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As FxMed docs, we’re committed to working with the body’s own capacity for health. Dr. Josh Mitteldorf offers a contrarian strategy, one which he says is grounded in a new breed of evolutionary medicine.
He tells us that diseases of old age are qualitatively different from the diseases we get when we’re younger, different because in old age, our bodies are part of the problem, not part of the solution.
Aging, says Josh, is the body deliberately destroying itself (for the sake of the population), via inflammation and apoptosis and autoimmune diseases. In this interview, Josh and I find common ground talking about hormesis. In Josh’s theory, the fact that the body lives longer when stressed (e.g. caloric restriction) is proof that the body isn’t trying its hardest to stay young when it’s not stressed.
It may sound like philosophy, but there are real consequences for the future of medicine.
These are challenging ideas, so I’m eager to hear what you think, and be sure to leave a review wherever you listen to New Frontiers! Thank you! ~DrKF
What if aging isn’t what we think it is? Astrophysicist and aging research Josh Mitteldorf studies aging from an evolutionary perspective. His book Cracking the Aging Code, written with Dorion Sagan and published in 2016 from Flatiron Macmillan, lays out evidence that aging is an evolutionary program and that the key to fighting the diseases of older age is to work against the body rather than with the body. In this podcast, Dr. Fitzgerald talks to Josh about his work’s surprising implications for medical research and anti-aging practice.
In this New Frontiers in Functional Medicine Podcast, you’ll hear:
- Aging as an evolutionary program
- The limits of functional medicine for combatting diseases of older age
- Working against the body as a strategy for fighting diseases of older age
- Intermittent fasting as a tool to interrupt the aging process
- Modifying gene expression in an unnatural way to defeat the aging program
- Hormesis
- Eating more protein in older age as a way to slow aging
- Resetting the methylation clock
- Growth hormone as it relates to aging
- Mitteldorf’s perspective on dosing vitamin D
- Mitteldorf’s key supplements for anti-aging, including aspirin and vitamin D
- The role metformin and botanical alternatives to Metformin can play in promoting longevity
- Insulin as an ancient mechanism for regulating lifespan
- Opportunities to work with Josh on and/or to participate in his upcoming aging study
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Josh Mitteldorf studies aging from an evolutionary perspective. His book, with Dorion Sagan, Cracking the Aging Code, (2016) from Flatiorn/Macmillan lays out evidence that aging has evolved as a compromise between fitness of the individual and stability of the ecosystem. He has gone on to explore the surprising implications for medical research and anti-aging practice. He comments on news in the science of aging at AgingMattersBlog.org and offers a personal anti-aging program at AgingAdvice.org. His political writings are featured at OpEdNews.com, while his poetry, essays and aphorisms appear at Daily-Inspiration.org. Mitteldorf’s current project is a large-scale study using an epigenetic clock to evaluate a broad range of anti-aging interventions in current use, and their mutual interactions. The study of aging is a second career for Mitteldorf. His original training was in astrophysics.
Contact John by Email: Aging.Advice@gmail.com
Chapter 9: Medical Implications (PDF from Aging is a Group-Selected Adaptation)
Book: Cracking the Aging Code, Josh Mitteldorf and Dorion Sagan
Study: Reversal of Epigenetic Aging and Immunosenescent Trends in Humans
Dr. Kara Fitzgerald: Hi everybody. Welcome to a New Frontiers in Functional Medicine where we are interviewing the best minds in functional medicine, and today, is no exception. I’m extremely excited to have somebody who’s actually, you’re kind of new, Josh, to the field of functional medicine, and you asked me to give you some sort of primers on functional medicine, but after I tell you about Dr. Mitteldorf, you’ll see that we embrace him and his thinking, and I think after you listen to what he has to say today, you’re going to start reading his blogs, as I do. So let me give you a little bit of the background. Josh Mitteldorf studies aging from an evolutionary perspective. His book with Dorion Sagan, Cracking the Aging Code, published in 2016 from Flatiron Macmillan, lays out evidence that aging has evolved as a compromise between fitness of the individual and stability of the ecosystem. We’re going to be unpacking that today.
You guys, he’s gone on to explore the surprising implications for medical research and anti-aging practice. He comments on news on the science of aging at agingmattersblog.org and offers a personal anti-aging program at agingadvice.org. His political writings are featured at opednews.com while his poetry essays and aphorisms appear at daily-inspiration.org. Incidentally, we’ll just pop all of this stuff into the show notes and any papers that he references, his links to his books and actually all of that stuff will be over in show notes.
Mitteldorf’s current project is a large-scale study using an epigenetic clock to evaluate a broad range of anti-aging interventions in current use and their mutual interactions. The study of aging is a second career for Mitteldorf. His original training was in astrophysics. Josh, welcome to New Frontiers. It’s great to have you.
Dr. Josh Mitteldorf: Well, thanks for welcoming me.
Dr. Kara Fitzgerald: I’m just happy that you answered our myriad pings and decided you were interested in talking to me. As you know, I’m interested in methylation and so just my meanderings online researching certain topics brought me over to your blog and I’ve been just a really big fan of your work ever since. So just thank you for all of that.
Dr. Josh Mitteldorf: It’s a pleasure for me to be here and I’m still celebrating the fact that 25 years ago I sent out my first paper and the response was that the Journal of Theoretical Biology shouldn’t touch this with a 10-foot pole. That was the only review I got from my first paper and I learned how strong the prejudices are in the field. I have some credibility now and the fact that someone like you is interested in the work, it’s very gratifying for me that the work is starting to achieve some acceptance.
Dr. Kara Fitzgerald: Oh, it is for sure. It is. And it’s kind of becoming exponential, in fact, you know what I was going to say to you as we were chatting before, and I’m just going to publicize this is the Personalized Lifestyle Medicine Institute started by Dr. Jeff Bland, who’s a dear deep important mentor for me, has an October conference and I’m thinking, I don’t know if you have any room or interest in your calendar, but Horvath will be presenting and Jeff is giving Randy Jirtle an award. There are just some awesome presenters there and had I thought of it sooner, I would have been pinging Jeff to see if you could have been on the docket. It’s a conference, I think you would find simpatico with who you are. Anyway, let me just tell you or let me ask you first. You’re an astrophysicist by training, so why the jump into… Do you call it geriatric medicine, what you’re doing now?
Dr. Josh Mitteldorf: Really, if I have anything to contribute to this field at all, it’s in theoretical evolutionary science. There are implications for medicine from that.
Dr. Kara Fitzgerald: Okay. All right. And so I want you to talk about that. First though, how did you come into this?
Dr. Josh Mitteldorf: Yeah, so I was an astrophysicist and there are so many really smart people in theoretical astrophysics, but I was dotting the I’s and crossing the T’s and finding esoteric data. And I discovered in 1996, it was the first time that I’d read that caloric restriction in animals makes them live longer. So this was news to me. It’s probably news to none of your readers at this point, but it was news to me at that time and I thought where does this come from and how can it be? What can the body do when it’s starving that it couldn’t do with all the food that it needed?
And just from that simple question, I decided aging must be a decision that the body makes. It must be an evolutionary program. It’s not something that the body is fighting its hardest to avoid, but somehow physical constraints overcome the body in the end and we have to die. The body is programmed to age just based on the fact that the body can age slower if it wants to. And it does that when it has less resources.
Dr. Kara Fitzgerald: Right.
Dr. Josh Mitteldorf: That was the original inspiration. And I thought, gee, here’s a contribution I can make to basic science. I was asking questions as an astrophysicist that only another astrophysicist could even be interested in. And here I have a chance to contribute to science where a three-year-old or a five-year-old can ask daddy, why do we get old and die? And if I can contribute to that, here’s low-hanging fruit. It’s a more important role for me than anything I can do in astrophysics.
Dr. Kara Fitzgerald: So it’s just so fascinating. So you’re really the person who kind of posited aging as a form of programmed self-destruction and it was born out of that 1990 CR’s article with this evidence that you can stop it. We’re on track to die. And all of the diseases of old age, you talk about autoimmunity, somewhat extensively, cardiovascular disease, diabetes, Alzheimer, in fact, some theories suggest that all of those are forms of autoimmune disease. But these diseases, which we put exponential effort into reversing in the larger conventional medical arena, and in my world you would argue are missing the point entirely. Is that right?
Dr. Josh Mitteldorf: Yeah, that’s right. The story I tell is look at medical science in the 1950s. This was a time when the Sputnik era was upon us. We thought science could do anything. Humans know a lot better than biology will fix things. I was fed infant formula rather than mother’s milk when I was an infant, because-
Dr. Kara Fitzgerald: It’s better.
Dr. Josh Mitteldorf: Yeah. Right, They designed, right?
Dr. Kara Fitzgerald: Yeah.
Dr. Josh Mitteldorf: So that’s the age and then there was a backlash against that in the 1960s. Nature knows best and we’ve had natural medicine and medicine designed to help the body since then. And functional medicine is riding on that inspiration and it’s absolutely right. It was a humility that the medical sciences really needed. But it works for diseases of youth and youth diseases of middle age. It works for infectious diseases. It doesn’t work for diseases of old age.
Why is that? Because the other diseases are things that go wrong with the body. But that’s not what cardiovascular disease is. That’s not what dementia is. That’s not what inflammaging and the inflammation that accompanies aging. That’s not what they are. They are programmed into our epigenetics. They happen on a schedule. And if we want to delay the diseases of old age or ameliorate the diseases of old age, the best thing that we can do is not to work with the body, to work against the body, to defeat the body’s aging program.
Dr. Kara Fitzgerald: So the collection of diseases of old age, we’ll get the phenotypic expression, it’s programmed into our genes and it’s going to happen in our journey. And we need to actually put down this idea of natural medicine, which I think in your argument, is it going to extend health span or lifespan? I know some in functional medicine would argue that pretty wholeheartedly. And actually a lot of the interventions you talk about certainly overlap with things that we’re doing in functional medicine. So some of what you talk about to actually go against our genetic programming or unnaturally go against actually arguably natural. Not to be too arcane here, but just kind of speak to that, and I want to hear some of the unnatural ideas, too.
Dr. Josh Mitteldorf: The biggest difference is for research in the future, not treatments in the present. Where you look for anti-aging medications is different. If you think the body is wearing out, and that’s what aging is, you’ll look for ways to repair the damage. Stem cell therapies and regenerative medicine are good examples. But if you think, as I do, that aging is programmed, then it must be coordinated through the whole body. You’d look to interfere with the signals that orchestrate the aging process and then trust the body to repair itself once it gets the right signals. But in present practice as opposed to research, there’s not that much difference.
To the credit of the whole medical field and functional medicine in particular, medical researchers are very attuned to the data and very practical. Some of these principles have been discovered. For example, nobody would suggest that you eat more to be healthier. We’ve just seen the data that people who are thinner live longer. In fact, diabetes is the biggest risk factor for Alzheimer’s disease. And of course, carrying extra weight contributes to diabetes. So in a practical way, functional medicine has very much embraced some of these ideas already, but the theory has not been embraced and there’s so much more that we can do once we’ve got the theory down right. That’s what I’m hoping to contribute.
Dr. Kara Fitzgerald: All right, so with this theory that we’re basically programmed to die at a certain time and with these collection of diseases of old age, so you say we need to do some unnatural thing.
Dr. Josh Mitteldorf: Yes.
Dr. Kara Fitzgerald: Talk about that.
Dr. Josh Mitteldorf: Well starvation, we would say that’s unnatural. There are people who argue, well, yeah … In the ancient times, our ancestors thousands of years ago went through periods of starvation. Maybe that’s true; maybe it’s not, I don’t know. But certainly intermittent fasting is one of the best things that you can do to maintain health and extend lifespan. There are other aspects of hormesis. And my best bet for the horse race of future medical research and anti-aging is to modify gene expression in an unnatural way to defeat the aging program.
Dr. Kara Fitzgerald: Yeah, right. That’s right. Yeah.
Dr. Josh Mitteldorf: This is part of hormesis. Most of your listeners are familiar with the idea that many of the hardships, challenges to the body actually end up with the body overreacting. The body is healthier and lives longer facing challenges than it would without those challenges.
And the one that’s probably most counter-intuitive is ionizing radiation. We think of that is the worst thing we can do. It destroys DNA. It makes mutations. It interrupts our chemistry. And a big dose of radiation is toxic. So the fact that animals with a modest dose of radiation, two or three times what we get from natural background, actually live measurably longer than animals who are not exposed to this radiation. This is an eye opener. I have to ask, well what’s going on here? Why is the body functioning better with the toxic radiation than without.
Dr. Kara Fitzgerald: And that is hormesis.
Dr. Josh Mitteldorf: That’s called hormesis.
Dr. Kara Fitzgerald: It’s turning on some endogenous systems to deal with the radiation that are actually sort of globally healthy and beneficial.
Dr. Josh Mitteldorf: Shock protein is high among them. And as a theorist I like to ask… There is no downside to heat shock protein. It doesn’t cost the body a lot metabolically to produce it. Why is the body only producing heat shock protein under conditions of stress? I’ve got a lot of thoughts about that as a theorist.
Dr. Kara Fitzgerald: Okay. So then I want to ask you about that but I do want to just say as an aside just I’m not sure if you’re aware, you probably are. Randy Jirtle actually looked at the impact of radiation on his Agouti mice and it was beneficial. It actually hyper-methylated the gene. They had good outcome. It was not dissimilar from administering the methyl donors, low-dose exposure.
Dr. Josh Mitteldorf: Of course. We know that high-dose radiation kills… It increases cancer rates as well.
Dr. Kara Fitzgerald: Kind of an interesting little sidebar. I guess I’ve got a couple of questions for you. One would be, well first of all, what are some of your thoughts around how to kick in hormesis and up-regulate heat shock protein? What are some of the things that you think are effective at doing that? I mean, I guess to kind of reverse the hands of time you want to start before folks have significantly aged for best outcome, or to have the benefits of hormesis, to have the endogenous production of protective compounds generate if they’re fairly deteriorated.
Dr. Josh Mitteldorf: Of course, dosage is everything. And a good example of what you say is that protein restriction is a life extension strategy when we’re young, but as we get older, sarcopenia is a threat and eating more protein is actually beneficial. The thing we have best evidence for in prolonging life is caloric restriction. If you can live chronically with a lower calorie intake, that’s one way to go. Other people find intermittent fasting is perhaps as effective in people, almost as effective in test animals. Fast on a schedule that works for you. There is the Longo Diet, the Fasting Mimicking Diet, which makes it easier to get 90% of the benefit of fasting with 20% of the pain. On my website it’s linked to a set of recipes that a friend and I developed… have the same macronutrients as the Fasting Mimicking Diet sold as ProLon using fresh foods to simulate the Fasting Mimicking Diet.
Dr. Kara Fitzgerald: Longo actually might challenge full-on caloric restriction as being somewhat immunosuppressive. I had the opportunity to podcast with him and it was really great conversation, just thinking about the biosphere and his mentor and some of the fallout. And that was also the impetus for his Fasting Mimicking Diet. Any thoughts on that?
Dr. Josh Mitteldorf: On suppressing the immune system?
Dr. Kara Fitzgerald: Yeah, with caloric restriction.
Dr. Josh Mitteldorf: I’ve seen evidence in both directions and I’m not enough of a medical scientist to know which to believe.
Dr. Kara Fitzgerald: Let me just ask you this; you and I were dialoguing earlier about the Fahy paper that just came out. And folks, I’ll link to it. It was just published. In fact, you couldn’t access it for a while, but now I think we can get the full text… “Reversal of Epigenetic Aging and Immunosenescent Trends in Humans.” And it’s an extremely small study, just nine middle-aged guys.
And they actually did. It’s actually the first report of an increase based on an epigenetic age estimator of the Horvath clock and some other epigenetic clocks in predicted human lifespan. So they increase lifespan. Now they weren’t tweaking the diet, they actually were doing some supplement interventions along with human growth hormone. So HGH, Metformin, D, zinc and DHEA, and not a ton of these.
And incidentally, Josh blogged about this, folks. So if you hop over to his website, you can find this. He just published it on the 7th, so it’s a new blog. I just want to ask you this: one of the things that Longo looks at is obviously… The whole caloric restriction piece is modulating mTOR, but one of the classic ways to up-regulate mTOR is of course human growth hormone.
One of the things that we’re adopting in functional medicine more and more of us, especially as Longo’s work really kind of takes hold of our thinking these days is looking at IGF-1, measuring it and thinking about it in a U curve. You don’t want too much, you don’t want too little. Generally speaking, we’re probably erring on the side of more IGF-1 I think. And we want to drop it down. In fact, I look at my own and mine was kind of on the high side until I reduced significantly the amount of animal meat that I was consuming. But I mean at a glance this study, which slowed the hands of time and caloric restriction sort of seem at odds.
Dr. Josh Mitteldorf: There’s so many things I want to say about this study. I’m just going to list some of them and then we’ll go back and talk about them in more detail. One is that it’s the interaction among all these things probably that’s having the benefit. Two, we don’t even know that the growth hormone was an essential ingredient in what produced the effect. That was Fahy’s idea going into it, but we only have these nine people-
Dr. Kara Fitzgerald: Yeah, very small.
Dr. Josh Mitteldorf: … and they had all five of these supplements, so we don’t know what combination of them was responsible for the effect. Another point to emphasize is that this is all dependent on the methylation clocks. And there’s still controversy about whether the methylation clocks really measure your biological age, whether setting the methylation clock back is doing your body a favor. Some people in my field would say setting the methylation clock back is actually hurting you because, gee, the body becomes damaged with age and maybe methylation changes are a response of the body to try to cope with the damage that accumulates with age. So that’s an essential conflict within the anti-aging community. And I come down firmly on the side of yes, set back the clock. And the mainstream I think is on the other side. If we interfere with the body’s clock, then we’re just making things worse for ourselves.
Dr. Kara Fitzgerald: I got what you’re saying. Yeah. I have definitely read that you want to shut down. If you hyper-methylate certain genes and shut them down, which we do as we age, aging globally is this hypo-methylation process. But then there’s these certain regions that are hyper-methylated and inhibited. And if we unlock those, if we open those back up using phase protocol or caloric restriction probably in some of the other things that we might actually be increasing risk of certain diseases.
And yeah, so there’s the camp that says we should just let sleeping dogs lie and let things become hypermethylated as we age, or those certain regions, but yeah, I’m with you. I think there’s enough evidence to suggest that we want to have re-expression of hypermethylated genes to exert a protective effect. I guess that’s the camp I’m lying on, yeah.
Dr. Josh Mitteldorf: I’m on the other side. I’m saying that the aging clock is a source of aging and if we set back the aging clock, we’re actually making the body younger.
Dr. Kara Fitzgerald: Yes, no. Yes, that’s what I am saying, too.
Dr. Josh Mitteldorf: Growth hormone and IGF-1, we should note here firmly that there’s powerful evidence that IGF-1 accelerates aging, that animals that have no growth hormone receptor, humans, Laron dwarfs who have a mutation for low growth hormone or no growth hormone, they grow up as dwarfs, but they’re healthier. They never get cancer and they live longer. It’s counterintuitive that growth hormone can have a beneficial effect. The jury is still out. We need a lot more experiments than nine people to know whether growth hormone in a short course can actually have an anti-aging affect.
Dr. Kara Fitzgerald: Yeah, that’s right. And they didn’t have a control group, so we don’t know. As far as I read, I mean. Did they have some sort of small control group? They didn’t…
Dr. Josh Mitteldorf: Faye believed, and I would argue he’s right, that the control group is everybody else who’s calibrated the-
Dr. Kara Fitzgerald: Oh, the clock?
Dr. Josh Mitteldorf: The methylation clock.
Dr. Kara Fitzgerald: Yeah.
Dr. Josh Mitteldorf: Those serve as controls, and the comparison that he makes, he’s not looking at people’s methylation age at the end of the period, but he’s looking at the difference between age at the beginning and at the end of the study. And remarkably, a year passed, you’d expect that the methylation clock would advance one year. And, in fact, the average of these nine people, the methylation clock went backwards a year and a half, so it’s two and a half years behind where you would expect it to be. And these are people who were already doing a lot of things. They’re Greg’s friends, so were already well-informed about anti-aging protocols, were already doing things to try to keep young. And perhaps not surprisingly, the nine people in the study were already retarded in the methylation clocks going into the study.
Dr. Kara Fitzgerald: Yeah, significantly.
Dr. Josh Mitteldorf: And they were two and a half years more retarded by the time the study was over.
Dr. Kara Fitzgerald: Yeah, it’s really, really impressive. It is true. Some of the clocks, they looked at a few of them and some of them, like the Levine clock, I think there were, what, 17 years behind?
Dr. Josh Mitteldorf: Yeah. And it’s hard to know what sense to make of that.
Dr. Kara Fitzgerald: Yeah.
Dr. Josh Mitteldorf: So, on the one hand, yeah, this is really intriguing. On the other hand, this is nine people. What can we learn from nine people except that we need to study more?
Dr. Kara Fitzgerald: Right. Right. And these nine people, since they’re already healthy, they’re his friends, as you said there, so they’re probably practicing some caloric restriction already, they’ve already got some of these interventions in the mix, and then they layered in these additional pieces?
Dr. Josh Mitteldorf: I don’t have knowledge of that, and it’s not in the study.
Dr. Kara Fitzgerald: It’s not. Okay. All right, so let’s talk about moving beyond caloric restriction or a fasting mimicking diet, and again, I’m excited to look at your ProLon hack and see what recipes you’ve got there. What kind of supplements or medications? Now, in the Faye study, they were using human growth hormone and they did 500 milligrams a day of Metformin in addition to D, zinc, and DHEA, what kind of supplements are you thinking are relatively key?
Dr. Josh Mitteldorf: So the best documented is aspirin. It’s a simple anti-inflammatory. It’s cheap, it’s really well-studied, and you can probably get a year or two of extra lifespan out of it as well as decreasing your risk of cancer, certain cancers and of heart disease.
Dr. Kara Fitzgerald: A baby aspirin?
Dr. Josh Mitteldorf: The studies show that there’s no difference between small and medium doses of aspirin. I take a full aspirin every night before I go to bed. I actually find that I notice the anti-inflammation when I’m recovering from exercise and in my stiffness doing yoga. One of the hats I wear is I’m a yoga teacher. I was doing yoga a long, long time ago and I’ve been teaching yoga at the rate of one class a week for 40 years.
Dr. Kara Fitzgerald: Good for you. Okay, so aspirin?
Dr. Josh Mitteldorf: So aspirin is certainly on the top of the list of anti-aging supplements. Vitamin D is also well established. There’s a minimum daily requirement, but gee, if you get 10 times that. I tell people to aim for a blood level in the range of 100.
Dr. Kara Fitzgerald: Oh, really high, okay.
Dr. Josh Mitteldorf: Optimal. And your doctor will tell you, “Yeah, you’re over 25 so you don’t have to worry about it.” Well, going up to 100 and maybe even past there, there’s evidence that you have better immune function and lower cancer risk. How much you have to take to get to a blood level of 100 varies greatly from one individual to the next so you should calibrate your intake not based on a set amount per day, but on how much it takes to get up to 100. For me, it takes a lot.
I found out much later through 23 and Me that indeed I have a genetic SNP that makes it harder for me to metabolize vitamin D, and so maybe I’m not too surprised that I find it takes 20 to 30,000 IU a day to get me up in the range around 100 where I want to be. Magnesium is another really easy supplement. Most of us are getting suboptimal amounts of magnesium. It’s dirt cheap. Well, that’s funny, it’s a component of the dirt all around us. More controversial, there’s Metformin, which has been well studied as an anti-diabetic drug, but statistics from large numbers of people taking Metformin indicate they have lower cancer rates overall and now Metformin is being studied as an anti-aging drug.
Dr. Kara Fitzgerald: Well, let me just ask you, before you go into Metformin.
Dr. Josh Mitteldorf: Sure.
Dr. Kara Fitzgerald: I want to know, any concerns about excess D and maybe some immunosuppressive effects, I mean, some of the negative conversation around very high dose D?
Dr. Josh Mitteldorf: You know more about that than I do.
Dr. Kara Fitzgerald: Okay.
Dr. Josh Mitteldorf: And I’m reluctant to comment. The only thing I know is that it affects the calcium metabolism at high levels and that it should be taken with vitamin K in addition.
Dr. Kara Fitzgerald: Okay. Okay. And then I wanted to just ask you one other thing, if you’ve thought about it at all. So aspirin, we know, can either inhibit Cox, cyclooxygenase, and that’s probably its anticancer effects, it’s inhibiting inflammation, it’s pretty amazing and effective at that, but we know that very low dose. So have you thought about resolvents or pro-resolving lipid mediators? Has that been something that’s crossed your path at all?
Dr. Josh Mitteldorf: No.
Dr. Kara Fitzgerald: Okay.
Dr. Josh Mitteldorf: Not on my radar screen, I’m sorry.
Dr. Kara Fitzgerald: That’s okay, no problem. There’s just interesting research out there, just a whole area of very cool science, that inflammation is actually a failure of resolution. So cleaning up, turning the info, programmed cessation of inflammations. And the way that we do this, interestingly, is through production in the immune cells, not of arachidonic acid and the pro-inflammatory fatty acids that go in and make prostaglandins and so forth. They make all the pro-inflammatory signals that aspirin inhibits. But in that same cell, sort of after the whole eicosanoid cascade has been turned on and inflammation has been turned on, there’s a signal to turn it off in a second pathway, turning on these, what they call non-classic eicosanoid production or AKA resolvents.
And aspirin and lower dose aspirin can actually potentiate resolution, the production of these compounds that clean things up, whereas higher dose aspirin can actually inhibit production of these. And they’ve also looked at nonsteroidal anti-inflammatories. So there’s like a class switch from pro-inflammatory eicosanoids to these cleanup non-classic eicosanoids, and it’s just extremely fascinating. So I think one of the reasons aspirin has some nice anti-aging qualities behind it is because of its ability to potentiate resolution. However, that said, there is some suggestion that too much, too high a dose of aspirin, will actually inhibit resolution. So that’s why I wanted to get your thoughts on it.
Dr. Josh Mitteldorf: I’m learning from you on this one and I’m really happy to learn from you. I will look it up and hope that you’ll send me more to read.
Dr. Kara Fitzgerald: I will, yeah.
Dr. Josh Mitteldorf: Low-dose versus high-dose aspirin. And I should note for your listeners that, of course, this connects into Omega-3s as an anti-inflammatory strategy.
Dr. Kara Fitzgerald: Well, does. It does, yes. Thank you. Because the resolvents, and there’s this whole class of compounds that clean things up and are coming from, by and large, Omega-3s, but arachidonic acid itself, sort of the key pro-inflammatory fatty acid, the so-called bad guy, actually has some of these clean-up molecules as well. And there’s a switch process, lipoxen comes from arachidonic acid and turns on that whole anti-inflammatory journey and that’s sort of the first one.
And then the omega 3s kick in and start producing theirs. There’s more and more science. It’s actually, Charles Serhan kind of identified these and has been doing the bulk of the research and supporting other labs who are taking it on. But really, really interesting stuff. So that I think might be one of the pieces why aspirin works. And then you mentioned, let’s see, where were we? Metformin.
Dr. Josh Mitteldorf: So I’ll step back here and tell a story about insulin and what’s the evolutionary history of insulin? We think of insulin is something in our pancreas that regulates blood sugar, deposition of fat versus burning it, but insulin is actually very old. The story is that it was the early 1990s Cynthia Kenyon was experimenting with worms and discovered a genetic defect in the worms. This isn’t some genetic add on. This is a defective gene for, it’s called daf-2. That makes the worms live twice as long, twice as long with a defective daf-2 gene compared to a wild type worms.
So of course, the next question is, what is daf-2? Daf-2 is the worms insulin receptor? And then you ask, well, worms have insulin? They don’t have blood, they don’t have blood sugar, why do worms have insulin? And what do they do with it? Insulin is an ancient mechanism for regulating lifespan. The more insulin, the shorter the lifespan, and this goes way back after Kenyon’s work. It was studied in yeast, even yeast cells long before there was a pancreas long before there was multicellular life, yeast cells are regulating their lifespan according to how much nutrition they’re receiving and the signal to do that is their version of insulin.
Dr. Kara Fitzgerald: So lots of insulin, shorter lifespan.
Dr. Josh Mitteldorf: Yes.
Dr. Kara Fitzgerald: That’s so fascinating.
Dr. Josh Mitteldorf: Metformin has been used as the go-to medication for diabetics for over 60 years now. There are tens of millions of people. There’s lots and lots of data on Metformin. So it was just 20 years ago that it was noticed for the first time that, gee, these people who have been on Metformin for a long time have lower cancer rates. They have not only lower cancer rates than other diabetics who aren’t taking Metformin. They have lower cancer rates than non-diabetics. Well, what’s with that? It’s suggestive of evidence that Metformin is affecting aging at some low level and that fits in with this insulin story. The less insulin the longer you live, if the body is programmed for a certain lifespan, Metformin talks to that program through the insulin levels in the body. Nir Barzilai, a colleague at Einstein in New York has been trying to raise funds for a study of Metformin as and anti-aging drug for five years now.
He’s trying to gather enough funds to do it. It may be that by the time the study is completed, 15 or 20 years from now where we’re well-advanced from that era, we understand Metformin’s action and his primary goal is to get the FDA to recognize that aging is a disease and the drugs that treat aging should be licensed by the FDA. It’s a political battle really that he’s… with the study and again it’s long overdue, but whether his strategy is going to be the thing that turns them around or whether they’ll be turned around long before the 20 years that it takes them to do the study. I can’t predict
Dr. Kara Fitzgerald: What else. Any other supplements or pharmaceutical?
Dr. Josh Mitteldorf: Yeah, I’m hesitant to recommend Rapamycin.
Dr. Kara Fitzgerald: I was going to ask you about that. Yeah, mm-hmm (affirmative).
Dr. Josh Mitteldorf: So all the other things that I say, the straight medical community will tell you pretty much the same thing that I’m saying. Rapamycin is recognized as a dangerous drug and we should take it only under careful medical supervision and only if you need it to suppress the immune system. But the fact is that Rapamycin is the best anti-aging remedy that we have for rodents. It really has effects for rodents better than anything else except caloric restriction. I think the landmark study was five years ago when they found that a single dose of Rapamycin at middle-age could extend the mouse lifespan by 20%.
It’s a spectacular result which has been replicated and more details have been added ever since. And there are lots of humans out there, some of whom subscribe to my blog who are saying, I’m not waiting for the data to come in, I’m experimenting on myself. And there are doctors who will support you in this and prescribe Rapamycin as an anti-aging regimen. And we don’t have data in humans, but there’s reason to believe that it may be the most powerful intervention we’ve got.
Dr. Kara Fitzgerald: You know, I mentioned this before in your bio and we have a link to it on the show notes, but this study that you’re doing, which is a survey of various antiaging interventions, will be looking at folks on Rapamycin, some of them I’m sure. Right? Do you expect that to be in there?
Dr. Josh Mitteldorf: I sure hope so. So can I take a couple of minutes to describe the study?
Dr. Kara Fitzgerald: Yep.
Dr. Josh Mitteldorf: It’s called data-beta for database for epigenetic evaluation of treatments for aging. And it’s data-beta.net is the website of the program. The vision that’s excited me is to recruit 5,000 people from a diverse cross section of people who are trying to lengthen their life with diet, with exercise, with supplements, and to use methylation clocks to evaluate what is working. My hunch is that no single thing that we’re doing is going to have a dramatic effect on methylation age, but we have just begun to study the interactions.
We know almost nothing about the interactions among these different supplements and lifestyle changes. Most of the interventions act on just a few pathways, so the interaction that we expect most often is redundancy, you take Metformin and you take berberine. Well they’re acting on the same pathway. They’re doing pretty much the same thing. You don’t expect that the life extension that you get from one will add to the next. There are combinations and maybe Faye and his recent study has found some of them. There are combinations that are synergistic, meaning one plus one equals three meaning that you get more life extension from combining two or three interventions in just the right amounts. Then you would expect to get from adding up the individual benefits.
Dr. Kara Fitzgerald: Are you, so how would somebody sign up as a participant?
Dr. Josh Mitteldorf: I’m hoping to start accepting people into the study within the next few months.
Dr. Kara Fitzgerald: Okay.
Dr. Josh Mitteldorf: I’ve got seed funding, I’m looking for collaborators to work with and when that gets resolved then we’ll start to accept people into the program.
Dr. Kara Fitzgerald: Okay. And I would imagine if anybody’s interested in, I mean, who are the collaborators? Other scientists, are you wanting clinicians, I mean is there anyone who might be listening to this podcast who would fit that bill or do you already have that piece kind of managed?
Dr. Josh Mitteldorf: What I most need is somebody with experience keeping track of thousands of experimental subjects, keeping in touch with them, keeping a database. The IRB requirements, the privacy requirements and all that. I know nothing about that stuff. And it’s going to be essential to have somebody who has experience running clinical trials. It’s not a clinical trial in the sense that we’re not telling people to do anything different. We’re just asking them a detailed questionnaire about what they’re already doing, and we’ll do that periodically to see if maybe they’re changing along the way, but we’re evaluating what people are already doing, not telling them to do something different.
Dr. Kara Fitzgerald: And then you’re going to be getting one of the epigenetic clocks at periodic time points.
Dr. Josh Mitteldorf: Once you take people’s methylation profile, you’ve got all the methylation clocks past and future at your disposal. A methylation clock is just an algorithm that you run as a mathematical treatment for all these methylation levels. So we can calculate all of the methylation clocks and if somebody invents a better clock next year, which they certainly will, we’ll use that one.
Dr. Kara Fitzgerald: Oh, so you’re getting, you’re basically getting their full methylome done.
Dr. Josh Mitteldorf: Yes.
Dr. Kara Fitzgerald: Okay. I got, I understand. Okay.
Dr. Josh Mitteldorf: This is 150,000 sites
Dr. Kara Fitzgerald: Yep.
Dr. Josh Mitteldorf: … Illumina array.
Dr. Kara Fitzgerald: You’re using the same array that we use, the Epic.
Dr. Josh Mitteldorf: Yeah.
Dr. Kara Fitzgerald: Okay, got it. Yep. Okay. Yeah. You’ll have a lot of, you’ve got a lot of data there. All right. So I just want to go back to Rapamycin. Well, I have two questions from what you just said. One, do you have any hunches around synergistic combinations?
Dr. Josh Mitteldorf: People say that Rapamycin puts you in high insulin mode, and there’s some evidence that Rapamycin and Metformin is a synergistic combination.
Dr. Kara Fitzgerald: Yeah, go ahead, sorry.
Dr. Josh Mitteldorf: It’s really unexplored territory, and I’ve played a role in pointing out that we know nothing about these interactions, except that they’re very important and unstudied. I really am reluctant to say more than that about it and you and your listeners are probably better positioned than I am. You have to know something about biochemistry to say what you expect the interactions to be, and I’m a mathematician here and once we have the data, how the interactions work, my job will be to extract that, but to theorize in advance, I’ll leave that to you.
Dr. Kara Fitzgerald: Mm, okay. Got it. Well, let me ask you about natural mimetics for the folks who don’t want to jump on rapamycin.
Dr. Josh Mitteldorf: There are natural substitutes for metformin that I know of, including Jiaogulan, it’s a Chinese herbs sold by Life Extension Foundation, I think under the name AMPK Activator. There’s berberine, which I mentioned, which there’s a small amount of data, but it looks really good and I think there were a couple more that I mentioned on my blog. If you go to the blog and then search in the upper right hand corner, search for can botanicals replace metformin, can botanicals replace metformin. I blogged about that a few years ago and I don’t know of alternatives to rapamycin. Rapamycin inhibits the target of rapamycin, mTOR, which was of course discovered after rapamycin was discovered and named for the drug. I don’t know that we have anything that affects mTOR to that degree as rapamycin, but that may be my ignorance.
Dr. Kara Fitzgerald: So listen, we unfortunately… I’d love to continue to pick your brain, but we have to head towards close. I want to ask you about in your bio… Yeah, you’re up to a lot of stuff in your life. In fact, when you and I first met, for some reason, I had just mentioned I was on my bike. I don’t know, maybe because I was late. I don’t know why I felt like I had to pop that in an email to you, but then you were on your bike as well and you were taking your horn downtown to go play in an orchestra and you’re doing yoga and you’re writing poetry. I mean, you’re really living a pretty full life. Is this a part of your anti-aging strategy?
Dr. Josh Mitteldorf: Well, I could say it’s a privilege to live the way that I live. I’m not rich, but I have just a little money in the family, enough so that I don’t have to be dependent on a salary. And I’ve used this, as you say, to expand my interests and do whatever I damn please. And it’s a very rewarding way to live, to be in touch with science, with mysticism, with philosophy, with literature, music and yoga, these are all big parts of my life and it’s a privilege to get to live this way.
Dr. Kara Fitzgerald: Will you capture those pieces in your study? Will you look at people’s lifestyle habits, hobbies, interests, and so forth-
Dr. Josh Mitteldorf: Some.
Dr. Kara Fitzgerald: … as a variable?
Dr. Josh Mitteldorf: We should all take notice that the most powerful way to extend your lifespan is by being well connected to your family, having loving relationships, being an outspoken voice in your community, having cooperative relationships with others, having a job where you really feel like you’re contributing something and you’re appreciated. These kinds of things, we think of them as soft data, but they’re good for 10 years and all the other things that I’ve been talking about in epidemiological studies, they’re a year or two.
Dr. Kara Fitzgerald: So this would be the rapamycin memetic, getting out there in your community?
Dr. Josh Mitteldorf: I don’t know. I don’t know the mechanism, but I do know that it has benefits for now and it definitely has benefits for your health and for your longevity. Have loving relationships with the people that you’re close to, meditate, be connected to your community, doing things that you think are worthwhile and that are fulfilling to you. If you compare people that have these fulfilled and actuated lives to people who are depressed, the difference is more than 10 years in life expectancy, and that’s bigger than any other factor that we have documented.
Dr. Kara Fitzgerald: I think that’s kind of a lovely and rather inspirational place for us to wrap up, unless there’s something else that you wanted to end with? Any other big thought?
Dr. Josh Mitteldorf: Thank you for access to your audience and I look forward to people who want to write to me or connect on any of the things that I’ve talked about. I’m really grateful to have had this conversation with you and to be connected with your community.
Dr. Kara Fitzgerald: Aw, well hey, we welcome you with open arms, Josh. I think this will be a synergistic interaction. I think bringing your brain here will be helpful to functional medicine.
Dr. Josh Mitteldorf: I’ve already learned a lot from you.
Dr. Kara Fitzgerald: Thanks. Thanks for joining.
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