The Peter Attia Drive - #123 - Joan Mannick, M.D. & Nir Barzilai, M.D.： Rapamycin and metformin—longevity, immune enhancement, and COVID-19

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.720 head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.740 here's today's episode. My guests this week are doctors, Joan Manik and Nir Barsly. Joan is the

00:00:56.740 co-founder and chief medical officer of Restore Bio, and that's a play on the word TOR, T-O-R,

00:01:03.280 target of rapamycin. Before joining Restore Bio, she was the executive director in the new

00:01:09.280 indications discovery unit of Novartis, which we discussed early on in this podcast. She's an MD

00:01:15.500 by training or receiving her MD from Harvard Medical School, completing her residency in internal

00:01:19.760 medicine and infectious diseases at the Brigham and Women's Hospital. Nir Barsly is making his second

00:01:25.500 appearance on the podcast, so that name may sound familiar to a number of you. He is the director

00:01:31.220 of the Institute for Aging Research at Albert Einstein College of Medicine in New York. He has

00:01:37.180 spearheaded one of the most impressive longevity gene projects, which basically looked at more than

00:01:43.000 500 healthy people aged 95 to north of 110, along with following their offspring, the centenarian

00:01:51.920 studies and the centenarian offspring study. Nir also has a brand new book that just came out,

00:01:57.020 oh, at the time of this recording, probably a week before. It's called Age Later, Healthspan,

00:02:02.420 Lifespan, and the New Science of Longevity. We get into a couple of funny stories about that.

00:02:06.960 Okay, this episode is one I've been looking forward to for a very long time because we discuss the two

00:02:12.960 drugs I get asked about more than all other drugs combined, namely metformin and rapamycin,

00:02:19.400 or the category of analogs to rapamycin known as rapalogs. Now, the reason we decided to do this

00:02:27.460 as a podcast with both Nir and Joan as guests was because, of course, there were many overlaps

00:02:32.680 between rapamycin and metformin, not just in terms of longevity, but also of recent note,

00:02:38.580 their potential for reducing the risk of SARS-CoV-2 infection or other infections,

00:02:44.840 and of course, COVID-19 morbidity. And we speculate on those things to a great deal. So basically,

00:02:50.980 the way this podcast goes is I want to make sure everybody has the appropriate background

00:02:54.120 information on metformin and rapamycin. So coming into this episode, you don't have to know anything

00:02:58.200 about those two drugs. If you do, I think you'll follow it a little bit better because these are

00:03:03.300 technical. And of course, the show notes will have all of the pictures and images and things that make

00:03:08.460 it a little easier to follow this. But you can come into this not knowing a lot about them,

00:03:12.140 though we have had many previous podcasts that discuss these things. And then we get into kind

00:03:17.260 of the clinical indications that focus specifically around this issue of how would these drugs factor

00:03:24.400 into the immune response, resilience, and the amelioration of a hyperactive immune response in

00:03:31.360 the presence of these diseases. So without further delay, please enjoy my conversation today with Joan and Nir.

00:03:42.140 Joan, this is a first for me. And it is also very exciting. It's a first in that it's the first time I have

00:03:49.720 interviewed two people virtually simultaneously. It is also incredibly exciting because I am just such a fan

00:03:57.260 of your work, Joan, and obviously yours, Nir. Nir, you've been a guest on this podcast before. And Joan, I have

00:04:05.140 been eagerly looking forward to having you on for probably since the moment the podcast released. So

00:04:11.600 I'm grateful to both of you for making the time. And then of course, to do this together

00:04:15.800 is something that I've been a little nervous about for the past month, because I've been thinking,

00:04:21.300 how do I integrate the stories of rapamycin and metformin? How do I integrate the stories of

00:04:26.100 these two incredible compounds that in their most native form came to us naturally? And then of course,

00:04:32.420 we now have evolved elaborate synthetic versions of these things that have these sort of magical

00:04:36.980 properties. So I have an idea for how these two can overlap. But before we do that, I think we

00:04:43.400 should assume that maybe the listener is not familiar with you, Joan, and even you, Nir, though

00:04:48.600 you've been on before. And maybe just help us understand a little bit about what you do, Joan. I know

00:04:52.880 you're a physician by training, and you're also one of the world's experts on my favorite molecule. So

00:04:57.960 help us understand how you got to be doing what you're doing. Sure. So I was actually started my

00:05:04.500 career in academic medicine. I trained in infectious disease and ran a basic science lab. But in my basic

00:05:12.020 science lab, I happened to read some papers by Cynthia Kenyon that were sort of transformative for me.

00:05:19.400 And I remember reading a review piece from Cynthia where she said the genetic mutations in worms that

00:05:29.740 cause doubling of lifespan show that organisms have the capacity to live longer than they normally do.

00:05:38.540 And I just thought that was the coolest piece of research and the coolest idea that sort of threw

00:05:45.100 medicine on its head. And so I started to do a little bit of aging research in my lab, but eventually

00:05:51.700 ended up at Novartis in a group called the New Indications Discovery Unit. And you heard a little

00:05:58.820 bit of this from Lloyd Klickstein, but it's a unit of Novartis where they tackle areas of drug development

00:06:05.960 that fall in between traditional big pharma silos. So when I got there, they said, what would you like to

00:06:13.920 work on? And I said, I want to work on aging. And when I first said this, I was told, we understand

00:06:21.720 that makes sense, but everyone's going to think you're wacky. So you have to pick a different area.

00:06:26.740 And I was really disappointed. But a few months after I got there, the CEO at the time, who was Dan

00:06:33.800 Vasella and the head of research, who was Mark Fishman, decided they thought Novartis should work on

00:06:39.560 aging. What year was this, Joan? This must have been 2012. Lloyd, who was my boss at the time,

00:06:47.440 said, Joan wants to work on aging. So they said, okay, Joan, go do something in aging. We just had

00:06:54.360 this blank slate of saying, do something in a clinical trial that is targeting aging biology,

00:07:02.140 and you get to pick what you want to do. So Novartis had a rapamycin analog, and there was a lot of data

00:07:09.840 that mTOR inhibitors have beneficial effects on aging and lifespan. So I decided I would take our

00:07:16.680 rapamycin analog. And I thought an organ system whose function I can change in a relatively short

00:07:23.780 period of time is immune function. So I decided, let's do a trial and see if we give older adults

00:07:30.400 an mTOR inhibitor. Can we make their immune function better? And the readout was a vaccine,

00:07:38.140 the response to a flu vaccine. So that was the beginning.

00:07:42.180 A couple of questions going back. I know your father was one of maybe six or seven people to

00:07:48.740 hold one of the most prestigious chairmanships in all of American surgery, John Manik, at the Brigham

00:07:55.000 and Women's Hospital. And you, of course, trained at the Brigham as well, correct?

00:07:58.720 Yes. What was your father's response to this career change? Which, in effect, it sort of was,

00:08:05.620 right? Which was, you're trained as an infectious disease doctor at a very prestigious, you know,

00:08:09.940 one of the most prestigious academic institutions in the world. And not only are you leaving academia

00:08:15.000 to go into industry, but you're also making what sounds like a very rash change in your focus.

00:08:22.660 Was that something you discussed with him? And if so, what were his thoughts?

00:08:25.160 I did. Everybody in my family was in academic medicine. But as you know, academic medicine has

00:08:33.060 changed a lot. And I was thinking, am I going to spend the rest of my life in academia? Or do I want

00:08:39.620 to do something else? And I had some friends who had left and gone into biotech and told me how much

00:08:47.080 fun it was. And so I was starting to get calls by recruiters. And I asked my dad, I said,

00:08:52.420 you know, should I do this? Should I leave? And he said, I was 50 at the time. And he said, Joan,

00:08:59.520 at age 50, this is the last time you have to really try something new with your career.

00:09:04.460 So go for it. Academic medicine isn't what it used to be. This is like an exciting thing you can try.

00:09:11.680 And so he was supportive. It was interesting. That's fantastic. The other question I wanted

00:09:16.640 to ask you going back to your first attempt at studying a rapamycin analog was you chose to go

00:09:23.780 after something that, as you said, could be modified in short order, which is the immune system. But of

00:09:28.000 course, as you knew very well, and we'll explain to the listener, the clinical application for rapamycin

00:09:35.900 was of course, immune suppression. So what made you think that you could actually use the same drug

00:09:45.060 whose clinical indication was to suppress the immune system in a transplant patient to do the

00:09:51.180 opposite, which was to enhance the response to vaccine? Novartis asked me the same question. I

00:09:57.220 remember presenting this proposal to the committee that approves trials and I go, why are you doing this?

00:10:05.000 Why are you taking the drug that we sell to suppress the immune system and think it's going to enhance

00:10:11.820 it? It was because of all the data that mTOR inhibition has beneficial effects on aging and every

00:10:20.100 organism tested. And so I said, someone's just got to do the trial in humans and see if this is true in

00:10:28.980 humans. And we're going to dose this really carefully to minimize any side effects. And either it's

00:10:34.920 going to work or it's going to turn out, none of this translates to humans, but we got to just

00:10:40.680 sort of have the guts to try it. So that's what we did.

00:10:45.760 Joan, I think it's interesting the way you frame that, which is, look, we had in 2012, at least

00:10:52.520 three or four years of very good evidence that rapamycin could be beneficial to extend lifespan

00:10:59.020 through the ITPs. So the interventions testing programs run through NIH. There had been several

00:11:06.260 indications either directly through administration of rapamycin or indirectly through genetic inhibition

00:11:13.320 of mTOR that you could extend the life of yeast, worms, flies, and mice. But of course you can't do a

00:11:21.900 lifespan extension study in humans. So your study that would be published in 2014, which any listener

00:11:29.380 of this podcast knows and has heard me refer to as the manic study, the 2014 Christmas gift we all got,

00:11:36.600 I still remember getting my embargoed copy of the day before Christmas. That was a very important paper.

00:11:42.660 And again, I still applaud you for the nerve because it's one thing to say the following,

00:11:51.080 we have reason to believe this could extend life on average. It's quite another thing to say it still

00:11:57.100 enhances immune function. In other words, there's a scenario under which rapamycin did extend life

00:12:02.800 across all those species and would extend life in a human on average, but still impairs the adaptive

00:12:11.120 immune system so that a subset of humans are actually dying sooner due to overwhelming immune

00:12:17.780 compromise. While on average, people are going to get cancer later or dementia later, et cetera.

00:12:23.340 In retrospect, it worked out pretty remarkably that the thing you chose to go after, which was in many

00:12:28.020 ways the riskiest thing to look at, turned out to work. Was that something that you noodled at the time?

00:12:34.680 You sort of had to have the stomach to do it. And I really wanted to do no harm to these

00:12:39.860 older people who were very bravely entering the trial, but you don't know till you do the trial

00:12:47.500 how it's going to work out. And I tried my best to, again, dose very lower intermittent dosing that

00:12:53.600 wouldn't be likely to be sufficient to immunosuppress because figuring the only dose that will ever move

00:13:01.740 forward is one that is low enough that it's safe and that it doesn't immunosuppress.

00:13:06.420 And there had been data in mice, older mice given and rapamycin that vaccination response was

00:13:13.340 improved. So I just said, someone's got to do this and see if this translates because if it does,

00:13:19.640 it will be the start of really being able to move medicine in new, important paths forward.

00:13:26.900 Now, Lloyd discussed the study in some detail, but just so that maybe someone who hasn't gone

00:13:32.820 back and listened to that, can you explain somewhat briefly, there were four arms in this study.

00:13:37.860 What were they dosed? What was the purpose of the dosing? How was it pulsed, et cetera? And what

00:13:42.680 were you measuring? And most of all, what did you learn from that study?

00:13:46.760 So we'd used very unusual dosing regimens of this rapamycin analog that we either dosed at a very low

00:13:55.080 dose once daily or once weekly. The reason we did this is we wanted to just partially inhibit mTOR,

00:14:03.580 not completely inhibit mTOR, because when you completely inhibit mTOR, you stop T cells from

00:14:09.460 proliferating and you'll get immunosuppressed. So these were chosen purposefully to limit the amount

00:14:17.040 of mTOR inhibition. And what we found is if you gave it one of these mTOR inhibitors for six weeks

00:14:24.720 and then gave people a two-week break and gave them a flu vaccination, they responded better to

00:14:29.920 the flu vaccination. What we found is the lower of the lowest two doses, either 0.5 milligrams once

00:14:37.120 daily of a varolimus or five milligrams once weekly were the best. And those gave less mTOR

00:14:44.040 inhibition than the highest dose, which was 20 milligrams weekly. What it looked like is just

00:14:48.980 turning mTOR down in the elderly, not turning it off, is the best for enhancing immune function.

00:14:56.640 So I'm going to hit pause on that for a moment. You mentioned the name of the drug,

00:15:00.320 avarolimus. It also went by another name, I believe, RAD001, correct?

00:15:04.560 Mm-hmm.

00:15:04.960 Okay. Let's bring metformin up to speed for folks so they now understand why would we want to talk about

00:15:12.440 these drugs together? And why are these the two drugs I get asked more questions about by my

00:15:18.500 patients than all other drugs combined? So Nir, take us back to the first time you started paying

00:15:28.040 attention to metformin outside of its normal clinical indication, which is of course an early

00:15:34.120 line treatment for patients with type 2 diabetes.

00:15:36.440 Serendipitous. When I came to the United States to do my first postdoc, which was at Yale with

00:15:44.800 Ralph DeFronzo, what I did that year was to find the mechanism of action of metformin. It wasn't in the

00:15:53.920 United States yet. Leafa Pharmaceutical just brought it in and commissioned some studies in order to show

00:16:01.520 that metformin works in the U.S. population as well, okay? Because we didn't accept anything,

00:16:07.000 still don't, from other populations. And my study was the first to show that metformin specifically

00:16:15.020 targets a hepatic glucose production rather than, or let's say the insulin sensitivity of the liver

00:16:24.600 rather than the muscle, although it's doing a little bit of both. So when I did that then, and we're talking

00:16:32.320 87, 88, I was actually doing aging there. I took people and did clamps, young and old people, but I never

00:16:39.500 thought that metformin is coming back. Metformin start coming back when all those data appeared, whether it was

00:16:48.560 with clinical studies or with association studies, that people on metformin in clinical studies will

00:16:56.860 not develop diabetes, the DPP, it will prevent diabetes, or in people with diabetes, it will prevent

00:17:02.960 cardiovascular disease, that's the UKPDS. The association studies with cancer, hundreds of studies

00:17:10.040 on cancers and all kinds of cancers, the association studies on Alzheimer's and also some clinical

00:17:18.420 studies on MCI. And the day that I knew we have to do that was when a paper from the UK underappreciated

00:17:30.420 that looked at almost 180 subjects in the United States into pharmaceuticals. And they looked at people

00:17:39.600 who were treated by the same doctors, some were diabetic and some were not, some were getting

00:17:46.240 sulfonylurea drugs, some metformin if they were diabetic, and controls for non-diabetic people.

00:17:54.100 The people on metformin who were diabetic, were more obese, had more diseases to start with,

00:18:01.720 had significantly less mortality. This kind of linked all of it together.

00:18:08.320 If metformin targets aging, which we kind of knew from animals, okay, it increased healthspan and

00:18:14.960 lifespan of animals, many animals, two weeks ago, killing fish, if you give killing fish metformin,

00:18:21.460 they live significantly longer. If you give it to all animals, they live longer, they live healthier.

00:18:26.700 And all of a sudden, we have everything. We have all age-related disease, clinical association

00:18:34.440 studies that would have mortality that just made metformin the perfect tool for us to push geroscience

00:18:43.200 ahead. I'm not as familiar with the metformin results in the ITP. I'm very familiar with all

00:18:48.560 of the RAPA studies. Did metformin show benefits in the ITP?

00:18:53.420 Complicated. And I get this a lot because there were, I think, 30 studies that I summarized in a paper

00:19:00.120 somewhere where we're giving metformin in many animals, increased lifespan. There are two stories.

00:19:08.120 So generally, people in ITP will say, no, we haven't shown. We haven't shown effect on metformin. But I

00:19:14.100 would say there are two exceptions. One is in male mice, ITP happens in three centers.

00:19:24.700 Explain to folks what the ITP is. We're going to link to it in the show notes because you're going

00:19:31.040 to explain why it's so rigorous. But they're in so many cohorts. I mean, I think cohort 12 will begin

00:19:36.940 to, we're going to start to see the results of cohort 12 this year. I follow the ITPs a little

00:19:41.820 more closely now than I used to because now they're looking at SGLT2 inhibitors and all sorts of other

00:19:46.340 really exciting drugs. But yeah, explain the rigor behind it and why people put a lot of weight into it.

00:19:51.300 Well, the interventional testing program was established in order to have like preclinical

00:19:58.960 multi-central studies of drugs that investigator could say without proving or without doing standard

00:20:07.600 studies would say this affects longevity. So the idea is you have a committee, you get the drug,

00:20:14.820 you have animals who are genetically heterogeneous because we want it to be aging and not genetic,

00:20:21.300 and they're giving in the same way in three different centers around the United States so

00:20:27.880 that we have a standard way to say yes or no. Those are two big caveats, right? I mean,

00:20:34.700 lots of times things will work in one lab and then they don't go on to work in other labs.

00:20:38.960 So that's an important bridge to cross. And as you said, I think the heterogeneity of the animals

00:20:45.600 also adds to the rigor because these models where we have mice that are homogeneous at each and every

00:20:53.000 loci, they are so genetically flawed that you run into trouble where they become so artificial in terms

00:20:59.780 of their model. Right. In the metformin study in males, in one center, they lived 10% longer.

00:21:08.060 In one, also 10, one was nine, one was 11 or something like that. In one center, it was 1% less. Okay. So,

00:21:19.740 you know, it's not significant. Although, by the way, there is a power for each study. There's a power

00:21:25.540 for each study to be significant because they're using 50 mice per arm. Wow.

00:21:30.220 The second point is when they added metformin to rapamycin, you could say, if you think metformin

00:21:39.700 has no effect. That was cohort seven. That was a nine-month intervention. Or they treated the

00:21:45.540 mice at nine months with metformin and rapa together. The nice thing of being young like you

00:21:50.900 is that you recall those numbers. They're seven, 11. That's the longest living animals,

00:21:59.120 I think so far in this ITP, they live 24% longer. Okay.

00:22:05.060 Right. And the rapa solo, which Joan is pretty impressive as well, was I believe 16% and 9%

00:22:12.760 by gender. Right. And I should add, it wasn't studied at the same time. Okay. So you can say

00:22:19.740 there's a cohort effect. There are people in the ITP. So that's what I want to warn people

00:22:25.200 against. Is the implication that two of the arms showed effectively a 10% increase in the lifespan

00:22:32.300 with metformin and one showed effectively no change. Are you saying it's possible there were

00:22:37.040 methodologic errors in the third site that again, if you had done it across 50 sites, which as a

00:22:44.120 purpose of a thought experiment, it might have shown a benefit, but three sites with one goes wrong.

00:22:50.580 I want to make a bigger comment. Maybe yes. I want to make a bigger comment. It's a little

00:22:57.300 bit too late to discuss mice now, right? Because we have all those data in humans. I think we have

00:23:04.760 to be careful with the ITP because it's possible that for example, in humans, metformin will have

00:23:12.060 better effects than in mice. Mice might have less effect in mice. So I don't think it's of the

00:23:19.780 interest of anyone to start saying, you know, some of the investors say, you know, we're not

00:23:25.140 impressed with metformin. I understand that there are other studies that total have shown that there's

00:23:31.740 other animal studies that have shown that there are model studies that have shown it, but who cares?

00:23:38.160 Yeah. Your point is, which I think is a great point, Nir, we probably have more than enough

00:23:44.020 information of the power of this intervention in humans that it's a little bit of the tail wagging

00:23:50.320 the dog if we're going to get wound up about which strain of mice does better on metformin or not.

00:23:55.740 And obviously, Joan, I think we're long past that point as well. And frankly, I think that's where

00:24:02.280 the focus of the ITPs are moving to other more novel compounds. They're looking at nicotinamide

00:24:07.820 riboside. They're looking at SGLT2 inhibitors. They're looking at Acrobose, which actually looked

00:24:13.880 like it did have a positive effect. So let's continue with the story, which is, and I remember

00:24:18.620 the paper, of course, you're talking about because it's one that people still often reference, which

00:24:23.500 is how is it possible that a cohort of patients with type 2 diabetes and all of the associated

00:24:29.740 microvascular damage that would come from the hyperglycemia, the macrovascular damage that's

00:24:36.660 accompanied by the hyperinsulinemia. I mean, the deck is really stacked against this patient.

00:24:41.620 And yet somehow, if you give them metformin and compare them to someone who has better

00:24:45.460 glycemic control, presumably less hyperinsulinemia, they somehow live longer. I mean, it shouldn't be.

00:24:52.120 Right. So I want to pass forward to 2020 because we published a cell metabolism paper. The figure is

00:25:00.840 open in front of me. But I want to make sense of what we try to do and go back to aging. You know,

00:25:08.340 we geroscientists kind of agree that there are hallmarks of aging and we kind of agree on the

00:25:14.640 hallmarks. We call them sometimes different. Some people say seven and some people say nine. Okay.

00:25:20.420 And the hallmarks are very important, mainly because once we had the hallmarks, biotechs started forming

00:25:30.380 because all of a sudden there were targets. Not only did we have the hallmarks, the hallmarks were

00:25:36.800 interacting. You don't have, you can target one hallmark and you affect the others. You can change

00:25:42.740 autophagy and improve insulin action and mitochondria function. Right. So we have these hallmarks and

00:25:50.100 in this paper, we try to do something very simple. We try to say, let's look at the mechanism of

00:25:55.780 action of metformin, the papers that were published, and let's see which hallmark exactly

00:26:02.240 metformin is hitting. And this was the great surprise. And I'll tell you the surprise and I tell you

00:26:10.800 my interpretation, but the bottom line is there's evidence that metformin hits every one of those

00:26:19.220 hallmarks. And you have a big figure there with the hallmarks on the bottom, the mechanisms of action

00:26:25.320 and all the papers that show, yeah, it does that. It does that. It does every one of them.

00:26:30.680 We're going to include that near in the show notes. It's a great figure. And we actually,

00:26:34.440 I believe included it from our first discussion, but it's so important that it is worth going through.

00:26:40.020 Do you want to maybe talk about what you think are the three most important of the mechanisms that

00:26:46.620 metformin targets? And Joan, I'm going to really ask you the same question in a moment.

00:26:51.340 What do you think are the three or four most important of those pillars or hallmarks that

00:26:56.780 RAPA or RAPA logs are targeting? Because I think these are very important for people to understand

00:27:02.120 where these drugs work and how. I'll tell you that, but just before I'm telling you that,

00:27:07.340 I want to tell you that I don't believe for a second that metformin independently targets all

00:27:14.900 of them. And I think that's what we should note. Metformin, let's say on the cellular level,

00:27:21.980 it fixes aging. Okay. Once it fixes aging, a lot of things improve. Okay. Maybe the fact that

00:27:30.060 insulin levels go down doesn't have to do only with metformin effect on glucose, but because

00:27:36.620 autophagy has increased, mitochondrial function is better, genetic stability is good, you know,

00:27:42.700 things like that. I think when you do an experiment at the end of which you see so much effect and

00:27:49.340 there's an argument because people say, hey, it's all epigenetic. Here's the study that shows

00:27:53.400 epigenetics. Well, yes, but the question is, did metformin do it or did what metformin did on aging do

00:28:00.300 that? So for me, there are three major arms of metformin. One of them is the metabolic, the

00:28:09.080 effect that it targets complex one in the mitochondria. And by that, and I'm skipping the

00:28:18.460 stages, it increased AMP kinase and it targets mTOR. Okay. And everything that metabolically

00:28:25.960 happens on that side. So let me ask you a question here. I've never been able to get a straight

00:28:31.340 answer out of anybody on this. Do we have a dose equivalence? Because what you just said for the

00:28:37.880 listener, I want to make sure is clear. Metformin is a weak mitochondrial toxin. It inhibits complex one

00:28:45.260 that tricks the body basically into doing something, which is thinking nutrients are scarce. AMP kinase

00:28:52.960 goes up. It thinks there's a deficiency of energy. We know that that has a downstream effect on the

00:29:00.540 inhibition of mTOR, something that we're going to talk about happening directly through the rapamycin

00:29:06.200 rapalog pathway. But what I'm trying to understand is using the cellular assays where we can read out the

00:29:13.980 extent of that inhibition, do we know that five milligrams of rapamycin or everolimus is equivalent

00:29:22.620 to a thousand milligrams of metformin? In other words, do we have a sense of what an apples-to-apples

00:29:29.600 mTOR inhibition looks like, even though one's direct and one is indirect? It's a good question. I can find

00:29:36.580 the answer on a cellular level because Ana Maria Cuervo, our Johns and my friend, is using metformin as the

00:29:44.200 positive control for autophagy. Okay? She actually uses metformin and not rapamycin. So she must have

00:29:53.440 tried and have the dose response on a cellular level. I'm not aware, Joan, are you aware? I'm not

00:29:59.740 aware. It's a good question. I don't know the answer for that. What's also complicated because

00:30:06.020 rapamycin actually isn't a good inducer of autophagy. The catalytic inhibitors are much better.

00:30:11.180 So it's not just which dose of mTOR inhibitor, but what downstream readout of mTOR is equivalent.

00:30:22.060 Are you looking at autophagy or are you looking at protein synthesis, each one?

00:30:26.640 So you're saying, I mean, we're going to come back to this, Joan, when we talk about the difference

00:30:30.460 between the allosteric and the catalytic inhibitors, but you're saying the way you go about inhibiting

00:30:35.620 mTOR will shift the lever more towards maybe inhibition of senescence versus protein synthesis

00:30:43.520 versus autophagy. So, okay, we'll come back to that. But Nir, sorry to interrupt. Let's go back

00:30:48.600 to what you were saying. So big pillar one is the metabolic complex one AMPK mTOR pathway.

00:30:57.440 Okay. Right. Which is what we just discussed. The second is there is a decrease in oxidative

00:31:05.580 stress in ROS production and therefore also on DNA damage that is the consequence of using a low dose

00:31:16.380 of a mitochondrial poison, right? So there is this aspect of that. And the third aspect,

00:31:23.820 the relations to autoimmune function and inflammation. So those are kind of the, I think,

00:31:33.140 the major effects on metformin. And it is because by accident, it's kind of doing those two arms,

00:31:41.460 the metabolic and the ROS inflammation. You're getting a two for one there. Can you say more

00:31:46.860 about the potential immune enhancement and presumably cytokine reduction if it's cytokine

00:31:53.800 that's sort of deleterious? Yes. It's doing both of them. I think

00:31:58.400 Joan will give a good example. Do you want the cellular mechanism of that? Because I don't want

00:32:05.580 to get into that now. I think Joan has a better explanation because we don't have the same,

00:32:11.440 we have the clinical data on metformin, but I wouldn't tell you what exactly is the most relevant

00:32:18.060 target in the whole thing. Okay? Okay. So Joan, let's go back to, we're still talking about

00:32:25.280 either rapamycin or RAD001, a rapalog. What do you think are the places where it plays the greatest

00:32:33.600 effect in longevity in terms of these cellular mechanisms or critical pillars?

00:32:39.880 Yeah, I think it's an area where we have to understand more. But one of the things that will

00:32:45.300 happen with a rapalog is that you'll get less protein and lipid synthesis, and that may decrease

00:32:52.840 proteotoxic stress just by having less proteins made that your protein degradation system has to deal

00:33:01.460 with. Then people have assumed autophagy is another mechanism. But actually, as I was just mentioning,

00:33:09.040 rapalogs don't consistently induce autophagy. It's cell dependent.

00:33:13.480 So how much of a role autophagy has in the benefits of rapalog is probably tissue dependent.

00:33:21.640 Where do we think it has the most effect versus the places where we think it has the least effect

00:33:25.840 on autophagy? We look in cell lines and we don't see in many cell lines, any induction of autophagy,

00:33:34.720 but then there'll be a few cell lines that do have induction of autophagy. And I can't tell you,

00:33:40.520 is it cells from the liver versus the cells from neurons? I don't know whether it's the tissue of

00:33:49.420 origin or if it's something like the level of FKBP12 in the cell. So then the third part,

00:33:58.900 which is, so it's interesting, it's similar to what Nir was saying for metformin is there's a

00:34:05.020 regulation of the SASP. So these inflammatory cytokines that are secreted by senescent cells

00:34:12.480 that accumulate as we age, that is regulated in part by mTOR. So inhibiting mTOR will decrease SASP,

00:34:20.480 which will decrease systemic inflammation.

00:34:23.320 When we think about that and go back to the results that you demonstrated in humans six years

00:34:30.860 ago, how does that story make sense? So now I want to bring both the stories of rapamycin or

00:34:38.760 rapalogs and metformin to, as Nir said, to 2020, where most of us are now focusing on something new.

00:34:48.220 And I'll just use myself as an example. I mean, you guys have been focusing on this forever.

00:34:51.320 I don't think I've thought about immune enhancement as much at a clinical level as I have in the past

00:35:00.340 four months. So prior to COVID, most of my interest around immune enhancement, and the reason I've been

00:35:07.660 so interested in rapamycin is more in my belief around anything that you can do that's going to

00:35:14.140 enhance the immune system at the adaptive level, which is what you're getting out of a vaccine,

00:35:18.860 is going to help with cancer surveillance. And in as much as delaying the onset of cancer is an

00:35:25.700 important pillar of longevity, that's the real reason we want to have enhanced immunity.

00:35:30.840 I would say I very naively didn't pay enough attention to the mortality from even influenza,

00:35:36.820 which of course is also getting more attention appropriately today. So it's not just that

00:35:42.200 coronavirus is, you know, we have a new strain of coronavirus that now adds to our burden of these,

00:35:48.640 but look, there's a non-trivial chance that a 75 or 85-year-old person is going to die

00:35:53.300 from an influenza virus. And now, of course, we have another virus that's going to be probably

00:35:57.700 five times more virulent. So how do you make this link? Why is it that the T cells got better at

00:36:05.600 recognizing an antigen when a patient was pulsed with a drug that is inhibiting senescent cells,

00:36:13.320 or at least the soluble factors of senescent cells? Is it, as you said, maybe there's some

00:36:17.980 tissue-specific or cell-specific autophagy reduction in protein synthesis and lipid synthesis? How does

00:36:23.700 that story go from the mechanistic story to the clinical story?

00:36:28.280 I think it's going to be complicated, but one of the factors on how you respond to a vaccine is

00:36:37.620 actually innate immunity. And you need innate immunity to bring in the adaptive T and B cells

00:36:45.320 to respond to antigen. One of the problems in the elderly is that they have a defect in type 1

00:36:52.200 interferon production after getting a flu vaccine. That's been shown by a group from Yale. And it's

00:37:00.280 also been shown by another group from Stanford that all sorts of stimuli to the innate immune system that

00:37:06.200 should induce interferon, there's a defect in immune cells from the elderly. What we've shown is

00:37:12.820 that with mTOR inhibitors, you can enhance that interferon production and interferon-induced gene

00:37:19.680 expression. And so the innate immune function, enhancing that may be one of the reasons that

00:37:25.300 the adaptive immune system is working better when you get vaccinated. We've also shown that there's

00:37:31.360 a decrease in exhausted T cells. We first showed that in older humans, and then Tyler Curiel showed

00:37:37.640 the same thing in older mice. So there's more T cell exhaustion. And when you give an mTOR inhibitor,

00:37:44.600 and particularly a rapalog, that decreases, and we don't know the mechanism for that yet.

00:37:49.260 Has anyone ever tried, this is sort of off topic, but to your first point, I was actually not aware

00:37:53.880 of the interferon issue. That's super interesting. If you vaccinate older patients with a low dose of

00:37:58.980 interferon, do you get around that? Nobody's tried. You have to be careful with vaccination.

00:38:05.540 Yeah, interferon is pretty dangerous.

00:38:07.120 Right. So I think what it looks like is that there's just enhancing kind of the response to

00:38:15.720 the vaccine antigen and not sort of just dumping interferon in.

00:38:19.380 Yeah. It's not the interferon per se. It's that the lack of interferon is a proxy for a failure to

00:38:24.520 recognize in the first place.

00:38:26.640 Exactly.

00:38:27.720 In your 2014 paper, remind me, did you look only at T cell or also B cell assays? Did you look at

00:38:34.340 neutralizing antibodies and T cell killing?

00:38:37.720 So we only looked at hemagglutination inhibition, HI titers, didn't look at neutralizing antibody and

00:38:45.000 didn't look at T cell function. We just looked at shifts in 76 different peripheral blood subsets.

00:38:53.060 And it was interesting. The rapalungs didn't shift any of the subsets very much, except there was

00:39:00.100 about a 20, 25 to 30% decrease in the PD-1 positive CD4 and CD8. These are the exhausted T cells that

00:39:07.560 accumulate with age.

00:39:10.400 I think I forgot that detail. So these are cells with checkpoint inhibitors on them.

00:39:14.800 These are CD4, CD8 killer cells with a PD-1 checkpoint inhibitor.

00:39:18.140 Exactly. So those go down, which may be another part of the adaptive immune system that's getting

00:39:24.400 improved from the rapalog.

00:39:27.900 Yeah. Which might also speak to, again, if you want to shoot for the stars,

00:39:31.840 you can see some cancer protection benefits potentially with that application.

00:39:36.540 Yeah.

00:39:37.660 So Nir, explain to me the immune benefits of metformin. I've obviously, first and foremost,

00:39:43.200 always thought of rapalogs as interfering with the immune system one way or the other, right?

00:39:49.220 If the dose is high and frequent enough, it's going to impair the immune system. But

00:39:52.820 as Joan has explained, if you learn how to thread the needle correctly, you can enhance the immune

00:39:57.800 system. When did it become apparent to you that metformin, which, I mean, the metabolic benefits

00:40:03.380 tend to jump out at us, but when did these immune benefits start to become really apparent?

00:40:07.760 There are papers in the 40s and 50s on biguanids that were actually looking like metformin. Remember

00:40:16.560 the history of metformin, it had a cousin, fenformin, that seems to be more active against diabetes,

00:40:22.780 but it was associated with lactic acidosis. So they went back to metformin. But in the 40s and 50s

00:40:30.300 and 60s, metformin was used around the world for influenza in the elderly.

00:40:37.760 And there's a lot of literature. Unfortunately, the literature is in Czech and Swedish and

00:40:45.240 Philippines. And I'm not starting to get a lot of translation, but all of them were positive

00:40:52.580 response to using metformin as an immune enhancer against the flu. And by the way, against malaria and

00:40:59.600 some other indications, this has started really early on. And unlike what John did to rapamycin,

00:41:09.380 this didn't really come back until recently. But we knew several things about metformin. We knew

00:41:19.560 that patients with type 2 diabetes, if they get metformin, they immunize better against the flu.

00:41:26.980 There is at least a study like that. And there are studies that showed... So when we talk about

00:41:37.020 metformin or rapamycin, we're talking about several things. We're talking about fixing the immune

00:41:43.980 decline. We're talking about the inflammatory response, right? And we're talking also with both

00:41:52.260 these drugs, not about their immune function, but do they help the elderly body sustain a severe disease,

00:42:02.700 right? In the case of COVID, we need all those things. We need to have better immunization,

00:42:09.660 not get to the cytokine storm. And if we are sick, you know, be tough.

00:42:14.240 Let's unpack that a little bit because it's a great point you raise, Nir, which is if you had

00:42:20.360 to wave a magic wand and make someone most resistant to SARS-CoV-2, you probably wouldn't

00:42:28.500 just increase their immunity by 10 to 20%. You would reduce their comorbidities first and foremost.

00:42:36.320 In other words, to use an extreme example, right? If you take a 30-year-old with no comorbidities,

00:42:42.240 their probability of succumbing to this virus is infinitesimally small. It's almost unmeasurable.

00:42:48.940 Whereas if you take even a 40-year-old with comorbidities, the risk starts to become non-trivial.

00:42:56.680 In as much as these drugs can reduce comorbidities, they may have at least as much benefit on protecting

00:43:04.300 against the mortality as they would on enhancing the immune system. And I don't think those are

00:43:09.260 necessarily dependent on each other, are they?

00:43:12.820 No, they're not. Let me just say one thing. Across the world, if you're 80 years old and older,

00:43:21.040 your chances to die is 180 times more than if you're a twin. But let's make sure that there

00:43:28.420 are young people who are dying too, okay? It's really an incredible ageism.

00:43:34.440 Let me not be hypothetical. Let me give you an example. There's a paper that was published in

00:43:41.440 China a little bit more than a week ago, where they looked at the 100 people with COVID that were

00:43:49.860 treated with metformin, comparing them to the 178 people that were diabetic and not treated with

00:43:59.100 metformin.

00:43:59.780 And just to be clear, these were prospectively treated with metformin or this was a retrospective

00:44:05.180 analysis of diabetics with and without metformin?

00:44:07.740 No. And it's a good point. I don't think any one of us are saying, you get to the hospital,

00:44:12.680 you get metformin. This will be a big mistake. We might kill people. They're in lactic acidosis

00:44:17.500 anyhow. I mean, we don't want to do that. Those were people that were hospitalized with metformin or

00:44:23.240 without metformin. So those are the 278 diabetic patients in Wuhan that were there.

00:44:29.120 And you're saying for the only difference that is apparent upon admission to the hospital is a

00:44:35.180 group of them are on metformin and a group are not, but they are otherwise as close to equal as

00:44:41.200 you would find them shy of being able to randomize.

00:44:43.800 Absolutely. The only significant difference is that actually the glucose level in hospitalization

00:44:49.820 of the metformin was higher than that of control. But otherwise, they're the same age,

00:44:54.300 gender distribution and everything. And they had, the people on metformin had 25%

00:45:01.100 of the mortality. Let's change it around. They had four times decrease in mortality.

00:45:09.700 But this is not what grabbed my attention. I went to the web and tried to figure out

00:45:15.120 how many diabetic patients in China are treated with metformin.

00:45:20.480 And there is an exact data. I did get a little bit indirect data because the people who give you

00:45:27.640 the exact data, you have to pay them $3,500. So I wasn't ready to do that. But the use of metformin

00:45:33.920 in China is between 60% and 70%. And you see the ratio of the people who were hospitalized

00:45:39.760 was the opposite. So I'm thinking less people on metformin showed up in the hospital.

00:45:47.940 And probably the mortality had to do more with the inflammatory, with a cytokine storm,

00:45:55.620 or with their ability to handle severe disease than the immunization.

00:46:03.140 Let's think about this for a second, because obviously COVID kills in several ways. And again,

00:46:08.360 when you contrast it with influenza, I think it's an important contrast, right? Influenza

00:46:12.600 influenza is probably more... And Joan, you should step in because I think you probably know more

00:46:17.980 about influenza than I'll ever know. But really the issue with influenza is that it can paralyze

00:46:22.920 the immune system. And it's these secondary infections that come in. So obviously there

00:46:27.800 are certain strains of the flu that can kill you through the cytokine storm. But isn't the way that

00:46:32.920 the majority of older patients die of influenza is just that their immune system gets sort of whacked

00:46:39.180 by this thing, becomes almost somewhat paralyzed, and they become more susceptible to other infections,

00:46:44.520 such as a bacterial infection. Isn't that a big part of the danger of influenza beyond just the virus

00:46:51.660 itself? Oh, you know, we used to think that, but there was a paper that came out from the CDC in New

00:46:57.500 England Journal in 2015 that looked at what actually causes pneumonia in the elderly that gets them

00:47:03.400 hospitalized. And it's not a combination of virus and bacteria. That is some of it. But the majority

00:47:11.380 is a virus. And the most common virus is actually rhinovirus, which is the cause of the common cold.

00:47:17.540 And it's that the elderly just can't handle viruses the same way as younger people do. So they can

00:47:24.300 actually die from the flu. Just to make sure I understand what you're saying, they don't have to get

00:47:28.760 bacterial super infection. No, even with rhinovirus and the virus itself causes damage. And then the

00:47:34.940 immune response to the virus also causes damage. So even without cytokine storm, you can kind of

00:47:41.140 get immune mediated damage. And I want to come back to Nir's point in a second, but I just want to go

00:47:47.480 down this path a little further. As you look at the damage from specifically SARS-CoV-2, seems like a much

00:47:55.660 worse virus in the sense that it causes much more direct damage to the pneumocyte. So you now get much

00:48:02.400 more direct damage to the end organ. And that's not saying anything about all of the other disadvantages

00:48:09.600 of it through its transmissibility. Do we believe that at the immunologic response level, it is

00:48:16.660 eliciting a much more toxic autoimmune response or cytokine response than say influenza, which itself is

00:48:24.720 quite nasty. The coronavirus infects cells, including lung cells, and that causes direct

00:48:32.440 damage from the virus. But then the host response to the virus is good because it will get rid of the

00:48:39.360 virus. But if it gets excessive, you'll get cytokine storm, which will cause major life-threatening

00:48:47.120 consequences independent of the virus. But if you can enhance the ability of the host to sort of get

00:48:57.680 control of the virus very quickly, the thought will be you won't be susceptible to that cytokine storm

00:49:05.100 and you'll stay with mild disease. So based on the little bit that we know about the ability of a

00:49:13.500 rapolog to enhance immunity through these early stage clinical trials, and then near, based on what

00:49:22.540 you know, based on these uncontrolled trials that have more relevant recent data, because they're

00:49:31.760 dealing with the virus of interest, what are your best guesses about the particular places where each of

00:49:40.420 these agents is exerting their benefits? So starting with you, Joan, where do you think a rapolog has the

00:49:46.280 greatest potential to reduce the risk of succumbing to COVID? What we also see is that in people who get

00:49:57.120 mTOR inhibitors, their innate antiviral gene expression is enhanced when they get a viral infection. So what this

00:50:05.680 suggests is early on, like as post-exposure prophylaxis or in a prevention mode, the rapologs or the mTOR

00:50:14.260 inhibitors may have benefit by boosting the body's response that is defective as we get older to the

00:50:22.000 virus so we can clear it better so that we don't go on to get severe symptoms from the virus.

00:50:27.660 Okay. Does that suggest that, well, I want to come back to this because I want to talk about it in the

00:50:37.580 context of RTB 101 and how you would think about, where I'm going to come back to, Joan, just is going

00:50:44.520 to be around how do you think about dosing this? Is this something where we think about these as

00:50:48.460 maintenance drugs that people probably ought to be on in anticipation of such a thing versus a drug that

00:50:54.380 comes in from a treatment standpoint. So while we park that thought near, let's go down this

00:50:59.960 sort of same path on metformin. So one thing that you suggested from the cohort that you just described

00:51:05.680 in China is, first of all, the people taking metformin were disproportionately less severely ill.

00:51:12.960 So fewer people who take metformin wind up in the hospital and the ones that do end up doing better.

00:51:19.340 Let me add to it that I've been looking for this literature and I've started

00:51:24.320 my own study at Einstein because I got emails from Spain and Italy from physicians who noticed

00:51:31.960 the same on metformin.

00:51:33.940 So this is like January and February when they're hitting that first wave.

00:51:37.700 Right. They said, do, you know, do I hear about that? And I beg them, you, you should publish.

00:51:43.740 I should say another thing. And that kind of links to the mechanism. There's a study that was published

00:51:49.780 yesterday in Medroxiv. So it's a study that was submitted, right? And not reviewed. Okay. And in

00:51:58.600 fact, when I'm reading this study, you can ask me questions there and I wouldn't know because they

00:52:03.360 don't give enough details, but they show two things that women on metformin have about 20, more than 20%,

00:52:11.480 21, 22% less mortality. This is from Minnesota.

00:52:16.060 I'm sorry. This is mortality due to COVID-19 or all?

00:52:19.800 COVID-19. They have access to 6,000 patients through the University of Minnesota. I'm sure they're all,

00:52:25.960 not all in Minnesota, access to 6,000 patients. And they found that females on metformin have 21%

00:52:33.440 less mortality. Now, I don't know if those are only diabetic patients or it's only women on metformin.

00:52:40.900 I don't know what's the, what's the one here. Okay. But, but there was a sex specific decrease

00:52:46.880 in mortality, but even more important, they had 80% decrease in peripheral, in plasma TNF alpha levels.

00:52:56.580 That was also highly significant. That kind of ties, I mean, I don't know why they measure only TNF

00:53:03.020 alpha, or if they measured only TNF alpha, but there's a kind of a link to the inflammatory response.

00:53:10.620 Again, let's think about that. Is there any indication, by the way, that metformin alters

00:53:15.740 ACE2 expression? No, there's no indication of that. I actually put ACE2 and metformin to see.

00:53:22.500 There is an early, one of the first studies that came on drug in COVID was an in silico analysis

00:53:29.580 that put 76 drugs or something like that, including eropamycin and metformin as potential

00:53:37.180 interacting with the COVID SARS-2 pathway.

00:53:42.180 Basically, the fact that there isn't some apparent link between metformin and its ability to alter

00:53:48.580 the tissue target, it would seem that any benefits that you're describing that turn out to be real

00:53:54.460 are either based on immune enhancement or immune modulation. Either you're turning up the immune

00:54:00.300 system when you want it to be turned up or toning it down when you need it to be toned down, correct?

00:54:05.300 Yeah, as long as you don't say it's the same mechanism that you turn on and up. I think-

00:54:11.260 No, no, no, no. That's my point. These are different. And what I'm really trying to tease out is,

00:54:15.320 first of all, is that the right way to think about it? That's how I would think about it. Secondly,

00:54:18.300 if so, which of those two do you think it's acting on? Well, I think both. That's why I made the point

00:54:24.840 that at least this study and some of the things I hear from Europe suggest that less people in

00:54:30.400 metformin are hospitalized. So they get their immunities better, right? And then when they're

00:54:36.300 in their hospital, less of them go into an inflammatory response. And the time course is

00:54:43.240 different. Remember, it's when you get the disease and the inflammatory thing is like five days later,

00:54:48.020 right? Did the Chinese data that you referred to that were published about a week and a half ago,

00:54:52.980 obviously your analysis suggests the first part of that. Your analysis, which is looking at the

00:54:59.480 proportion of patients in China taking metformin versus those hospitalized would suggest the immune

00:55:04.660 enhanced piece of that. Do you have data beyond the obvious, which are the survival data that suggests

00:55:12.000 that you actually saw attenuation of a pathologic immune response? For example,

00:55:17.840 did they measure cytokines in the Chinese cohort? No, no. It was just the outcomes?

00:55:23.020 No, it was just the outcomes. Again, I want to say I'm interpreting lack of data

00:55:28.540 to suggest that maybe not enough for the hospital, but I don't know that maybe in one only 30% take

00:55:36.800 metformin, right? And the others do not. So let's not make too much out of it. I use this more

00:55:43.100 to say that we really need to look at both issues, the immune response and the cytokines. And then the

00:55:51.580 third is the ability of the body to sustain severe disease.

00:55:55.340 You were going to say something, Joan, on that.

00:55:57.420 Oh, I was even wondering in someone who's critically ill, would they not receive metformin

00:56:02.980 anyway? Would it just be DC discontinued and not to your patient?

00:56:08.060 I want to say about that, you know, we've done this study, we talked about it before, Miles, where

00:56:13.320 we gave metformin for six weeks and then crossed over to elderly people, crossed over. We were

00:56:20.140 taking biopsies and we're doing transcripts, two weeks off and then six weeks. And there was

00:56:25.900 an effect of metformin in those who got metformin first on the placebo results. There was still

00:56:32.920 lingering effect of metformin. So I think, okay, you stop metformin and you should, and we shouldn't

00:56:39.600 say we, people should get metformin to prevent COVID, not to, not to treat COVID. But I think that

00:56:46.880 when you so substantially change the aging phenotype of a cell, it's not, it's not that you stop and it

00:56:54.760 goes back to old. So I think it's okay. Five days later, it can still be effective.

00:57:01.300 Yep.

00:57:02.080 So Joan, what is your take now on basically the role that a rapalog could play in the prevention of

00:57:12.360 mortality from COVID-19 along these two axes? Let's posit that a rapalog plays no direct role

00:57:20.700 in inhibiting the virus from getting into a cell. It's not going to play a role on that pathway.

00:57:25.480 So instead we focus on these two immune properties, the ability to enhance immunity

00:57:30.560 to fight the virus versus the ability to tone down the immune response when it becomes over

00:57:36.080 exuberant. How do you see those two playing out?

00:57:39.340 First, there is some data that mTOR inhibitors may interact directly with COVID and inhibit

00:57:46.960 replication.

00:57:47.960 Meaning the virus, the SARS virus.

00:57:49.980 The virus. There may be a direct antiviral effect that's seen with CMV and BK virus in

00:57:55.700 transplant patients where they have lower CMV and BK viral infections probably because of

00:58:01.040 a direct effect of mTOR inhibition because the virus needs it.

00:58:04.880 That's interesting. Is there any evidence of that in the other four coronaviruses that commonly

00:58:09.220 occur?

00:58:09.600 No, but to Nir's point, there have been a bunch of transcriptomic, metabolomic, proteomic,

00:58:19.080 big data analyses that have identified mTOR and rapalogs as potential drugs that would

00:58:26.240 interfere with the replication of SARS-CoV-2.

00:58:30.340 Okay.

00:58:31.340 And Joan, in your study, you also had less coronavirus as an outcome.

00:58:38.240 Right. So that's what we think is probably not a direct effect on the virus. That's immune

00:58:44.320 function.

00:58:44.900 Okay.

00:58:45.200 I was getting before in studies where we've looked at laboratory confirmed respiratory tract

00:58:51.300 infections. In our phase two study, we looked at 17 different viruses that caused respiratory

00:58:58.320 tract infections in older people. And four of them were the common coronaviruses. And what

00:59:04.580 we saw was that mTOR inhibitors upregulated antiviral gene expression and reduced the incidence

00:59:12.380 and severity of coronavirus infections. SARS-CoV-2 wasn't circulating at that time.

00:59:17.720 Right. And if I recall, Joan, and we're going to, this would be just as good a time as any

00:59:21.400 to go back and talk about RTB-101, which was the drug you're talking about. But it was the

00:59:26.540 coronaviruses had a huge difference between drug and placebo, as did the rhinovirus you've

00:59:31.820 already alluded to, along with RSV. And I think one of the influenza strains, right? Not

00:59:36.840 both.

00:59:37.160 Right.

00:59:37.600 So let's do that. Let's detour back for a moment and talk about what came out of the

00:59:47.540 RAD-001 trial, which is the one we talked about in 2014 that showed enhancement to flu vaccination.

00:59:55.980 And then what this new compound RTB-101 is. You've already made one reference to it when

01:00:02.800 you casually mentioned that it's a ATP competitive mTOR inhibitor, as opposed to an allosteric

01:00:08.380 inhibitor. You might have to explain to people what that difference is, but we've now talked

01:00:12.240 about it twice. So I think it is worth an explanation. And I think it does become germane.

01:00:16.780 And then let's talk about the difference between the 2A and the 2B study.

01:00:20.980 Sure. In that first study where we just looked at rapalogs to enhance flu vaccine response,

01:00:26.580 we noticed in a clinical trial, you always collect adverse events reported by people. And we noticed

01:00:33.500 that the people who were getting the mTOR, the rapalog, were reporting fewer respiratory tract

01:00:39.980 infection as adverse events. And they weren't flu. They were just all common respiratory tract

01:00:44.920 infections. So it made us think, hey, if this is enhancing immune function, it's not going to be

01:00:51.040 enhancing just the response to a flu vaccine. It's probably going to enhance the response to all sorts

01:00:56.200 of different pathogens. So in our phase tube, we said, let's not only look at vaccine response,

01:01:03.340 but let's actually look at infections that occur to see, are we decreasing infection rates?

01:01:10.480 And in that phase tube, we also said, if mTOR inhibitors really do enhance immune function,

01:01:16.160 this shouldn't be specific to a rapalog, which is a drug that changes the confirmation of mTOR,

01:01:23.800 and that's how it inhibits it. And we said other kinds of mTOR inhibitors, which block the catalytic

01:01:30.880 site, mTOR is an enzyme, and they block the catalytic site, they should also have benefits if this

01:01:37.340 is really an mTOR mediated effect. So we looked at a rapalog, and we looked at a catalytic inhibitor

01:01:44.360 called RTB-101, and we looked at the two together. And we looked not only at vaccine response, but we

01:01:50.920 looked at infection rates for a whole year. Now, RTB-101 also has some PI3 kinase

01:01:59.400 inhibitory properties as well, doesn't it? So in a biochemical assay with, you know, an isolated

01:02:07.140 enzyme, it inhibits PI3 kinase. And Novartis made this drug in the hopes that it would be a dual

01:02:12.640 mTOR PI3 kinase inhibitor for cancer patients. But when you bring it in cells and in humans,

01:02:18.480 you need much higher concentrations of RTB to inhibit PI3 kinase. And at the concentrations that

01:02:25.100 are achievable in the clinic, it's mostly just a TORC1 inhibitor. It doesn't even get concentrations

01:02:31.080 easily high enough to inhibit TORC2. So there's two mTOR complexes that contain mTOR, and this is

01:02:38.460 most potent inhibitor of the TORC1 complex. Now, you achieved that in the first study by using

01:02:47.160 the rapalog dosed intermittently at the lower doses. So I know the higher dose, which was 20 milligrams,

01:02:54.960 you probably still get some C2 inhibition. But at the 0.5 daily, you probably don't get much.

01:03:02.580 At the 5 weekly, you're probably mostly just hitting 1, correct, and not hitting 2.

01:03:08.580 Exactly. Like we didn't see any real hyperglycemia or hyperlipidemia, which are the TORC2 side effects.

01:03:15.140 So is it safe to say that at the doses you give RTB101, it has comparable mTORC1 inhibition to RAD001

01:03:23.900 at 5 milligrams weekly? Would that be the closest comparison?

01:03:26.880 Probably more 0.5 milligram daily, because we give RTB every day.

01:03:31.340 Got it. Okay. And the reason you give it daily is, of course, the selectivity, the catalytic

01:03:37.340 selectivity. And also, it has a shorter half-life. Its half-life is four to six hours. So if you dose

01:03:44.160 it once a day, it's inhibiting TORC1 for a shorter period of time than Averolimus. And if you give it

01:03:49.820 twice a day, it's a little bit more persistent inhibition. Now explain, were there two studies,

01:03:55.460 one that was combining these two, RAD001 plus RTB101, and then there was, was the protector study

01:04:03.060 just RTB101 by itself? Correct. So we had two phase two studies looking at RTB alone and in

01:04:11.400 combination with Averolimus. In the first study, the combination looked the best when you dose it for

01:04:16.900 just six weeks. In the second study, when we extended dosing for 16 weeks in a sicker population,

01:04:23.580 the RTB alone was better. So in both studies, RTB alone decreased respiratory tract infections.

01:04:31.320 And in one, the combination did, and the other, it didn't.

01:04:35.300 So the study that did not meet its hard outcome was RTB101 alone, but not for vaccine response. Was it

01:04:43.080 for, it was for total respiratory tract infections? No. And that's part of the problem. For our phase

01:04:51.000 three study, the FDA said, we don't want an endpoint of laboratory-confirmed respiratory tract

01:04:56.300 infections where we had seen the benefit. And they said, people don't care, this was pre-COVID-19,

01:05:02.400 if a respiratory tract infection is laboratory-confirmed. All they care about is how they feel

01:05:07.740 and function, and that's their symptoms. So what you have to do in the phase three is show you can

01:05:12.680 decrease respiratory symptoms that are consistent with a respiratory tract infection, but don't have

01:05:17.920 to be due to a respiratory tract infection. And we couldn't decrease the total respiratory symptoms

01:05:23.840 that the elderly have. What it does look like we did was decrease the severity of the symptoms.

01:05:30.600 But you weren't powered to detect that, or were you?

01:05:32.980 If you're looking at the laboratory-confirmed infections, we were underpowered because there

01:05:36.860 weren't very many. I think what the mTOR inhibitors are doing is not stopping people from getting

01:05:44.180 infected. But if you get infected, there's a better immune response and your symptoms will be milder.

01:05:51.000 Yeah. I mean, Nir, I've heard you say that, because I want to come back and really talk about TAME in

01:05:56.100 some detail. But, you know, it's a bit of a blessing in disguise that you didn't start TAME a year ago

01:06:02.120 because obviously it would have been interrupted as a result of this. I mean, all the clinical trials

01:06:08.120 that I've been following closely have been interrupted by this. I follow very closely, for

01:06:12.720 example, the clinical trials looking at liquid biopsies in cancer, and all of a sudden these trials

01:06:17.880 are completely interrupted. So there's that component to it. Of course, the flip side of that is,

01:06:23.140 depending on how large the study is, you might have actually inadvertently got another look at

01:06:28.800 an indication you weren't necessarily thinking about. And I guess my question for you, Joan, is

01:06:33.060 do you have enough subjects from the protector where there might be some lingering benefits,

01:06:38.880 or do you think that that window has closed and there's no benefit to going back and looking at

01:06:43.580 the patients who received active drug in protector to see if they had any downstream benefits

01:06:49.520 in terms of protection from SARS-CoV-2? We haven't even thought about it. You're the first person to

01:06:55.000 suggest it. No, it's a great thought. When did those patients finish enrolling?

01:07:00.440 In November, last November. Like November of 19? November of 19.

01:07:07.260 And those were in New Zealand too? New Zealand and Australia.

01:07:11.220 So New Zealand doesn't have the COVID yet, right? Maybe...

01:07:15.900 No, it hadn't, but it... It was pretty mild. They were very well controlled.

01:07:20.700 But we also had... I don't know how things are going in Australia. So we also had sites in Australia.

01:07:26.780 I mean, I guess it would be an interesting exploration because, again, this is one of those

01:07:31.100 things where you now wonder if you repeat the protector study, either as it was done with RTB-101,

01:07:39.520 or with RAD-001, or in combination, but you now do it specifically for this virus, do you get a

01:07:47.220 different outcome? And I do think we're learning as we get more and more data. I think we're actually

01:07:53.620 doing a trial in nursing homes now, looking at severity and not just incidents. Because I think

01:07:59.240 what's happening is once you get infected, you're better able to upregulate that interferon-induced

01:08:05.660 innate immune response. And my guess is that's why you're having less severe symptoms. It's not

01:08:12.440 happening before you get infected.

01:08:14.400 I want to make, I think, an important comment because we spend time... And Peter, you try

01:08:20.080 to really look at those drugs apropos mechanisms of COVID-19. But I think that what we are trying to

01:08:29.940 sell out there is that we are reinforcing, we're not fighting the virus, we're reinforcing the host.

01:08:37.800 Okay, we're defending the host. And the claim is that what we sow to influenza is relevant to COVID

01:08:45.080 because, after all, what's the difference between the people who are dying? It's their age, right? It's

01:08:50.780 the biology of aging that is different. And by the way, you previously said multimorbidity. For me,

01:08:57.380 multimorbidity is how old you are biologically. That's all it is, okay? 65% of the people have

01:09:03.700 more than two diseases and 65% have more. Chronological and biological age are different.

01:09:08.940 So I really think that part of what we have to discuss is the fact that we are defending the

01:09:16.840 older individual. Whether there's something specific that can help is really great. But this goes not

01:09:25.660 only to the immunity, doesn't go to the inflammation, but goes also to how do we develop vaccines now?

01:09:32.220 Because the vaccines that I'm seeing developing are not considering the older host in several ways.

01:09:40.020 The New York Times today says that they even are going to test it over the age of 65, okay?

01:09:45.260 I think the vaccine is going to be such a trap. And the way to go over that is either realizing

01:09:52.900 how to do it with the biology of aging, and there's a way I'm ready to discuss with you some mechanisms,

01:09:57.960 or the elderly have to be on metformin or apologue in order to get their immunity going. I think this is

01:10:05.600 the next disaster. If we have a vaccine that doesn't protect the elderly, we did nothing.

01:10:10.540 Let's talk a little bit about it. This is a topic that's near and dear to my heart. I'm getting

01:10:14.720 involved in a study that's looking at a question from a slightly different angle, which is what's

01:10:18.720 the durability of immune response? Historically, as you guys probably know, coronaviruses are not

01:10:24.020 exactly the most robust at inducing durable immunity. In fact, if you remain immune for a year,

01:10:30.220 that's considered reasonable. This poses a huge problem, which is what if after all the trouble of

01:10:37.960 getting SARS-CoV-2, getting sick with COVID-19 bouncing back, you only have a year of immunity,

01:10:44.180 the probability then that a vaccine is going to provide lifelong immunity, the way we get it from

01:10:50.640 several of our most famous vaccines seems quite low. And so now you're in a situation of saying,

01:10:56.340 well, gosh, what is the efficacy of a vaccine going to look like? Is this going to look like a 30%

01:11:01.360 efficacious vaccine that you're going to need every year? Is it going to need to be supplemented by

01:11:06.640 monoclonal antibodies in the most high risk populations? I think we're all basically saying

01:11:11.340 the same thing, which is there's a real risk here. So taken in order, what is the probability

01:11:17.160 this virus is going away? Zero. I mean, it's somewhere between zero and epsilon, but the likelihood that

01:11:23.140 SARS-CoV-2 magically mutates its way out of impacting humans is so low, it would be foolish to entertain

01:11:31.000 that. So we now have a fifth coronavirus that's here to stay, except unlike its other four cousins,

01:11:36.740 this one can really whack you. And then let's assume we can make some safe and efficacious vaccines.

01:11:43.820 Are they really likely to keep you protected for five years, 10 years or more, even without the

01:11:50.120 genetic drift? Based on what we know of other coronaviruses, that seems unlikely. Again, we're going to do a

01:11:55.560 study to try to answer that question, but I think we do have to get ready for something that says,

01:12:01.040 oh man, we could be in a really unpleasant place where we never really naturally acquire herd immunity.

01:12:08.260 And if that's true, not to fear monger, it means we need a better strategy around immune enhancement.

01:12:15.260 I mean, that's sort of my general take on this. Would you guys tone that down or ramp it up?

01:12:19.500 I think it's quite a reasonable stance. And I think finding things that help generate persistent

01:12:29.300 immunity is going to be important. Especially for the vulnerable population. I mean, that's the part

01:12:34.880 that I think is really frustrating is you were all struggling to come to grips with, well, what is

01:12:41.260 the implication of this for school kids where the restrictions seem so impossible to manage that

01:12:46.800 it seems ridiculous, right? Like a seventh grader shouldn't have to be completely quarantined in

01:12:53.500 the manner that we would think about quarantining a 70 year old. So we have to be able to now think

01:12:58.980 about immune targeted therapies for the most immune vulnerable. I mean, I guess, Joan, how do you now

01:13:05.320 think about juggling these things? Because I know that prior to COVID, you guys were already looking at

01:13:11.080 an indication in Parkinson's disease, right? Help me understand from a preclinical standpoint what that was

01:13:16.600 about. But then also, how do you now think about juggling resources, including time and just

01:13:23.220 cognitive bandwidth around Parkinson's, which was sort of the path you were on with now something that

01:13:29.560 seems even more pressing and maybe even closer? I don't know if you think this is closer just based on

01:13:35.880 on the data. Yeah, we have, you know, just reams of data now of using mTOR inhibitors to enhance immune

01:13:45.600 function and older people's safety data and data on incidents, severity of respiratory tract infections,

01:13:52.440 and a lot of biomarker data to start understanding what is actually going on in the immune system.

01:13:57.500 So we're farthest ahead there. When we used to go and try to raise money for, you know, doing this kind

01:14:04.180 of research, investors would just, we'd mentioned respiratory tract infections, and they would start

01:14:09.320 to yawn, like nobody cared. They cared about cancer, and they cared about rare diseases, but they thought

01:14:15.980 respiratory tract infections were boring. The nice thing about COVID-19 is it's making it obvious why

01:14:23.960 enhancing immune function is a really important area, and giving us a little bit more bandwidth to see

01:14:30.700 if we can get it right. For the Parkinson's disease, it turns out neurodegenerative diseases,

01:14:38.020 there's an accumulation of toxic protein aggregates, and if you enhance autophagy in preclinical models,

01:14:45.440 that is, has benefit. I mentioned rapalogs aren't great at inducing autophagy. RTB at high doses is very

01:14:54.000 good, but it's hard to achieve those concentrations in the brain. If you use the two of those together,

01:15:00.220 you can lower the concentration of RTB that's needed to induce autophagy, so you don't have to

01:15:06.480 get so much across the blood-brain barrier, and that was the reason we did the trial of that

01:15:12.020 combination in Parkinson's disease. Now, Matt Caberlin wrote a really elegant piece, gosh,

01:15:17.440 it's probably been a year ago now, where he said, and I thought it was just great, but I'm obviously

01:15:21.520 biased, that like, why in the world are we not pouring more resources into rapalogs and Alzheimer's

01:15:28.100 disease? And he basically gave the argument you're giving, which is when you look at their potential

01:15:33.840 to both ameliorate and potentially clean up a lot of the protein aggregation, disaggregation

01:15:40.980 that's occurring in the CNS, it seems like almost a crime. When you look at some of the cockamamie

01:15:47.020 ideas, especially that are being proposed to treat Alzheimer's disease, Nir, that brings me to a

01:15:52.620 question for you about this. What is the state of the art of understanding the role of metformin in

01:15:58.140 the risk reduction for Alzheimer's disease beyond the obvious? In other words, anything that normalizes

01:16:04.720 glucose and insulin is going to have a direct benefit on dementia. And you mentioned MCI earlier,

01:16:12.060 but do we have any other data that suggests that metformin should be a part of the toolkit

01:16:17.700 to reduce the risk of Alzheimer's disease? Not directly. There are several other funded NIH

01:16:24.540 projects that will take a couple of years to look at people with MCI. The two studies that looked at

01:16:31.520 MCI, metformin for six months and one for nine months, had decreased deterioration in some of the domains

01:16:40.040 of Alzheimer's. For both of them, name recalls, which is a real problem for me.

01:16:47.240 Are you saying you're an MCI, Nir? No, I'm on metformin.

01:16:53.480 But I think it's a common problem to some of us. The Alzheimer is more complicated. The good studies

01:17:03.700 all showed that people with metformin have less Alzheimer's. There are some studies that don't

01:17:10.120 show that. And there are two reasons for that or possible explanation. One, they're from China.

01:17:16.580 Okay. Either it's not similar mechanisms, genetics and environmental interaction somehow,

01:17:24.860 you know, possibly. But more likely is that, think about it this way. You really have to do it good

01:17:35.840 because if metformin delays mortality by 20%, okay, that means you'll get more people on metformin

01:17:47.500 lingering longer, right? And it might be just that effect that all of a sudden the people with

01:17:53.740 Alzheimer's are hanging around longer. So those studies, it's kind of why we need clinical studies

01:18:01.020 and not associate studies. Absolutely. Because there's so codependent dependency of things that

01:18:07.840 we're looking at. That's a great point. What have you two ever discussed about the combination in

01:18:14.840 humans of metformin and rapologues? What are your thoughts on that? Are these drugs that are accretive?

01:18:20.660 Are these drugs that should never be combined? I mean, I'll just share personally my experience.

01:18:26.640 I've taken both together. So, so near knows all this stuff, Jonah. I started taking metformin in 2010.

01:18:32.880 That's when I sort of became pretty convinced about the data. I started taking rapamycin in,

01:18:39.840 I want to say 2018. It's been about two years. That was a bigger thing for me to jump,

01:18:47.020 but I stopped taking metformin around the same time, though not because I thought one shouldn't

01:18:52.860 be on one or the other. And near, I want to come back and talk about why I stopped taking metformin.

01:18:57.960 So see if you can talk me into taking it again, but I want to, I want to give you all my reasons why I

01:19:02.400 stopped. But, but what, what are your thoughts on how these drugs would combine in humans?

01:19:06.760 Well, for me, it's simple. Look, as you already know, we're trying to advance the field. Okay. And

01:19:14.900 the reason I chose metformin, it's not because it was the best drug. I think rapamycin should be better

01:19:20.740 drug, but it's because we didn't want to kill anyone on the road to success. That's really is.

01:19:27.360 And I think combining metformin and rapamycin is like just, I mean, the rapamycin part is the one

01:19:34.920 that we want to be careful with. But on theory, look, that's where it's going. Let's say tame hands.

01:19:42.620 Okay. And let's say the FDA agrees that aging can be prevented, age-related disease can be prevented

01:19:49.340 and everybody can take metformin because it's so cheap. I think the next stage is combination of drugs,

01:19:56.340 better drugs, timeline, you know, different timeline. When is the best time to start rapamycin?

01:20:03.480 When is the best time to start metformin? Senolytics, we don't want to start when you're

01:20:08.200 20 years old. There's not an obstinacin cell, right? So there'll be a lot of calculation. So

01:20:13.120 I'm not against that. I'm, I'm trying, I'm focused on achieving a goal that the FDA,

01:20:20.020 you know, metformin is a tool to pave the road for an indication. That's all I'm trying to do.

01:20:25.300 In the meantime, I'm a believer in transforming, but-

01:20:27.960 Tell me where we are with tame. Joan, will you remember that I want to come back and hear your

01:20:31.620 opinion about the combination? Cause I do. And really I'm asking from a mechanistic question.

01:20:36.400 I, I, Nir, I appreciate your point, which I think is the voice of reason and wisdom, which says by

01:20:42.020 doing them sequentially in parallel like this, we can risk stratify a bit better. But, but I'm also just

01:20:47.340 interested in just sort of speculating mechanistically, but Nir, give us kind of a brief

01:20:51.740 update on tame and help me understand, by the way, metformin, as you said, is a free drug

01:20:57.660 effectively. Who has a financial interest in this? I mean, there's, there's no drug company that could

01:21:02.240 be interested in this, right? It has to be sort of philanthropic or NIH driven, correct?

01:21:06.360 First of all, I will quote you on what you said. I feel totally lucky now that somehow metformin was

01:21:13.860 delayed. It was very frustrating, but it's almost, uh, we, we get help of, of God. The second help,

01:21:19.660 I hope is this COVID-19 story. So we're lucky in a way that company that's going to give us the

01:21:27.760 metformin, which is cheap and the placebo, which is expensive is, is Merck Germany. Okay. Merck

01:21:37.080 Germany holds the, a world license for metformin. So they're contributing it, which is not a simple

01:21:45.200 contribution. Part of the problem with tame is that there's no commercial interest. So nobody was going

01:21:54.720 to pay for a phase three, like study, right? For five years. And the NIH, which is a longer story,

01:22:04.480 and I don't think I told all of it last time, but the NIH bottom line found that it's too risky to do

01:22:12.740 the study. The major comment, what if it doesn't work? Well, if we knew it will work, we didn't,

01:22:20.920 we didn't have to do the study. Interestingly, we know it works separately for each one of the age

01:22:26.420 related disease and mortality. So I don't know what chance we were looking. And there's also politics

01:22:32.520 of the NIA. I have to tell you, there's also a politics there. So this is what we're doing.

01:22:39.100 American Federation of Aging Research has non-profit people, people from non-profit

01:22:46.940 and non-industry that are supporting tame. In fact, we're expected to get the money any day now.

01:22:56.320 Sorry, what is the total budget for tame going to be?

01:22:58.540 So we have a study, $78 million, that was our initially budget. And now we have three pockets

01:23:09.580 because we had three specific aims. The primary outcome is the FDA outcome. It's prevention of

01:23:17.540 age-related disease and mortality. Okay. This is about $35 million. And this is the AFAR grant.

01:23:25.340 The second part is biomarkers. We want to make sure that we know what are the biomarkers for

01:23:32.580 metformin action and for aging. And this was funded by the NIA and we'll get the money once the

01:23:43.160 attain is funded in order to take plasma and blood and DNA and everything and be able to do omics and

01:23:52.060 other things and find biomarkers. The third part could come later. And this is the geriatric part.

01:23:59.880 You know, how many hospitalization and what's the ADL and the frailty index and things like that.

01:24:07.620 We have enough power to do it at the end of looking at people at the end and people with

01:24:14.160 metformin and without metformin. But of course, it will be better to start at baseline,

01:24:18.540 but we're not funded for that yet. And how many subjects in each arm?

01:24:24.000 Well, we are discussing now, we are planning 3,000. Our power is based on 3,000 subjects,

01:24:30.480 but we might have enough money to increase to 3,500 subjects with the hope that it might accelerate

01:24:38.220 our results. It's not necessarily so. It's possible that you need the time that you need,

01:24:45.060 but it's 3,000 subjects now, but could be more later.

01:24:50.620 And does your budget permit for serology testing or other things to now include potential,

01:24:57.720 given that your subjects, I assume are older, you have a beautiful population to also study

01:25:02.540 the effects of metformin on immune function, specifically with respect to COVID-19.

01:25:07.220 Right. So the way we organize the study, and this is also in negotiation with the NIH,

01:25:16.000 we will have auxiliary, ancillary studies that will be reviewed. Sometimes you need only 250

01:25:24.240 people, so it can be in one center. We have 14 centers. And part of the examples we gave is

01:25:31.420 actually immunity. That was the example we had. It was against the flu. But of course,

01:25:36.280 now we're talking about, if we start before immunization, we'll immunize for influenza the

01:25:42.300 first year and see the response. And then for COVID-19 the next year and see the response.

01:25:50.120 Joan, back to you on this other question then. What do you think about the idea of,

01:25:56.320 could there potentially be a benefit in combining metformin with a rapologue? Knowing what we know

01:26:01.080 now about the potential pillars, there's not a huge amount of overlap, at least in the most

01:26:06.460 fundamentally important pillars, right? I mean, the two really clear things that rapologues are doing

01:26:13.120 is impairing synthesis and probably inhibiting SASP. I mean, those two seem undeniable. And then

01:26:20.840 there's probably some autophagy depending on the way that you inhibit and or the tissue.

01:26:26.040 So how does that fit with the double down effect of the metabolic side of metformin along with the

01:26:32.540 potential increase of ROS and some of these other benefits around inflammation that come from

01:26:38.380 metformin? Is there a synergy with these things? Yeah, I don't think we know enough. As I recall

01:26:44.720 from the ITP study where they use both, the effect was driven by one center, but I had seen that data

01:26:51.700 early before the whole study was finished. I have done analyses of people who are getting

01:26:58.460 the rapologues or RTB who are on or off metformin just to see if I could see a difference, but we're

01:27:03.920 way underpowered. So I can't say anything yet. And Nir, you may understand the biochemical rationale for

01:27:13.840 using the two together. But I do think, to Nir's point, every drug that has a biologic effect has a

01:27:19.920 side effect. And so if you use two drugs that have a biologic effect, you're just going to get more

01:27:24.180 side effects. So you've got to make sure that the benefit's outweighing the risks.

01:27:29.860 Let me give you an example. If both of them are enhancing autophagy, okay, which is good and

01:27:36.340 it's synergistic, but the patient has cancer, then it's when we want to stop autophagy.

01:27:43.420 But Peter, can I ask you a question? I love hearing people who are taking rapologues or

01:27:48.640 metformin. What did you notice on each of them? Yeah. Why did you stop?

01:27:53.200 Sure, sure. So, well, as I said, I started metformin in 2010, the spring of 2010, May of

01:28:00.300 2010. I remember it very well, actually. And I stupidly just started at 2,000 milligrams a day.

01:28:08.060 I didn't escalate the dose. So I remember having lots of nausea for about two months. And again,

01:28:15.120 some people, if they just go straight to a high dose, they do feel nauseous. Others, usually when

01:28:19.920 I put patients on it now, we titrate them. We go 500 at night, then 500 BID, 1,000 at night,

01:28:26.040 500 in the morning, et cetera. So that was my first. Beyond that, I didn't even notice I was taking it.

01:28:31.120 So never a side effect again. So why did I stop it in 2018? In 2018, I started to very,

01:28:37.420 very closely track my lactate levels during exercise. And in particular, I was tracking my

01:28:44.400 lactate levels during a type of exercise called zone two exercise, which is when you're basically

01:28:50.480 trying to see how much work you can do under purely aerobic conditions. The definition of this is,

01:28:59.020 is actually how much work you can do while keeping lactate below two millimole. I used to do a lot of

01:29:05.740 lactate testing on myself when I was an athlete. So I was familiar with what these levels looked like.

01:29:10.320 And I was kind of surprised at how high my lactate levels were, even at baseline. You know, I was

01:29:15.280 walking around at a lactate level of 1.6 millimole. Now it would dip a little bit when I would start

01:29:20.320 exercising, but I was realizing that I just had, you know, higher lactate levels than I wanted to.

01:29:28.580 And I thought about it and I was like, wait, this is obvious. I'm taking a mitochondrial toxin.

01:29:32.840 Of course, my lactate levels are going to be higher. So then I did the experiment and I did all

01:29:38.580 this sort of talking with a friend of mine, Inigo San Milan, who's also been on the podcast of

01:29:43.280 stopping metformin and starting it again, just to see if we could reproduce the effect. And sure

01:29:47.960 enough, it was clearly the metformin that was allowing my lactate levels. And this, you do this

01:29:52.940 at a fixed power level, right? So you, on an ergometer, you would just say, look at this many

01:29:58.380 watts or this many miles per hour on a treadmill. You could watch your lactate level go up and down

01:30:04.180 as a function of metformin. And then, you know, we looked at a couple of studies and you saw that,

01:30:11.340 look, there were some things that metformin was blunting with respect to exercise. Some things I

01:30:17.120 didn't care much about, but you could certainly see, I think in the master's trial, you saw, and

01:30:20.960 Nir, I'd love for you to talk about this trial a bit, some blunting of hypertrophy. So muscle mass,

01:30:27.260 though, I don't think they looked at muscle function. So maybe it wasn't having any impact

01:30:31.580 on, on muscle function. They looked, they hid it well. Did they look? Yeah. So we have a paper in

01:30:39.240 review now that, by the way, it took us a lot of time because the authors just disagreed on the

01:30:44.100 interpretation of the same data. Joan, it was everybody exercised half of them with metformin and

01:30:50.900 half without. And they got a grant because they said, it's going to be synergistic, you know,

01:30:56.440 through AMP kinase. We're going to have better effect. The people with metformin and exercise

01:31:00.980 are going to do better. And what happened, the people that were exercised with metformin had

01:31:06.700 significantly, not, they all increased muscle mass, but they had, they had less muscle mass.

01:31:13.420 In the supplement, they show you that the function was actually the same. In other words,

01:31:20.900 gram of muscle when you're on metformin is doing better work when, than gram of muscle,

01:31:29.380 when you exercise only, it was a little bit hidden. And that's why I took this study and I said,

01:31:35.120 I want to see the transcript. And the transcript all showed what you kind of missed in this whole idea.

01:31:42.660 Metformin is decreasing mTOR and exercise is increasing mTOR. So all the mTOR transcripts,

01:31:50.660 were higher in the exercise only group and were blunted by metformin.

01:31:56.640 And were these elderly or young?

01:31:59.260 75 years old.

01:32:00.600 75?

01:32:01.360 Yeah, all elderly.

01:32:02.620 Because there's other papers where mTOR inhibitors don't decrease muscle mass in older people. So that's,

01:32:08.920 you know, it doesn't seem to...

01:32:10.640 Just a minute. Let me just tell you the main result. 516 of the transcript were different between

01:32:17.460 them. They were only in the metformin group. And those were the transcripts that we want to see with

01:32:23.960 aging, such as transcripts for autophagy. So basically what I'm saying, in this elderly population,

01:32:32.400 what the metformin did is kept the young profile of the muscle. And at the end, yeah, maybe you had

01:32:41.500 less muscle, but the same function. But you gained by metformin protecting 500 transcripts that are

01:32:50.200 aging transcripts.

01:32:52.760 And then what do you make of the changes in aerobic efficiency? Wasn't there another study? And I was

01:32:59.520 thinking while you were talking, I could find it and I just can't find it. I think it's the

01:33:03.600 Konopka, right?

01:33:05.100 From Colorado, a group in Colorado. I forgot the name. But what you said about lactic acid,

01:33:11.640 I saw it in my first study with the Fronzo. All our patients increased their lactic acid. Some of

01:33:18.300 them above two, some of them below two, all of them increased. And the increase in lactic acid was

01:33:23.900 associated with better glucose control.

01:33:27.240 Interesting. Yeah.

01:33:28.420 It's one thing to have lactic acidosis.

01:33:30.720 And to be clear, my concern was not at all lactic acidosis. It was, are my mitochondria less

01:33:37.740 efficient as someone who is exercising so much? So it was really my concern was this.

01:33:44.680 I still have many patients who are taking metformin. My thinking became, if you are

01:33:50.220 metabolically healthy and if you are exercising to a maximum degree, if you are maximizing the dose

01:33:56.400 of exercise, is there additional benefit that comes from metformin? Or is this a drug that is

01:34:02.280 better reserved for people who are not taking the maximum dose of the drug known as exercise?

01:34:07.180 That basically is my question.

01:34:08.940 My answer is there is an independent effect of metformin when you're exercising,

01:34:14.500 at least if you're those people. And that's why I'm taking metformin and I'm exercising daily.

01:34:21.240 And when you say those people near, you mean people above a certain age?

01:34:25.160 Yeah. Those were a group that were above 70 years old. Okay. The study that I'm telling you,

01:34:31.320 I don't know at 40, 50 and stuff. And I don't know about maximal exercising, right? It's not,

01:34:37.080 I didn't describe a study that you were the example of the patient.

01:34:42.220 And what dose is TAME going to be testing one gram twice a day?

01:34:46.120 1,500 milligram of extended release. They'll get three tablets every morning or every night,

01:34:53.180 whatever they choose. 300, 500 milligram extended release pills.

01:34:57.640 And is that what you take personally is 1,500 milligrams?

01:35:00.860 Yes.

01:35:01.860 Okay. So then going back to your question, Joan, when I started rapamycin, and I think I've talked

01:35:08.980 about this maybe even with Lloyd on that podcast, I knew I wanted to take rapamycin going back to

01:35:15.540 2011, 2012. Again, based on just the data in the mice, the yeast, the flies, the worms,

01:35:23.820 my biggest fear was immune suppression. Your paper comes along in 2014. Now, all of a sudden,

01:35:30.700 I'm feeling much more emboldened, still not sure how to dose it. But again, if your paper suggested

01:35:37.120 anything, five milligrams once a week was a pretty good place to start. Then triangulating from some of

01:35:44.240 the data in Matt Caberlin's dogs and some other folks, I sort of arrived at, I think I arrived at

01:35:50.740 six milligrams once a week was the right place to go. What wasn't clear to me and still probably

01:35:56.000 remains unclear to me is how to cycle it. I mean, I have a protocol where I sort of go on for eight

01:36:02.320 weeks and off for six, or I think it's on for eight, off for five. So it works out to be exactly

01:36:07.320 a quarter. But truthfully, you know, without more advanced testing, I'm really making it up. And

01:36:13.160 therefore, I don't like talking about it. I just did. But, you know, I don't want to suggest that

01:36:18.020 I know anything more than I'm extrapolating. That said, I definitely do get side effects from it. I

01:36:24.980 get apthous ulcers, not as many as I used to. So there must be some acclimation I'm having. But

01:36:30.200 I remember I used to get apthous ulcers in residency all the time. I mean, I don't think I

01:36:35.880 went more than two weeks without a horrible apthous ulcer in my mouth during my residency.

01:36:41.200 And I remember the day I walked out of the hospital for the last time, never getting one again until I

01:36:48.100 started rapamycin, you know, 12, 14 years later. That's been the only thing I've noticed. One other

01:36:54.080 little thing I've noticed, which is really odd is when I'm on it, and it's not surprising,

01:36:58.460 my fingernails grow slower. For example, I'm not taking it right now. And this is going to sound

01:37:03.980 dumb. I feel like I have to cut my fingernails like every four or five days. Do you feel any

01:37:08.860 benefits of from either of them when you were on them or not really? Nope. I don't feel anything

01:37:14.320 that I can, that I can comment on. Joan, you didn't see him before, but he looks so much older these

01:37:20.200 days. I bet you he looks younger. I looked like a spring chicken until I started taking it.

01:37:28.460 Nir, talk to us a little bit about your book. I want to kind of go back and talk about a couple

01:37:33.700 things. There was some funny stories in there that I was unaware of, and I want to at least

01:37:38.080 have you tell one of them. I had no idea that you were one of the reviewers on the University

01:37:43.920 of Wisconsin program. I'm writing about this experiment in great detail for my book that

01:37:51.340 will hopefully be out in the next 10 years. And I talk about the NIH monkeys and the Wisconsin

01:37:57.100 monkeys, et cetera. But talk to us about, I don't know if you know this story, Joan. Do you know

01:38:01.360 the story about what Nir found when he was doing this? No. So set the stage, Nir. This is the single

01:38:06.920 biggest experiment ever on caloric restriction. Right. We couldn't do longevity in humans. So

01:38:14.540 let's do it in primate and make sure that we're making progress. So Wisconsin set up their experiment.

01:38:20.660 They go for, I think it's already 10 years, actually. I'm not sure it was five years or 10 years, but

01:38:27.480 there's the renewal. Okay. And they write the renewal and the committee meets in Wisconsin the night

01:38:34.620 before. And we go first over our comments. I'm reading their preliminary data and I see something

01:38:44.220 very interesting. The elderly animals are before the body weight were separated and parallel. And all

01:38:53.120 of a sudden the monkeys are older, but they're starting to weigh the same. Although they're

01:38:59.420 calorically restricted, supposedly, there's a disappearance of the delta weight. And I'm thinking

01:39:07.100 first, maybe, maybe it has to do with aging. It's, you know, it just doesn't work as well.

01:39:14.600 Metabolic rates are slowing.

01:39:15.960 Right. Something is slowing. I don't know. But then I'm noticing that those cohorts were started

01:39:24.140 at different times. They had like three cohorts. I don't remember exactly, but three cohorts that were

01:39:29.220 started at different time. So there were different ages, but all of them in the last year, their weight

01:39:36.540 disappeared. And I'm sitting in the committee and I said, there's only one possibility that I can

01:39:43.460 think of that all cohorts are doing that. And that's somebody's feeding the monkeys. Okay. And,

01:39:49.480 and not noticing them. And indeed, they're coming with those guys in the morning. And they say,

01:39:54.920 before we start, we want to tell you somebody was feeding the monkeys.

01:39:59.720 Extra food.

01:40:00.680 Out of compassion.

01:40:01.780 Oh, my gosh.

01:40:03.160 Okay. And basically ruining this study. The Wisconsin monkeys took a year, a year break.

01:40:12.560 And we're at living bed.

01:40:15.740 But nobody talks about this and the difference between the NIA and the Wisconsin.

01:40:19.760 I know. And maybe there's no difference. But I'm telling this story for another reason,

01:40:24.800 because, you know, you realize I have all those monkey, all those rats that are caloric restriction,

01:40:31.420 because that's my positive control. Right? So I'm going to Einstein and I said, I want, you know,

01:40:37.060 you're, you're meeting the animal caretaker. Are they meeting? He said, yeah. I said, I'd love to

01:40:41.860 talk with them. And very simply, I'm telling you, you know, we're looking at aging, caloric restriction

01:40:46.760 extends lifespan. And we were doing it in animals. And I'm telling them the story of Wisconsin. And

01:40:55.160 since then, they were, I mean, nobody did anything wrong, but I knew that those guys are with me.

01:41:02.420 I said, it's better for those who are caloric restricted. They're less sick. They live longer.

01:41:07.060 Don't feed them.

01:41:08.600 Right.

01:41:09.420 I love that story, by the way, because it speaks to the human nature of science, right? And at the end of

01:41:14.760 the day, science is still an operational discipline and you can have the most perfect

01:41:19.420 idea imaginable. You can have the most beautiful theory imaginable, but it is so difficult to do

01:41:25.480 clinical trials. And even though that was a trial in primates and not in humans, it's as complicated

01:41:31.900 as any human trial imaginable. And whether it's that study or any of these studies we're talking about,

01:41:38.720 the decisions you make can come back to haunt you forever. If you pick the wrong patient in which

01:41:44.600 to study this, if you pick the wrong indication. I mean, I'm constantly amazed at how often science

01:41:49.600 actually works out when you consider all of the permutations in which it could go wrong.

01:41:54.700 Absolutely.

01:41:55.580 All the washout periods. Did you wash out long enough? Did you not wash out long enough?

01:41:59.960 These things amaze me. Let's pivot a little bit to talk about epigenetic clocks. They're getting a

01:42:05.240 lot of attention lately. There was a paper that came out probably three weeks ago,

01:42:10.960 looking at some changes in methylation. Do either of you want to just take a stab at sort of explaining

01:42:17.520 to the listener what an epigenetic clock is, given that we're talking about aging, and then maybe we

01:42:22.100 could talk a bit about them?

01:42:23.580 With aging, there are epigenetic changes. It would mean it's not the sequence of the DNA, right? But on

01:42:30.320 top of the DNA, there is a way to control whether gene is activated or not. And one of the ways to

01:42:36.860 control that is methylation, which is a relatively simple reaction. And methylation is one way where

01:42:44.760 the environment interacts with our genome. And the methylation with aging are either increasing or

01:42:50.780 decreasing. Both of them happens. And very often, the consequence is change in gene activity.

01:42:59.480 David Sinclair, in his book, you can see that I'm seeing it as one of the hallmarks of aging.

01:43:04.740 David Sinclair really thinks that that's not only the major cause of aging, but also the major

01:43:10.400 way we change that. Anyhow, Horvath and Morgan Levine and some other people around the world

01:43:18.040 have looked at methylation sites and tried to correlate them to chronological age, okay? And it's a big

01:43:26.680 process. It's also with artificial intelligence. You have to take lots of methylation sites. You have to do

01:43:32.820 and see the chronological age, but more important, and the most important thing is to distinct between

01:43:39.540 biological age and chronological age. And there's a huge body of work that really showed that methylation

01:43:47.540 clocks, and they're in development, there's newer and better, that methylation clocks are good.

01:43:54.360 They're really good clocks of biological age. In particular, when you see if they predict mortality,

01:44:01.600 for example, but also predictions of a lot of diseases, not all of them. And so all of a sudden,

01:44:09.980 this methylation became not only an important biology, a predictive biology, a biomarker, but

01:44:17.240 also became a business. And this is kind of available out there.

01:44:22.220 I mean, I think what's interesting to me is, are these changes all pathologic or are some of them

01:44:30.060 compensatory and actually good? And so is reversing a biologic clock going to mean you're in a better

01:44:39.160 state or not? So it's independent things.

01:44:43.640 And I would add to that, I think, Nir, you and I have maybe even talked about this, or I feel like

01:44:48.240 I've talked about it with somebody, so I don't know if it was you, but we don't know if a person

01:44:53.320 has a, let's just say, person shows up at time T-naught and they have methylation status M-naught.

01:44:59.700 You then apply an intervention that is beneficial. You give them rapamycin, you give them metformin.

01:45:04.860 You go down to, you know, another time point. Even if you have not undone methylation,

01:45:11.700 how do you know you haven't done good that is proactive as opposed to retroactive?

01:45:17.260 Exactly. So we, it's one thing to have a biomarker that predict biological age,

01:45:23.640 but we want much more than that. We want biomarkers to predict if we're targeting aging,

01:45:29.840 right? We don't want to do phase three studies for every drug that we have and spend billion of

01:45:36.940 dollar over five years to find that it doesn't work. We need something that will show it in

01:45:41.760 weeks or months that it's doing that. My fear though, I just want to insert my concern on this

01:45:46.760 is every time I've looked at one of these, I have found the data to be somewhat unhelpful because I

01:45:52.000 don't know what to make of them. So I just had a patient use one of the very famous clocks. So he's a

01:45:59.000 healthy guy, you know? So his baseline test said he was 34. His biologic age was 34, which was younger

01:46:06.080 than his chronologic age. So you are to the gate. You're thinking, well, that's already great news.

01:46:10.480 So then we put him through a five day water only fast. It's a pretty extreme measure. And then we

01:46:17.500 checked the blood test immediately after. And sure enough, on the same biologic clock, his age went

01:46:22.920 down to 27. So does that really mean that in five days of water only fasting, he got seven years

01:46:32.180 younger? I mean, it's nonsensical to me, truthfully. And I find it a little bit annoying

01:46:38.340 that people look to these clocks as though there's some, you know, stone that comes from a deity that

01:46:44.960 tells us something like, you know, you can reverse engineer these things in any way you want actually.

01:46:50.460 Right. And I think that's the problem. I think that methylation are kind of stable. So what we've

01:46:57.400 been doing, we had a nature medicine paper at the end of last year with Tony Weiss. I don't know if

01:47:04.000 you know Tony Weiss, Corey from Stanford, but, and we had a paper just accepted too, but we were

01:47:10.880 looking for proteomic and doing a clock from proteomic. So I have a study where I have, I took thousand

01:47:20.460 patients between the age 65 and 95. And by optomer technology, we looked at each one of the thousand

01:47:28.860 patients on 5,000 proteins. And we asked, what does change between age 65 and 95? And we got hundreds

01:47:37.340 of proteins. The most important thing about the proteins, they were a bunch of proteins that were

01:47:44.940 breakdowns. Okay. Breakdowns of collagen, of metrics, of granulocytes, of platelets. And initially

01:47:53.720 I said, oh, give me a break. That's, you know, what do I do with that? Coming to realize that that's

01:48:00.860 possibly the best biomarker that we have, because no matter what we're going to do, whether it's with

01:48:07.480 rapamycin or metformin or autophagy, what we're going to do is stop the breakdown that is typical to

01:48:13.720 aging. And also proteomics are much more reactive than methylation, I think. Although Peter just said

01:48:22.040 in five days, the methylation responded. Well, and in fairness, I don't know how much of that

01:48:27.760 clock response was methylation versus the other biomarkers. So these commercial tests are using

01:48:34.140 methylation is one thing, but they're using glucose level, insulin level. They're using a whole bunch of

01:48:40.460 biomarkers. And again, I just know from having looked at the inputs, you never know what the

01:48:46.060 algorithm is, but you know what some of the inputs are. You know, vitamin D level is one of them.

01:48:51.180 Well, you take somebody whose vitamin D level is 20, which is low. You could give them 5,000 units a day

01:48:56.580 and normalize it. And that change alone improves biologic age in a manner that's simply inconsistent

01:49:03.900 with a single clinical trial that has ever suggested you can extend life with vitamin D.

01:49:09.400 And so these are the problems I have with these things. But I agree, like to me, the really

01:49:14.560 interesting stuff is at the metabolomic, proteomic, transcriptomic level of which maybe methylation

01:49:21.500 becomes an additional thing that matters. But I think I just struggle with any one of these things

01:49:27.740 being a magic bullet. But again, I might just be too jaded on this one.

01:49:31.640 Well, there is an aging cell paper where somebody tried to rejuvenate the thymus and they took

01:49:39.080 patients and gave them a growth hormone, right?

01:49:42.480 Growth hormone, metformin and DHE.

01:49:44.240 Yeah, I was hiding that. I think it's a metformin effect, but they showed methylation reversal.

01:49:50.540 So I don't want to say that methylation doesn't go back. I don't know this biochemistry to be like

01:49:57.440 that. And I'm doing lots of methylation on my centenarians and their children. And so I'm like

01:50:02.780 you, I'm excited of other omics and their potential as biomarkers that change with aging.

01:50:08.520 And I'll just say we've done some of this at Novartis with proteomics and aging. And the problem

01:50:15.040 is some of the proteins that go up with age are actually, they've been shown in the Framingham

01:50:20.560 Heart Study to be beneficial. Like it is a compensatory good thing. So saying, oh, I'm moving

01:50:26.480 my proteome to a younger age can sometimes actually be bad clinically. So that is part of the mix.

01:50:35.340 Absolutely. When we get the proteome, that's why I looked at the breakdown. When you look at the

01:50:40.660 proteome, you don't know what's... In fact, a lot of them we know are compensatory, like a GDF-15,

01:50:47.440 MIC, right? There's a lot that are obviously are beneficial and we don't want to take them down,

01:50:54.900 but we need to find the ones that are moving most. I want to say two more things about the

01:51:00.780 proteomic data. Of those thousand people, 500 are children of centenarians that we know are slowing

01:51:06.840 much, much later. And we published about them. They had about a third of the proteome of the 500 that

01:51:15.280 are just usual people who are aging. So we have some relationship to longevity. Also really

01:51:22.800 interesting. And I think, Peter, this is worth a whole program. The gender effects of aging are so

01:51:31.620 incredible and we've missed them in every model in, you know, in mice, in rats, in humans. But while in

01:51:40.780 men, there are 700 proteins that are changing, actually 560 that are changing, in women, there are

01:51:49.940 only 200 that are changing. The proteome of women is much more stable. Okay? So we'll need to think of

01:51:59.980 different biomarkers that are gender, are sex dependent, not only a common to all aging.

01:52:06.780 Why do you think that is, Nir? Well, we don't know. It's not as simple as saying sex chromosomes.

01:52:13.860 Okay? It's much more complicated. And I can get you to people who have NIH grant with lots of

01:52:21.320 innovative ID to do that. You know from the ITP that it's all sex dependent. You know,

01:52:27.320 thanks God that they did it. There was a discussion whether we should do it at all,

01:52:31.560 but it's different. Could it be possible if it's not sex chromosomes that it's endocrine related? And

01:52:38.360 because women go through menopause, older women have a more homogeneous... No, because even with HRT,

01:52:46.720 you'd think that would mess that up, huh? That's interesting. I wouldn't have guessed that,

01:52:50.600 by the way. If you'd turn that into a multiple choice question, I would have got that one wrong.

01:52:54.220 Well, I fulfilled the idea that women live two and a half years long was like a fact that I didn't go

01:53:04.040 on and thought that, you know, even if we cure heart disease today, we're not going to get two years

01:53:09.860 back. You know, that this is huge. And we said, yeah, but they live longer and they are sick. And

01:53:15.880 there's some truth to that. But I think there's the rate of aging itself is actually different.

01:53:22.580 And a lot of the ITP, what they do in male, they get them to the lifespan of women, of females,

01:53:28.220 right? In the mice. Going back to the idea of aging more broadly, bringing it back to your

01:53:34.880 centenarians. I think there is, you know, I think some people talk about centenarians as being escapers

01:53:41.960 versus survivors, as you put them. I talk about this with my patients a lot. I talk about centenarians

01:53:48.440 having a superpower. And our goal is to understand the superpower and try to emulate the superpower.

01:53:54.160 And the way I describe it to patients, which is based very much on your work near is that their

01:54:00.220 superpower is not that they survive better when they get diseases. It's just that they phase shift when

01:54:06.380 those diseases hit them. They just, you know, when they're 80, they're just acting like physiologically

01:54:12.680 60 year olds. But, you know, once they get cancer and once they get heart disease and once they get

01:54:17.660 Alzheimer's disease, they're not bulletproof. They just happen to be able to dodge bullets better.

01:54:22.260 So then I invoke images of, you know, Neo and the matrix and things like that. Do you think,

01:54:28.360 I mean, do you think I'm interpreting your research correctly? Or do you think that they

01:54:32.180 are super survivors and who actually can take bullets on the chest and have them bounce off?

01:54:38.160 No, look, their aging is slowed. And when I'm saying their aging, from an age-related disease

01:54:45.120 perspective, they live 30 years longer than a cohort that's 20 years younger than them. I mean,

01:54:51.940 their friends died when they were between 40 and 60. So they already more than doubled life expectancy,

01:54:57.920 right? Their aging has been delayed. What happens though, their aging has been delayed enough

01:55:06.000 to prevent major age-related diseases, but it's not obviously that they didn't age. So when they get

01:55:15.900 to their end of life, they are just almost frail enough that whenever disease they get, it kills them,

01:55:25.600 okay? I don't know that I want it out there like that, okay? Because they still live longer,

01:55:32.560 still live healthier, and still have a contraction of morbidity. But why does it happen? Because

01:55:38.560 they're old. I have always this argument, like with Tom Pearls, who's doing centenarian study. I said,

01:55:45.680 I don't care how they look when they're 100 years old, because now 30% of them will die next year.

01:55:54.280 So no matter what I measure, it will either be the predictive of their death next year,

01:55:59.500 or they're predictive of their longevity before. Right. The better thing is, when they were 80,

01:56:04.720 how do they look compared to their 80-year-old non-centenarian peers?

01:56:08.060 Right. And so we have their offspring who are now becoming 80. And it's really interesting,

01:56:15.360 because the offspring inherited only half of their genetic makeup, right? But they're so much healthier

01:56:22.700 than control. I think our best paper was in American Journal of Cardiology, when we showed

01:56:29.920 their habits. Well, their BMI and their food intake and social economy and everything like that. But

01:56:38.420 they had 40% of the heart disease of the control, okay? So genetics plays a major role here,

01:56:47.360 and it's slower their age-related diseases. Nir, you were quoted in an article, maybe it was taken

01:56:55.360 out of context, but it was very recent. And the quote is something to the effect of rapamycin could

01:57:02.220 reduce the morbidity of COVID-19 by 50%. Maybe it's out of context. I'm referring to

01:57:08.280 Joan's phase 2B study, where severe disease was decreased by 52%. Am I right, Joan?

01:57:16.620 You are right. With that, Joan, what is your dream experiment right now? If you could go right

01:57:24.760 back to RestoreBio tomorrow and say, guys, we just got an unlimited amount of funding to do

01:57:32.440 the definitive experiment. And the FDA came in and said, guys, the stakes are high enough

01:57:38.160 with the appropriate monitoring in place. We're going to let you go right to a phase 3 trial.

01:57:44.340 What experiment do you want to do right now to test the hypothesis of this agent with respect to

01:57:51.040 immune function? Yeah, I would do the phase 2B as a phase 3. I would do lab-confirmed respiratory

01:57:58.480 tract infections, including COVID-19, and just show that elderly people who take RTB-101 have decreased

01:58:08.680 severity of illness. You would not include RAD-001? You would just do RTB-101 versus placebo?

01:58:16.380 So in our phase 2A, we saw that the benefit for RTB was better than for averilibus. But yeah,

01:58:24.920 why not? It's a dream experiment. You can have three arms.

01:58:27.200 Add a rapalog tube. Add averilibus. Add RTB-101. I wouldn't add the combo because that gives you,

01:58:35.140 that didn't work as well in our phase 2B. So I'd use those head-to-head and just show we could

01:58:41.200 decrease the severity of illness. And now to the point that says these are things that presumably

01:58:47.180 have to be in the system before you encounter, these aren't drugs you start giving patients who

01:58:51.220 show up sick, how would you then think about the on versus off cycle of the drug specifically? Would

01:58:59.700 you dose it as eight weeks on, four weeks off? I mean, what would these patients be enrolled to take?

01:59:06.460 So there's a peak of hospitalizations and deaths in people, particularly 70 and older, right during

01:59:14.080 four months of winter cold and flu season. So that's when I would give it to them, where there's the peak

01:59:19.780 incidence and peak healthcare resource utilization, take it during that period and show that we have

01:59:27.340 decreased hospitalization, decreased severe symptoms. So your view is that the benefit is

01:59:33.400 coming when they're on drug, not post washout. Exactly. There may be some benefit post washout, but

01:59:40.320 we saw that in the phase 2A. In the phase 2B, we didn't have enough events after they stopped

01:59:47.020 taking drug because the season was over. So where I'm most confident is while they're on drug.

01:59:53.380 Okay. That's interesting. So that's a big deal.

01:59:55.580 I had a webinar that I called to be or not to be. And the two was the number two. And it's an ethical

02:00:04.360 dilemma. We are at war now. Okay. This is not normal times. And we're at war. Like when we went to Iraq,

02:00:12.860 we chased Saddam Hussein, we chased the terrorists. But in the meantime, we had to also build better

02:00:19.960 Humvees, right? To defend the soldiers, right? We have to attack the virus and we have to defend

02:00:25.420 the host. And you have, Joan, who's telling you very convincingly of many studies that showed that

02:00:34.260 immunity was improved. And the price from a matter of side effects, the safety was actually this,

02:00:42.360 the safety profile were better because it was treating their aging too. And you have metformin

02:00:47.800 that's been in so many years out there. We know that it's safe. So should we actually come and say,

02:00:56.400 you know, it's a war. You cannot stop the deaths of the elderly. Why don't we do those studies and

02:01:03.960 monitor them? It's not going to be controlled. But is there something that we lose? Are we putting

02:01:10.140 them in enough danger? Tell me, you're a clinician. You're such a thoughtful guy. What would you think

02:01:16.880 we should do? Well, first of all, Nir, you give me far too much credit, but I understand your

02:01:21.520 question. And I think it's a question of risk versus reward. And those are not static. And what

02:01:31.220 you're basically saying is when you ask this question in the summer of 2020, it's a very

02:01:36.680 different question from what it was in the summer of 2018. And as such, our regulatory environment and

02:01:43.780 our appetite for risk had better have changed in those two years or else we live in a static risk

02:01:49.820 environment and we're not adaptable and therefore we're really ineffective. So in many ways, I

02:01:57.240 struggle with this all the time, guys, because I don't prescribe rapamycin to my patients, though a

02:02:02.840 number of them have asked. I prescribe metformin to my patients, some who need it for the standard

02:02:09.000 indication of hyperglycemia, hyperinsulinemia, but a number who say, look, Peter, I've read enough of

02:02:14.900 your stuff. I've listened to enough of your podcasts. I want to, you know, I want to take metformin

02:02:19.480 for these other benefits. And look, I think it's completely ethical to do so. They're paying for

02:02:24.520 it out of their own pocket. It's not like we're asking an insurance company to buy it for them.

02:02:28.000 So that's fine. I don't know what it is with rapamycin that has me hesitating a little bit

02:02:32.800 more, though I would completely concur. It is probably as safe as any other. In fact, I mean,

02:02:38.440 I feel less nervous taking rapamycin personally than an antibiotic. You know, every time, I mean,

02:02:44.380 I had to take a cephalosporin a year ago. I mean, I was like, God, oh, I just don't want to take

02:02:48.820 this drug. You know, I mean, so we know that these drugs are safe, but yet there is still some

02:02:54.160 hesitation in me. And that waffling speaks to, I think, a broader issue. Now, of course, that's at

02:03:01.240 the personal level as a clinician who has to make that decision with each and every patient. I do think

02:03:07.940 that what we have talked about today, I think it needs to be on the radar of whatever entity is going

02:03:16.180 to be self-appointed as the czar of getting us through this mess and all subsequent messes.

02:03:22.640 You know, I was on a podcast with Stanley Perlman recently, and we talked about how do you think

02:03:29.740 about the no regret moves that need to always be in place for the subsequent pandemics? Like there

02:03:37.060 are just certain things that we should always have in place, right? We should always have a national

02:03:42.020 stockpile of PPE. We should have a national stockpile of every reagent you would ever want

02:03:48.600 to do PCR. We should have a national stockpile of any form of, you know, antiviral therapy or immune

02:03:56.280 modulating therapy that could be effective. And then, of course, the moment we find out about viruses

02:04:02.440 and we sequence a new virus, we should have the infrastructure in place that we can rapidly

02:04:06.480 test and have the electronic infrastructure to do the appropriate amount of contact tracing and

02:04:12.160 surveillance. But somewhere along that way is why wouldn't we also in parallel have an enormous path

02:04:18.700 around doing rigorous research around immune enhancement? So I'll give you an example.

02:04:25.100 Why hasn't someone done the definitive study to test the effect of sleep on immune function?

02:04:31.080 I mean, really, let's put this to rest and be done with it. Does it matter if you get eight hours

02:04:35.920 versus six hours of sleep? And if so, how much does it matter? Does vitamin D matter? Does it matter if

02:04:42.000 you get it from the sun or does it matter if you supplement it? Does vitamin C matter? I mean,

02:04:47.040 you can say, oh, but Peter, each of those studies would cost tens of millions of dollars to which I

02:04:52.220 say, and shutting down the economy of this country cost how much? Such a good time. Yep. Right. So I

02:04:58.640 completely agree with you. And I would love to see a full out scientific assault on these questions.

02:05:06.860 And obviously my view is that there are agents like metformin and rapamycin that could play a

02:05:13.320 significant role in preparedness. And basically what it really comes down to is resilience. I mean,

02:05:18.400 that's really what you're talking about is host resilience. These are not drugs, as you say,

02:05:24.160 that you want people taking in the ER when they're already sick. These are drugs that you should have

02:05:29.500 taken long before that so that A, you don't get sick, or if you do get sick, it's less severe as

02:05:35.880 the Chinese data that were published a week and a half ago suggest. Or before you immunize when you'll

02:05:42.760 have the immunization. That's right. I could keep talking about this stuff forever. Anything else that

02:05:48.060 you guys want to talk about with respect to this particular subject matter? I want to be kind of

02:05:51.900 mindful of our time. I know we've been chatting for quite a while here. I was thinking the dose

02:05:56.840 response too. You had asked me, would you use a rapalog early or late in the disease? Low doses

02:06:05.980 you'd use to prevent. High doses that immunosuppressive doses actually might have benefit for that

02:06:12.040 over reaction of the immune system. That's really, really interesting. So has anybody talked about

02:06:19.740 that, which is when you, when you have that patient who is now in the second wave where the immune

02:06:25.520 response is what's going to kill them, you hammer them with 20 milligrams of Everolimus on three

02:06:33.280 consecutive days or something. Anybody discussing that? There was a small study showing, I think it was

02:06:39.180 out of Hong Kong showing there was a benefit in patients with severe influenza. And I think there's

02:06:45.660 one trial looking at rapamycin in hospitalized patients with COVID. So I think the jury's out,

02:06:52.800 there was a, people are thinking about it, but whether it's going to work or not, nobody knows.

02:06:56.920 But the other thing I wanted to bring up to your point, Peter, is I do think these shouldn't be used

02:07:02.360 until we prove that they have benefit. And I think NEAR is going to get some really important data from

02:07:08.440 metformin. Hopefully, you know, respiratory or someone will start getting placebo controlled,

02:07:14.660 really compelling data showing where there is and isn't benefit of these drugs.

02:07:19.700 Yeah. You don't personally take these agents yet, I'm guessing.

02:07:22.980 No.

02:07:23.900 And that says something, right? I mean, that, do you, do you, do you think of yourself as a

02:07:28.020 particularly risk averse individual, or is that just sort of the way you, you, you think about

02:07:32.440 things and unintended consequences?

02:07:33.920 I like data. I want the data to decide what I'm going to do. So I want to generate

02:07:38.920 the data. If I, I would want to be in a clinical trial where there's data generated

02:07:43.820 to say, what is this doing so that we learn?

02:07:48.700 Yeah. I want to say two things. I think for metformin, what needs to be considered

02:07:54.720 is that TAME will answer some of the questions. Let's say we decide it's, we don't know what to

02:08:04.820 do. We're going to give metformin now. Okay. Because people are dying. The TAME study will

02:08:11.640 provide maybe later, but will provide some more evidence. It could be a little bit different,

02:08:18.060 but I actually want to say something else to the scientists, to Joan and the scientists.

02:08:24.740 We, no matter how it's going to turn out, I believe that we won. Science won here. The

02:08:31.360 scientists have been much more popular, right? Than the president or other things. Science has won.

02:08:36.980 You could see that the Pope is asking people not to go to church, right? And rabbis are asking

02:08:42.280 people not to go to synagogues. And Ramadan was not in mosques. So there was an influence. And

02:08:49.800 the influence was because they saw that we know and that we are responsible. And I certainly don't

02:08:57.860 want to change that. Okay. That's why what I'm saying is an ethical dilemma. But as a physician,

02:09:03.980 I don't want to see studies that are not clinical studies, right? That's my whole shtick here.

02:09:09.780 So I think we won and we need to find how we do things effectively as fast as possible

02:09:18.540 and that it's still led by science. The last point I'd add to that, Nir, is

02:09:24.440 it has to do also with, I think, how you get to the stage 2B, right? Which is, if you look at

02:09:30.400 oncology, I mean, why does oncology have such an abysmal track record in clinical trials? Well,

02:09:35.920 it might be that a lot of the preclinical work is subpar. It's being done in animal models that

02:09:42.780 are not particularly representative. It's being done in cell lines that are not particularly

02:09:47.240 helpful. And so it's really less about what are we doing in phase three versus how efficient is the

02:09:55.320 pipeline to get an agent into phase three? And so I guess to go back to your question of me a minute

02:10:01.020 ago, I would say that the other thing to be thinking about is how much more efficiently can

02:10:07.120 drugs be scrutinized in the pre-phase two so that you're taking better things into phase three? Because

02:10:14.280 there, everybody wins. The investor wins because you just have a much more efficient ROI. The patient

02:10:22.140 wins because the probability of success to failure goes up. And then society wins because you're

02:10:29.020 you're basically improving outcomes broadly, not just at the individual level. And again,

02:10:35.040 I think it speaks to all these challenges we've talked about, which is what's the right question

02:10:39.540 to ask? What is the right outcome? What is the right indication? And how, you know, you alluded to

02:10:45.380 something earlier, which is look, the ITPs early enough figured out. You better be really clear on

02:10:50.640 which animals you're studying this in, or you will miss effects. And so I don't know. I just think,

02:10:56.740 I don't know if enough time in science goes to this type of question, because it's not a very sexy

02:11:01.640 question, right? Like if you're myopically focused as a scientist on your problem, well, then that's

02:11:08.540 all you want to think about. You don't really want to think about these broad structural things of

02:11:12.100 reproducibility and blind spots and things like that. But I think you have to start thinking about,

02:11:18.240 when I say you, I don't mean you individually. I mean, we collectively have to be thinking about

02:11:22.280 those things if we want to accelerate therapies to the clinic safely.

02:11:26.020 I think the other thing, Peter, that people don't oftentimes think about is there is

02:11:31.140 the issue of regulatory authorities. You're absolutely right. You have to get the phase to

02:11:36.580 be right. But the FDA has never had a drug to give immunoresilience and decrease all sorts of

02:11:43.660 infections. So they have to figure it out. And I think we also have to have a little bit of

02:11:49.560 willingness to have a learning curve here, to figure all this stuff out with the regulatory

02:11:55.840 authorities. And we don't always have complete control over these designs. And we're going to

02:12:01.820 have to just, they educate us, we educate them and have an iterative process.

02:12:07.520 And I think your phase three demonstrated, you know, I'm joking always that geriatrician

02:12:13.380 are telling their patients, if you wake up in the morning and you have no pain, you're dead,

02:12:18.820 right? So this idea that the FDA decided to take 70, I don't know, 75 year old people and have a

02:12:28.680 subjective assessment of how they are, it's crazy. It works. If you're young and have arthritis,

02:12:35.040 you will say if it's gone or not. But to elderly people about their health, they'll complain no matter

02:12:42.080 what, or they'll shut up no matter what, you're not going to get the signal like that. So it's just

02:12:47.000 crazy. Sometimes what the loops that you have to go through, and they lead you terribly.

02:12:54.520 And it's just life. I mean, the FDA admitted they're trying to learn too. But I think there's

02:13:02.000 this perception that, oh my God, a phase three failed that was because it's, you know, people

02:13:09.460 don't know what they're doing or the mTOR doesn't work. It's so much more complicated than that. As Peter,

02:13:15.340 you were referring to, there are so many ways for things to go wrong that sometimes you can control

02:13:23.860 and sometimes you can't, but we have to have the perseverance to go, hey, you know, let's look

02:13:30.000 through this and see what's there and what isn't. If there's a silver lining in the last

02:13:35.560 four months, then I think there are a couple, right? If we're going to be brutally honest, I think,

02:13:41.220 you know, for example, many more people have figured out you don't have to get on airplanes nearly as

02:13:44.800 much. I don't exactly have any love lost for the airlines. So that's certainly a win. But I think

02:13:50.860 to your point, Nir, I think, I think biomedical research has been elevated a notch. And look, if the

02:13:57.460 right studies can be done, and that, by the way, it goes back to something that we haven't discussed

02:14:01.400 or you discussed earlier, but I think we should bring back to your question, which is better

02:14:04.540 biomarkers. Better biomarkers is going to allow for better studies, bottom line. And right now,

02:14:10.200 our biomarkers are so crude as to border on unhelpful at times. So imagine you could three

02:14:18.620 months into a study, have a biomarker that tells you you're on the wrong direction. You're on the

02:14:23.840 right direction. You need to pivot. You have a phase three design that is flexible enough to allow you to

02:14:29.740 make the dose change or take a certain population out of the study. And, you know, these things matter

02:14:36.600 because of the cost and the logistics of doing this study. So look, a lot of those things, again,

02:14:41.320 they're not that interesting to people. Who wants to study biomarkers? It's not that fun. But I think

02:14:46.380 we are in a new environment. And I think people are going to say, wow, we really need to invest in

02:14:50.380 biomedical research, even for something that's not an immediate threat, like immune enhancement.

02:14:58.380 Guys, thank you for tolerating me through a very awkward three-person video interview.

02:15:04.080 Thank you. Thank you so much. Thank you.

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The Peter Attia Drive - August 10, 2020

#123 - Joan Mannick, M.D. & Nir Barzilai, M.D.： Rapamycin and metformin—longevity, immune enhancement, and COVID-19

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