February 8, 2021

Treatments

#148 – Richard Miller, M.D., Ph.D.: The gold standard for testing longevity drugs: the Interventions Testing Program

“I don't really care what causes aging. What I care about is: What is the process that can postpone all the different aspects of aging?” — Rich Miller

Read Time 45 minutes

Richard Miller is a professor of pathology and the Director of the Center for Aging Research at the University of Michigan. He is one of the architects of the NIA-funded Interventions Testing Programs (ITPs) animal study test protocol. In this episode, Rich goes through the results of the long list of molecules tested by the ITP—including rapamycin, metformin, nicotinamide riboside, an SGLT-2 inhibitor called canagliflozin, and more. Many of the discussed outcomes have had surprising outcomes—both positive and negative findings.

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We discuss:

  • Rich’s interest in aging, and how Hayflick’s hypothesis skewed aging research (3:45);
  • Dispelling the myth that aging can’t be slowed (15:00);
  • The Interventions Testing Program—A scientific framework for testing whether drugs extend lifespan in mice (29:00);
  • Testing aspirin in the first ITP cohort (38:45);
  • Rapamycin: results from ITP studies, dosing considerations, and what it tells us about early- vs. late-life interventions (44:45);
  • Acarbose as a potential longevity agent by virtue of its ability to block peak glucose levels (1:07:15);
  • Resveratrol: why it received so much attention as a longevity agent, and the takeaways from the negative results of the ITP study (1:15:45);
  • The value in negative findings: ITP studies of green tea extract, methylene blue, curcumin, and more (1:24:15);
  • 17α-Estradiol: lifespan effects in male mice, and sex-specific effects of different interventions (1:27:00);
  • Testing ursolic acid and hydrogen sulfide: rationale and preliminary results (1:33:15);
  • Canagliflozin (an SGLT2 inhibitor): exploring the impressive lifespan results in male mice (1:35:45);
  • The failure of metformin: reconciling negative results of the ITP with data in human studies (1:42:30);
  • Nicotinamide riboside: insights from the negative results of the ITP study (1:48:45);
  • The three most important takeaways from the ITP studies (1:55:30);
  • Philosophies on studying the aging process: best model organisms, when to start interventions, which questions to ask, and more (1:59:30);
  • Seven reasons why pigs can’t fly (2:08:00); and
  • More.

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Rich’s interest in aging, and how Hayflick’s hypothesis skewed aging research [3:45]

Upbringing, education, and interest in aging

  • Born in Philadelphia and raised in Cheltenham Township, the northern suburbs of Philadelphia with his parents and two brothers
  • He took an interest in science at age 5
  • I decided early on that aging was bad for you. It made people sick and then die. I was kind of against that. And the best way to fight against that was to learn something about aging and to develop ways of slowing the aging process down.”
  • Got his MD and Ph.D. Degrees at Yale in the 1970s

Refining his focus on aging

  • Rich always wanted to work on aging so his initial Ph.D. project involved somatic cell hybridization
  • He wanted to mix together two kinds of cells—one that could divide and one that couldn’t divide—and immortalize the T lymphocytes that couldn’t divide
  • But the more he learned about the Hayflick hypothesis and all of that cell senescence stuff, the more convinced he was that it wasn’t going to teach him anything about aging
  • He switched focus and became an immunologist in order to study immunology and how aging modified the immune system
  • Starting about 1990, he gradually transitioned into focusing on aging more broadly 
  • Today, he does very little immunology: His focus is now on what is controlling the aging process and using that information to develop interventions

History around division of cells [7:30]

  • History of the Hayflick hypothesis and how it skewed aging research
  • The phenomenon that Hayflick more or less discovered was that if you take normal, non cancer, human cells and you let them grow in tissue culture, they will divide but only a limited number of times (about 50) and then they will stop
  • Hayflick decided that was akin to aging and that he had found a way to study aging in culture — “Now that’s nuts. It’s nothing like aging in the slightest.” says Rich
  • But people were really excited by tissue culture and a whole generation of superb cell biologists spent their life investigating the Hayflick system under the illusion that they were studying aging
  • About 20 years after this, Rich spoke to Vittorio Defendi, an old colleague of Hayflick:
    • On one occasion, Hayflick had been complaining to Defendi that his cells in culture “already stopped growing” 
    • Defendi (allegedly) told Hayflick in a joking manner, “Maybe they’re just getting old.”
    • Hayflick, whose sense of humor is notoriously absent, did not understand he was being joshed
    • He thought it was a scientific hypothesis, and after a while, he persuaded himself that it was HIS hypothesis and then that it was the correct hypothesis
  • It later became established that the limitation of growth—the Hayflick limit—was actually due to the shortening of telomeres
    • This was a very important, and true, finding 
    • However, people convinced themselves that, because they thought it was like aging, the telomeres were something to do with aging too
  • Now a whole new generation of people bought into the Hayflick idea and the telomeres concept as a central cause of the aging process, despite all the evidence to the contrary

⇒ A prime example of how the line of thinking has skewed our thoughts is a recent study from Israel on the anti-aging effect of HBOT:

  • This story is being sold as the most rigorous study in the history of humans demonstrating the anti-aging benefits of hyperbaric oxygen
  • A group of volunteers were exposed to hyperbaric oxygen and their telomeres lengthened a bit and therefore, many believe, hyperbaric oxygen is the “fountain of youth”
  • The problem, of course, is that aging and telomere length are not the same thing

Rich points out

  • It’s entirely possible that hyperbaric oxygen could well have health benefits under certain circumstances — “There’s no evidence that that statement is true, but it’s also not silly.
  • “If you want to prove that hyperbaric conditions, suitable doses, and at suitable time intervals, et cetera, might be good for you, that’s a very plausible idea worth testing. It’s just that you don’t test it by measuring telomeres.”

The exciting part about telomere research:

  • The work that Blackburn did is really amazing biology (and worthy of a Nobel Prize), but it doesn’t really explain aging — “And those two statements can co-exist.” says Peter
  • Telomere biology is also a critical element in cancer biology — the telomere story is a fundamental advance in our understanding of cancer in people
  • And it may also have an interesting sidelight in evolutionary biology (some species, mice, for instance, have extremely long telomeres)
  • Vera Gorbunova’s work looks at how different species with different body sizes and lifespans differ in their ways of stopping the cancer process
  • So, telomere research may be a fundamental step in our understanding of cancer biology in people and the way in which anti-cancer defenses evolve
  • However, “the notion that it’s sort of a shortcut for actually working on aging in my view does not hold up very long” 

 

Dispelling the myth that aging can’t be slowed [15:00]

Rich’s role in starting the ITP (Interventions Testing Program)

  • The National Institute on Aging (NIA) has a division of aging biology, which at that time was headed by a visionary guy named Huber Warner about 18 years ago
  • Warner commissioned a committee of about 12 of to sit down with him and Nancy Nadon to discuss what the NIA might do to develop a program in which potential interventions were tested directly
  • Together with Arlan Richardson, Rich put together what they viewed would be the best way to do this focusing on mice which they presented (successfully) to Warner

⇒ See An aging Interventions Testing Program: study design and interim report 

Dispelling the myth that aging can’t be slowed

Around the same time (2002), Rich wrote Extending Life: Scientific Prospects and Political Obstacles

  • Rich was asked to give a talk at the law school at the University of Michigan which became the basis 
  • Rich laid out the basic thesis of the paper, “Look, discussions of anti-aging medicine aren’t silly. The development of an anti-aging strategy is starting to make headway and further work here would be worthwhile.” 
  • Rich adds, “It’s still an evolving process. We’re not there yet. But 18 years ago, we certainly weren’t even close to there.”

Around that time, Rich attended a Gordon Research Conference on Aging where he got into a disagreement with his friend, George Martin

 

{end of show notes preview}

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Richard Miller, M.D., Ph.D.

Richard A. Miller, M.D., Ph.D., is a Professor of Pathology at the University of Michigan.  He received the BA degree in 1971 from Haverford College, and MD and PhD degrees from Yale University in 1976-1977.  After postdoctoral studies at Harvard and Sloan-Kettering, he began his faculty career at Boston University in 1982 and then moved to his current position at Michigan in 1990. 

Dr. Miller has served in a variety of editorial and advisory positions on behalf of the American Federation for Aging Research and the National Institute on Aging, and served as one of the Editors-in-Chief of Aging Cell.  He is the recipient of the Nathan Shock Award, the AlliedSignal Award, the Irving Wright Award, an award from the Glenn Foundation, and the Kleemeier Award for aging research.  He has been a Senior Scholar of the Ellison Medical Foundation, and is a Fellow of the American Association for the Advancement of Science and a member of the American Association of Physicians.  At Michigan, he directs the Paul Glenn Center for Aging Research. 

His research program includes ongoing studies of the mechanisms that link stress, nutrients, and hormones to delayed aging in mice, development of new approaches to slow aging and disease through drugs and targeted mutations, and studies of the ways in which cells from long-lived birds, rodents, and primates differ from those of short-lived species.

For fun he sometimes photographs wildlife or landscapes; you can check it out here.

Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user's own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.

13 Comments

  1. An interesting talk; thanks. Re the synthetic estrogen derivative’s apparent ability to extend lifespan in male mice, why not provide a quantitative figure in %? Was it a 5% average extension? 10%? 50%? 100%? 1000%? And how much variation was there? The omission of quantitative data is puzzling. Even approximate values (in case Rich’s memory has faded re old exp’ts) would be better than nothing.

  2. A fascinating and informative discourse. I enjoyed it immensely.

    Might I suggest a future podcast featuring one of my favorite evidence-based nutrition experts who also offers “no-advertising” content, Michael Greger, M.D. His most recent book, How Not To Diet, is an encyclopedic but very readable resource that I frequently recommend to patients.

  3. I’ve listened to many of your podcasts and many of them before the drive. This was by far the most generally thought-provoking one. Rich’s way of looking at these problems, his pragmatic focus on isolating the right questions fundamentally altered the way I was thinking about all of this. Thanks, that was well worth this year’s subscription.

  4. Have you ever considered making an episode about the use of animals in research? There are a lot of misconceptions around and people often do not realize that there are ethical committees involved and what the whole approval process looks like. I know it might be a very controversial episode but I think there is a void in high quality scientific/medical communication when it comes to this issue.

  5. Please do a podcast on Spermidine. The name of the supplement alone should ensure one of your most downloaded episodes ever 😉

  6. wow! what a tour de force on longevity drug science/evidence. thanks!

    based on this researcher/interview, I’m cutting Resveratrol from my routine and will put the money on others with good evidence. thanks again!

    Would love for Dr. Attia to assess and detail what the state of the science is on PQQ. My surface check/read on the literature seems to show it helps much with mitochondrial function/genesis, Metabolic dysfunction-associated fatty liver disease, and maybe T2 diabetes (which I’ve got); e.g., see:
    https://medcraveonline.com/MOJBB/effects-of-pyrroloquinoline-quinone-and-vitamin-c-on-diabetes-associated-cardiac-oxidative-damages-and-hyperlipidemia-in-mice-biochemical-and-histopathological-study.html

    https://www.tandfonline.com/doi/abs/10.1080/07315724.2019.1705203

    https://www.mdpi.com/1422-0067/22/3/1458/pdf

    Long live Peter Attia! Please keep this up for years to come.

    I’m a new paying member, but a long time comprehensive follower. I wish NIH would fund Attia’s operation to enable even more awesome contributions to science and our health…

    cheers!

  7. Hi,
    After listening to this podcast I was confused. (I’m not a doctor or a physiologist so confusion might not be surprising.) I’m confused about the fact that it seems to be the case that large muscle mass leads to better glucose clearance but if I understand it correctly rapomycin knocks out mTORC1 which then might inhibit muscle hypertrophy. Trying to work out what is going on I found the following article and am still confused how the rapomycin is life extending given that the impact on muscle atrophy would seem to imply the reverse.
    https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/2044-5040-3-6
    Am I just too ignorant of all the upstream, downstream effects? Or have I misconstrued something?
    Help?

  8. Could the ITP experiment be flawed from the very beginning?

    I liked the way you described the results for Resveratrol. Findings are that it is beneficial only for a specific kind of mice, with a specific kind of damaging diet (High Fat High Carb) and with a specific kind of consequential disease (Liver growth and imflammation). So Resveratrol have not shown beneficial results for any other context and, of course it does not show any benefits in the ITP protocol. (Neither NMN nor green tea.)

    On the other side, Ascarbose and Canagliflozin have shown clear benefit in the ITP protocol. They show benefits on a heterogenous mixed population of mice, who eat a “healthy” diet. BUT! Are you sure this diet is healthy for your mice? You confirm that all (or most) of the mice are dying of cancer! Is that normal in nature? All animals dying of cancer? I do not know, but I do not think this would be the case.

    But, besides that, for me it is not surprising that these two anti-diabetes medicines help to extend the life of your mice. Are you sure that a healthy mice eat a diet based on cereal? I doubt it. I simply can’t imagine a natural environment with so many cereal available that then mice will end eating only cereal, or even a diet based on cereal!

    So, what I hypothesize from your experiments is that your cereal-based diet is not a healthy diet. It seems more to be a unhealthy diet that promotes signs of metabolic syndrome on your mice. And then, the compounds that you will find to be effective to treat those mice and extend their life are going to be medicine that tries to fix the damage caused by this unhealthy diets: anti-diabetes medicine.

    So a similar approach to that you used for Resveratrol, what I think your findings are is:
    “you are finding compounds that treat a specific syndrome (metabolic), caused by a specific unhealthy diet (cereal-based) to a genetically mixed mice.”

    My hope is that your control mice are really exposed to an optimal life style, close to what they might be exposed in nature, with seasonal variation of types and amounts of food (even with periods of fasting), nature based. You may even try to optimise lifestyle with TRE, ketogenic, cycles, exercise, etc. And, from there, then check for the benefits of compounds. As you can see, it is a bit like taking your own philosophy for the experiment, but starting on a real healthy state/diet/lifestyle as the control. Or, at least, not from a cereal-based life style which seems to be promoting disease.

    Thanks a lot,
    Fantastic research!

  9. Why Prof. Longo has not been in the show yet?
    I hope you have already scheduled an interview with Prof. Longo, I can’t wait for your perfect questions and his interesting answers.
    I’m sure all the audience will love it!

    To be honest, this may be the biggest mystery about this podcast: Why not Longo? Why not Panda?

    It would be nice to have them. Or, if you are not planning to interview them, it would be nice to inform your audience why not!

    Thanks a lot!

  10. A recent Israeli study extended mice lifespan by 30% by modulating sirt6 activity. Looking for natural sirt6 activators, cyanidin stands out as a very potent one. Can this be a candidate for testing?

  11. Both Resveratrol and Curcumin failed in the ITP studies. Both are have extremely low bioavailability. The ITP has not stated if either molecule was delivered in a liposome form (mixed into some type of fat). This is possibly one of the biggest problems in clinical research into many different molecules.

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