The Tim Ferriss Show - #193: My Life Extension Pilgrimage to Easter Island

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Starting point is 00:03:22 It took place in the middle of nowhere, effectively, on Easter Island, a very hard place to get to. And you could think of it, in a sense, as my life extension pilgrimage for a whole host of reasons. And I was surrounded by three incredibly brilliant people, and I'm going to describe each in intern. The first is Navdeep, goes by Nav, Navdeep Shandell, PhD. I'm going to butcher some pronunciation here because I don't know how to read some of these words, but he's a David W. Kudgel, I believe, C-U-G-E-L-L, professor of medicine and cell biology within the Feinberg School of Medicine at Northwestern University. Nav is extremely good at questioning

Starting point is 00:04:07 assumptions, testing assumptions, as are the other people I'm going to mention. And I'm just going to give you one example. Many of you listening probably take antioxidants. And here is a description of interests on Nav's faculty profile. And I'm going to blaze through this, but I do think it's really, really fascinating and just kind of opens the door to discussions that many people are not having. Here we go. Historically, reactive oxygen species, ROS, have been thought to be cellular damaging agents lacking a physiological function. This is why many of us, this is Tim's voice now, take antioxidants, right? We want to snuff out these reactive oxygen species. Back to Nov. Accumulation of ROS and oxidative damage have been linked to multiple pathologies, including neurodegenerative diseases, diabetes, cancer, and premature aging.

Starting point is 00:04:57 This guilt by association relationship left a picture of ROS as a necessary evil of oxidative metabolism, a product of an imperfect system. Yet, few biological systems possess such flagrant imperfections, thanks to the persistent optimization of evolution. And it appears that oxidative metabolism is no different. More and more evidence suggests that low levels of ROS are critical for healthy cellular function. And in his lab, he says, we are testing whether mitochondrial release of H2O2, that's hydrogen peroxide, has evolved as a method of communication

Starting point is 00:05:31 between mitochondrial function and other cellular processes to maintain homeostasis, example given stem cell function and immune responses, and promote adaptation to stress, example given hypoxia. So this is very much a counter view to what you would find in media. And for that reason, and many, many others, I enjoyed hanging out with Nav. Now his partner in crime comes up next. And his partner in crime, one of his best

Starting point is 00:06:00 friends is David Sabatini, MD, PhD. You can find him on Twitter at DM Sabatini, S-A-B-A-T-I-N-I. He's a member of the Whitehead Institute for Biomedical Research, investigator at the Howard Hughes Medical Institute, professor of biology at the Massachusetts Institute of Technology, otherwise known as MIT, and a senior associate member at the Broad Institute. David is on, you could think of it as a shortlist for the Nobel Prize, at least according to Reuters, for his work in elucidating the role of rapamycin and something called mTOR, which we're going to talk a lot about. And for those of you out there who have thought a lot about life extension and looked for silver bullets, you've probably come across metformin and rapamycin. Well, in these two gents,

Starting point is 00:06:50 Nav and David, you have respectively two of the world's foremost experts in how, say, metformin and rapamycin function. Next up, we have one of my faves. He's been on the podcast at least twice before. Peter Attia, MD. You can find him on Twitter at PeterAttiaMD, A-T-T-I-A, eatingacademy.com. He is a former ultra endurance athlete, swimming races at 25 miles and crazy stuff like that. Compulsive self-experimenter like yours truly and one of the most fascinating human beings that I know. He makes my OCD look like a light case. He is also one of my go-to doctors for anything performance or longevity related. Peter earned his MD from Stanford and holds a Bachelor of Science in Mechanical Engineering and Applied Mathematics from Queen's University in Kingston, Ontario. Did his residency in general surgery at Johns Hopkins and conducted research at the National Cancer Institute under Dr. Steven Rosenberg, where Peter focused on the role of regulatory T-cells in cancer regression and other immune-based therapies for cancer. And we get into a lot in this wine-infused jam session on Easter Island. And I try to guide it best I can. I had a fair amount

Starting point is 00:08:06 of wine, as did one or two others, perhaps, in the group. We discuss antioxidants, their role or lack thereof. We get into all sorts of serious stuff. We also talk about, and it might even have an impersonation of Borat, talk about what is ass-cr crack voting exactly, how to staple, that's courtesy of Peter Attia, fonts, and a supplement that many of you have asked about, which is Basis. And I believe the company is called Elysium. So there you have it, folks. Sorry for the long intro, but I felt the context would be important. These guys are absolutely brilliant. And I was playing catch up the entire trip. But that is how you grow. You got to be the weakest person in the room sometime. All right. I hope you guys enjoy this as much as I enjoyed recording it. Thanks

Starting point is 00:08:58 for listening. All right, folks, here we are on Easter Island, Isla de Pascua, of all places. And we have a number of folks here, one doing something obscene with his hands. I'm not going to mention who. And we're going to start with some introductions. We have one known character, two new faces. Nav, would you mind introducing your friend, David? Well, Tim, I want to thank you for inviting me to your wonderful podcast in this lovely magical place called easter island i'm here with my good friend

Starting point is 00:09:31 david sabatini who's a professor at massachusetts institution of technology it's known institute what i say institution whatever it MIT. Not an insane asylum. What can I tell you? That's what friends do. They correct each other all the time. In his case, he just corrects me. Anyways, David is a professor at MIT, and David made a remarkable discovery about 20 years ago. He hasn't discovered anything after that, but it was remarkable 20 years ago. She hasn't discovered anything after that, but it was remarkable 20 years ago. And that was on a serious note, which was he figured out what's called a protein called mTOR, mechanistic target of rapamycin. Rapamycin, and we'll get in a lot into this, was actually found in Easter Island. And for David, this is kind of like a pilgrimage to sort of pay homage and other things to this great little molecule called rapamycin.

Starting point is 00:10:37 And obviously, we're going to talk a lot about what all these magical things rapamycin could possibly do. Fantastic. And just so you guys realize, since it may not be obvious at first listen, these two have known each other for a very, very long time. So the way that Peter and I bust each other's balls, you may hear occasional busting of balls between these two. David?

Starting point is 00:11:04 Sure. So thanks, Tim. I just want to thank you and also Peter. Peter actually was the person who took an incipient idea and had this actually happen for us to all be here. So Navdeep Shandell, I've known him, I don't know, probably maybe 10, 15 years, somewhere in that range. He's a professor at Northwestern in Chicago. He is, I think, my best friend in science. He has worked in an area of biology. Actually, he started working in area of biology that, frankly, a lot of people were not that interested in for a long time. And these are these things called mitochondria inside our cells. And sometimes, probably people

Starting point is 00:11:43 have heard of them as the powerhouses of the cell because they make a molecule called ATP, which is an energy molecule. And Nav, I think it's safe to say, was the first person who realized that these really important compartments in the cell did a lot of other things. And this idea that they're so-called signaling organelles

Starting point is 00:12:01 really initiated with Nav. These are now very popular things to study and nav was there at the beginning to do that he's also one of the most charming people in science he is friends with everyone he's the social butterfly of all meetings and really a meeting without nav is no fun strikes an incredible resemblance to a bollywood star i thought you i thought you were going to say julie from the love boat you know the cruise director as he just sort of pointed out but you know nah i'll take the bollywood star yeah the ones who don't get the girls usually

Starting point is 00:12:35 so uh peter how did you come to know these two guys? So I've known David for a few years. We actually met. I don't actually remember who introduced us, but kind of took an interest in trying to better understand how inhibition of this thing that Nav alluded to, mTOR, could be valuable in the treatment of cancer. And about a year and a half ago, we were having dinner and he mentioned that one of the things he always wanted to do was have a meeting on Easter Island to commemorate the 20th anniversary of the elucidation of how rapamycin works. So I guess as Nav alluded to, we'll talk a little bit about that or maybe a lot about that. And so this idea kind of seemed amazing to me because I thought the story of rapamycin's discovery, which I'm sure we'll get told at some point this evening was about one of

Starting point is 00:13:45 the most interesting stories in science not just from the standpoint of the expedition um the isolation of the molecule or identification of it but also how close it came to never happening and then to the story of how its mechanism of action was identified independently by different groups. And, you know, the story of how David did it, uh, at such a young age is kind of amazing to me. So David and I kind of crafted this idea about a year ago, which was, we'd come to Easter Island to scope it out, to basically see first and foremost where Rapa was discovered, but also to figure out if there was a way to have a conference here. That idea quickly took hold. And then I think I just talked you into it.

Starting point is 00:14:31 And that took about, I don't know, 10 to 11 seconds. And I think David similarly talked Nav into it. And that's what took 11 minutes, 11 minutes. Yeah. So that's,

Starting point is 00:14:43 that's what got us here. You want to share a room with me and i made sure that did not happen once i disabuse him of that so peter you've you've told me before and i kind of ask you to retell it like a bedtime story because i like it so much and of course everybody can jump in at any point but the lore of and connection between where we are east island otherwise known as rapa nui and rapamycin yeah so in 1964 an expedition from mcgill university uh set out um they i believe arrived on the island uh in early december of 64 and they spent what probably half a year here dude you just watched a movie about it last night yeah youtube wasn't

Starting point is 00:15:34 working it took like an hour to get through the first four minutes of the documentary i think i know less now than i did before we tried to watch it um Rapa Nui is great for many things. Connectivity is not one of them. So this group returned to McGill University and by about 1972, I believe, the soil that contained Streptomyces, which one was it, David streptomyces hydra hydropicus they had collected near a volcano here that's right which we saw the first day we got here which was mind-boggling um this made its way into the hand of a chemist named seren sengal who sengal sengal who was at a biotech company that is no longer in existence. Another Bollywood star. It was based at a pharma company called Iris. Yeah, Iris.

Starting point is 00:16:27 It had offices around the country, but he was in the Montreal office. He spent, I think, the next three years purifying the compound, the active compound within this, which he named rapamycin. Rapa, obviously paying respect to the island on which it was discovered mycin being uh sort of the thing we'd add to the name of something that was uh an antimicrobial agent um what was the lore among the locals or the purported background of this volcano so the word on the street which was reiterated to us this week was that more than once actually right yeah yeah any anytime natives were sick the the the local the rapanui they would go and spend an evening

Starting point is 00:17:12 in the marsh area of the volcano and it would seem to rid them of all their ales um now in truth it's not clear to me that that's why they were prospecting there. I think they were looking for biodiversity, but it certainly makes for a great story. The story gets interesting back in Montreal. This happened sometime between 1975 and 1980. I don't know the exact details, but this company went through a series of layoffs. The majority of the people in Montreal were basically released. Surin was one of the few who was not. He was transferred to the New Jersey office. However, he was ordered to destroy all non-viable compounds, of which rapamycin was one.

Starting point is 00:17:56 Now, he'd already figured out something pretty remarkable about rapamycin, which is it was a potent inhibitor of yeast. As the story goes, he believed this was going to be a game-changing drug for athlete's foot. I don't think at the time, David, they really understood its full anti-proliferative effects, did they? No, but it was pretty early. They started seeing things in human cells too, right? In immune cells.

Starting point is 00:18:27 So, Saren and his son, Ajai, who was actually supposed to be on this trip with us. So, it's super sad that he had a work commitment and he couldn't make it here. They actually packaged up the rapamycin into little dry ice containers and manually, like, wouldn't even let the movers do it. They were the ones that physically brought it to New Jersey where it sat in their freezer for almost a decade. It wasn't until Wyeth bought this company in 84 or 85 that Soren approached his new bosses and said, hey, I've had this compound I was working on a decade ago. Do you mind if I get back to it? To which they said, knock yourself out. And that really began the new birth of rapamycin, which as David said, really went on to show these remarkable anti-proliferative properties. And in particular, was really potent against the type of immune cell called T cells, which is what ultimately

Starting point is 00:19:16 led to its FDA approval in 99 for the treatment of kidney rejection. But it had been so long since rapamycin was discovered, actually the patent on the chemical entity, which is the most valuable kind of patent you can have, had expired at that point. So it was really a use patent that they could get. And people would criticize why, how could it possibly have taken, I forget what patents were, like 17 years at that point. So it was an incredibly long story to get clinical utility. How did you connect with rapamycin?

Starting point is 00:19:46 Yeah, so that's a bit of a long-winded, maybe complicated story. So I was a student at Johns Hopkins, and I was an MD-PhD student. And I went into the lab of probably one of the most prominent scientists at Hopkins, a man who's still well. His name is Solomon Snyder. And Saul is like a real character in science. He was a psychiatrist, a neuroscientist, pharmacologist. And when I got to that lab, it was an interesting lab because he gave you, or at least he gave me a lot of freedom. So basically let me do whatever I wanted to do. And so that was great, but at the same time, very nerve wracking. How did you choose his lab? Why did you want to go to his lab?

Starting point is 00:20:29 It was pretty simple. It was a lab that lots of other students like me, I was an MD, PhD student, so a joint student. Lots of students went. It had a reputation of having lots of smart people in it. And I also think that it had a reputation for people getting out of that lab fairly quickly. It was sort of a work hard, play hard type of lab. So mostly it was my friends were there, which as I tell a lot-506, which Peter and Nav know pretty well, has some structural similarity to rapamycin.

Starting point is 00:21:09 And the reason they were using it is they were just using it as a control. They were using rapamycin as a control. As a control, exactly. So they were working with this other FK-506, which is also an immunosuppressant. They were doing these things in neurons, but they needed a control. And they started using a related drug, which is a fairly typical thing to do. And I realized two things. One is that we had rapamycin, which at the time you couldn't buy. And I'll tell you how we had rapamycin. And two, that from what I read about it,

Starting point is 00:21:41 it was at least as interesting and probably a lot more interesting than FK506 and we didn't know how it worked. And the reason we had it is, and this goes back to the story Peter told, is that Saul was a very prominent person. And so when he saw in the literature a molecule he liked, a drug molecule, particularly a molecule that was very potent, which basically means it acted at very low concentrations, he would typically write whoever reported that and say, I'm Saul Snyder,

Starting point is 00:22:04 and it'd be great to get a sample of your drug. In this case, he had written Saran Sehgal, who came up earlier. And Saran, who I unfortunately never met, was incredibly nice and sent us a ridiculous amount of rapamycin, which technically at that point was priceless because it was not purchasable. But when it did become purchasable, I calculated at one point the street price would have been like $10 million or something. Wow. The amount that he sent you. The amount that he sent us, which at some point we actually lost, which is a little

Starting point is 00:22:33 bit bad. But the more important thing he sent, which again, you have to remember this was before there was a lot of sort of electronic papers. It wasn't that easy necessarily to search things online. That was pretty primitive. lot of sort of electronic papers. It wasn't that easy necessarily to search things online. It was, that was pretty primitive. He sent us a book with it that said rapamycin bibliography, which he had put this little note that just said perhaps of interest. And basically this book had everything ever published on this drug, which again, reignited my interest in sort of the molecule because there's a lot of cool things. And most of these were abstracts. These were

Starting point is 00:23:03 sort of little, actually mostly from meetings where people had reported little things about this drug so that's how i started working on it so i decided well why not try to figure out how this drug works and for a for a lay audience we can get a little technical of course we probably will but what are the most interesting app potential applications or applications of rapamycin in humans? Wait, can I just interrupt? I think that's a great question. But just to put it in the larger context of biology, so what David did as a graduate student was to discover the target of rapamycin. So in other words, what does rapamycin bind to? What protein? That protein today we call it mTOR, mechanistic target of rapamycin. Now, you know,

Starting point is 00:23:55 I was a graduate student at the same time that David was at the University of Chicago. I mean, I think I had heard of mTOR, and I was working on mitochondria and metabolism, but not really caring about mTOR. But you look back now over what's happened in the last 20 years, mTOR unequivocally is the most dominant player in regulating metabolism. What does that mean? You think of nucleotide synthesis, lipids, right? DNA, how you make DNA, how you make RNA, how you make new lipids, how do you make amino acids,

Starting point is 00:24:35 all of that stuff, mTOR controls. And also mTOR itself is sensitive to changes in amino acids, growth factors, has a lot of different inputs, oxygen, and perhaps even glucose. So this thing is really an integrator of, you can think of like nutritional things, keep it simple, and also how it outputs things like what you make, lipids, DNA, RNA, it is clearly the most dominant player in the world of metabolism. And that's, you know, so that's a big deal, right? That's like saying the equivalent of that, you know, some protein that regulates gene expressions, right? And there's a very famous one like MYC. It doesn't matter. But so it's at that level it's one of the big big proteins that's ever been discovered in the field of biology so you can't you know underestimate david's contribution in biology because it's a big big deal and now you have a drug called

Starting point is 00:25:39 rapamycin that can affect this major player that regulates metabolism. And if you think metabolism is the key to understanding many diseases out there, including diabetes, which is unfortunately rampant in the United States, cancer, lots of things, if you buy into that larger idea that metabolism holds the key to understanding many diseases, the big ones, you know, atherosclerosis, neurodegeneration, autoimmunity, then you have to talk about mTOR and rapamycin. And that's, you know, probably David's legacy. And just to revisit a term you mentioned a few times, because I know the word metabolism is perhaps overused in many

Starting point is 00:26:25 different contexts there's a simple definition so yeah exactly no no exactly that's what i'm going to ask you how what should people how should people define metabolism my simplest definition comes actually from my daughter anjaliali. I always tell this story. She was little. She's going to be 15 next week. I asked her, what do you think of metabolism? She said, isn't that when you grow things or you break down food? And so what does that mean?

Starting point is 00:26:59 The act of growth we call anabolism. So that's half of the equation in the metabolism field. And the other one is breaking down food, which is catabolism. So metabolism is a sum of either anabolism and catabolism. Either taking food and making stuff, muscles, for example, or breaking food so you have enough energy to use those muscles and go on Ironman tri man triathlons like our friend peter atia does all the time just for fun including this week as i've observed myself the tahiti swim the tahiti swim i know yeah we'll go to the beach it's like all right we're gonna take a quick swim and i don't even swim where's peter and then it seems like he's en route to tahiti and we see him

Starting point is 00:27:44 about an hour later actually here there's a birdman con there's a birdman competition historically and peter can describe exactly what that competition had to do with but so i've nicknamed him the birdman now that's his official new nickname the birdman we called tim g.i. joe though right well yeah well that's more obvious by the way david what uh when you and tim were on the same flight down here what was your first observation of tim on the plane oh that was hilarious so i had no i mean i i think i'd briefly seen who you were so i had some hint of what i was looking for but but i i was changed from a flight from uh from houston into one from Miami.

Starting point is 00:28:26 And so there's this guy in front of me, obviously quite buff. He keeps getting out of his seat. He opens some big luggage, always in the middle. And we were lucky to be in business class, but people couldn't cross on the aisle. He opens it and he's taking a lot of pills. And he seems like a very high-maintenance man,

Starting point is 00:28:41 I have to say. Things are coming out, taking out. And the poor flight has tried to cross, and he't really care he's still just didn't have any we're looking for bottles and bottles like oh my god this guy's a little bit of nutty i was like i wonder if that's tim ferris the official term is freak show freak show and i and i thought to my head i hope it's not actually but then when i landed and i and uh then i found from peter that because i assumed since you're coming from California on the same flight as Peter, but he's like, no, he's on the Miami flight.

Starting point is 00:29:07 So I was like, oh my God, that guy. That's the guy. But so can I take my definition of what mTOR does? Yes, please. Because I give talks on this all the time. And I think Nav put it in a very good way. It's a very simple thing. It senses whether there's nutrients in the environment

Starting point is 00:29:21 and it decides whether our body is catabolic or anabolic. It makes that decision. And the reason it does so many things is that we don't think about this in our lives because of anything we're overfed, or at least most people are overfed. But if you think in our evolutionary history, the life of most animals out there, food scarcity is likely the rule, and likely we went from boom and bust periods, right? You might kill an animal, eat for a bit of time, and then really go into a bit of a fast or prolonged fast. And so this is this protein that's making the decision and knowing which state you're in

Starting point is 00:29:56 and all of your physiology, right? From your fertility to whether your muscles are growing to even hair growth, all of these things should be controlled whether you're in a nutrient rich or nutrient poor environment so that's the way i like to uh to think about it so i have a question actually for now do you um do you can you're not going to tell about the birdman competition we'll talk about that let's cover birdman real quick all right but i might come back to a question about autophagy but okay so the birdman competition is kind of this thing that i think the moment we heard about it we all decided we wanted to do no first of all i don't swim let's be clear about peter wanted to do it very only peter wanted to

Starting point is 00:30:35 do it okay no i i have to say i was tempted you would do it i would well i might not because i would die but but i would be tempted to do it i don't think i can do it justice to describe because it's hard to explain what easter island looks like but maybe we could post a couple pictures of this or something but it's a cliff you have to jump there's like what i don't know how high is that cliff it's got to be 100 100 meters 150 meters yeah probably 100 to 200 all right so you picture a 250 to 200 meter vertical wall which is the side which is the side of the yeah of one of the points it's a basically a triangle shaped island and then about a kilometer out you have no actually one and a half kilometers out you have two small rocks which are just more pieces of lava and the

Starting point is 00:31:19 birdman competition the athletes would start at the top scale down the 200 meter cliff again i don't know how anybody did that without dying swim out to the island climb up it which itself looks almost impossible get one of the eggs of the bird what's the name of the bird it was a turn but some sort of a bird and then you had your family no longer exists using a piece of cloth, strap the egg to your forehead, swim back, climb the 200 meter cliff, and you would present that egg to the leader of your village or tribe. And he would then become, I don't know, the de facto ruler of the year. Yeah, for the next year. At the quarry, though, apparently he also got that extraordinarily small house that we remember. So you were going to ask about autophagy.

Starting point is 00:32:15 But before we get to autophagy, because this may be, well, I'm sure it'll come up many times but again just for people who are who may not like me have a biochemistry background what are some of the most interesting potential applications of rapamycin yeah so you know the first one was this antifungal potential use that actually never took off interestingly enough so that that it never got approved for that but the thing first that was approved for was organ transplant right and particularly kidney transplants. And so you need to suppress the immune system. And that was the first major use. So that your body doesn't reject it.

Starting point is 00:32:51 Doesn't reject it, exactly. And more recently, it was approved actually for pancreatic islet transplants. So the insulin producing cells. It had a lot of use in cardiology and these things called stents, where you open up coronary vessels. And then more recently as an anti-cancer agent. in cardiology and these things called stents, where you open up coronary vessels, and then more recently as an anti-cancer agent. So those are all FDA-approved clinical trials, validate the use of the molecule. At one point, the cardiology one was actually a major use, a major market from an economic point of view. The aspect of it that has been tantalizing and probably the

Starting point is 00:33:23 reason we're having this conversation, and certainly reason that peter got interested in it is that starting some time ago first actually in worms in very small worms called the c elegans it was actually found that inhibiting this system the mtor pathway increased lifespan by how much um you know it depends 20 30 15 30 but a non-trivial a non-trivial amount if you extrapolate to our lifespans these are organisms that live you know in the order of a week to 10 days type thing and then it was it was validated in yeast which of course single cell organisms and then it was validated in mice which are obviously much more similar to us and so that captivated a lot of people's attention and And I think it's fair to say that of all the molecules that have been shown to have an effect on lifespan,

Starting point is 00:34:10 this is probably the best validated in the sense that multiple different investigators have done. You know, lifespan studies are notoriously fickle. Multiple people have done this one. It's been done in multiple organisms that span a large evolutionary range, right, from a single-cell yeast to a mammal. And so this has captivated people's attention as to whether it would have that impact in us. Obviously, a next-to-impossible clinical trial to do in a human being, but it is now being done by people like Matt Cabral and dogs. And so that's potentially quite exciting and now part of what makes we're going to bounce around a lot that's just the nature of how these things go so the the study including or using dogs that you just mentioned is not part of what makes

Starting point is 00:34:57 that interesting these dogs are not say a single breed that have been raised specifically for lab purposes exactly so i think there's a couple aspects that have been raised specifically for lab purposes. Exactly. So I think there's a couple aspects that make it interesting. So one, if you want to be cynical about the mouse studies, which are so far the ones that have been done the most by multiple labs, we've even done them. If you want to be cynical, you say, well, these are mice living in a cage. They're completely inbred. They're bored out of their minds. They're probably overeating.

Starting point is 00:35:31 You know, these are equivalent of a couch potato type of human. And sure, it's helping them. But what if you had a mouse that was living in the wild, you know, was entertained, right? Things that would be very different than this kind of mouse. And so the reason that the dog study is interesting is first, it's many breeds. So it's not just type of inbred mouse strain. And they're also, these are dogs living with people. So they're going to be in many different environments and presumably they're going to have more entertainment and exercise than these mice did. So my fear of the mouse studies is, okay, are we just treating chubby, bored, depressed mice and okay it's helping them but if they

Starting point is 00:36:06 weren't that maybe it wouldn't help them right in so much as if you're treating the homer simpson meets uh you know inbred fill in the blank i'm blanking on this movie why am i blank help me out banjo playing oh god Oh, God. Horrible joke. Oh, deliverance? Yes. Deliverance. Like the Homer Simpson meets deliverance of mice. You may see...

Starting point is 00:36:31 Squeal like a pig? Exactly. Squeal like a pig. So you might see a large improvement in, say, a... Whatever. N of 10 of these mice. But if you have the Peter Tia of mice, you might not see. Right.

Starting point is 00:36:44 And of course course we could help the mice by making them exercise right so it wouldn't be something so unique so if it works on the dogs i think that will be quite a sort of milestone moment but but david it's i mean lifespan is one output but the other one that you and i always talk about, and Peter's a big fan of this, and he can probably comment a little bit more about this, is healthspan, right? And I think perhaps for the audience, it might be worth just discussing, and maybe Peter or David can talk about, what does lifespan versus healthspan mean? I mean, again, there's a philosophical debate about what these what's how much you weigh health span versus lifespan in other words how healthy you live but you still diet you know as a male at 85 let's say or you live but you die like at 110 and perhaps not so healthy those last

Starting point is 00:37:40 20 years so so peter yeah i mean i think about this problem a lot just clinically because um i think the way you've described it is what everybody's concern is right i mean my practice focuses on longevity um but most people misinterpret that to be lifespan only which is the mathematical elongation or extension of number of years of life, which, you know, if the quality of that life does not get extended, most people would not opt for that. So sort of think about life. Is that true? No, no. I'm saying most people are afraid of that, right? Most people say there's no value to me. If my expected lifespan is 79 years and you're going to make it, you know, if we, you could make it 85, but I'm continuing

Starting point is 00:38:26 to deteriorate in my quality. That's not what I want. I mean, most people feel that way. Right. And so it has been shown that if you do look at metrics of health in mice, many, but certainly not all are affected by rapamycin. And there are even now some- In a positive way. In a positive way. And, you know, the the study that got the most interest which is in people and elderly people looking at immune function using a derivative rapamycin that works the same way but it's slightly chemically different from from a company called novartis also caused that was the turning point for that's the moment which i i mean we all have these moments when we kind of like the light bulb goes off but that was december 24th 2014 i still have my copy of the paper which still has embargo stamped on it because i got it on the 23rd

Starting point is 00:39:11 so it said you know basically for 24 hours you can't do anything with this paper but just just for the audience again one of the major issues as we age is our ability to fight infections decreases, right? So, in other words, the immune system is not as robust as we age. And what this study suggested is that perhaps by taking rapamycin not early in life, actually quite late, given to these elderly people, it allowed you to boost your immune system. And that could potentially translate into fighting infections like the common flu, which many elderly get, right? Yeah. I mean, this study was remarkable, right? Because people, I think at this point, David, it's safe to say people realize, because it was really 2009 when the sort of landmark mice studies were coming online.

Starting point is 00:40:08 But you still had this five-year gap where people said, yes, so what? It extends life, but at what cost? These are laboratory animals. They don't have the same infectious risks. This is, you know, you're going to trade one problem for the other. What this study did was it took, and it's a relatively small study, 50 to 60 people per arm. It was a forearm study. They were 65 years. So, so there were four groups of people, people randomized into four groups. Each group is called an arm. There were, like I said, but somewhere between 50 and 60 people in each group

Starting point is 00:40:36 or arm, and there was a placebo group. So they were giving nothing. The next group was given 0.5 milligrams of this rapalog or rapamycin analog every day. The next group was given 0.5 milligrams of this Rapalog or rapamycin analog every day. The next group was given five milligrams once a week. And the final group was given 20 milligrams once a week. The primary outcome, and by the way, they were only treated for six weeks. Then there was a two-week washout, which means you get none of the drug. And then the vaccinations began. What the study actually measured is the response to vaccination, which would be a pretty decent proxy in a sample size this small for infection response. And I mean, the gist of it, it's been a while since I've actually read the paper, but I remember knowing every detail of it at one point. The gist of it is that the patients treated with rapamycin or the rapalog all had a better immune response than the controls.

Starting point is 00:41:29 What was the difference or the differences between the dosage range and the dosing schedule? Yeah, I was worried you were going to ask that. I don't remember it for the immune response. I do remember it for the side effects. Do you remember what the immune response looked like? I think all of them had. They all had a benefit of the placebo, but I don't remember which one. I don't know where it plateaued. I don't remember either. Yeah. The most common side effect to my recollection was the mouth sores, which we certainly saw a lot of in transplant patients. So transplant patients, a kidney transplant patient, which is, you know, when I was in residency, we used to give rapamycin out like it was water. I think we were giving

Starting point is 00:42:07 patients somewhere between one and two milligrams a day. It was about the right dose. And certainly one of the more common side effects were these aphthous ulcers. I'm assuming, although I mean, I assume it's just because mucosal cells are so proliferative that when you're giving a drug that inhibits proliferation, you know, we're going to see a deterioration of those cells. And so certainly the ulcers were probably the most common side effect and they seem certainly what people would complain the most. Yeah, yeah, definitely. Um, at some point we should remember to come back to finish the story of Saran cause there's actually kind of an interesting story there, which we should come back to at some point. But, um, just what you said made me think of that.

Starting point is 00:42:45 But there is definitely a dose response to side effects, right? Sorry to yank. I've had an audio complication. So Pete and I are sharing a mic. What is the logic or rationale behind intermittent dosing of rapamycin? I'm going to give you the short answer. David, I'll give you the long answer. The other thing David did was he figured out that there were basically two complexes for mTOR. So mTOR, if it organized around a protein called Raptor, was known as mTOR complex one or mTORC1. If mTOR organized around a protein called Richter, it was mTORC2 or mTOR complex 2. The thinking behind intermittent dosing versus constitutive dosing,

Starting point is 00:43:35 where you just give it constantly, is intermittently you can target mTORC1 and not cross over to mTORC2. And I'll let David say more on that, but that's the gist of it. So I think that's certainly true because it's clear from genetic studies largely inhibiting mTORC2 is not a good thing. But I would add the other thing that intermittent dosing might allow you to do, and I think this is going to be increasing. Sorry to interrupt. Intermittent dosing, does that mean once per week? Does that mean once every other day? What would that hypothetically look like? It could mean anything. It basically means that at some point, the drug in your blood goes to a

Starting point is 00:44:09 very, let's say, ineffectual dose, right? So that you're basically relieving the inhibition of mTOR caused by rapamycin, as opposed to a continuous dosing where you basically want to always have an inhibit, which in many cases is what pharmacologists might try to actually optimize around, is to keep that inhibition. Although there's been quite a bit of a, I would say, ground change in how people are thinking about this in many fields. In this case, if you look at the function of mTOR in many different tissues, it's quite clear that it's an essential protein.

Starting point is 00:44:41 And what I mean by that is if you knock it out in a particular tissue, that tissue dies. How about the muscle? It's very clear. And really almost every tissue. In contrast, if you hyperactivate it, that is turn it on to a very high level, the tissue also suffers. And so this is an example where too little is bad, too much is bad. It's really in between. And so you need to basically figure out a way where you're going to let at some point, let's say the muscle actually have its mTOR and do the things, which as Nav said, is going to be anabolic, you know, make muscle. But at other points, you want to be able to inhibit the system, and that's actually going

Starting point is 00:45:16 to drive this catabolism. And many people think that it's this catabolic process that's why it has these anti-aging processes. And very simplistically and i would say that this is this is conceptually interesting but probably not well proven the idea that is if you make a cell like a muscle cell degrade lots of its components and force it to remake them if there was things that were messed up that had aged that were defective you might clean them up and replace them with good things, right?

Starting point is 00:45:45 So a bit like cleaning house. And so this cycle of anabolism and catabolism, which we think is what the pathway normally does in response to food, right? Or absence of food. You might actually want to mimic that with rapamycin as well. So inhibit, cause the cells to clean house

Starting point is 00:46:01 by degrading lots of stuff. But now you got to remake stuff, right? You can't just clean house and throw everything out and not make things. And so, you also need to let the system rebuild. And so, intermittent dosing would let you do that. So, just for the audience, and it's actually this concept that David just talked about, this clearing up of perhaps of damaged goods in your muscle or in your body, is a process called autophagy. And just last week, the Nobel Prize was given for the discovery of autophagy to a Japanese scientist. Not the discoverer, the genetic analyst. Sorry, the genetic analyst.

Starting point is 00:46:43 Did you discover autophagy? Autophagy meaning eating itself or eating yourself. Auto-eating. Auto-eating, sorry. The molecular basis and the genetics really of autophagy. But the actual observation was done in the 70s or 60s? Probably, yes. Yeah, by Christian Deboe, who also won a Nobel Prize for a different thing. So, in other words, an mTOR is controlling this process when you inhibit it. That's a fair statement, right, David?

Starting point is 00:47:12 Yeah, it normally suppresses autophagy, so it prevents catabolism because it's in a high-nutrient state. So, when youits mTOR, and that then activates autophagy. There are certainly studies in worm that suggest that. What about in higher organisms? I don't think there's any that have done that yet. Do you have a good explanation as to why rapamycin might have a positive effect on healthspan and lifespan then?

Starting point is 00:47:51 I personally like that idea. You like the topic. I like the idea. Oh, you do like it. It's never been tested. I have a question, one for each of you guys. David, does intermittent dosing, is it plausible that, way mimic fasting going through feast and famine phases? could. And I think the issue is that none of us really fast. If you really think about it, right, if you have dinner at six, you get up at six, a 12-hour fast is probably not that big a

Starting point is 00:48:32 deal for any of us, particularly if you've got a little bit of extra heft on you. And so I don't think as sort of modern humans, we probably ever fast, right? And so in a way, when you're giving rapamycin, you're forcing a fast at the molecular level. You're not doing it by depriving food, but you're tricking the system. That's one way of thinking about rapamycin is it tricks the system into thinking that the animal's fasting

Starting point is 00:48:55 and triggers all the responses that you'd normally get with fasting. So I definitely think what you're saying is true. But I think what we realize now is that you can't put the animal into a constant fasted phase. You need to have this kind of recovery. To make stuff, right, you break down,

Starting point is 00:49:11 you have to make back. And so that's why I think the intermittent dosing is very appealing. And at the same time, it has this enormous benefit that probably, and this is almost certainly true, you're gonna reduce potential side effects, right? Because other cells that are the ones that are getting hurt that cause a side effect for example the mucosa of your mouth can also recover to some extent so it's really a win-win but but but david to go from a fasted state

Starting point is 00:49:37 sorry a fed state to a fasted state you can imagine imagine maybe has benefits. But when you go from a fasted state back to a fed state, are there any downsides? Because the regimen is you go from fed to fasted back to fed. So, there's two curves there, fed to fasted, fasted back to fed. The refeeding, are there any potential, I mean, have we thought about the potential hazards of the refed state? I can think of a few. Sure, but on the other hand, that's always going to happen, right? Or you think in evolution it happened all the time, so we've adapted to that. Well, it to happen, right? Or you think in evolution it happened all the time, so we've adapted to that. Well, it has to, right?

Starting point is 00:50:28 Yeah, I would argue, but... So David, I have a question for you, if I may interrupt just for a moment, or for many moments. I'll probably do that more than once. Many of the people listening, certainly a decent percentage in Silicon Valley, will be asking themselves,

Starting point is 00:50:46 what is the difference between rapamycin and something perhaps they've heard more of, which is metformin? How would you answer that? Well, metformin is a drug. It's one of the most commonly prescribed drugs. I don't know if it still is the most common, but as you know, it's prescribed as an anti-diabetic drug. And I'm certainly not an expert on it. Nav knows a lot more about it. And the reason is that it's quite clear that metformin is an inhibitor of respiration. And the way it works is by inhibiting the mitochondria.

Starting point is 00:51:14 Now, in this case, what do you mean by respiration? It's oxygen consumption. Yeah, so oxygen consumption at the cellular level. So, you know, the cells use oxygen to generate energy. And the way they do that is using the mitochondria. And they use something called the electron transport chain. And metformin is quite clearly an inhibitor of the electron transport chain. And so, and I'll let Nav speak in a second, the mTOR pathway, we kept saying it's sort of is turned on by food.

Starting point is 00:51:40 But food is obviously a complex mixture of many things, and it's composed of many different nutrients in it. And some of those nutrients, they contribute to energy, right, inside cells. And so the mTOR pathway, what's, to me, actually, from a scientific point of view, has been always the most fascinating aspect of it is it basically detects everything. Amino acids, glucose, and it turns out energy and so by inhibiting the mitochondria which is generating energy you're also inhibiting the mTOR pathway and so you you certainly might expect that there's a lot of overlap between metformin and rapamycin and indeed in cells and culture if you treat them with metformin you will also inhibit the mTOR pathway rapamycin does it directly by attacking mTOR itself, while metformin does it, as we say scientifically, much more upstream, much more in an indirect fashion. What are the benefits or disadvantages of using one over the other? Four, I should say, of course, when I mention people in Silicon Valley, they are using metformin for what they believe to be life extension properties. Well, metformin is obviously prescribed to probably hundreds of millions of people.

Starting point is 00:52:56 And it is generally considered to be a very, very safe drug. Rapamycin, as we talked about, used more limited in a more limited fashion and also has more potentially you know side effects such as such as these mouth ulcers but as well as others so i think the perception is that metformin is a much more tolerated compound what i would say is is perhaps if we think if we think m-torn inhibition is a good thing right for prolonging lifespan and i think substantial evidence suggests it is, metformin turns out to act mostly in one tissue, which is the liver, and then the effects in the liver have then secondary effects in other tissues.

Starting point is 00:53:36 But rapamycin is going to act basically in all tissues in your body. It's going to get everywhere, inhibit mTOR everywhere. So the degree of inhibition of mTOR that you're going to get with those molecules is likely to be very different, just on the face of how we know how they work. But one, so that's one difference between the two, obviously, as David stated. But the other one is because rapamycin

Starting point is 00:54:02 directly inhibits mTOR, while metformin indirectly inhibits metformin and mTOR. So one key aspect of potentially inhibiting the respiratory chain, metformin, would be the respiratory chain is a lot of other things. And so you can imagine that there are multiple outputs that are linked to the respiratory chain, and by inhibiting, including possibly mTOR, so by inhibiting the respiratory chain by metformin, you could be affecting three, four, or five other parameters, which might be quite beneficial. But the downside is it's restricted to its effects on a few tissues. And I don't think the studies, and Peter will know this much better than I will, I'm not sure there's lots of studies that really show metformin itself

Starting point is 00:54:59 as a pro-lifespan agent. I think there are some. What captivated people's excitement about metformin is large epidemiological studies of diabetics using metformin or not using metformin and showing a pretty profound difference in cancer rates. That's what grabbed people's attentions with metformin. I think there's a lot of assumptions that it would have lifespan effects. Certainly, it would, perhaps, from reducing cancer, that would be one. But I'm not sure that animal studies have validated, like rapamycin

Starting point is 00:55:30 clearly prolongs lifespan. In mice that I described maybe are a little bit artificial compared to free-living mice. But Peter, I don't know, has that been shown for metformin? You're exactly right. I mean, there are half a dozen really good cohort studies looking at not just diabetic patients, but obese and insulin resistant non-diabetic patients taking metformin and not taking metformin. So again, always important to point out the disclaimer, these are not a randomized controlled trial, so you can always be fooled by confounders, but the relative impacts are strong enough. So the, you know, I think the aggregate effect is something to the tune of about a 20, 15 to 20% reduction in the incidence of cancer and about a 25 to 30% reduction in mortality or extension of survival in the presence of cancer. Now,

Starting point is 00:56:27 the majority of the evidence for this is in breast cancer, only because that's where we have the most studies that have looked. But, you know, it certainly appears that two-thirds of cancers may be impacted by this. Now, something we talked about earlier in the week. So you could argue perhaps positively affects health span rather than maybe lifespan. Has the mouse study been done, for example? Does metformin prolong lifespan in a mouse? Yeah, it was a Nature Communications paper from the NIH group Rafael de Cabo,

Starting point is 00:57:03 and it was interesting. I think they tried two different doses, as one was more beneficial than the other. I think one of them was not as beneficial. So the question that we, I know we talked about this week, but it's, that I think remains still unresolved. Just to clarify, I think David is absolutely right. Rapamycin clearly, I think the consensus is clear that it does increase lifespan and as robustly as any compound that's out there. But metformin, it's not so clear. I mean, I always tend to think of metformin

Starting point is 00:57:44 for more of a health span, right? It's a reasonable anti-diabetic drug, perhaps has some anti-cancer effects, at least the epidemiology supports that. And there's some other effects that people have noted with metformin in just terms of health span. And I think that's what has captivated people rather than just pure increase in number of years, right? I mean, you and I have talked about this. So, I'm going to quickly ask a question of Peter and then we can continue on this thread, which is definitions. Epidemiology, it's come up a couple of times already, but I'm sure there are people in the audience who are not familiar with that term. Could you

Starting point is 00:58:29 describe what that means? Yeah. These are basically observational analyses of data that were not gathered through the process of randomization. So in some cases, they can be really, really disorganized. In some cases, they can be quite organized where you go back and get surveys of people to look at behaviors and things like that. So that's what epidemiology is. And sometimes epidemiology really gives amazing answers. One of the things we were goofing around talking about at lunch the other day was how no one ever needed to do a randomized control trial to show that smoking caused cancer. Now that happens to be a very powerful example because the epidemiology demonstrated something called a hazard ratio that was very high. A hazard ratio is the ratio of the people who do the thing you care about and get the

Starting point is 00:59:17 condition you care about to those who don't. And in the case of smoking, I think the hazard ratio was somewhere between 10 and 14 X. So, um, and when you look at the sort of godfathers of epidemiology, uh, they would, they would make the case that when a hazard ratio is above four or five, the likelihood of a causal relationship is stronger, meaning epidemiology at best gives you a correlation. Um, the problem with many things that we use epidemiology for today, like nutrition is the hazard ratios are very low. They're typically below two. And so you can't really infer cause. So that's always the law of drawback. And that's the problem with the metformin data is there, the RCTs, the randomized control trials,

Starting point is 01:00:00 which are very small, but they are happening right now, are looking at non-hard outcomes. So the two big studies, the one was out of Toronto, the one out of Oxford that came out about a year and a half ago now, they were looking at women who were recently diagnosed with breast cancer who were in what's called a neoadjuvant window. So a woman gets a diagnosis of breast cancer. She's about to start something called neoadjuvant therapy in a few weeks, which is therapy before she undergoes surgical correction. And in that window, they would give some women metformin and other women a placebo. And so it's a very short time to treat them. And these were studies that were tried to get at a question that I think Nav was sort of alluding to a minute ago, right?

Starting point is 01:00:46 Which is, does metformin exert its effect directly by doing what David said, right? Going into the mitochondria, inhibiting complex one, creating a lower ratio of NAD to NADH and interfering with the electron transport chain? Or is it an indirect effect by inhibiting the amount of glucose that comes out of the liver, which keeps not only glucose lower, but insulin lower, presumably IGF-1 lower? And Nav, I think the consensus from those studies is we don't know. Certainly mouse models that try to look at the cancer effects suggest that they are what we call cell autonomous, right?

Starting point is 01:01:25 Nav did really the first of these, is that it's the metformin acting in the cancer cell itself that matters. But for these healthspan effects, particularly the glucose-lowering, insulin-lowering ones, it's almost certainly the indirect effects. So it's probably going to depend on what you actually care about and and and just you know to be clear the it's there's not unlike what rapamycin does and largely thanks david's work i mean i think everybody believes that rapamycin inhibits mtor right david there are there's still some outliers out there but 20 years later there's still some outliers there uh i doubt okay there might be

Starting point is 01:02:05 but still some flat world yeah exactly but yes um but with metformin you know i think that the cancer data at least using uh laboratory models does suggest that metformin inhibits the respiratory chain and the mitochondria. But there's not a good consensus on how it works as an antidiabetic. It has reasonable anti-inflammatory properties as well, and it's not clear how it quite does that. Unlike rapamycin, which is highly potent, metformin not. And people wouldn't. So, drugs that typically work at high concentrations, people tend to find lots of potential. There could be multiple targets of metformin to explain all these things that

Starting point is 01:02:59 metformin does. Anti-inflammation, anti-diabetes, anti-cancer. But, you know, I think David and I have talked about this before. I always say that the reason rapamycin works so well and because it can do so much is because it hits a protein like mTOR, which really sits at the heart of metabolism. Well, I would argue mitochondria, if you open open up your textbooks also sits at the heart of metabolism and so one way to simply explain all the multiple effects of metformin is what if it hit the same target all the time just like rapamycin hits the same target all the time in this case rapamycin hits mTOR metformin hits mitochondrial complex 1, and that could explain all these multiple different effects. I mean, the rapamycin, just to be clear, is hitting mTOR. Whether

Starting point is 01:03:56 metformin works exclusively by inhibiting mitochondria is still an ongoing work in progress. So let me ask a couple of questions of both of you. The first is, I'll start with just an observation. The friends I have who take metformin are very rarely those who, some finger pointing going on. Very rarely, not always, those who can read the literature and understand the studies. So my question to you is, do you take metformin? Why or why not?

Starting point is 01:04:37 I do not take metformin. Why not? It's laziness. What was that? Laziness. Laziness. Well, it doesn't have much side effects so there's well i um i generally think of metformin as a you know as a drug that um is used for anti-diabetes right that's clear it's been used that for a long time. All this other stuff like anti-inflammation, anti-cancer, that's still ongoing work. I mean, that's not, you know, all of that data isn't completely…

Starting point is 01:05:12 Many people think though, okay, what's the downside? And so I exercise, right? I play soccer still. I'm in my mid-40s. I'm my, as Peter can talk about this, but the things that Peter likes to look at, I think I would say that I'm pretty healthy. So I don't feel, why should I take metformin? What is the downside? Plus, one thing that has not been said here, we were once at a dinner with 20 or so people, and the topic came up whether anyone wanted to actually live a very long time. I have to say, I was the only person, plus a very small angry man

Starting point is 01:05:58 who was there too, but Nav was not in that category. Nav did not want to necessarily extend life. Nob did not want to necessarily extend life. No. No. Why is that? So David wanted to live till 600.

Starting point is 01:06:13 I think that was the exact number. Well, that's the number apparently if you're immortal, you'll get hit by a bus at that point. Right. So you've got another... Those buses 600 years from now are going to be really fast. You've got another 550, 80 years left. I think everybody has an internal clock that they want to get the most out of life. And I think about 80 years, maybe 90, no more than 100 for me. Do you think having a lifespan, an expected lifespan of more than 100,

Starting point is 01:06:48 would make you less sort of effective in your life because you would just see more slack in the system ahead of you? Oh, yeah. That's already happened. But that's you, though, right? Right. I mean, the original four-hour week guy, right? This guy stole it from me, I think.

Starting point is 01:07:07 You know? I mean, it's clear. I mean, he's a little bit younger, so, you know. David, how many scientists who you would consider credible, or people, for that matter, who are just informed, take rapamycin for longevity purposes? I think very few. I mean've um it's obviously i have no real data on it but i can tell you so i've given talks and and throughout the world on rapamycin

Starting point is 01:07:34 and it's not infrequent that when i put up a slide that shows some of the clinical effects including immunosuppression i will then have people at the end of the talk quite angry at me and telling me that by putting up that it's an immunosuppressant, which of course it's an FDA approved use, so it is an immunosuppressant. Peter gave it for kidney transplant patients, will tell me that I'm now dissuading people from taking it and quite angrily saying, look, that you're doing a disservice because people who might otherwise take it now see that it may have this side effect. So clearly people are thinking about this. I probably know maybe two people that take it.

Starting point is 01:08:13 And some of it is that it does have potentially more side effects. I think what we don't know is if you were to take it at these very low doses, this once a week dose, those side effects might be quite tolerable. Up to what dose on a weekly basis

Starting point is 01:08:28 do you think those side effects could conceivably be tolerable? You know, I think probably a couple milligrams would be the range.

Starting point is 01:08:40 You know, the mouth sores is what, and you probably saw this when you were giving Sounds miserable. I mean, I don't want mouth sores. It's been described to me as having like a full, you know, the mouth sores is what, and you probably saw this. Sounds miserable. I mean, I don't want mouth sores. It's been described to me as having like a full, you know, an entire cold, a cold sore

Starting point is 01:08:50 throughout your mouth, which is obviously not going to be so pleasant. But I do think at these lower doses, it's a much more minimal tolerable thing. Why would you not take it yourself? You know, it's again, it's a bit of, of i mean it's a bit of a laziness thing right i i'm not such a quantitative self kind of person now just just to put things in perspective also we were talking about phosphatidylserine pre-bed to lower cortisol and david you seem very worried about phosphatidylserine you're like no it just doesn't make any sense to me well it didn't make any sense so actually let's talk about this because there are a couple of things no no but i do wait just just to be clear

Starting point is 01:09:27 so as people get angry when like david was saying sometimes after his talk uh so people come up to me all the time and say you know your friend david looks remarkably young which he does as you can see i just tell him oh he uses rapamycin well when, when I was pretty high, I ingested a lot. But the reality is you might have been exposed to it as a young man. That would be an incredibly intermittent dose, right? It would have been a dose over about a year and a half period, probably quite high, but never again. You do look young.

Starting point is 01:09:58 He does look young, doesn't he? He's like an Argentine cherub. That is not a good statement. Argentine cherub. That is not a good statement. Argentine cherub. But my parents actually look quite young too. But no, maybe, look, maybe all you need is one big bolus when you're young. When you're young, early in life.

Starting point is 01:10:17 And that's it. I think that's reasonable. What would be the downside? Because I don't buy laziness. You're the guy who runs through the airport like 500 meters ahead of enough to maximize those 15 minutes in between flights so i'm not sure i buy the laziness argument why not do intermittent low dosing of reprimanding somebody you know the will is not there to figure so if someone came and actually did some trial

Starting point is 01:10:46 if a peter-like person did that and figured out some intermittent dose which clearly didn't have a lot of side effects yeah sure i would do it but someone's gonna have to do that right i'm not sure that i'm the person to experiment on myself i so i want to come back to you right now which is you mentioned i i just the the foster-tetan argument didn't make sense to me for a bunch of reasons. And we're not going to dwell on that. But there's a lot of bad science out there and there's a lot of bad reporting on science. So Nav, I wanted to ask you about antioxidants. Oh, wait, wait, we'll get to that in one second.

Starting point is 01:11:21 I just want to just finish this idea as to why I don't take metformin or why David doesn't take rapamycin. And I think ultimately, for us as scientists, and maybe this isn't for everybody, but for us, we'd like to see large-scale clinical trials done on these molecules, right? And what's metformin has been done over and over in large scale is in patients that are diabetic or pre-diabetics perhaps. So as I said, I don't, based on my diet, which is reasonable, based on my genetics, which diabetes doesn't run in my family, based on the fact I still play hardcore soccer, I don't see myself as a risk for diabetes.

Starting point is 01:12:08 And that's the clear indication where metformin does have some potential efficacy. So why should I take metformin, right? Now, there is accumulating evidence that metformin might be a preventative for cancer. Again, as Peter mentioned, some epidemiological data. There's some new data on anti-inflammation, but it's not like we've, you know, taken thousands of people. And there are trials people are doing this where we say one group gets metformin plus chemotherapy and the other group only gets chemotherapy, the standard care for some particular cancer. And those studies will come out and people will do it in, I know someone's trying to do this in lupus, someone's trying to do this

Starting point is 01:12:50 with TB with metformin. And as these trials come out, maybe we'll get to the point where it will look like metformin is a reasonable, safe drug, which has clear anti-cancer, anti-inflammatory properties and maybe then i'll consider taking it but until then i just don't see i mean it all boils down to what we said before right are these things helping either you know chubby animals in a cage or diabetics have a whole bunch of things going on are they going to help you know the peter aches the world who knows right that that's that's what we don't, we can't tell you. So, do you take antioxidants?

Starting point is 01:13:27 A lot of people do. I do not. I do not. Why not? I thought there was no, are there really good studies showing antioxidants? I thought there wasn't, right? Yes. So, the dietary antioxidants have consistently failed on these large-scale clinical trials that I just talked about that we all like to look at.

Starting point is 01:13:50 So they've failed in infectious settings, like in the intensive care unit where people are septic. They've failed in cancer. If anything, in cancer, people who've taken antioxidants, it seems like it increases the cancer burden so I don't think dietary antioxidants are I mean they just haven't shown over and over to have any potential beneficial effects so why would you take something that you know we've ran over and over and over and so then the question becomes well oh why didn't they work? So logically, there are two reasons why they might not have worked. One is that the antioxidants, the dietary antioxidants, they're just not very effective, right? The ones that are out there or in your

Starting point is 01:14:39 general nutrition center, they're just, you know, they're not made properly or they're not made potent enough to do what they're supposed to do, right? Which is to scavenge oxidants, right? That's what they're called antioxidants. The second thing, which is much more provocative, is that perhaps the theory behind oxidants, which is always that, and they're sometimes called, also people call them free radicals, is that they're bad, right? And one of the leading theories as to why you age and why you get cancer and why you get diabetes and why you get neurodegeneration is that you just accumulate these oxidants, these bad things called free radicals. And therefore, if you take antioxidants, you suppress them and buy them

Starting point is 01:15:25 some miracle, everybody's going to be healthy. That just hasn't panned out. So I actually think the second theory that maybe this idea that oxidants are always bad is wrong. And so one of the things is that in every organism, going all the way back, including bacteria, archaea, throughout the animal kingdom, you can always detect the generation of these oxidants. And these oxidants are essentially hydrogen peroxide at low levels. And so nature has gone out of its way in every organism to make proteins that get rid of these oxidants, right? They themselves have antioxidant functions. There's tons of them in every cell, but yet you can still detect them.

Starting point is 01:16:15 So there must be some advantage of having… Some evolutionary function. …of having these little H202 molecules running around. This is not a big soapbox. Right? It is my soapbox. Big soapbox. And so myself and others have consistently found that these H2O2 molecules, hydrogen peroxide,

Starting point is 01:16:36 at very low levels have positive functions. For example, we were talking about immunity earlier, right? How you need a robust immune system to fight infection, especially as you get older. Like, you know, my own laboratory found that when you activate the immune cells, they increase the production of these oxidants. They generate more H2O2, and that H2O2 is actually necessary. You remind me, what is H2O2? Hydrogen peroxide. Sorry, hydrogen peroxide.

Starting point is 01:17:11 So they make hydrogen peroxide not just as some waste product, but they actually use that hydrogen peroxide to function as a robust immune cell. And so if you get rid of that hydrogen peroxide, that immune cell doesn't work anymore. It doesn't do what it's supposed to do, which is fight infection, right? So in other words, it's just like the rapamycin mTOR example that David talked about, you know, that Goldilocks principle of biology, a little bit is good, too much is bad. And I think this is now gaining more and more acceptance in the biology community that, you know, throughout evolution, we've selected to always keep a little bit of hydrogen peroxide because it has normal

Starting point is 01:17:52 biological physiological functions to maintain homeostasis. And of course, if you get to a certain threshold, it can cause damage to the cells and cause cell death or or make the cell not functional so so peter we were chatting about this at some point over the last couple days but uh on a related point when i was chatting with a professor who i won't mention by name because she wasn't expecting to be on the podcast but we're discussing uh hydos intravenous vitamin c and there are all sorts of clinics all over the place that do intravenous vitamin c although this is but the the difference is this woman is very well trained and doing it at an academic institution And one thing that is done in many of these clinics that she does not do at all is a glutathione push,

Starting point is 01:18:48 adding glutathione after the vitamin C. Because what she emphasized to me is that the vitamin C, what someone would think of, or most people would think of as an antioxidant, is actually a pro-oxidant in many respects. And she wants that pro-oxidative effect. Precisely that effect. And the glutathione negates that.

Starting point is 01:19:09 So that is something she does not do at her clinic. Nav, where'd you grow up? Where did I grow up? Yeah. You're going to get now the world tour. And you're going to get the word Himalayas multiple times. It's so funny. You know the story. You want to say? London word Himalayas multiple times. It's so funny. You know the story.

Starting point is 01:19:26 You want to say? London. Miami. Born in London. Himalayan mountains. I lived there for about a year, followed by living in the Himalayas for almost a decade. Miami. Followed by living in Miami in the 80s during the wild, wild west.

Starting point is 01:19:44 Not participating. Not participating. Not participating. Too scared to see what was really going on. But did have a huge impact on me. All of those places, including Miami. And then after that, I went to the University of Chicago to do mathematics in the late 80s. And then I've been in Chicago ever since

Starting point is 01:20:04 because I fell in love with that city. How did you end up in Chicago? Oh, because I went to the University 80s. And then I've been in Chicago ever since because I fell in love with that city. How did you end up in Chicago? Oh, because I went to the University of Chicago. No, no, no. I understand. But I mean, you're in Miami. We were talking about 90s hair bands and all sorts of music from the 80s and 90s earlier.

Starting point is 01:20:17 So you're rocking out. Don't forget freestyle as well. Yeah, freestyle. Freestyle is one of my favorites. So I'm on, now I'm on record. You're sort of at the tail end maybe or, or the middle point of, like, the Pablo Escobar. You've been watching Narcos. I have been watching Narcos, but the sort of the Pablo Escobar reign and mass exportation of cocaine into Miami.

Starting point is 01:20:40 How did you end up doing mathematics at UChicago? Oh, it was clear. So in my high school in Miami, on any given day, you walk in and all you see is, you know, on the dashboards of every car, not every car, there's a little bit of exaggeration, tons of little white lines, right? And you have a choice. Either you participate and you see perhaps some of the end results of that and had some friends which didn't clearly have positive effects. There were more acquaintances, but one particular was a friend.

Starting point is 01:21:19 Or you're so scared of it, you actually use that frightened experience of watching what's going around you. And you find something that will occupy your mind. Now, I still have a little bit of an accent. I'm sure people can tell this. I had a pretty strong accent coming out of India, right, with the whole head bobbing and the whole deal. And so... Which he can mimic. You should do the accent for people.

Starting point is 01:21:49 Yeah, but, you know, not everybody appreciates that. Definitely. I have a lot of Indian listeners. Well, it's not an... You know what I don't like? What I love about the Indian accent is I find it quite a natural love. You know who can probably do the accents? Peter.

Starting point is 01:22:05 Yeah, Peter. Well, Peter can do Borat. Yeah, you can do a good Borat accent. We might have Peter do Borat later. But, you know, I've always wondered about accent. Like, why isn't the Indian accent a sexy accent? Right? Why don't people think of that as a sexy accent?

Starting point is 01:22:19 Why isn't that as good as Antonio Banderas? Yeah, right. Why is, like, some dude who's got long hair? I mean, I've got long hair, you know. But if I have an Indian accent versus a Latin accent, why does the Indian accent not get the love? But that's a different story. So it was clear it was time for me to buckle down

Starting point is 01:22:38 and English wasn't going to be my strong suit. I mean, I can barely speak English right now. But, you know, what could be is math, right? Also, for those people who've done math, math is a great language. It is a language, right? Peter is a mathematician as well. Peter can maybe talk about this. I mean, math is a very logical, precise language. And there's something very nice about that and attaching yourself to it. Having said that, by the time I got to college, and I thought I was a pretty good mathematician, math is the only subject I know you can reach a glass ceiling eventually, right? So, my first year of college, got into a high math group, did okay. Second year, third year. My fourth year, I'll never forget this. There's five of us.

Starting point is 01:23:32 You get a math exam. It's a take-home exam. Great. You get a week to do it. Five questions. I stared at it for a week. I got maybe one question done. I turned it in, feeling like I'm going to fail the class. Afterwards, I realized one person did it in one hour, got all five right. Second person maybe did it in a few days, but got like four or something right. Another one struggled like me, got about two and a half. But that's a glass ceiling, right? There's nothing i could have done meaning you just live you just hit a point where if you're not like michael phelps you're not gonna be that's it right right and i think this is a clear case of math at and also

Starting point is 01:24:16 the other thing about math is it's quite lonely you sit by yourself you don't you know because not everybody can is at the same level oh biology which I was doing just to make a little money in the hospital because they paid the best jobs, biology is great because at the end of the day, it's an observational science. And David has much more insight because he's actually thought about this, what are some of the key ingredients that makes a great biologist. But I would say one of the good ones is that it's an observational science, right? All four of us can be presented with a piece of data,

Starting point is 01:24:52 and we can have four different, not interpretations, but four different implications, perspectives. It's like rational. Right. The interpretations are interpretations. And so I always say, you know, every schmuck can get a little lucky there's something nice about it story of my life but in math no not much luck involved but as david he has much more insight about what so hold on we're gonna get back to david but how did you choose your area of focus within biology?

Starting point is 01:25:28 What did you choose? Like, how did you segue from math to biology? That just doesn't seem like a hop, skip, and a jump. One day you're doing math, the next day you're doing biology. So, I needed some money. I worked in actually a surgery lab. They actually paid quite a bit of money. And the surgery lab had a very practical goal, which was to preserve organs because it was a transplant lab, right?

Starting point is 01:25:53 And Peter, who's an active physician, and we talked about it, and how making solutions that preserve organs before their transplant is a big deal and continues to be a big deal. And so, it seemed like, well, that's an important problem, right? You can see the implications of it. And so, then you had to think about molecules, mainly metabolites, that would do that. And that got me hooked to metabolism. The other thing is metabolism ultimately is governed by one principle, thermodynamics. It's got some equations in it. Entropy, enthalpy, you know, some of the people in the audience probably recognize these terms. And, you know, so there are equations. And there's enzyme kinetics. So I did a PhD on enzyme kinetics.

Starting point is 01:26:47 I never did any of the cool stuff that most of my colleagues did, which was genetics. You know, in genetics, it's the world of DNA, which was clearly in the 90s very supreme, especially with the Human Genome Project by the end of the decade. So it was, you know, it was an easy transition. It's not that, you know, was an easy transition it's not that you know from math to doing enzyme kinetics but one of the things i realized um as i was working on metabolism that at the people who did metabolism and i was totally guilty of this just did metabolism for the sake of metabolism, right? In other words, in isolated systems. And it's probably maybe too long to talk about it, but the ultimate jump I

Starting point is 01:27:32 made was to think about how metabolism now can regulate biology, that it just wasn't a bystander, and at that time, the dogma was, it's all about your genes. Or perhaps what David was discovering, which turned out to be totally true, which is it's all about these proteins like mTOR, which are these kinases, they're called. They were at the center of the action. So it was genes and kinases, and metabolism was in the background. It's always there. It gives you energy. And so probably the only insight I've ever had throughout my career was perhaps metabolism wasn't just a bystander, right?

Starting point is 01:28:10 It actually was a player, just like your genes, just like the kinases. It is part of the decision-making process. Whether you live, you die as a cell, you function for immune functions. As a stem cell, you know as a stem cell you behave like a stem cell and that's basically the transition so i want to i want to i'm not gonna leave you alone yet so peter mentioned earlier observational studies epidemiology correlation uh this made me think of a conversation we had. We talked about it today, but I think the question that I asked was, what are the most important things that you teach your kids?

Starting point is 01:28:56 Could you describe what you think is important? Well, Peter asked me this, and then you asked me again. So... I never get it the first time. I have four, but thanks to Peter, I have a fifth. The fifth one, I think Peter has to explain, but I definitely have written it on my iPhone note. So the first is confidence, right? I mean, it's amazing to me how many people have fear of failure, including in science. One simple example that I always see is when it comes to grants.

Starting point is 01:29:31 So people like me and David rely on writing grants to the government and other agencies. And a lot of times, most of the times, you get rejected. And so you put all your effort in trying to write this perfect little grant, and paper's the same thing, and the reviewers who say, no, not good enough. Now, there's two kinds of people. One person says, gee, I'm so bad. I don't know what to do. They go through a crisis.

Starting point is 01:30:01 The other person says, you know what? Not a big deal. It's just stochastic i just have to redo it they take the comments and move on it's kind of stochastic it's just there's a probability yeah it's random event it's you know or there's a queuing or people who came first get it first it's kind of like i always tell people and i've said this openly and my saying just to be cute on a podcast for me it's like a you, if you're at a bar, you only need one at the end of the night. And how you get there and, you know, the males in your audience, which I hear are 87%, apparently.

Starting point is 01:30:38 That's true. We can relate to this, right? True fact. Either the first one says no and then you say, oh, well, okay. Or you just, you know Or you just keep on going. And I've always had that attitude. And people have told me I've been crazy for a long time, and they continue to, it doesn't bother me.

Starting point is 01:30:54 So I think confidence is one aspect. The second one is your ability to write those grants, right? I mean, you do have to convey it in a manner, your written communication, right? I mean, you do have to convey it in a manner. Your ability to communicate. Right? Because they only see you in a written format. So that's very important. And the third one is the ability to communicate when you give the talks. Verbal communication. Verbal communication. So written communication and verbal communication are definitely two and three. What's four? Correlation versus causality.

Starting point is 01:31:28 Oh, causality. Right. This drives me insane. And I think this comes from the math background. So my favorite one is, and everybody, you go to a dinner party, people, especially in metabolism, once they find out, they say, I hear eating chocolate makes me live longer. I hear eating avocados is really

Starting point is 01:31:45 good. Like, you know, I hear that, and rapamycin right now, as we talked about, and metformin. It's the sexiest girl in the bed. Well, people say, I heard dogs are taking rapamycin and their dogs are like doing gymnastics. Okay. And, you know, wait a second, the way we do clinical trials, and Peter can talk about these, you know, they have to be double blind. They have to be blinded. Some get rapamycin, some just get a PEZ, you know, like a little pill. I mean, right? I mean, and then you have to see in a blinded fashion who did better or worse, not just us. And every single person, including my lovely mother, likes to tell me about her. She, by the way, is in great shape. And she'll tell me,

Starting point is 01:32:30 oh, I do yoga. Yoga is the key to living long. I'm like, but mom, lots of people have to do yoga and not yoga who are in your age group with your demographics. I said, let's see what happens. So that's correlation versus causality. Now- Things that happen at the same time versus something that causes something else. Yes. And then Peter told me a fifth one, your ability to distinguish between absolute risk versus relative risk. And within it is something called asymmetric risk.

Starting point is 01:32:57 And I will let him explain the biology of risk. Are we talking about you're teaching your children or lab members? But all of those four things I've taught. I mean, Anjali, my lovely daughter, I tell her all the time, correlation versus causality. We work on her ability to. A lot of people just obviously want good grades for their kids. That's important. But the things are simpler than that.

Starting point is 01:33:22 But for me, it's the simple things is you got to learn how to write. You got to learn how to speak. Things are simpler than that. It is shocking how many people I know that I've come across who quite don't appreciate that last concept. Aren't able to distinguish between the two. How do you instill confidence? And then this risk. Oh, no, we're going to get to asymmetric risk and all good things. How do you instill confidence in your kids? We have confidence as one of the five pillars, number one. But it was number one.

Starting point is 01:34:06 No, it's number one. So how do you develop that in your kids, condition it in them, facilitate it? David is a very confident young man. Go for it. These were not on my list. I don't think it's that hard. You just have to not care what other people think that much. I just tell my son, like, who cares?

Starting point is 01:34:26 Don't be ashamed of things. If you want to do that, go ahead and do it. It's not like, it's not that big a deal. If you sort of criticize or make shameful things, then people lose confidence, right? I think the way not to do it is to praise everything, right? Oh, you did that. That's fantastic. You should write that. That's definitely not the not to do it is to praise everything, right? Oh, you did that. That's fantastic. You should write that.

Starting point is 01:34:45 That's definitely not the way it is. You let someone be original and not criticize them when they're original. Wait, explain that to me. So you're not praising your kids all the time. So what are you doing instead of that? I, you know, my child's young. He's six, right? And so they do a lot of wacky stuff, right?

Starting point is 01:35:05 They're exploring the world and they get into trouble. They do new things. I try to make sure that whatever he does is okay. Obviously, if he does something that's hurtful to others, I try to teach him a lesson from that. But most of the things, it's okay. It can be something that they can learn from rather than it be, oh, don't touch that. Could you give me an example? So you're not

Starting point is 01:35:27 praising, like, you're a genius, let me give you a gold star for everything, which I think makes perfect sense. Well, like, for example, I like to curse a lot. We all like to curse a lot. So my son, once in a while, will hear a curse. And it turns out that once in a while, he'll use them actually quite appropriately. And certain people in my family will quickly try to shut him down. Okay, and say, this is inappropriate. You shouldn't be saying that.

Starting point is 01:35:55 Those are bad words. My approach is, look, that's a word. It's okay to use it once in a while when you have certain feelings. It's an appropriate word to use. It's a word you shouldn't use all the time, and maybe you shouldn't use it around all people, but it's okay. So it's not a criticism. It's like saying, you are still a young thing, and you're still learning what is the best approach to life. But what you just said is an okay feeling to have. And in fact, I actually don't like people who don't curse. I don't trust

Starting point is 01:36:23 people who don't curse. It just shows a falseness. Because everyone, at some point, wants to say fuck you. Or a bunch of other fantastic words. And so why should I tell a young thing who's learning from me that, that this is completely wrong? It just seems like an absurd type of thing. So that's one obvious example. Probably going to get me in me in trouble what else is on

Starting point is 01:36:46 your list david i should say my son did once when i asked him different letters he did say a is for asshole which is really not a great thing did he do that in school no no he did it with me i was like look don't don't do that one don't do apple instead okay in school and they called you in how would you explain that to the teacher i would tell them that I think cursing is good once in a while and that he's learning and that why should I shame him into using words that have a potential use? He just needs to learn when to use them appropriately, that's all. But the key point that David hit on is this idea of failure, right? You only learn by failing, right? You got to work things out, be original or unoriginal or whatever. You can put the definition, but you have to fail in order to succeed. I mean,

Starting point is 01:37:32 this is such a cliche, but today there is so little room to fail because parents view their kids as a vicarious reliving of their lives. Well, it's not only the reliving, as a judgment about their parenting. Oh, Johnny cursed. Well, therefore, David must curse a lot. Well, David does curse, you know, but so what, right? I mean, there's this correlation.

Starting point is 01:38:00 What was that? It's a true statement. But you know what I'm saying? So for me, confidence has to come from, you know, a healthy dose of failure and being actually comfortable with failure. And the other one is being comfortable with conflict, which is another thing that gets whitewashed all the time right right like not conflict like physical conflict but the ability to just banter i mean one of the reasons i really appreciate my uh my relationship with david is there's plenty of discourse so fucking much. You talk so much. Here we go. It went from being charming earlier in the interview to you talk so much.

Starting point is 01:38:50 You talk so much. But the failure one, actually, you know one thing, though, just about science, people tend to think that scientists are some of these sort of perfect beings that design experiments, do them, and implement them.

Starting point is 01:39:05 What? And then they mentioned you. No, but I think what they don't realize is that most good science comes only after a massive amount of failure and that massive amount of failure is required to do good science, right? If you're actually not failing a lot of science,

Starting point is 01:39:18 it means you're not being adventurous. It means you're doing incredibly safe things that you could actually predict, right? And this is the ridiculousness of our granting system, is you write things in a way as there's no possibility of failure with backup plans and these other ideas. So you need to think incrementally

Starting point is 01:39:35 to get the proper grants. To get the money. But all of us try to do things that hopefully are going to be really new, but that means that most of the ideas that we have are wrong. They're just plain wrong. You have these beautiful ideas, and it turns out that Mother Nature decided

Starting point is 01:39:49 that that wasn't the answer. But it's okay, right? And so, but that's the hardest thing for young scientists, is that they go in with a certain kind of idea, and they do experiments, and they're wrong. And they do another experiment, it's wrong. And 10 times in a row, it's wrong. And so for me, when I, you know,

Starting point is 01:40:06 I think the things that make a good scientist and good child-rearing are actually quite similar. To me, that capacity to get up and keep going. When you fall down. We have a bar gender singing in the background. That's okay, continue. Is actually one of the most important properties you can have as a scientist.

Starting point is 01:40:24 Because the most thing you face is actually one of the most important properties you can have as a scientist. Because the most thing you face is actually failure. What advice do you give to the students in your lab or the people in your lab when they come to you for, say, career advice? What's the most common, atypical advice that you give them? I don't know if it's atypical because I think we're all at good places that people tend to, I think, do things fairly well.

Starting point is 01:40:49 To me, it's pretty simple. Just do something new. If in science you just do two things, you will make a major discovery. If you do something new, and you do something that's true, that's all you have to do to make a major discovery, because if it's true,

Starting point is 01:41:04 biology uses it in many, biology reuses it in many, many different things. The problem is that most things that people do are not new. They're derivatives of what's been done already with some variation. And sadly, in many cases, they're not even true. Because they're just not well done experiments.

Starting point is 01:41:20 Experiments that... They're just sloppy. They're sloppy and it's noise or it's not... One of the biggest issues in science now is that things are not generalizable. They'll do something in one system and it may give an answer. And then that's sort of extrapolated to being true in many, many different systems. Well, it's not. It happens to be a little idiosyncratic case.

Starting point is 01:41:39 So if you simply try to do something new, so that's what I tell my people. If you come to me and say, look, I read this paper and I want to do what's predicted by this paper, like, I hate you. Like, it's the worst thing you could possibly... Can you share your one to ten rating system?

Starting point is 01:41:57 Oh, the Ask Crack factor? But that's for data, actually. Oh, okay. So wait, what's the Ask Crack rating system? That's just... So I have a strong aesthetic sense, so I like data to be pretty, which is kind of ridiculous because all it has to be is really true and reproducible. It doesn't actually have to be pretty. And some scientists actually... What makes data pretty? Well, that, you know, it's symmetrical, that if it's an image, it has the right color. Not skinny, symmetrical.

Starting point is 01:42:28 I mean, we do a lot of things called Western blots where there's little... Oh, I know Western blots from my disease. Right, so little black bands. I like them to be about the same shape and the same intensity. I don't know what, I just want them to look pretty. P-size. What? P-size?

Starting point is 01:42:44 No, no. Wait, how is it that you were ripping on me for the staple thing hold on we're gonna get to peter staples hold on i'm not but i i'm very anal about these okay so tell so no no so start in the lab the first few experiments they do have what i call a high ass crack factor which is basically that the data is not aesthetically pleasing it might be true but i will not put my name on a paper with that data so it might start at ass crack 10 which is the worst or seven or something and i always tell them get it to ass crack three ass crack three is about the threshold that i'll tolerate ideally you know ass crack one is what you want so sedated all right send you some data so soon no you're you have a lot of ass crack data but my lab does not if you

Starting point is 01:43:32 look at my papers uniformly we have beautiful pretty pretty data beautiful day and actually reviewers always comment on this universe data so p, how should people staple properly? And what are the origins of this particular focus? Well, first of all, this is one of the few things where the answer is known. So much of what we're talking about now, should we be taking rapamycin? Probably. At what dose? Not clear. Intermittent. intermittent likely right how do you staple a piece of paper that is i mean we know that like we know what happens if you drop an apple from a tree so uh the first thing that's essential is the paper has to be um lined up perfectly so you can't have like 10 pages stapled together where they're not aligned obviously right so if one's off by like half

Starting point is 01:44:25 a millimeter something that's totally unacceptable so the second thing is you always have to staple upper left corner and it has to be a vertical staple so a lot of people do this goofy sort of diagonal staple or some nonsense even a horizontal staple this is totally unacceptable so it has to be a vertical staple the next thing that's super important, the third factor is that the upper corner of the vertical staple must be equidistant from the top edge of the page and the left edge of the page. And the ideal distance, proper distance, proper distance is about seven millimeters. But I would say because I'm an engineer first, maybe mathematician second,

Starting point is 01:45:06 I think it's okay to have a plus or minus on that. So I really think we're talking about six millimeters plus or minus two. Um, and, and so when you do so, cause if you go too close to the left edge or too close to the upper edge, such that you've lost that equidistance, you run the risk of tearing the staple through the vertical. And again, I know some of the people are listening to this and they're just thinking, I can't believe I'm wasting time listening to this, but I will tell you this, you do this, you fold your papers over and you tell me that that's not honestly the best thing in the world, the best feeling. I'm going to grab the mic here for a

Starting point is 01:45:43 second. Now, who would you convey this to and what else would you convey to them? What were the other, the other tenants of, uh, functioning under the iron fist rule of it? I mean, this really, I think I've always had these tendencies.

Starting point is 01:46:02 Uh, I think my, yeah, I think I've always been this way, but it flourished at, yeah, I think I've always been this way, but it flourished at, um, I worked at McKinsey and company, uh, for a while. And I was, I just found that it was a culture that really enabled that tendency, the obsession with fonts, spacing, stapling, clipping, like how you could make everything perfect. And I'll tell a funny story, right? So I had a team of folks that worked for me maybe in a previous life. I forget it. I

Starting point is 01:46:31 got a biotech company, I think that I was working at many years ago and they used to really kind of get annoyed with my tendencies, right? I mean, there was no stone left unturned. And I felt a little vindicated when someone who worked at that company went up to present something at Pixar one day and came back and said, you know, Peter, it's sort of interesting. I used to sort of think you were an idiot for this obsession. But interestingly at Pixar, when they storyboard, they have a very particular way that they do things, which is they put the pieces of paper up and they all have these clear thumbtacks and it has to be four thumbtacks on each piece of paper. Each is one centimeter down, one centimeter over from the

Starting point is 01:47:10 corner and they do this thing. And so the friend of mine who saw this said, my, my question for the person in the room leading this session was, you know, isn't Pixar one of the most creative companies in the world? How can you guys be so dogmatic about this one issue? And the person said, well, because we're so creative, we never want there to be a distraction in the room when we're undergoing our creative process, which is reviewing the storyboard. And I don't think up until that point, I don't think I'd been able to understand why I'm so obsessive about what seems like nonsense. But if I'm looking at a document, I don't want to be distracted by the staple being diagonal or the font being crappy or the spacing being off or any of those things.

Starting point is 01:47:52 What are your favorite fonts and sizes and why? Well, up until medical school, I refused to work with a word processor. So I only used a system called latex, which is spelled L A T E X. It's spelled like latex. So we start and Nav knows what I'm talking about. Cause any math idiot would have gone through this. So I think Tim knows about latex. Do you know about latex as well? Yeah.

Starting point is 01:48:16 So we use tech or latex. And so you were, you're right. I meant he knows about latex. No comment. latex no comment so uh um yeah so you write this code into a compiler and then you would create a format after it and so the font in latex that i found far and away the most elegant was called roman um so this was a serif Um, and then eventually it got to the point where you just couldn't share documents with anybody because people just wanted to use word. And so I finally caved, uh, obviously word doesn't have exceptional fonts. Um, but you know,

Starting point is 01:48:58 I think there are a handful of fonts that are like borderline acceptable. Um, frankly, these days, my Sarah font of choice is actually times new Roman as pathetic as that sounds on the sans serif side. I like, um, um, probably the last couple of months. Cause I switch every once in a while, there's a, a myriad pro condensed version that I'm working with that I find reasonable. Um um i actually did font research one summer which i we won't talk about that have you seen a documentary called helvetica i i have and i'm i i actually find helvetica lt45 to be a pretty decent font so what about comic songs so wait no we're gonna get to comic sans so so my so my my font of choice is verdana 11 long story like so comic sans i love that one that's all my talks are in comic sans they're not

Starting point is 01:49:54 i made that i was making fun of you that's that's true that's pathetic you know what that says you know what that says yeah it says i don't care i'm a child says you're in the audience and i want to visually insult you i want you i'm entitled are you suggesting i'm entitled this is is this an entitlement lecture it could be it actually could be turned into my data are so good that i can actually insult you while presenting this, and you're still going to sit here and look at this comic sans. I use trebuchet for talks, but we use Helvetica. So in my lab, you better make figures well. That means Helvetica for the figures.

Starting point is 01:50:35 That's for the paper. For the paper. No, no, no. I'm talking about for talks. I don't use comic sans in the paper. I hope not. But you know what I can't stand? I have no knowledge of comic sans.

Starting point is 01:50:45 When people make figures in PowerPoint, that's horrible. Like, you have to make them in Illustrator. Right, Peter? You need to draw in Adobe Illustrator if you're going to make a figure. Yes, although for those... For the paper.

Starting point is 01:51:00 No, he's talking about for presentations. No, for the paper, I completely agree with you. You shouldn't draw anything in PowerPoint. No, there's talking about for presentations. No, for the paper, I completely agree with you. You shouldn't draw anything in PowerPoint. No, there's a really cool plugin for PowerPoint called ThinkCell, which is not for drawing, but it's for actually doing way better graphics. So you don't have to import from Excel. People use Prism usually in time. ThinkCell is pretty solid.

Starting point is 01:51:23 No, for papers, i completely agree with david but my verbal presentations might be your your your fonts are like for the visually impaired right you're pretty visually impaired but they're like you can barely see i mean so actually no no so i'm gonna i've had a couple glasses of wine. So David, you don't have fantastic vision. I used to until about a year ago. Why don't you have glasses? Because if I get glasses, I think that I'll be

Starting point is 01:51:54 completely dependent on them. And then you have to carry these things around. No, explain what you mean by that. It means that... What happens if you put on glasses? Because now... No, so I tried someone's glasses.

Starting point is 01:52:03 I know Nov is sort of chafing your nuts about this but you also decided not to have glasses yeah but i'm not visually impaired like but i'm not he's blind that's not true when i'm tired it's harder to read things you put look at the font size on your iphone look at that no no the other one so i just think that once you start wearing glasses, your lenses, whatever compensation you're doing for the shape of your lenses

Starting point is 01:52:28 with your ocular motor muscles will all stop. And you're completely dependent on it. And the idea that then you can't see anything where you really can't see anything and you need glasses is kind of scary for me. Where you have to have them with you. You become more muscularly dependent. Well, I think you, I don't remember now,

Starting point is 01:52:44 but you you really you don't whatever dependent on the glasses completely right and and i've been certainly told by by ophthalmologists that this is true so i talked to them ophthalmologists look i can put you on glasses but you'll be 100 dependent on them in a couple months do you think you'll lose your sex appeal. What are you talking about? It's more you have to carry something. So, all right, I'm going to get this train back on the rails, or do my best to do that.

Starting point is 01:53:14 How do you guys think of, because a lot of people ask me about this, Basis, the product Basis, by a company called Elysium. Either. He's your colleague. I think these are territories that one should be very careful about.

Starting point is 01:53:30 I think that their goal is to eventually look at this nutraceutical market and do things of high quality. I think there's some basis for NAD boosting as connected to aging. I think there's been a number NAD boosting as connected to aging.

Starting point is 01:53:45 I think there's been a number of papers that have shown defects in NAD. Whether that product has an impact or not, I actually have no idea. And I should say I have no position on it. You're the NAD, NADH person, right? I have a clear position on it. Again, it goes back to why I don't take metformin, right? I told you why. If I am a diabetic or pre-diabetic, I would consider taking metformin because we've done large-scale clinical trials for that. Now,

Starting point is 01:54:15 we're doing large-scale clinical trials for people for cancer and perhaps for anti-aging in a big, large aging trial. And until you do that for NAD, you know, it's another interesting molecule. There's got to be a lot of things you do that are not based on a clinical trial, though. That was one of my questions that I might follow up with. In terms of taking a

Starting point is 01:54:39 drug, I personally don't. And do you? I mean, do you take anything? I mean, once in a while I'll take a vitamin, I guess. I don't take anything. But again, a lot of people would, I think this is what Dave is alluding to, and perhaps Peter can talk about it. Do you wait for large-scale clinical trials until you take a supplement or

Starting point is 01:55:09 a drug? So I think, and I don't know any firsthand knowledge of it, but what I've read, I think it was a New Yorker, no, New York Magazine about Elysium, they sort of argued, they pushed back on this idea, well, you know, maybe it's too, you know, you can't wait to do these clinical trials. How do you do it? It's an aging trial. We're talking about NAD supplements, Peter. And so, I, you know, I just think even if you didn't do the clinical trial, let's say, I would at least like to know the biology of NAD.

Starting point is 01:55:46 I would, and I think this is a fair statement, and I'm happy to challenge anybody out there on this one. I think, thanks to David, we know, not only David, but largely, you know, David clearly is a pioneer in this. We have a pretty good idea of what mTOR does, right? I mean, we have a reasonable, as things go in biology, right? We know the inputs, you know, what activates or not activate mTOR. We have a reasonable idea of what mTOR itself then, you know, what turns it on and what

Starting point is 01:56:17 does mTOR turn on, right? With NAD, it's not so clear. I think it's actually a great part of biology that people like me and david and many of our colleagues are quite interested in what the hell does nad do and if anybody's going to tell me what it does as in they think they know it you know you could look me up and come to chicago and i'll buy you dinner so you can explain it to me because i've thought a lot about what nad does so so this is this is a good question for Peter since he and I both consume copious amounts of legitimate and probably partially illegitimate compounds for dubious purposes and sometimes

Starting point is 01:56:55 scientifically sound objectives. Peter, what are your thoughts on how do you run the calculus on when to take a given compound? Because there are certain, it seems to me as a relatively scientifically illiterate lay person, but someone who tries very hard, that there are some studies that are just not going to get funded. And then there are studies that may get funded, but the results could take five, or more years to come in in the meantime if say for instance

Starting point is 01:57:31 you are me tim ferris and you have uh neurodegenerative disease on both sides of your family pretty much everyone uh having a head start of five or ten years could mean quite a lot. So how do you run the calculus on when to take something or not? By the way, we didn't touch upon this, but I think you can squeeze this in with this discussion, which is about asymmetric risk, right? This is an example to the audience. I actually learned a great concept this week, which I sort of intuitively knew about, but thanks to Peter, who beautifully stated this over and over, and I think he's going to give an example of what asymmetric risk means by telling us when you should take a particular drug or a supplement and when not to, right? Yeah, I mean, I do think a lot about this concept of asymmetric risk, I guess, just to sort of define it. I think it's self-explanatory, right? But it's generally a situation where the risk of not doing something or doing something can be far in excess to its opposite, right?

Starting point is 01:58:48 So, so yeah, it came up so many times today. What was the most recent? Oh, that's right. That's right. So today we're on a, on a hike and Easter Island, of course, being formed by volcanoes is basically just an enormous set of volcanic rocks and so there's these really cool caves and so our guide was taking us to this cave inlet and it was basically just a i don't know 25 foot drop down and it had a tree with one branch that you had to sort of shimmy down the branch that you would at the midway point get some support of looked like it could break at any second. And he was like, hey, do you guys want to go down there? And I think it looked pretty cool, but I sort of scientists want to go, though. Yeah, that was a funny part.

Starting point is 01:59:38 Yeah. And my thought was, eh, you mean to go down to go down? Yeah, yeah, exactly. Going down. Yeah. Yeah. And I was like you're good at going down right

Starting point is 01:59:46 that idea to do this podcast with alcohol um so so the point here was what was the upside of going down the upside was you got to get inside the cave. You got box lunches usually. The downside was that branch breaks and or you slip, you break your ankle, you're stuck on Easter Island. It's a miserable day. So I just decided that missing the opportunity to go down that cave, which would be a cool story for me at that moment, wasn't worth the risk of the injury. So that's asymmetric risk. So David, I have a question for you, which is you're talking about your lifespan goal of 600 before you get hit by the hypersonic bus that will exist at such a point in time. If you are not taking rapamycin, how are you going to get to 600?

Starting point is 02:00:43 Yeah, let's clarify. I said I wouldn't mind. Well, many people said they would be sad, they see their loved ones die, all this stuff. I don't have any illusions. I thought when I was younger that people would solve the aging question by now. But clearly things have gone much slower than I would have imagined. And even things like rapamycin would give you maybe 30%. Who knows, right?

Starting point is 02:01:07 So what I always find quite interesting is that given the fact that it does have these profound effects, there's still a lot more to go, right? In terms of what actually happens. So I have no plans right now, Tim, but I have no good idea. At what point would you start taking rapamycin? Is there any given trigger or observation in your own life that would lead you? Aside from a large scale, randomized controlled trial that would definitively show intermittent dosing of rapamycin delivers X benefit.

Starting point is 02:01:39 Would anything that comes out of Matt's experiments convince you? The dog ones? Yeah. I think if the dog ones, and I don't know what the dosing regimen they're doing, but the dog ones show an impact. My biggest fear is that it's not going to have a big impact in free living, relatively healthy animals. That's my biggest fear. That's a lousy fear. That just basically says there's not enough upside.

Starting point is 02:01:59 The big fear should be, is there a hidden downside we don't see? And my view is that's a risk i'm willing to take because the upside is so high right 30 yeah although we we have no idea what the downside is the mental model here is the following is taking rapamycin picking up a penny in front of a bulldozer is it picking up a penny in front of a tricyzer? Is it picking up a penny in front of a tricycle? Is it picking up a gold coin in front of a bulldozer or a gold coin in front of a tricycle? I think every intervention has to be viewed through that lens. Now, metformin to me is either picking up a penny or maybe a gold coin in front of a tricycle i just think the

Starting point is 02:02:47 downside of metformin is so low metformin i'm using most people agree with you right yeah yeah so that's why i don't understand why nav isn't taking it um but that's that's it's probably because he's too busy looking at comics songs font nonsense um now rapamycin is different right i think the challenge now so first of all i'm convinced rapamycin is different, right? I think the challenge now. So first of all, I'm convinced rapamycin is a gold coin, so we're not dealing with pennies anymore. The question is, is it a gold coin in front of a tricycle in which it's a no brainer or is it a gold coin in front of a bulldozer? In which case it's worth doing, but you have to then, what did we talk about on asymmetric risk? You have to come up with ways to bracket the risk. You have to come up with early warning indicators of, is this going to be bad? And I think that's the reason I'm not yet taking rapamycin.

Starting point is 02:03:33 But I mean, I bug David about this all the time. Because the mouth sores. No, the mouth sores don't faze me because you stop the drug, they go away. It's the unknowns, right? Stuff we don't know that I think is the much bigger issue. It doesn't have a 30-year history of people using it. It could give you cardiac disease. But I mean, to me, the most interesting use of rapamycin would be that you could do like a rapamycin holiday.

Starting point is 02:03:53 And what I mean by that is you'd go somewhere and take like a two-week treatment rapamycin, maybe every six months or maybe once a year. Yeah, rapamycin spa, we're talking about. Maybe you do it on holiday. And that would do the cleaning out this is how i treat fasting yeah exactly i'm doing so if it's a fast per quarter right so if it's a chemical based way of doing fasting that i would strongly consider doing the idea of having another pill that i mean i don't have any pills now but if i had to have a pill to remember i know it seems like one needs a mind a little bit like yours where you're my life i think is more scattered than you're in terms of

Starting point is 02:04:28 think i gotta take this i not take it it seems a lot it is really laziness so this is gonna seem like a complete non-sequitur and it is a complete non-sequitur but since we mentioned it earlier, Peter, could you do a brief borat for us of your choice? The man and the horse. In Kazakhstan, we say that a horse is like a man. If a horse is sad, it's like if a horse is a sad is like if a man is a sad and if a horse is a happy you know happy is like if a man is a happy and if a horse is a tall is tall is like if a man is a tall, it's tall, it's like if a man is a tall. In Kazakhstan we say if a horse is a have foot is like if a man is a have foot. So a horse is like a man. What is a horse like usually? I mean, you know, in Kazakhstan,

Starting point is 02:05:50 you cannot go to a girl's father and trade cans of insecticide. You must do something called dating. I'm not going to say that. Pieces of paper being passed around so so the man is like a horse is from just to be for those people want to look it up it's from a uh a bit that

Starting point is 02:06:18 borat did where he's at an equestrian event talking to this sasha baron cohen sara sasha baron cohen talking to this poor woman who just tolerates these go to youtube what should they search a horse is like a man this poor woman listens to like three minutes of so i so peter why are you so good at borat actually can you can you tell the OR story, please? The texts that would get sent to us. Yeah. So back in the day, we used these alphanumeric pagers and you could either type directly into them.

Starting point is 02:06:56 This is at Hopkins. Yeah. Or you could go on onto like there was a server on the website and you could actually just manually type in. And if your message was too long after X characters, it would get truncated and you'd have multiple, you know, page one of two, page two of two, whatever. And so the first time I saw the horses, like a man, I sat in front of my DVD and I typed them. This is, you know, typed all of them up just so I could know every single one off by heart. There were like 20 of them. And then I

Starting point is 02:07:25 would cut and paste it into the browser and text all of my buddies with it when they were in the OR and it would get broken. Yes, the operating room. And it would get broken into like six pages. And what happens when you get all these text pages is the nurse in the OR starts reading them to you out loud. And so my friends, that's right. So my friends would get these pages that would say, but of course the nurse who probably had a Filipino accent instead of the Kazakhstan accent that Borat mimics would just be reading these things out. And it didn't make any sense. And it was like, uh, you know, Dr. Ferris, uh, you have a text here from Dr. Atiyah. It says that if a horse is tall, it is like if a man is tall.

Starting point is 02:08:06 And if a horse is happy, it is like if a man is happy. And she would just proceed to read all of this. And I think that's probably some of the story I shouldn't have just told. We'll edit that one out. That's a Tim Ferriss exclusive, folks. You heard it here first.

Starting point is 02:08:24 It'll be a Hopkins retroactive investigation. So we're going to shift gears a little bit. These are rapid-fire questions that doesn't necessitate a rapid-fire answer, so don't worry about it. He cannot do rapid-fire answers.

Starting point is 02:08:40 You can't do... No, no, no, no. He can do rapid-fire questions. He can offer longer answers, which is fine. face you can't do no no no he can do rapid fire questions he can he can't do rapid fire answers which is fine the first is most gifted books uh nav what book or books have you gifted most other people i usually uh like to give at least younger people um siddhartha by Herman Hesse. Why is that? It's a nice book about a journey of an evolution of a young man, young boy, teenager, young man into an adult. And that transition I still struggle with. And so it's a good read all the time.

Starting point is 02:09:23 It's a short book too. That's the real key. Could use a few more pictures but generally it's this and for those people listening uh sit heart and i mentioned this earlier when we were chatting is probably in the top five or six most frequently given answers to this question uh josh waitzkin naval ravikant there is a pretty long list so for those who haven't read it i think that is a so it's not original though i actually i'm saying it's a classic i'm saying but it it you know I've actually, I read it maybe 25 years ago and it struck, but I come from that world anyway. So maybe I was programmed a little bit. For me, you know, the experience is more important than the end goal. And I think that's one of the messages of that book.

Starting point is 02:10:23 You know, you collect experiences rather than objects and other things. And so it's about the journey and the experience rather than just plowing through it and getting to the end. So-called objective. Just never the end. Right. What about you, David? I tend to like historical fiction. Me too.

Starting point is 02:10:48 And so some of the books that I've liked a lot and have given others have been Gore Vidal books. Gore Vidal? Gore Vidal. Yeah, like Lincoln or Burr. You know, so they're American history historical fiction. So, you know, got a lot of true history. So I like history, but they're a little bit, bit i don't know there's a little bit of creative license taking with them what do you hope the recipients will get out of those books you know i don't think i've thought about it as deeply

Starting point is 02:11:16 as nov has i i for me anything that i read or watch has to not bore me. That's been the number one criteria for me. And I find them fun to read and that you also learn something from them. And I think in his case, they tend to also be very nicely written. So, Corvidalia. What does that mean, nicely written? How do you define something nicely written? That the sentences are interesting, right?

Starting point is 02:11:43 That there's perhaps more style. Like, for example, the sentences I like the most are kind of that there's perhaps more style like for example the sentence i like the most are kind of new yorker type sentences although they can drive you crazy i like i actually like long sentences that are incredibly well crafted so there's no confusion out of them some of the new yorker ones are like crazy but like when you look at them you're like they're quite masterful some aspects to that I also like when there's a variation in sentence structure, so it's not one type of style. You like Salman Rushdie? I don't know if I've read much.

Starting point is 02:12:12 I mean, was it Satanic? Was that the first? The Satanic. Yeah, I think I tried reading that one. I don't know if I read much more of his. I mean, lately I've been more on that history. You like his ex-wife you better right you better i met her once on a top chef filming yeah

Starting point is 02:12:31 for for she's indian that's the only reason i brought it up um anyhow nav so i sometimes read sort of more like Roman historical fiction or American historical fiction. No, it was a one-track mind. If you could put... Dude, take your foot off my shit. If you had a huge billboard, or could have a huge billboard anywhere, what would you put on it? What would it say?

Starting point is 02:13:01 I like women. Don't smoke. Don't smoke. It's a public health. All right. Wait, wait like women. Don't smoke. Don't smoke. It's a public health. All right. Wait, wait. Speaking of don't smoke, did you ever see, this was on Twitter like about two months ago.

Starting point is 02:13:12 It was a great billboard. That's true. What am I talking about? It was probably one of the best billboards i've ever seen it was um a canadian like anti-smoking campaign and it was a pro quote-unquote pro smoking billboard sponsored by a funeral house and it was like a fake funeral house the funeral house was actually like this not-for-profit i think it was anti-smoking and of course i'm not doing it justice i don't remember exactly what it said but it was like certainly top 10 billboards i've ever seen what would you put on your billboard

Starting point is 02:13:46 david um i think i might put like uh either of two things something like an interesting artwork something that was really pretty to look at but depending on what the background was or like uh like make it seem like there was like a forest or something that started like so forest all right so we we chatted a little bit about this uh but if you were thank you peter if if you had to give a ted talk on a topic outside of what you're known for or a subject area what would it be and i know i'm cheating a little bit because we chatted about this i mean the thing that i like a lot besides science is like plants and gardens so i'd probably have to do something around that but probably more about why i like it rather than any kind of deep knowledge of it because i think my

Starting point is 02:14:35 why do you do it why do i like it yeah i do like it i mean a couple reasons i think and what type of plants okay so i i so I don't like flowers. I mean, there are some flowers I like more because of the aroma, but I don't get like attracted by a rose. I like plants that have like interesting bark or leaves on them. And they're a little bit different than others. I just like how they look. And I like the fact that they're calm and sort of intelligent in some way. I've always liked like Japanese gardens. I know you spent a lot of intelligent in some way i've always liked like japanese

Starting point is 02:15:06 gardens i know you spent a lot of time in japan that that has always inspired me there's a certain piece about a garden that i don't get ever from like people or other stuff besides like this freak show here right that there's something very peaceful about a garden that i've always i've always really wanted to be able to spend time to create a garden that i've always i've always really wanted to be able to spend time to create a garden that i would really like i don't have time and i have a tiny i live an expensive place so i have a tiny little garden so i tend to collect somewhat strange plants like what like for example there's one that i like a lot which actually i saw i think i saw one here as we were driving around um it's called the monkey puzzle trees from patagonia it's a

Starting point is 02:15:45 monkey puzzle tree that's what it's called i think it's latin name is adocadia adocadia actually which is it's actually related to norfolk pine which you also see around it's a tree that has these sort of spikes on it we were we in glasgow together once we went to the botanical garden there and i showed it to you that was someone someone else. I like trees a little bit different from where I live. It goes completely against this trend of trying to go native. I should be getting New England wildflowered, but it's not

Starting point is 02:16:14 the time. That's what you meant by native. What about you, Nuff? If you were going to teach, or not teach rather, but give a TED Talk on something outside of the subject area or areas you're known for what would it be on i think um it would be on um the concept and and maybe it's a cliche but i don't think it is The idea that every relationship you enter into, the premise should be mutual beneficial. So some people argue, you know, I am altruistic,

Starting point is 02:16:55 right? That implies it's only one way. Some people say I'm selfish. That applies the other spectrum. And I think both of those are not at least healthy. So, I'm arguing against, clearly against selfishness, which is obvious maybe to people, but the other one is altruism, right? And I think the best ones are mutual beneficial, right? And that's something, maybe it's cliche, maybe it's obvious, but I think if you think about it, most of us are taught to think about one or the other, right? So the goody two-shoes are all like, oh, I need to be altruistic. Oh, it's all about you, not me. And the selfish people are like, well, me being a little selfish allows me to create interesting things and make the world eventually better.

Starting point is 02:17:44 But I think within any given situation, there are ways to do both. And David and I have talked about it, just how we run our own labs, right? And David can speak about this much more eloquently since it's late at night. But I think the concept of mutual beneficial is something that I talk about openly with people in my lab or people in general. I think it's a concept that is an important concept that perhaps is obvious, but maybe needs to be explicitly stated. so let's segue to something i view as maybe related which was a conversation we had uh on the beach yesterday in fact it's not clear how this podcast is mutually beneficial wait a second what do you mean it helps me but it doesn't help you you can ask for anything you want this is like a this is like a genie bottle that you can rub. Actually, this is mutually beneficial, right?

Starting point is 02:18:50 Because you have your podcast and I'm just having a good time. So I'm benefiting from having a good time. That's a nice wine. So we were chatting yesterday and I observed and not to claim that I know David very well, but I said, well, you know, David, Peter, and I tend to run pretty hot. Not a bad thing. You guys are hot guys? Meaning we're ready for the

Starting point is 02:19:13 Thunder from Down Under auditions. No, that means that we're a little... We just run hot temperamentally. And I asked you, have you always been this even keeled? Because you seem very even keeled and very calm in most circumstances I've observed you in. Could you perhaps repeat and elaborate on your answer? So I would say till the age of 22, no, not at all. And I found myself quite unhappy and actually very unhappy at one point. And I sort of pulled, just to be funny here, I pulled what's called one of my great shows, Seinfeld, George Costanza. So if people remember George Costanza,

Starting point is 02:20:06 in a Seinfeld episode, like nothing was working for him, right? Hey, like he was just like, and one day he decided, I'm gonna do everything opposite, right? And, you know, I say this in a joking way, but I did. I used to, I mean, as you can tell, I've gotten older,

Starting point is 02:20:22 will probably lose my hair eventually. You've got quite a bit of hair.. You've got quite a bit of hair. But I've got quite a bit of hair, right? And I always had it a little bit on the long side. But if you take up pictures from my high school, college, as a kid, up till 22, I had very, very short hair. As my lovely wife likes to say, oh, you had the Dunkin' Donut Boy haircut. She describes it as.

Starting point is 02:20:48 And then, you know, I just, for whatever reason, said, you know what, I'm going to grow my hair long. Like, that's just one example. I mean, it's a very superficial example. And so after that, literally, I did many things opposite from what I used to do. And slowly, it just, I got to this point. What was the catalyzing moment or conversation or dinner, whatever it was, at 22?

Starting point is 02:21:17 Why did you change your ways? What was the setting or the moment or anything? It was nothing in particular. It was just simply that I was not, A, I was unhappy with what I was doing. What were you doing at 22? I mean, superficially, I was doing all the right things, but internally, I was unhappy, right? I mean, look, when you're an immigrant,

Starting point is 02:21:44 and Peter's also an immigrant, he can relate to it, you have your family that comes from a different country, has expectations that are expectations based on like, you're still back in your own homeland, right? But you haven't grown up there since the age of 10, essentially. And now you're 22. So you spend actually more time in the United States and you feel like much more of an American at some level. Of course, you still retain certain key aspects of your Indian heritage, your Himalayan Indian heritage. And so there's that internal conflict and how you settle that. And from that internal conflict, probably create some

Starting point is 02:22:22 sort of uneasiness and unhappiness, lack of confidence, perhaps even, and insecurity. And either you just stay in that perpetual state, and I know plenty of immigrants, and Peter can probably also comment on this, who stay in that perpetual insecurity of not knowing where they belong, or you start to make some firm decisions. And I started to do that. And one of them was that, you know, this isn't working for me, whatever I was doing. And there was just that anger about, am I Indian? Am I American? I mean, there are books written about this sort of subject. Then once I decided, look, I'm going to be in America. I like certain parts of America.

Starting point is 02:23:03 I like certain parts of India. And I started to solve that sort of stuff. I realized that one of the things that I really like are people. I really like people. I'm afraid of dogs, but I like people. A lot of people like dogs, but not people, right? So I like people. And I started to engage people at a deeper level, and I get satisfaction from that consistently. And that just made me a happier person and a very tolerant person. And from that, you probably notice a sort of not running so hot. And also made me less entitled, which is key. What were some of the decisions you made aside from growing your hair out that's that stand out to you as memorable or important either i and it'd be interesting what david thinks about this

Starting point is 02:23:57 i actually think everybody's interesting you just have to get it out of them that i did not have an appreciation growing up i clearly you know it was kind of like sadly winners losers that kind of thing right and i just you know i think everybody's got their own interesting story most people probably aren't enough self-reflective to even um and this is maybe judgmental, that they can articulate their story, but it's there. It's just a matter of getting it out. Teasing it out. Teasing it out.

Starting point is 02:24:31 And I think that's what your podcast does, essentially, from what I can tell. Yeah. No, that's definitely the goal. So, David, there's a common expression in Silicon Valley, but elsewhere, it's become very widespread, which is you're the average of the five people you associate with most. You spend a lot of time with Nav. Why are you guys friends? Why do you continue to spend so much time together?

Starting point is 02:24:57 I wish there were cameras here. Yeah, I think it's an interesting question because I, unlike Nav, have a harder time. It takes me a while to actually like someone. And I frequently accuse people of being potatoes. This is a term that we use quite a bit of someone. Potatoes. like if you see him coming down the hallway you run into the bathroom to get away kind of thing and and you know sadly and i and i do agree with nov i think it's probably that's probably not a true statement but i have less and as you've noticed i'm very impatient i have less patience and um and and pulling that out of someone i think what nov and i share and i think is also not so common amongst the interactions that we have, is we're very open. And you could say it's sort of, it's not intimate, obviously in a physical way, but intimate sort of like that you just share. Trust me, Nav, it's definitely clear to me.

Starting point is 02:25:58 But just that one can be open and frank. And I think you and Peter are also. Yeah, for sure. And that's a really great quality i i think so many people always have a facade particularly people who are quite prominent and in our world in the science world you know we interact with lots of prominent people and there's never kind of like knowing who that person is there's always what they are rather than them and that's why people get upset at me because I just say whatever I think, right?

Starting point is 02:26:25 And Nav does that too, right? And it doesn't necessarily always make you the best friends of others, but I really appreciate that about him. The other thing I really like is that we treat each other just as two dudes do. It's not a like, what paper did you publish and what did you discover

Starting point is 02:26:44 and how many people are in your lab? And this is what scientists tend to say. Like, did you see that cell paper I had? Or I have 25 people. There's just a lot of that competition stuff, which maybe matters at times, but we don't have any of that between us. And it's very rare that that happens.

Starting point is 02:27:00 And when we talk about science, we just talk about science and like pure science, like what's interesting, what's what's not true not in that kind of more i don't know scheming way that it's not a jockeying it's not a definitely not a jockeying i like him for who he is he likes me for who i am it's not that i need something for him he doesn't need anything from me and a lot of times that's not quite the case i mean it you know we also have obviously other friends and we actually have we actually are part of probably a group of what five or six people that end up at similar meetings throughout the world that we interact with quite

Starting point is 02:27:35 nicely but i like that kind of sort of frankness that he has and i think he appreciates my frankness as well well i've uh i've asked some guests on this podcast i'm not going to do it because i think the answer is really obvious at least in this case who do you rely on to tell you when you're wrong and i'm not going to say you guys tell each other when you're when each or the other is wrong but just the level of bickering has been so fantastic to observe it's non-stop it's great but it's but it's not a competitive if you guys were alone just the two of you you'd be having the same conversation it's not a posturing or a political chess match. It's like just the pissing contest. People call us the David and Nav show.

Starting point is 02:28:28 And we provide entertainment. We'll be at a big dinner table and no one's talking and we entertain all of them just by arguing. And not on purpose. I think I said this earlier. Maybe I didn't. In case I didn't, I'll just say I remember Nav and I were talking

Starting point is 02:28:43 and you said something along the lines of I bet you weren't expecting us to be such dumbasses or something like that which of course is not the case I mean I feel like I've I've needed Wikipedia and Google

Starting point is 02:28:59 and a glossary to just feel able to tread water and a lot of these conversations yeah David and I feel with but I said you know what I feel like and glossary to just feel able to tread water in a lot of these conversations. That's how David and I feel with Peter. But I said, you know what? I feel like I've stumbled into dumb and dumber meets limitless. And I think that's a pretty good analogy.

Starting point is 02:29:19 He calls me dumbass in front of other people. He'll scream across from, dumbass, come over here. You call me douchebag a lot i call you all right peter peter has a mouthful of of nuts nuts in his mouth i know it's ridiculous um you know one thing that has been awesome this week that it's unfortunate can't be captured in this podcast two things one is all the inappropriate discussions so that's just that is what it is that's the limitation of it but the other thing that i have found incredibly fun is the totally nuanced scientific discussions that have taken place in one of the most beautiful places i've ever been on this planet right so it's really

Starting point is 02:30:05 cool to be sort of sitting i don't know on a cliff overlooking the pacific where you're really in the middle of nowhere and really trying to figure out if it's the ratio of nad to nadh that matters more or the activation of amp kinase and coming up with thought experiments. And so are you going to fast for five days or 20 days? I mean, what's the most important question I think we've bantered about this week has been how can you measure autophagy? How can you clinically measure autophagy or with the mTOR integrator? I mean, like, freaking one of my favorite problems on the face of the earth. It drives me crazy. And I don't, I just think that that's kind of been the, not, not just the highlight of the week, but I think when you have people in your life that you can have that kind of

Starting point is 02:30:54 complete discussion, you know, you can have that discussion with, and you can go, you can immediately interchange between complete and utter bullshit. And that, I think that's like, that's the whole. And then it's a back and forth, Peter. You know, we unfortunately meet, many people are highly intelligent, but many people want just airtime and to give a lecture.

Starting point is 02:31:12 And that drives me back and nuts. We all have gone back and forth, argued, have different ideas. That's awesome, right? That's like having a non-potato relationship. Can I just elaborate just for two seconds, which means two minutes, on what David said? You know, it's difficult as you get older. So I think this is definitely a function of age, but also within your own field as you

Starting point is 02:31:42 sort of rise to the ranks. And it's like, you know, who do you trust that you feel comfortable telling you when you're off your rocker, right? And I think it's important to have that. And, you know, I'll give you one quick example, which goes back to this idea that low amounts of hydrogen peroxide perhaps have been, H2O2 have beneficial effects, right? And nature has selected this idea. You know, it's a new way of thinking. But David is actually my biggest critic on this idea, right? So a lot of people, you know, say, this is kind of an interesting way, maybe explains a lot. And David says, yeah, yeah, it's very interesting.

Starting point is 02:32:31 It's, you know, blah, blah, blah. However, how does it work? So in other words, okay, so you think H2O2, everybody says you put enough peroxide on cells or if they accumulate enough, it can damage. And the chemistry, you can explain that. It oxidizes lots of things, DNA, lipids, and it's bad. That's an easy concept. But the concept that H2O2 now has specific proteins that it acts on, maybe even mTOR, which David once had a paper on, how does that work mechanistically?

Starting point is 02:33:10 He's done beautiful mechanistic work on showing what mTOR does. How does peroxide work? And I think for that idea eventually to really take off and make a huge difference for public health is what I got to do. And nobody hits me harder than David does, who's my best friend in science easily, right? But privately and publicly, also a big critic. But not like, I mean, I agree with them. This is what my lab has to do over the next, you know, five years at least. That's a fair statement, right? David,

Starting point is 02:33:47 what, uh, how, how old are you now? 48. 48. Jesus, you do look young.

Starting point is 02:33:53 I told you. Holy shit. People, the dude takes rap from us. I know he does secretly. So, uh, David,

Starting point is 02:34:01 what advice would you give to your 30 year old self? And place us where you are, what you're doing at the time. So 30-year-old self. You could choose 30 or 20, 25. It's up to you. So I did an MD-PhD at Hopkins, the same institution that Peter was at, although a little bit earlier than you were.

Starting point is 02:34:21 And then I decided not to do clinical work and i decided just to do research and so i needed a job so i but i decided to go for these sort of independent positions where you could kind of get a little lab on your own and i went to this place called the whitehead institute where i am now which is affiliated with mit to start a little lab there and eventually join the faculty. So I was basically when I transitioned to Boston, I guess, when I was 30, it was really, really anxiety producing to have your own little lab just coming out of your PhD and frankly not really knowing what I was doing. What would I have told myself? I probably would have told myself, yeah, I worked like crazy. I think it's fair to say that's the only thing that I did well. I probably would have tried to be a little bit more what

Starting point is 02:35:20 Nav described himself as. So this is clearly at a later age than him. But one thing I'd never thought much about and probably haven't even until much more recently is the kinds of relationships one wants with people. I think I did those relationships in the easiest ways possible to sort of optimize my capacity to do work and do experiments. And that probably in the long run, I think I would have wished, I wish I would have thought more about that in terms of, well, what does it mean to have a good friend? What does it mean to have a girlfriend? You know, what's your relationship with your parents?

Starting point is 02:35:53 I don't think I, I don't think I ever thought about relationships in any kind of serious way other than they exist. And there's some things you get from them. Have to be tolerated. I think so to some extent. And I don't know why that was, but it took me a- Potato or not potato, right? No, but at that time, I don't think I gave people even the time to fall into those categories.

Starting point is 02:36:17 I wish I had thought more about that. Do you think if you'd had that conversation with your 30-year-old self and taken the foot off the gas a little bit with the work focus do you think that would have precluded the progress or advances you made over the subsequent say five years or inhibited probably yeah i mean i've been always a ridiculously impatient person it's my Would you have willingly made that trade-off? No, probably not. But maybe if someone had said, look, these things, if you think about them now, have an impact much later in life,

Starting point is 02:36:53 maybe I would have, right? I mean, I could have done some cost-benefit analysis. But certainly back then, I would have seen things as a distraction, which is how I did see them. I was just really impatient and couldn't them. I was just really impatient. I still am really impatient. I cannot stand to be in a line. I can't stand walking

Starting point is 02:37:11 out of an airport with Nav. He walks so slowly. He drives me insane. He'll be in the back of the plane. He's like a person who allows himself to be put in the back of the plane. He's fine with it. Right? Like our flight from Santiago, he was in the last row of the plane, he's fine with it. Right, so. Like our flight from Santiago, he was in the last row of the plane.

Starting point is 02:37:29 All by myself. How does that happen? The beauty was there was nobody around me. And I had the whole three seats to fall asleep in. Anyways, but I think that's what I would have, I would have said, give more intelligent thought to relationships with people, just like you're giving to your career. What about you, Nav?

Starting point is 02:37:52 30, 25, 20, you pick the age. So I think mine is almost the opposite, right? So up till the age of 22, was all iq right no eq right emotional quotient and which is what david's talking about for his iq oh it's not a lot i actually have a fantastic emotional no no i can it's more about my own relationship right right right but i'm just what do Yeah, no. Thank you for clarifying that. But I'm just sort of putting them into two categories. You know, your intellectual work, work-worths, relationships.

Starting point is 02:38:32 And I'm just sort of broadly classifying them as IQ and EQ. And that's not an exact term. And I think till the age of 22 is all about being a math guy, probably having some of the characteristics that David said, but for whatever reason, it didn't make me very happy. And so I probably spent those years well into my 30s working on relationships and sort of being more well-rounded. But at the same time, that probably came at a cost, right? I mean, I think there is, I mean, David and I talk about this all the time.

Starting point is 02:39:14 And when he says what he just did, I push back and say, dude, that allowed you to do certain things that were incredibly insightful and important for biology, right? And in some ways, I feel like I'm just playing catch-up. Not to David, I mean to my own self, right? I mean, I know what I have to do, right? I know the experiments, I know the questions. I mean, I think I'm reasonably intelligent and I have good scientific taste.

Starting point is 02:39:40 I know what the right questions are, but I'm kind of playing catch-up. Now, you know, can you play catch up when you're 46 years old? I don't know. I hope you can. So, you know, did I lose some time by working on myself, you know, in relationships? There's no right or wrong, right? It's the journey. I mean, if I had to do it again, would I still do it the same way? Yeah, right? No regrets. You can. It is what it is. So there is no right. I mean, I think that's one of the reasons why we get along so well because today we probably have a similar view of what we want going forward, right? We've arrived at the same place in many ways, but from completely different approaches based on a variety of factors. Is that a fair statement?

Starting point is 02:40:31 Yeah, for sure. What, Nav, would you view as the best or one of the best investments you've ever made? And by that, I don't necessarily mean stock investment or something like that. It could be an investment of money, time, energy that was kind of speculative at the time, right? So for instance, a guest on this podcast, Amelia Boone, was on the law track and invested $450 in her first entrance fee for something called World's Toughest Mudder, which is an obstacle racing competition. And now she's the best female obstacle course racer in the world. So it opened up a million doors,

Starting point is 02:41:15 but at the time, $450 was a big stretch. Does anything come to mind? Oh, yeah. So I have a dirty little secret. You said the four-hour work week, and I joked that I invented that. And I've been teasing our good friend Peter about how efficient he is. My best quality by far is how efficient I am. In a week, I go through a schedule of running my lab, traveling, being with the wife, being with the kids, going to rooftop with friends, playing soccer. I mean, I do a lot of, lot of stuff. I'm doing things for the university, for the scientific

Starting point is 02:42:00 community. It's not only one thing. I do like 10 different things. It's all in a meaningful way. And the reason I do it is because I have a very strict, regimented mental, thanks to the calendar as well on the iPhone, and where everything is accounted for, right? I have a huge list of things I want to get through in a week, and it's all accounted for mentally in this. And I still get a reasonable list of things I want to get through in a week, and it's all accounted for mentally in this. And I still get a reasonable amount of sleep, usually about seven hours. And I purposely became efficient in graduate school. So most people, including some of my own graduates, I don't understand why they come in at 10 o'clock.

Starting point is 02:42:42 I really don't get it. So in graduate school, I realized I love soccer and I want to play soccer every day. That was around six o'clock, our games. I got in as a graduate student, which is unheard of, by seven or 7.30. And I used to party way late in the night. It didn't matter. I will always get in. And I just cranked. I didn't want to work 15 hours, come in at 10, stay till 3, and brag about how I stayed till 3. Well, you started at 10. By 11.30, you're already at lunch. At 1, you finally set up.

Starting point is 02:43:15 It wasn't very efficient. For me, come in at 7.30, just crank through. Usually by 6, I would be done on most days. I think you were talking about a very smart graduate student that you have currently who seems to be very efficient and who's very successful, who's been able to do amazing work, but he's very efficient about how he likes to go about many things he does within the lab and outside the lab. And I think, but for me, it was a, again, I spent 12 years from the age of 10 and 22 sitting in a library doing math 18 hours a day and watching the world go by me.

Starting point is 02:43:50 So my reaction was, wait a second, I can spend 18 hours and get nowhere. Maybe I should do the George Costanza movie. Maybe I should just work for nine hours, my butt off. That way I have enough time to go play soccer, go watch the great Michael Jordan and the Bulls every night on TV in the pub. You know what I'm saying? So I got very good. And to this day, even when I'm at meetings, as David knows, I plan out dinners.

Starting point is 02:44:18 I actually organize many meetings. But at the same time, I find time to have dinner with friends and stay out late, be social, get up in the morning, still give a talk, ask questions. It's a conscious choice of living and being efficient. What are some of the biggest differences between, or what are some of the most common mistakes that inefficient people make in your mind? And that could be people in general or it could be people sort of within your field. For me, it's very easy. When do you give 110%?

Starting point is 02:44:53 And when it's just good enough. So for you, how do you think about that? When I have to give a talk, it's 110%. It's about 25 minutes usually, right? Sometimes 45 minutes, right? It's an insult to maybe the Comic Sans is an insult, but at least the data is insulting if it's not presented in a manner for the 50 or 500 people that are listening, right? It's insulting that you're just going to get up there and bumble your way through. You got to give. But there's a lot of stuff that we're dragged into where people, as David said earlier,

Starting point is 02:45:30 just like to talk all the time about whatever. They schedule a meeting for two hours and want you to be there. I'm like, we can do this in 30 minutes. I know we can. Why are we here for two hours, right? That's inefficiency. So I'm very clear about this is what I bring to the table. Well, if you think this is a benefit, again, mutual benefit. If you think this is a benefit because this is all I'm going to give you, because I don't think you need more than that, take it or leave it. And I'm at a position where I can do that. But most people, you know, they think by spending more time in anything, like, it makes it better. Yeah.

Starting point is 02:46:08 I mean, that's just crazy. It's just not the case. It's just not the case. Yeah. There's something called the mythical man month in the world's software development where they say if you have a software project that is behind schedule, if you double the number of people working on it, you effectively double the delay. It actually makes it take longer. Right. And so, believe it or not, as a kid,

Starting point is 02:46:28 I worked my butt off much more harder than this because my father said nobody died from working hard. That was our motto. Well, you look bad. That's really bad advice, okay? I mean, yes, you want to work hard, but I mean, you know, people do die from working too hard, let's be honest. And so, you know, people do die from working too hard. Let's be honest. And so, you know, it's more about working efficiently. So I teach my daughter constantly how to prioritize what's important, especially as kids. They think everything is important, right? Are there any particular questions that you ask your daughter to help her prioritize?

Starting point is 02:47:01 Or how do you instill that? Oh, for me, it's really easy. I mean, does this have to do with confidence, ability to write, causality, right? It comes down to, again, the same sort of principles. The pillars, yeah. That's right. So for me, being good at math is really important. Maybe that's just me. Being good in our history and writing classes is good. Some other classes, you know, I mean, these days they give you so much homework. You know, they have some crazy touchy-feely classes about visual this or whatever. I'm like, you know, kid, if you got to it, you got to it. It's not a

Starting point is 02:47:35 big deal, right? You don't have to be A at everything. But there's a few things, it's not even being A, do you really understand, you really understand geometry? Do you really understand how to construct what David was saying, sentences? My wife luckily is very good in English. She has a Romance Languages and Literature major originally. And so she's very good at helping her construct and find her voice as a writer, right? So I mean, you try to work on the real stuff. David, in terms of your best investment or best investments that come to mind, I mean, you can really think about them as decisions,

Starting point is 02:48:14 allocations of time or resources. Yeah, I was thinking as Nav was talking, I guess I've never really thought them as investments, but certainly the best decision I did was not pursue clinical medicine. What is clinical medicine? Well, be a doctor and see patients and work in a hospital. I mean, when I was an MD-PhD student and I finished my PhD, and this was after the mTOR work, and I was confident I had done something that mattered i went back to the hospital you know there was a lot of pressure to continue in that uh in that

Starting point is 02:48:50 world my my parents my mother in particular and in general it was it was nowadays i've had several students several md phd students of my own not pursue medicine but at the time was actually not as common and um and not doing that and staying just with the research side even though my mom said you know you're gonna starve you're not gonna have money you're not gonna have food you know mothers worry about those things she i think she had very low expectations because she said if you do an md if you finish your do your residency you do an internship at least you can go to some small town in the south and they'll take you as a doctor twin peak style exactly but that was probably the best decision i made and it was one of the

Starting point is 02:49:34 hardest ones how did you make that decision i mean you had your family on some level doubting the decision how did you come to make the decision well it was I think it it was pretty simple actually when I went back to the hospital and you have to do what I call rotations right you do different services you do medicine surgery ob-gyn I just I found myself when I was talking to patients or reviewing their cases, thinking about my own scientific work. And I thought that that was really wrong. It's one thing to be a bad scientist, which there are many, but to kind of be a bad doctor and not really care is really bad. It's really terrible.

Starting point is 02:50:21 And I realized I was going to be a bad doctor. I was not thinking about this person. I was thinking, how soon could I get back to my lab bench and do an experiment? And that's just bad. I definitely avoided certain work as a medical student that I should not have avoided. So that was it. I think you know. It's like whether you like someone you don't like someone it's it's it's you really do know that feeling and you just have to sort of convince

Starting point is 02:50:51 yourself and here it wasn't that hard because it was sort of unethical to be interacting with a patient and not giving my 100 i mean it's in a way fortunate that that moral conundrum existed right because it assisted in the decision it assisted tremendously my advisor saul snyder also was like look david yeah those people used to also make the argument if you do the clinical stuff you'll get paid more this is a very common argument because mds make more than than phds i remember him telling us like i don't pay attention to that that's you know it countered my mother's kind of argument. But it was really that I was treating patients without giving the full attention of my mind. And that seemed fundamentally wrong. happy was that as an indian male i was thinking about your mother they wanted me to be a doctor right so i was doing math but and i took all like physics and math and all this hard stuff which you

Starting point is 02:51:51 don't get very good grades in and eventually i started like biology oh good you're going to become a doctor so i actually i don't know if you even know this david you know how many times I applied to medical school? Three times over a span of 20, 22, and after even my PhD. You know, the guy who now heads Sloan Kettering Memorial Hospital, arguably one of the two best cancer hospitals in the world, a very famous scientist, physician, and a mentor, a good friend, both of David and I, we see him all the time, Craig Thompson. And he even went straight after the PhD to the dean with my dossier. And this was right after the OJ thing. He goes, you know, now you're like OJ Simpson.

Starting point is 02:52:45 You have to have a Hail Mary to get away with this. Because, you know, they care about grades, right? And so I didn't have great grades because I did math and physics and all this stuff, right? Just for learning. And so I didn't get in even the third time, right? So I tried and maybe it was a good thing, right? Blessing in disguise. Blessing in disguise. And blessing in disguise.

Starting point is 02:53:05 So that was part of the other failure. Well, it goes back to not fearing failure, right? Sort of conditioning yourself against it. So Peter, I want to pass the mic to you because I think we have maybe a good ending story as we start to wrap this up. So I'm going to pass the mic. Yeah, so it's kind of hard to believe. It is, what, in 24 hours we're going to be out of here right that's right yeah sort of a bummer this week has gone by fast um i think um the only regret i have was that uh ajay wasn't here. I think, uh, who's, who's Saren's son. Um, and actually, yeah. So, so Saren was the, uh, gentleman who did, you know, the majority of the work on identifying what it was in the soil, um, that they, that they, that they found here at, uh, at Easter Island in 1964 that, uh, it was so special. It was this, uh It was this bacteria that purified it. It was

Starting point is 02:54:07 rapamycin. And one of the more interesting stories, so first of all, it's kind of interesting how I met or got connected to his son, which was I was on another podcast discussing a little bit about rapamycin and mentioned that I knew that Saren was dead, but that his son was still alive. And I wished I could connect with him somehow. Somebody heard the podcast who knew him, told him, and he connected with me through LinkedIn. And then that's when I got told about this trip. And, um, he, he made a pretty big effort to come. Um, he told me some interesting stories that I think one is worth sort of closing with, because it brings back to this question that, you know, frankly is front and center on my mind, um, which is when can I start taking rapamycin?

Starting point is 02:54:54 How much should I dose it? How often should I take it? I'm not sure I want to wait until 20 years from now, um, to know the answer to that question. And so in the late 90s, Soren presented with metastatic colon cancer. So that's a pretty unfortunate presentation. That means that you're not only diagnosed with colon cancer, but at the time of diagnosis, the cancer has already spread to the liver, completely to the liver, which is the first place it usually spreads. And so at that point in life, pardon me, at that stage of a diagnosis, your life expectancy is really short. It's again, it's hard to know exactly because I didn't see the x-rays, but you know, it could be six months, it could be a year, but it's not a long life expectancy once

Starting point is 02:55:39 you have that. And he decided to start taking rapamycin. Now, this was even before rapamycin was approved. Rapa was approved in 1999 by the FDA, but again, for this very specific indication around kidney transplants. But he started taking it because, of course, he had a reasonable supply of it. And he took it for about three or four years. And during that period of time, none of the tumors grew. None of them shrunk, but none of them grew. He was in completely stable situation. And he, this is all according to his son who told me this story that, you know, he decided he was never going to know if rapamycin really worked unless he stopped it so he stopped it and sure enough as soon as he did the tumors basically exploded throughout his body and within three months he was dead um he told his son on his deathbed that you know he sort of regretted this and it was the biggest mistake he ever made was not taking it and so i think it was like maybe 10 days ago, I emailed Ajay and I was like, do you remember what dose of rapamycin your dad was taking?

Starting point is 02:56:52 And he's like, I don't, but I bet my mom will know. And he emails me back an hour later and I forwarded you this email and I forwarded to you as well, David. He said, I can do one better than that, Peter. The, um, she, my mom still has some of it in the freezer and he sent me the photograph of the prescription because by the time he was at the end of his life, it was already post 2000. And so this drug was already in the market and churn up, you have the little, you know, it was like a Safeway or Vons pharmacy thing and it's got his name on it and it's rapamycin and it was one milligram per day and so um you know i think that so to me this kind of

Starting point is 02:57:31 this this this this week has been unbelievable um i think the thing that's sort of funny this week by about is like finding out that that plaque is gone you know one of the first things david said to me when we planned this trip was we can't wait to see this plaque. There's a very famous plaque that is sitting on a stone at the outside of the crater where they found the bacteria. And what the morning we were going to go, we were like, oh, there's some good news and bad news. The good news is we now know where the plaque is. The bad news is it was online. You couldn't find where it was. It was just a picture, just a picture of it. And you couldn't always. And the bad news is because online you couldn't find where it was it was just a picture just a picture of it and you couldn't where it was and the bad news is it

Starting point is 02:58:06 was stolen in 2011 so we went and saw the rock that once held the plaque and um you can see where it was but yeah you can see yeah it's uh so anyway i think our hope is that and we're trying to figure out what the right way to do this is but is to sort of collectively put the put that plaque together send it back to the folks here put the, put that plaque together, send it back to the folks here and have them put it back up, uh, and maybe add something to it. Cause it,

Starting point is 02:58:30 the plaque was already, um, you know, obviously a tribute to this, but I think there's, there's a, there's probably a bit more that could be said. So just to wrap up.

Starting point is 02:58:40 And I loved getting that email and that might, you remember my response? 2000 question mark, exclamation point, exclamation point. Uh, And I loved getting that email. Do you remember my response? 2000? Question mark, exclamation point, exclamation point. So just in closing, I'd love for people to know where they can find you guys if they can find you guys. And you are hard to find, as it turns out,

Starting point is 02:58:59 because you're not on social media, except for, it would seem, a potential Twitter account. We'll come back to that. We'll'll see i think it was a joke account if you can recall the joke account that was made that may at some point be active that was the account we made i'm in a meeting as a joke a friend of mine made an mtor man twitter handle and started just tweeting nonsense which a lot of was erased because it was sort of making fun of some of the people at the meeting and they asked me to erase part of it.

Starting point is 02:59:28 All right, so you may be able to find, and I'll try to correct this in the show notes. Old people like us use email, right? At mtorman, you probably don't want to give out your email address on this podcast. But our email addresses are trivial. There are other people who have done that so so yeah all right so you can find their email addresses but but let's so let's start with that

Starting point is 02:59:55 actually David so people may or may not be able to find at mtor man on Twitter I think it still exists because I keep getting like people keep asking me whether to follow me, even though there's nothing been put on it in years. Okay, alright. So some people may be able to reach out through that avenue. Otherwise, is there a particular website or

Starting point is 03:00:16 otherwise where people can learn more about your lab? Yeah, I mean if one just searches my name and puts David Sabatini Lab. Whitehead Institute, they'll find the website. I think if you put Sabatini Lab, it probably goes to that. And Nav? Same thing.

Starting point is 03:00:32 Same thing. We just put... What should they search? My name, Navdeep Chandel, and it'll pop up, Northwestern University. Navdeep, N-A-V-D-E-E-P, last name C-H-A-N-D-A-L. D-E-L. D-E-L. There last name C-H-A-N-D-A-L D-E-L. D-E-L. There we go. I think Google will fix that.

Starting point is 03:00:49 We'll sort it out. His name is pretty unique, actually. There's not a lot of people with it. Is that right? And the last question is do you have any asks, suggestions, or recommendations for those people listening?

Starting point is 03:01:06 Any requests that you would like to put out to those people who are listening to this podcast? Anything whatsoever, really. It's a shame we don't have a video here. I mean, something that Peter and I have talked about is I do think there's going to have to be a new era of sort of molecular nutrition where one understands nutrients at a much deeper molecular level in an integrated way. And it's clear they have a major impact on our physiology. And a lot of this we've known for a long period of time.

Starting point is 03:01:40 But how they all combine to affect many different systems over long periods of time under different situations, a lot of that is really unknown. And it's not really clear how we're actually good or bad responsible for a lot of the food pyramid places dismantled their physiology departments. You know, those are things that I think we have to start thinking about. We've done so much at this sort of deep molecular biochemical level, going back and integrating this in an integrative fashion, I think is going to be interesting. That's what I would say. Nav? Any closing thoughts yeah i think i concur with david uh one of the things um that does perturb me sometimes for an even keel kind of guy is that everybody's an expert on diet and nutrition and metabolism. It's amazing to me, right? When people talk about genes and genetic information, and I'm talking about the larger public,

Starting point is 03:02:53 people sort of go, well, I'm not quite sure how genes and DNA, RNA, I don't even understand that. But when it comes to metabolism, diet, nutrition, all of this stuff, everybody is the world's expert on and you know it's as complicated as learning about genetics x and uh and it takes a long time to figure out uh at a deep level what metabolism means how it works. And like David said, diet and nutrition, I mean, I don't know much about it because I think it's infancy.

Starting point is 03:03:30 It needs really a revamp. And so I would just tell the general public to treat the world of diet, nutrition, and metabolism perhaps with the same sort of respect that they have for genetics and not try to just tweet out stuff that they may think, I think, based on anecdotal evidence is true. Correlation with causality.

Starting point is 03:04:00 And have skepticism and have the same scientific rigor. And I think one of the things that I've enjoyed talking with Peter and yourself is that you guys do sort of think about this from a very, you know, you use the classic scientific method in trying to decipher what metabolism and diet and nutrition really mean. But I think most people just don't. They think the world's experts on it. And I'm like, I've spent a whole lifetime doing this stuff and still feel like I'm in the dark. You're entitled to your own opinions, but not your own facts. Well stated. Peter, any final parting thoughts

Starting point is 03:04:43 or any questions you'd like to pose to the universe slash my listeners? Well, I mean, a lot of what we talked about this week, we didn't get to because I think it's probably more technical. But I think the really interesting stuff here is. And it kind of actually gets to what Nav's point is right i mean one of the things that keeps me maybe keeps me up at night is too strong a statement but it's what certainly um frustrates me is that we don't have a great way to evaluate for example different protocols that are used to um mimic caloric restriction right so called intermittent fasting um and we can all agree on why that would be beneficial, probably something to do with autophagy. We don't know how to measure that, right? We can measure it at a point in time, maybe do a muscle biopsy. But to me, one of the most exciting things we

Starting point is 03:05:35 talked about this week was what would it take to put together even a small N of one or N of five experiment where we sort of shotgun this thing and look at what are the metabolic signatures of autophagy that can then allow us to have a tool to evaluate dietary strategies that go beyond hard outcomes right because hard outcomes mean you got to do studies for 20 years look for people who live die longer those things just aren't going to happen so we we kind of i think we need to come up with a new way to think through this problem um and i don't know that i haven't asked at the moment but i know i'm going to peter where can people find you nowhere that's not true kazakhstan that's right i'm in Kazakhstan yeah I mean I have a Twitter handle that I use occasionally

Starting point is 03:06:30 and I blog once or twice a year that's extremely nebulous any further instructions eating academy yeah just google my name okay Peter Tia,

Starting point is 03:06:45 ladies and gentlemen, uh, thank you all very much for the time guys. And, uh, to everybody listening, there'll be show notes, links to everything that we discussed at four hour work week,

Starting point is 03:06:57 all spelled out.com forward slash podcast. And as always, and until next time, thank you for listening. Signing off from Easter Island. would you enjoy getting a short email from me every Friday that provides a little morsel of fun before the weekend? And five bullet Friday is a very short email where I share the coolest things I've found or that I've been pondering over the week. That could include favorite new albums that I've discovered. It could include gizmos and gadgets and all sorts of weird shit that I've somehow dug up in the, uh, the world of the esoteric as I do. It could include favorite articles that I've

Starting point is 03:07:47 read and that I've shared with my close friends, for instance. And it's very short. It's just a little tiny bite of goodness before you head off for the weekend. So if you want to receive that, check it out. Just go to 4hourworkweek.com. That's fourhourworkweek.com all spelled out and just drop in your email and you will get the very next one and if you sign up i hope you enjoy it

Pet Camera - EBO Air 2

The Tim Ferriss Show - #193: My Life Extension Pilgrimage to Easter Island

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Pet Camera - EBO Air 2

The Tim Ferriss Show - #193: My Life Extension Pilgrimage to Easter Island

There aren't comments yet for this episode. Click on any sentence in the transcript to leave a comment.