SASP. This is marker of senescence.
But when we were working on this, 16 years ago and later, we found that it prevents most importantly geroconversion from normal cells to senescent cell. This marker, like SASP, I never considered even important because it was expected that antiinflammatory agent, like rapamycin, would inhibit SASP. I thought it would not be convincing in our work. We mostly used golden marker that we prevent irrevesability of senescence, and also large cell morphology and so on, but mostly that rapamycin might prevent ability of cells to restart proliferation when cell cycle is released.
For that reason, I called these drugs, it’s not only rapamycin, but MEK inhibitor, gerosuppressant, or gerosuppresants. The reason because rapamycin was known is immunosuppressant. I changed to gero. Glucocorticoids and, for example, antiinflammatory agents also inhibit SASP, but in no way glucocorticoids extend lifespan. Focusing on SASP, it’s only one of hyperfunctions.
There are thousands of hyperfunctions besides SASP, which help the old cells, depending what they’re doing in the organism. SASP is more or less universal, but it’s not the only one. In other example, what was rediscovered, so-called geroscience hypothesis, which basically I described in many papers, like with title Treatment of age-related diseases by slowing down aging, and Validation of anti-aging drugs by treating age-related diseases, and so on.
It seemed to me all so obvious at the time. It was known. This was discussed even before my work, that inhibiting aging would delay age-related diseases. Now, it’s known as hyperfunction hypothesis. There are some other examples, but probably I don’t want to take too much time on that.
Dennis Mangan:
Okay. You had this idea, and hyperfunction theory, and how it related to senescence and the hyperfunction of all other cells.
Mikhail Blagosklonny, M.D., Ph.D.:
Right.
Dennis Mangan:
It was new to aging science. You injected this new idea into aging science. Certainly, I’ve read all of your papers on aging. I certainly don’t think there are many other people in the field who are discussing it much, or emphasizing it in any case. Yes, that’s all very interesting that you brought these fresh ideas into the study of aging.
Mikhail Blagosklonny, M.D., Ph.D.:
Right.
Dennis Mangan:
Is that a good characterization of the way it is, the way I described it?
Mikhail Blagosklonny, M.D., Ph.D.:
Right. But also, hyperfunction theory made many testable predictions, which I probably have done most complete paper in 2006. Four years after this publication, I also published about hyperfunction theory, four years later. At that time, already was shown that predictions are working, including that rapamycin extends lifespan in mice. First paper was by Harrison published in Nature in 2009. We also published one year later in American Journal of Pathology life extension. And then, it was 40 publications of life extension. Some effects were very dramatic. I like some papers by Matt Kaeberlein also later on, that show that the higher dose of rapamycin, the longer life. It’s never reached plateau. It’s important.
I would not say that no one at all accepted this. It was a few people, but they were, for example, David Gems from London. He developed it for the hyperfunction theory, quasi-programmed diseases to C. elegans. He showed that C. elegans also die from age-related diseases, but they’re, of course, very different from human diseases, but it was completely like hyperfunction theory predicted.
Also, one doctor, a practicing doctor, accepted this. It was Alan Green who started treating himself with rapamycin. Effect was so dramatic. Probably you can read on his website the story. Now he’s treated 700 patients. It’s not really necessary that everyone accept it. It’s important that those people who accept it, they can develop it further.
Dennis Mangan:
Right. Okay. For the benefit of those watching and listening, let me just state more plainly that Dr. Blagosklonny once wrote that if rapamycin does not extend lifespan, then everything we know about biology is wrong. Of course, Dr. Blagosklonny was completely right in his prediction. I think that shows incredible insight.
You mentioned Dr. Green, Dr. Alan Green, in New York. What would you say is the significance of him starting to treat patients with rapamycin, in terms of the bigger picture, in terms of more widespread recognition or use of rapamycin?
Mikhail Blagosklonny, M.D., Ph.D.:
Yes. It was turning point, because otherwise, medical doctors would be afraid to do this. He showed example. It was really bold to start such practice at the beginning. Now, other doctors accepted this. He showed that it’s very safe and effective. I know at least five, six clinics in the US and heard about some clinics in Europe that use rapamycin for life extension. I think there are a lot of them now opening.
Dennis Mangan:
Okay. Very interesting. Yes, like you say, there are more now that are doing that, more doctors prescribing it. I’ve seen, I don’t know, half a dozen or so doctors around. I’m guessing there are probably many more that are maybe not so public with their willingness to prescribe rapamycin.
Do you see rapamycin as the most important antiaging intervention currently available now? And, what other promising antiaging interventions, if any, do you see coming along in the near future, say in the next decade?
Mikhail Blagosklonny, M.D., Ph.D.:
Besides inhibitors of mTOR and MEK, now they’re also clinically available, very interesting results on life extension. Not so many drugs extend life in mice, by the way. It’s more talking about this, but no data. Drugs that extend lifespan in mice repeatedly is Acarbose, which you know very well, of course, and alfa-estradiol. It’s not beta-estradiol, which make feminize effect.
About Acarbose, it’s basically close to a very low calorie diet. It prevents, let’s say, absorption of carbs. In my mind, it can be substituted, Acarbose, with the ketogenic diet, a very low carb diet. Alpha-estradiol is unique. It probably has not the same effects as any fast, low carb, or whatever. It’s different from rapamycin. This is pretty interesting. It extends lifespan only in male mice. Men live shorter than women. Although it could be used probably mostly for men’s longevity, it’s also important.
What else will be coming? I don’t know, because it’s unpredictable. Discoveries are unpredictable, otherwise they are not discoveries. Otherwise, we already know them now. Actually, I like your ideas about iron in aging. I think that some agents or interventions that decrease excessive iron, excessive it’s against hyperfunction, maybe will work. I don’t want to speculate too much on that.
Dennis Mangan:
Well, yes. You’re totally right. If we could anticipate the discoveries, they wouldn’t be discoveries. Yes, Acarbose is very interesting, because basically it mimics a low carbohydrate diet.
I want to thank you, Mikhail, for agreeing to do this interview with me. It’s been a very interesting and productive conversation. Thank you.
Mikhail Blagosklonny, M.D., Ph.D.:
Thank you, Dennis.
Dennis Mangan:
Okay. Great. Well, I hope I’ll be talking to you soon. Thanks again. Bye now.
Mikhail Blagosklonny, M.D., Ph.D.:
Bye.
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