Tim Ferriss on Biomarkers, Ketosis, Microbiome, and Lyme Disease
Posted on July 21st 2015 (almost 4 years)
Tim Ferriss, notorious self-experimenter, angel investor, startup advisor, NY Times bestselling author (3x), and much more.
- Rhonda: All right. Dr. Rhonda Patrick here. Today I'm very excited to be sitting here with my friend Tim Ferriss, a notorious self-experimenter, a three-time New York Times bestselling author, an angel investor, startup advisor, and much, much, much more. So before we start, I really just want to say that I really enjoyed the last time you had and I had a conversation.
- Tim: Me too.
- Rhonda: It was about a year ago, I think, on your podcast.
- Tim: Oh my gosh. Time flies.
- Rhonda: Micronutrients, aging, epigenetics, stem cells, all that stuff, super fun. So I'm very excited to have the opportunity to interview you on my podcast.
- Tim: Yeah. I'm intimidated. But I'm looking forward to it.
- Rhonda: Great. I kind of want to start off with the self-experimentation.
- Tim: Sure.
- Rhonda: We were actually just having this interesting conversation that we've stopped so that we can continue it live and that has to do with a little bit about the night you just had and what you're doing to recover from that night. Do you want to talk a little bit about that?
- Tim: So I had, like a lot of people on Saturday nights, a little more booze than intended or anticipated. We were talking about mineral excretion. I was talking about some of my pregame tactics, whether that's consuming carbohydrates. I tend to drink the most booze on cheat days for that reason because I'm retaining whatever it is, I guess 4 grams of water per gram of carbohydrates, something like that. So it helps to counteract the effects of inhibition of vasopressin because vasopressin is an anti-diuretic hormone, which means it prevents you from peeing or minimizes peeing. So it's used in children who bed wet past a certain age. I think they use desmopressin. I became, jumping around a little bit, but I became interested in vasopressin first because when I was in college, I was reading up on the smart drug literature at the time and it was purported for being very effective for boosting short-term memory. So you would take hits in each nostril, study whatever you had to study and then quickly scurry off to the test before it evaporated.
- Rhonda: Right.
- Tim: But then you had some very interesting comments on vasopressin.
- Rhonda: Yes.
- Tim: So I did use vasopressin for a period of time, found the headaches and side effects ultimately not worth it for me the way that I was using it. But it is something that's kind of stuck with me when someone says, "Oh my god. I was at the bar and then all of a sudden I time traveled and I was at Denny's." I'm like, "Aha, it might have something to do with vasopressin because you just gave yourself sort of a reverse smart drug."
- Rhonda: Very interesting. Yeah. I'm familiar with vasopressin because it's also a hormone. It's a social hormone. And it's particularly important. It's kind of like the counter, or not the counter, it's the male version of oxytocin. So in females, oxytocin is this notorious love hormone. When you produce oxytocin, you feel good, you bond, social bonding, things like that. Well, in males, vasopressin serves a similar role to oxytocin in females. Vasopressin is associated with pair bonding and specifically with monogamy. So they've done studies in prairie voles where they actually genetically engineer them to not be able to respond to vasopressin. So they like engineer their vasopressin receptor to be non-responsive. And these prairie voles, which are monogamous become polygamous like that. So it's very interesting. Also, they've done human studies where they've looked at gene polymorphisms which are just variations in the sequence of DNA of a gene that changes the function. We all have various polymorphisms. You're familiar with that. So there's a particular variety of this polymorphism in the vasopressin receptors that males have that make them less responsive to vasopressin. These males are more likely to be either divorced or never been married, whereas males that don't have this polymorphism are more likely to be happily married.
- Tim: Surprise, surprise.
- Rhonda: So yeah, alcohol, there may be actually a mechanism through vasopressin that leads to polygamy or being more promiscuous, I guess.
- Tim: I wonder if that's in the water in San Francisco. It's sort of ground zero for all the polyamorous flag wavers.
- Rhonda: So on the self-experimentation topic, you've been self-experimenting for many years and I was wondering if throughout your years of experimentation if there are three or four biomarkers . . . so, you typically measure blood biomarkers routinely. If there are three or four really important ones that you think are important that you routinely measure and if they have anything to do with performance or mental acuity or perhaps aging.
- Tim: Yeah. There are a few . . . well, there are many blood markers that I look at. I had a fun conversation with Pete Attia on the podcast not too long ago about this. But my markers, the markers that I'm following right now are number one, my millimolar concentration of ketones. So I have a device just on the counter over there, a Precision Xtra device by Abbott Labs that allows me to use both glucose strips and ketone strips. So I can look at my fasting or waking fasting glucose level and then ketone level and monitor that after certain types of, say, exercise when the ketone level can drop and so on and so forth. Because I've identified for myself, part of the reason I have fat in my tea, is I operated best mentally at around 1.1 to 1.7 millimolars and I only figured that out by tracking.
- Rhonda: Very interesting.
- Tim: Some people, for instance, perform much better the higher concentration. The higher the concentration of ketones, the better they feel. I don't fall in that camp. I was having a conversation with a scientist a few days ago about this. He said, "Well, really," and this is not a new observation, "But your blood level of ketones can be gained or increased in many different ways." So you can just eat a meal that's full of medium chain triglycerides or eat a meal that's just full of fat in general and you can spike your ketone level. That's not necessarily indicative of an endogenous production of ketones or you could be fasting and like deep fasting after five or six or seven days. In my particular case, I think you also want to look at--and this is true, a lot of very smart people like Pete Attia, Dom D'Agostino, very, very smart guy, Dominic--would say likely that it also could be some people utilize ketones better than others.
- Rhonda: Yes.
- Tim: So just because you have a high level of ketones, doesn't mean you're necessarily doing a lot with it. So in my case, a high level of ketones, my hypothesis is well maybe past a certain point, my kind of machinery gets very inefficient or gets damaged. So between 1.1 and 1.7, my brain operates functions at a level reminiscent of pre-Lyme. That's a whole separate thing. I kind of knocked out normal cognitive function for nine months due to severe Lyme disease. But when I am focused on at least a nominal amount of ketones, I feel like my old self. So that's one. Other things that I focus on or look at . . . there are some esoteric things that I play with every once in a while. But if you're looking at the routine levels, I'm going to look at obviously the sex hormones, look at free testosterone. I'll look at free testosterone as relative to sex hormone binding globulin, for instance. I'm not convinced that higher sex hormone binding globulin is always a bad thing. That's a whole separate. Because my testosterone in experimenting with high fat, total testosterone has gone from 650 to 950 in a span of nine months. It's a non-trivial increase. Now, sex hormone binding globulin has also increased over time. But I've gained so much lean muscle tissue that I have other ideas. I was talking to Steven Phinney about this--scientist, very well known for looking at the ketogenic diet--and what he was saying is independent of insulin levels, insulin made very anabolic . . . sorry, we're getting into the weeds here. It's possible that my lean mass gains can be account for by decreased degradation of branch chain amino acids. I was like, "That's really interesting." Maybe that explains by fasting plus chemotherapy is very, very effective, for instance. People can recover faster from chemotherapy. So you have the ketones. You have the sex hormones. Hemoglobin A1c, sort of like your running three-month average of glucose levels just as an insurance policy to ensure that I'm not skewing towards pre-diabetic in any way. And then a laundry list of like five or six different pages of stuff.
- Rhonda: So your biomarkers tend to be a lot of performance-related biomarkers.
- Tim: Yeah. And I've done the genetic stuff. So I know, let's just say that I'm a poor methylator, the motherfucker gene, as they say.
- Rhonda: Yes, MTHFR.
- Tim: Yeah. I'm not in an ideal spot. So taking, say, l-methylfolate could be a good option for me and I've experimented with that in the past, looking at how that can lower homocysteine or things like that.
- Rhonda: Have you noticed any differences after experimented with 5-methylfolate, L-5-methylfolate, methylcobalamin?
- Tim: Yeah. I haven't noticed many changes in blood markers and I haven't noticed subjective changes in, say, performance or clarity or anything like that.
- Rhonda: Yeah.
- Tim: It doesn't mean it isn't doing things.
- Rhonda: Yeah. I have an anecdotal story. So I'm very into looking at different gene polymorphisms. 23andMe is a great service that can do that. So my friends, family, etc., I'm telling everyone to do it. So my mother-in-law got genotyped and we found out that she is homozygous for MTHFR, meaning that her MTHFR enzyme only is working at about 10 to 20% efficiency. She's always had really high blood pressure, to the point where doctors were wanting to get her on medicine for it and she's always refused. Nothing she did . . . she's done various diets, lots of exercise, lots of things she's tried, nothing has gotten her into a normal range until we identified she had MTHFR, got her supplementing with 5-methylfolate and methylcobalamin. But she's been taking pretty high doses of it. But now her blood pressure for the first time is in like a normal range. So I was kind of curious if you had ever . . .
- Tim: I have very consistently what you would consider excellent blood pressure. So I haven't looked closely at that. The question that comes to mind for me always because I've noticed . . . so, I'm a big fan of Richard Feynman. Richard Feynman, and I'm not saying this is the case with your, you said mother-in-law?
- Rhonda: Yes.
- Tim: But the importance of not tricking yourself because you're the easiest person to fool, basically, is what he would say. I know that what I have initially thought were sort of causal relationships with high correlative value . . . for instance, I've talked to people who have gone on fill in the blank diet. They're like, "This thing changed. I'm so glad I found this diet." I'm like, "So you haven't changed anything else?" "No, no, no. I started running in the morning. I started doing this. I started doing that." I'm like, "Hell yeah" . . . because like one, it's so hard. That's where the observational data gets so challenging, when you look at, say anything, whether it's the China study or whatever. We don't need to get into that one. That's a sensitive one. But any observational self-reporting and so on, the data is almost always so flawed because humans almost never change just one thing.
- Rhonda: Yeah. I think that's why it's so important when you're looking at epi studies that are associative that are not a clinical, randomizable trial, coupling that data with mechanistic data done on animal models or lower organisms, I think coupling the two is very important because then you go, "Oh, okay. We've noticed this observational data and here we've done X, Y or Z to manipulate it in a worm or in a fly or a mouse."
- Tim: Right. So you have a plausible mechanism.
- Rhonda: Right. So you have a mechanism. That's where I think looking comprehensibly at the whole . . .
- Tim: At the intersection.
- Rhonda: Yeah, scientific is very important.
- Tim: Totally agree.
- Rhonda: It's interesting. You mentioned the ketone thing. I just want to briefly give you my story.
- Tim: Yeah.
- Rhonda: So I've never noticed, really, any extreme mental benefits or mental acuity changing when I consume large amounts of MCT on empty stomach, on whatever. I found out that I have one ApoE4 allele. And of course, at that point, I became terrified of Alzheimer's because it increases the risk for Alzheimer's by two-fold and I'm writing an academic paper on this right now and getting into all the mechanisms--diet, lifestyle, things like that. But what I found really interesting are the studies that they've done where they give, for example, people who have dementia or people in the early stages of Alzheimer's, they give them beta-hydroxybutyrate, which is a ketone body. And there's improvement.
- Tim: I have some synthetic jet fuel in the freezer if you want to try it. We'll probably both vomit on my couch. So let's do it later.
- Rhonda: Yeah. I've heard it's disgusting. So people who were ApoE3 responded very well. So they had improvements in learning and memory.
- Tim: With a supplemental MCT?
- Rhonda: With beta-hydroxybutyrate. They gave them beta-hydroxybutyrate. But what was interesting to me and also very discouraging was that people with ApoE4 allele did not have those benefits. If you look at Alzheimer's, people with Alzheimer's, between 65 and 80% of all people who have Alzheimer's have one allele of ApoE4.
- Tim: Oh, well I bet I have that on both sides of my family, then because I have Alzheimer's on both sides.
- Rhonda: Yeah. I wanted to ask you, so you mentioned that you have Alzheimer's and Parkinson's on both sides of your family. So I'm curious. Has this changed your diet, your lifestyle?
- Tim: Oh, definitely.
- Rhonda: How so?
- Tim: Well, the Parkinson's maybe a bit less so. But on the Alzheimer's side, I have just looked at it like some scientists look at it, which is as brain diabetes. I think that's a helpful, simplified way of looking at it. You I'm sure know much more about this than I do. But there's the prevalent theory of why I say Alzheimer's has the effects it has on cognitive performance or, in this case, degradation or otherwise. For a long time, I was like, "It's the plaques, kind of like, plaques, it's this, it's that." And it turns out to be more complicated than that because you have people who have massive tangles of plaques but they seem asymptomatic. They're 100 and x years old but they still play the piano every day or whatever it may be. Great movie called "The Lady and Number Six" as a side note, 109 year old piano player. It doesn't get into Alzheimer's. But where it has led me is just to be more cognizant of insulin, things that are related to and/or affect insulin. To look at not only ketosis but fasting, to look at cyclical ketogenic diets and so on, targeted ketogenic diets where you're timing carbohydrate intake near workouts, which a lot of endurance athletes do so they can consume like 300 or 400 grams of carbohydrates in a day and still say in ketosis, pretty wild stuff.
- Rhonda: Wow.
- Tim: But what I start wondering, for instance in the case . . . because if I take supplemental MCTs or even beta-hydroxybutyrate, and there are tasty ways to do it now. I think it's Patrick Arnold and Prototype Nutrition. They have a . . . well, people say KetoCaNa, C-A-N-A, but it tastes like Gatorade, basically and it's beta-hydroxybutyrate. If I take that when I'm not, say, above 0.6 millimolars ketones, I don't feel much. But when my body has shifted into that fat-adapted state, I do feel it. Off hand, I don't know what my status is from the genetic standpoint. But what's been very interesting say for me when I'm thinking about it from the standpoint of brain diabetes is it's not just enough . . . and this comes back to how people, if they focus solely on the millimolar concentration, they can fool themselves because you can be in non-nutritional ketosis but consuming a lot of supplemental beta-hydroxybutyrate and be like, "Oh, I'm killing it. I'm at two millimolars concentration." Whereas I'm also taking my glucometer readings precisely because I don't want to be running at 120 glucose and dismiss that. If I wake up and I'm fasting 120 glucose each morning, something funny is going on that I need to pay attention to. Whereas if I drop into nutritional ketosis and let's just say I'm at 74, 80, even lower and I have high millimolar, my response to at that point supplemental beta-hydroxybutyrate is totally different.
- Rhonda: That's interesting.
- Tim: Anyway, I'm still kind of a novice in this space, but it's interesting stuff.
- Rhonda: So the cyclical ketogenic diet is something that you do now practicing. And that's, you think, as a consequence of thinking of Alzheimer's like type 2 diabetes. It's really interesting, that connection between insulin resistance and type 2 diabetes. I don't know if you measure any blood biomarkers or if you're aware of this, but there is a biomarker that is present in blood that's called insulin-like receptor 1, IRS1 and it's recently, very, very recently been shown to be a diagnostic for Alzheimer's 10 years in advance with 100% accuracy.
- Tim: [inaudible 00:19:13]
- Rhonda: So I don't think it's like something that . . . well, you can modulate. So 10 years in advance is a long to change.
- Tim: Just by the way, you are fucked.
- Rhonda: You're screwed.
- Tim: Good luck with that. Yeah.
- Rhonda: It's inactive.
- Tim: IRS1 using [inaudible 00:19:32]
- Rhonda: Yes. What's interesting to me is I typically think of the connection between type 2 diabetes and insulin resistance and Alzheimer's as the connection between inflammation and a nerve degenerative disease because inflammation, we've now recently found that the lymphatic system connects directly to the brain. The lymphatic system is what carries blood cells, cytokines, inflammatory molecules and inflammation is a major, major downstream consequence of being insulin resistance. Inflammation causes reactive oxygen species, things that damage all sorts of cells. But the inflammatory molecules get into the brain and they do start causing all sorts of immune type reactions and aggregation of more amyloid beta plaques and all that stuff starts to happen more quickly. So I think that the inflammation . . . because if you look at people, type 2 diabetics, being type 2 diabetic, you have a two-fold roughly increased chance of getting Alzheimer's. But if you look at people with Alzheimer's, a small percentage of them have type 2 diabetes. So I think that it's not just the insulin resistance. I think there are the consequences, the byproducts, the indirect things that are associated with . . .
- Tim: 100%
- Rhonda: . . . type 2 diabetes that lead to Alzheimer's.
- Tim: Yeah. It's rarely, if ever, just one thing. I think humans strive for simplicity and in sort of a sea of noise, especially if you're not a trained scientist, it's like, "God, thank goodness somebody gave me a definitive answer. Now I know A causes B." It's like, okay, maybe as a temporary holding bay, we can use that answer. But it's probably not right. But on the inflammation side, I've been thinking a lot about this recently because number one, and this is not that uncommon, but I've noticed that if I consume carbohydrates, cycling carbohydrates and I'll do a cheat day like yesterday where I'm eating an entire pound cake by myself, this kind of thing, and then even several hours later, I get acupuncture and that's a whole separate conversation, but I will bleed more. I will bleed much more than if I am, say in a ketotic state. But then I have all these questions that come to mind. For instance, I'm consuming like turmeric with ground pepper. I always read it. I never say it, piperine?
- Rhonda: Yeah, piperine.
- Tim: There we go. So to increase the bioavailability and absorption. So that's pretty old school. You've got turmeric, curcumin pills or whatever. There are a million ways to go about it. But I've tried to whenever possible . . . so, you have like L-methylfolate, let's say. Very interesting to me. But unless I'm mistaken, pretty new kid on the block. It's a relatively new addition to the supplement arsenal. Whereas like turmeric, it's like, Ayurvedic medicine, they've been doing that for thousands of years. I feel pretty comfortable bringing in turmeric tea with some ginger and black pepper to counteract unnecessary inflammation. At the same time I'm like inflammation . . . this is where maybe you can help me gain some clarity, but I'm like inflammation also serves some really important purposes, right? If, for instance, you have people go do a weight training workout, there's a fair amount of empirical data, I don't know if there's research data to support this, where athletes will be like, "Oh my god, I don't want to be so sort out of my workout. I'll take like NSAIDs, Advil, Ibuprofen, whatever, to facilitate recovery." In fact, then they have less hypertrophy and they have less muscle growth as a result. So it's like what is the inflammation that we want to not interfere with versus the inflammation that we should try to prevent.
- Rhonda: Yes. I think that it's something I've been thinking about in a similar way with inflammation and also antioxidants because I think that the type that you want to interfere with is the colonic inflammation, the kind that's coming from your gut, that's leaking endotoxin, which is released from like dead bacteria and it causes all sorts of damage because it binds to cholesterol. Anyways, I can get into this whole conversation. But it's the bad stuff. The inflammation that's causing that chronic reactive oxygen species which damages DNA, proteins, lipids in your cells which gets into the brain and stops serotonin from being released, so it causes depression and things like that.
- Tim: Sounds like a bad cycle.
- Rhonda: Yes. Very viscous cycle too because then you start to activate more inflammatory molecules. I think the good type of inflammation, the good type of damage, the good type of stress is when you exercise, is when you're doing that type of exercise or heat stress or cold stress or that type of transient stress on the body that induces all these, the expression of genes that deal with stress so you're increasing the expression of all these good genes that deal with inflammation expressed. Having that inflammation, having that stress is critical to do that. That's how turmeric works and curcumin. One of the ways it works is it's actually slightly toxic to us. Because it's slightly toxic to us, our body goes, "Oh wait a minute, I need to increase the expression of all these genes so they make more of the gene to do all this good stuff, to fight inflammation, to fight reactive oxygen species, all that bad stuff. So I think it's sort of like . . .
- Tim: It's like what Dread Private Roberts did in "Princess Bride" with iocane powder.
- Rhonda: Yes.
- Tim: A little bit every day.
- Rhonda: Yes. But it's like the chronic versus acute, good type of stress. So that's what I think about. I also have been thinking about it in regards to supplemental antioxidants. I used to take a lot of vitamin C, supplemental vitamin C. And there were studies that we're showing taking two grams of supplemental vitamin C a day with lower C-reactive protein and there are all these reasons why I was taking it. But then, studies started to come out where if you take the supplemental vitamin C like after a workout, the half life is like an hour in a half in the plasma or something. Then, when you work out, you create oxidated stress and you want that. That's what induces mitochondrial biogenesis. That stress is what signals to the mitochondria to make more mitochondria. But if you dampen that by like sequestering that stress with an antioxidant, we're not going to get those benefits. There are studies now showing this both in humans and mouse animals. So now I'm kind of a little more cautious about supplemental antioxidants specifically because they can sequester some of that good stress that you want from things like exercise or intermittent fasting, for example, things like that.
- Tim: Wow. Interesting. So you think antioxidants could negate some of the benefits of, say, intermittent fasting.
- Rhonda: Yes. They can. And it's been shown that that can.
- Tim: That's good to know.
- Rhonda: Supplemental antioxidants, because when you're intermittent fasting, a lot of things are going on, but it is a type of stress. When you're stressing your cells, you're creating reactive oxygen species. That's what happens. And part of that, there's a hermetic effect. So when you create these reactive oxygen species . . . and this is the good type of stress. Creating the good type of species because you're chronically inflamed because you're eating processed carbohydrates and you're poking holes in your gut leading to inflammation and blah, blah, blah, that's not the good type. You don't want that constant reactive oxygen species being made every day. But when you're intermittent fasting or you're exercising, that burst of it, which is much more powerful, so it's not like a little bit each day, it's like, "Boom, here I am." It's enough to signal to your genes, to other cells, "Make more of this gene that deals with inflammation. Make more of this gene that deals with stress. Make more mitochondria." It's just enough to do that. You want. Some of the benefits of intermittent fasting and exercise rely on that.
- Tim: You know, just as another random side note, this could be the alcohol that I was fed by Polish people yesterday, but you said reactive oxygen species, ROSs, sounds a lot like ROUS, rodents of unusual size, also from "Princess Bride." I'm wondering how much biochemistry you can teach using metaphors from "The Princess Bride." But that's a whole separate conversation probably not worth having. But the one thing that I've been pondering, I'm not an expert in this area, but vitamin C, if you look at protocols being used at, say, the University of Kansas for antiviral purposes or anti-cancer purposes, the vitamin C is thought of when it's delivered intravenously as a pro-oxidant. So then I'm wondering could you use vitamin C in a pro-oxidant capacity, or I guess it's being converted into like hydrogen peroxide, to not mitigate but exaggerate the benefits you want of, say, intermittent fasting.
- Rhonda: That's interesting. Yeah.
- Tim: If you were doing not even necessarily intermittent. Let's say you do a seven-day water fast. Could you do like 50 to 75 grams of vitamin C each day? Would that end up nullifying a lot of the effects or dramatically enhancing the effects?
- Rhonda: So here are my thoughts. I'm speculating here. Intravenous vitamin C, you get much higher, up to millimolar concentrations of vitamin C in your blood. So vitamin C is constantly going through the cycle of being reduced and oxidized and reduced and oxidized. When it's oxidized, it can act as a pro-oxidant. That's part of the way it kills cancer cells because cancer cells, they're ready to die but they've found a way around death by increasing all these genes that stop them from dying. But all they need is a little push. That little push is like reactive oxygen species or a pro-oxidant like vitamin C. It just pops them, pushes them to death. So intermittent fasting, for example, one of the benefits of intermittent fasting is that your autophagy occurs. Your body is clearing out all these damaged cells. So that would, in theory, if you've got damaged cells . . . so, the problem is with damaged cells, if they don't die, they become senescent. When they're senescent, they sit around and they secrete pro-inflammatory cytokines. So then they damage nearby cells because the inflammatory cytokines. So it's like this vicious cycle and it's why you need to get them back.
- Tim: You need to get the cellular Zamboni to clear that stuff.
- Rhonda: That's a funny analogy. I used to be an ice skater.
- Tim: That's my ring name. Oh, really?
- Rhonda: For many, many years I was a competitive ice skater, both freestyle and drills team. So you want to clear them out. I would think that if you have this senescent cell, that would help get rid of it. So very, very interesting observation.
- Tim: I've been thinking about it also because cancer generally . . . by the time you're 40, we all have pre-cancerous little cells. But the question is do they grow? Do they then metastasize or become a problem, or do they just remain these little mutations that don't cause any particular harm among other things obviously? For me, I've become also interested in . . . I'd love to get your opinion on metformin. There are people who'd say, "Well, if you want to try to dodge that cancer bullet, we know that cancer cells, they love sustaining themselves anaerobically . . . or let me rephrase that, with glucose. They love glucose. So if we can dramatically lower, whether it's storage of glycogen, plasma, glucose, whatever it might be, then in theory, we should be able to lower the risk of cancer and limit cancer growth, cancer cell growth. What are your thoughts on metformin and why are you taking it or not taking it?
- Rhonda: I'm not taking it. The reason I'm not taking it . . . I think it has been shown, like you said, it can possibly prophylactically prevent cancer so far. I think the studies that have shown that have been pretty short-term. My concern with metformin is the feedback mechanisms that happen when you're taking this drug. How is that going to affect other cells and how they respond to glucose and things like that over the long-term, like 15 years down the line? I think that limiting your sugar intake is probably . . . if you haven't damaged yourself by eating a bunch of crap, a bunch of processed sugars and carbohydrates and things like that, then I think limiting your sugar intake is probably good, good enough. To a certain component, there's a certain component of cancer that there is a genetic component. What I mean by that is not that you're born with it but . . . so, downstream of a cell that's glycolytic, that's only using glucose to make ATP through this glycolysis pathway is inflammation again. I come back to it because it's just downstream of everything. And inflammation damages DNA and eventually you get it in the right gene that's saying, "Oh, this gene usually protects," whenever there's any damage, it kills a cell. It's called a tumor suppressor gene. You get it in that tumor suppressor gene, you're screwed. Now any time you get damaged, that pathway isn't activated to go, "Whoa, wait a minute, this is not good. I'm going to die. And it just keeps living."
- Tim: Yeah.
- Rhonda: If you look at, for example, our lymphocytes, our lymphocytes are glycolytic and they're not cancer. So it's not as simple as a glycolytic cell is going to give you cancer.
- Tim: No, no.
- Rhonda: But definitely starving . . . I think before you get to the point where you're starving a cancer cell, you can kill the damaged cell before it becomes to that point where it's shifted its metabolism.
- Tim: What do the lymphocytes do in a ketotic state?
- Rhonda: I don't know.
- Tim: Do they derive glucose form lactate or something?
- Rhonda: Yes. They do get it from lactate. Lactate is something that they do use. Yeah.
- Tim: Cool.
- Rhonda: It's interesting because lactate also is much like ketone bodies, energetically thermodynamically favorable. So it takes less energy to make energy.
- Tim: Yeah.
- Rhonda: So you're consuming less oxygen because you don't need as many ATP molecules to make ATP. But back on the ketones since we're back on the ketone, I do want to get to the Lyme disease because it's a topic that I avoid. I've never talked about it.
- Tim: It's one I avoid too.
- Rhonda: I always have this knee jerk reaction because the signal to noise ratio is so small. I feel like there's just a lot of confusion.
- Tim: So much nonsense.
- Rhonda: But I'd be really interested because you're a very analytical person.
- Tim: I try to be.
- Rhonda: So obviously it's a real disease. People suffer from it. You can observe spirochetes under a microscope. So it's definitely real. It's just a lot of craziness that seems to be associated with it. But maybe you can talk a little bit about . . . because you mentioned going on the ketogenic diet to treat your Lyme disease. Can you talk a little bit about what you found in terms of your experience with Lyme disease and how you got to treating it with ketogenesis?
- Tim: Yeah. I can talk about it. So where to begin with this . . . First of all, I'd just like to agree with you and sort of emphasize for everybody that the amount of nonsense and charlatanism out there surrounding Lyme is just beyond belief. There are so many fraudulent companies and practitioners who are just printing money by either misdiagnosing people with Lyme or treating Lyme in the quackiest of quackery.
- Rhonda: Why Lyme?
- Tim: So here's my thinking. So I contracted Lyme on Easter in Long Island. If you look at the CDC map, the Center for Disease Control heat map for Lyme disease, that is ground zero. That's where the bomb went off. Lyme is named after Lyme, Connecticut. So it really has historically focused on that Northeastern area--Pennsylvania, Upstate New York, Hudson Valley. I think Lyme has become this popular topic of conversation for a few reasons. Number one, it's poorly understood on a lot of levels. So there are ample opportunities for non-scientists and quacks to sort of invent stories around it.
- Rhonda: That makes sense.
- Tim: Number one. Number two, it's scary. It involves a bug biting you and you catch this disease, so the media loves it. The media loves it. The media writes about it. Then the media sometimes correctly, often incorrectly lists the symptoms of Lyme disease--joint pain, depression, fatigue--it's like, "Well, that's one out of every two people in the United States at some point every year." And then people go, "Oh, my god. I've had my . . . " I got an email from a friend of mine who says, "My shoulder has been bothering me for a couple weeks and two of my friends said it might be Lyme." I'm like, Oh, god. I would bet $1,000 it's not Lyme disease. Given where you live, given the likelihood of having contracted it, it's just so unlikely for most people. Now, all of that having been said, Lyme is a real thing. Like you said, you can observe the spirochetes under a microscope. I think another reason it's popular to talk about is people love saying the word "spirochete." I'm not kidding. They love saying spirochetes. They imagine this screwdriver, this horribly evil like Maleficent like spiral bug that like digs into your body and like the antibiotics come in and they're like, "Oh no, we're going to hide from the antibiotics." It's not that sentient.
- Rhonda: My husband's grandmother says spirochetes like at least every conversation that I have with her.
- Tim: People love saying spirochetes. So you get it.
- Rhonda: Yes.
- Tim: So for all these reasons it's popular to talk about. I think primarily because the symptoms overlap with a million other conditions. What I came to realize for myself is like yes, it's a real thing. It's almost certain after Western blot tests and ELISA tests and looking at all the diagnostics, which are really primitive, it's very likely that I already had Lyme disease at some point because I've been bitten by ticks hundreds of times. Almost everyone in my immediate family has had Lyme disease. On Long Island, it's just kind of like, "Suck it up. Take some antibiotics. You're fine. Move on with life." It's not viewed as like a huge crisis by everyone who gets it on Eastern Long Island because it's so common. So I shrugged it off. I took three or four deer ticks that were embedded off of me in the span of two or three weeks. It historically hadn't been a big deal. So I was like, "That sucks." Pick it off, make sure the head is not in there, move on. I did not develop what's thought of as the trademark bullseye rash. So I ignored progressively worsening symptoms for eight weeks where my joints started getting very sore, swollen. I had trouble getting out of bed in the morning. I started getting slow cognitively and had trouble recalling friends' names and just really common words and eventually got to a point where my assistant was like, "I've seen you sick. I've seen you tired. I've seen you burning the candle at both ends. This is none of those things. You need to see a doctor."
- Rhonda: It sounds like dementia, like not remembering friends' names.
- Tim: Yeah. Things are really funny. If you look at the advanced symptoms of severe Lyme, it takes on dementia-like qualities, even cerebral palsy in some cases, really scary stuff. So long story short, then I get diagnosed with Lyme. When I walk into the clinic on Long Island, to give you an idea of how common it is, so this walk-in emergency clinic open on the weekend, they had a poster up that was like, "Hey, allow us to send your blood sample to such and such lab, Upstate New York, to do research on Lyme," and there's a picture of a tick, "And we'll give you a free $50 Amazon gift card." It's that common. But then the question was, "Okay, I have Lyme." I'm taking doxycycline. I do that for eight weeks or 12 weeks, whatever it was. I still feel really shitty. Now what?
- Rhonda: That's a long antibiotic course.
- Tim: Yeah. Some people take antibiotic for years, which I think is not the thing to do. This is where I am and I'll try to sum it up because this can be a very long conversation. I think that there are very, very credible scientists and infectious disease specialists who do not believe that chronic Lyme exists. Their position would be there's no evidence that the whatever it is, the borrelia spirochete cannot be eradicated with broad spectrum antibiotics like a doxycycline or something else. There's no evidence to suggest that they burrow away and hide and come back, hide in biofilm or whatever.
- Rhonda: Yeah, right.
- Tim: Right. Then you have people, and there aren't that many, but a handful of people who are like, "Well, it is possible that this Lyme could behave something like herpes simplex," where it's like a recurring infection essentially and maybe it takes root in the nervous system somehow and only comes back out in times of stress. There are people, credible doctors who have been like, "It's not completely beyond the realm of possibility that is has some recurring nature." Okay. Still, kind of descriptive, not prescriptive, what do we do? Right? Then the theory that I kind of came up with, and I'm sure other people have come up with it, but I haven't read it, I was like, "Well, let's look at the symptoms of Lyme. You have like depression, fatigue. What are other potential causes after a long course of antibiotics? Well, maybe you just completely scorched earth your microbiome among other things. So one of my theories is that what people perceive as chronic Lyme is in fact a collection of similar symptoms caused by the long course of antibiotics. So you should focus on prebiotics, probiotics. I have had a tremendous amount of difficulty, at least as measured in common stool testing and so on, in repopulating my gut diversity. It's been extremely hard. I have consumed just about every type of pre and probiotic imaginable. I've also tweaked my diet to be more favorable for certain types of gut repopulation. It's been really tough. I did like a three-month intense protocol of all sorts of stuff. So I'd love your thoughts. I did a follow-up stool sample analysis and it was still like, "No, you're fucked." I was like, "Wow . . . " depressing.
- Rhonda: So you're talking about measuring your fecal bacteria population using uBiome?
- Tim: Yeah. UBiome or there are others, like Rocky Mountain blah, blah, blah doctors data, whatever it was.
- Rhonda: Okay. There are other ones.
- Tim: Yeah. UBiome has a slightly different approach, but along those lines.
- Rhonda: I agree with you for one. First of all, I heard a podcast that you did with Jessica Richman from uBiome and I think you had talked about this and that's how I became first aware the link between . . . when you mentioned having this hypothesis that you thought possibly some of these symptoms of Lyme disease were a symptom of complete gut disbiosis where you're taking several rounds of antibiotics and you are obliterating your gut bacteria, a lot of the good ones are going away. If you don't take a very strong probiotic immediately after antibiotics, it repopulates with all the bad stuff and it's really hard to get because they occupy space. They're sitting in what's called the mucin in the gut. They have to stick in the mucin to stay, otherwise anything you take will kind of just flow through. It's kind of like the flow through. So it's really hard to repopulate. I've been doing a lot of self-experimentation. I've been using uBiome to track my gut bacteria genotypes. But have you tried VSL3?
- Tim: I have it in the refrigerator right now.
- Rhonda: Do you?
- Tim: Yeah.
- Rhonda: Okay. So the sachets are what I recommend because . . .
- Tim: Yeah. I have the capsules.
- Rhonda: The sachets have 450 billion, which is more than what the capsules have. 450 billion is ten times more than what most probiotics have. The thing about VSL3, very interesting, so it's the probiotic that I take. I'm taking it because I've had some gut issues that started in graduate school because I got MRSA.
- Tim: Yeah. That's not fun.
- Rhonda: Antibiotics were the prescription and I had several courses of strong ones. Finally, it kept coming back and I was like fed up.
- Tim: How do you get MRSA?
- Rhonda: I don't really know. I worked in a hospital.
- Tim: Is that methicillin-resistant Staph?
- Rhonda: Yes. Aureus. Staphylococcus aureus.
- Tim: Staphylococcus aureus, yeah.
- Rhonda: So I worked at a children's hospital.
- Tim: That's a good place to get it.
- Rhonda: They're everywhere in hospitals. Who knows where I got it? The point is I got it and it sucked. Finally after like, I don't know, three or four rounds of antibiotics, I would take it and it would go away and then a month later it would come back again and again. I was like, "I can't do this." So I read the literature, with the help of my husband Dan, that garlic and grapefruit seed extract, a concoction of things, I applied both topically and made a cream and I orally took and within 24 hours I got this thing to come to a head, pus out, it never came back.
- Tim: Interesting.
- Rhonda: But as a consequence of antibiotic use, I had serious gut issues, led to IBD. I've finally been able to recover.
- Tim: IBD, irritable bowel disorder.
- Rhonda: Inflammatory bowel, yeah.
- Tim: Inflammatory bowel disorder.
- Rhonda: But it's been a really, really long journey in tweaking my diet. Doctors, of course, I went to see doctors and they were just like, "Here, take an SSRI, it helps with the pain." I'm like, "I'm not going to take an SSRI.
- Tim: Yeah. No thanks.
- Rhonda: I walked out of that doctor, like, "You're insane." This was like a pelvic pain specialist doctor. So I've just had terrible experiences with doctors. Finally, I'm like, "Why aren't you asking me about my diet, fiber, things like that?" So I tweaked my diet and did lots of things. But VSL3 . . .
- Tim: With the uBiome testing, have you seen . . . I haven't done a follow-up test in a few months, but I have been taking VSL3, so now I'm optimistic hopefully.
- Rhonda: So I did a 30-day VSL3 course with the sachets, which are 450 billion and did a stool test. I'm still waiting for those results. My husband and I both, Dan, he's done a recent course of antibiotics. So I had him do his baseline and then right after, literally the day he stopped taking antibiotics, did a sample for uBiome. I got that data back, so I've been looking at that. So I'm going to talk about all that. It's really complicated and things in the literature are confusing and some people think some things and they're actually not true. So I've been looking at other people's uBiomes. I'm going to be doing a series of talks on this.
- Tim: Cool.
- Rhonda: I'm pretty excited.
- Tim: I'll check them out. May I add just a little bit of color on the ketosis?
- Rhonda: Yes.
- Tim: The color there is I began looking at fasting as a tool for many, many different reasons. And whether that be related to, say, longevity or the reason I was excited about it is I was looking at it as a reboot of the immune system, even shorter fasts, three days. I began playing around with fasting. Then, of course, you fast long enough and you go into pretty deep ketosis.
- Rhonda: Correct.
- Tim: So it was almost an accidental discovery for me whereby I had not been in nutritional ketosis for 10 years, 15 years. I did a lot of experimentation with the cyclical ketogenic diet when I was in college and competing as an athlete. Then I just stopped because it was kind of a pain in the ass and it was really boring. But then I did this fasting to help reboot my immune system. I'll keep it simple. So rebooting my immune system kicked over into deep ketosis and it just felt amazing. My cognitive function just went through the roof compared to what I had felt up that point after Lyme disease. I was like, "Well, this is very interesting, isn't it?" I said, "Well, I don't have to fast to be in nutritional ketosis. So let me now play around with ketosis and see what I can discover just by tracking and logging a lot of data." So I have my pet hypothesis about the gut biome and the antibiotics leading to symptoms that appear to be Lyme when in fact they're caused by something else. Another hypothesis, and the reason I'd like to dig into this, but I haven't come up with a great plausible explanation for this, is that Lyme or the antibiotics or both somehow interfere with carbohydrate metabolism. That's just a starting point. But because I've been public about the Lyme stuff because I was incapacitated, I had to tell people. I was like, "Sorry, I'm not going to reply to your email. I'm archiving 2,000 emails. Sorry." "Why?" "Lyme." And then people started coming out of the woodwork to be like, "Hey, my wife has Lyme. She's been debilitated. What should we do? What have you learned?" And the only advice that I gave a few people was like, "Look, there's a lot of BS out there." So number one is put your thinking cap on and be a good scientist to the extent possible. Number two is try a carb-restricted diet. Ideally, go into ketosis. All of the people who have gone into ketosis have had the same experience I have. Now, it's a handful of people. So the sample size is really small. These are people that like, "Cannot function, had to quit my job," serious cases, go into ketosis, "Wow, I feel like my old self."
- Rhonda: Have you measured any changes in gut bacteria after going into ketosis or after doing the ketogenic diet?
- Tim: I haven't. That is also a very interesting topic of discussion. So what effect does ketosis have on the gut biome or the repopulation, the rate or the diversity of repopulation? The short answer is I don't know. Part of it is, and this is where maybe I'm not being a thorough scientist. But I felt it worked so well to me that I'm so excited to get back to building things and creating things and being my old self that I haven't taken the time to dissect it to the extent I probably should.
- Rhonda: Your carbohydrate . . . I have this interesting hypothesis that sort of is related. People that have a severe imbalance of gut bacteria, let's say they have a lot less of the commensal bacteria which is making short chain fatty acids and metabolites like lactate that are feeding other good bacteria, they're feeding your gut cells. So you have less of those and you have more of the bacteria that are methane or hydrogen sulfate producing, so you get bloated, more of the more pathogenic type of bacteria. So you have this overgrowth of bad bacteria. The thing is let's say you eat something that's typically supposed to be good. You eat something that has a lot of fiber or like vegetables. So you're getting this fiber that's supposed to be not digested, but the bacteria can digest it and make it into this good stuff. Well, bad bacteria can digest that as well. So you're feeding this bacteria substrates to keep going and to make more of the bad bacteria.
- Tim: Right.
- Rhonda: Now, the interesting thing that I don't know is there are certain species of bacteria. There's phyla, class, species, it's incredibly complicated, but certain species only metabolize fat and I don't know which ones those are and if they're good or bad. It sounds like you've had a positive experience. But that would be really interesting to measure in general. But I'm glad you're feeling better.
- Tim: Yeah.
- Rhonda: The ketogenic diet is something that I'm interested in diving into and understanding more about. I'd like to talk to Peter.
- Tim: Peter is a smart guy.
- Rhonda: I've listened to the podcast. I don't know if he's done more than one podcast, but I listened to one he's been on.
- Tim: Yeah. He did one with me which was our conversation and then he did a follow-up with me which was answering the 10 most popular questions submitted.
- Rhonda: Okay. I listened to the conversation and I heard him and I was like, "I want to talk to this guy. He's a scientist. He thinks like a scientist. I respect what he's saying and I think that he and I have a lot of interesting overlap."
- Tim: He's also compulsively performance driven. And he walks the talk. What I like about Peter is that he's not an academic who takes his breaks at the hospital like going outside and smoking cigarettes and has like a paunch. He's a competitive athlete. I say that because I literally saw a bunch of people standing outside of a hospital in their scrubs like smoking cigarettes on break.
- Rhonda: I can't believe people smoke still. It's crazy.
- Tim: Oh, my god. But Peter on the other hand is still a very competitive, driven athlete. So he just has a unique perspective on all this stuff.
- Rhonda: So on the athletic side, I have a question for you. In "The 4-Hour Body," you talk about the minimal effective dose. You mention high intensity interval training and how you can get long lasting effects with less effort, basically. At first I was like, "Hmm . . . " and then you went on to talk about biomarkers and studies that have shown high intensity interval training increases mitochondrial biogenesis as much if not more than, let's say, like an hour and a half or something of cardio. And then you went on to the brain. That was my real concern. I was like, "Well, fine, if you're going to get the same amount of muscle mass or more by doing this, but what about the brain benefits?" Because I'm interested in staving off Alzheimer's. Like I mentioned, I've got an increased risk. So exercise has been shown to people with ApoE4 allele are much, much less likely to get Alzheimer's if they exercise, the more intensely the better. Part of that is your BDNF, your increasing neurotrophic factors that are growing your neurons because you need to repair a lot of that damage that's going on in the brain. So I'm interested in whether or not you are still engaging in high intensity interval training and what, if anything, you measure to know that minimal effective dose is working.
- Tim: Yeah. That's a good question. So I am coming off of and rehabbing some very serious leg, knee and ankle injuries that inflicted on myself doing the crazy parkour episode for my TV show. So I'm not doing a lot of interval training that would be recognizable as, let's just call it tabata training or some type of sprint training because it's too high impact. So I have concluded yes I am still practicing the minimal or minimum effective dose in a lot of facets of exercise. I think that most people do as much as possible, not as little as is needed. You can land somewhere in the middle. But the higher the level of athletics, generally speaking, the more coaches work on holding their athletes back and not pushing their athletes. I think this is a very poorly understood idea. But at the highest level, pushing the athletes is not the problem. With some team sports it's different, like even in the NFL. But if we're talking about, say, track and field, the coaches spend more time pulling their athletes back. So in my case, for instance, most people go to the gym one hour a day, five days a week if they're trying to change body composition would get better results by doing two or three sets of kettlebell swings per weeks. I've seen this hundreds of thousands of times in readers already. For me, with mental performance, and there's the book "Spark" that talks about a lot of this stuff and like you said, the brain drive neurotrophic factors and so on, from a subjective standpoint, I've seen as good results if not better results in terms of cognitive performance from resistance training of almost any type when compared to, say, steady state or even higher intensity interval training that could be thought of as cardio, like sprinting or cycling or what not. Mechanistically, I don't have specific before and after biomarkers that I'm tracking. But I am looking at, say, pages per day output, quality of writing, which can get very subjective. But I think that as these studies hopefully get funded, we will see that resistance training, if you think about it, weight training is very effective cardio.
- Rhonda: Yes, if you push it.
- Tim: Either way. If you're using, and Doug McGuff has talked about this quite a bit, if you're utilizing musculature to move your body through space, particularly with resistance, your heart has to work really hard generally to supply all the necessary nutrients and so on to get that job done. So I think that on top of that, if you're looking to prevent age-related cognitive end physical decline, one of the key correlates with all the bad stuff is sarcopenia, so loss of muscle mass, to which I would say targeted resistance training, much more effective bang for the book in not only preventing lean muscle tissue loss but increasing muscle gain than say most types of internal training, even if you're temporarily spiking certain hormones. But that's also because I hate doing endurance work.
- Rhonda: Yeah.
- Tim: I really hate doing metabolic conditioning. I find it miserable. I usually avoid it. But I do think if you were to just do two, three sets. I really focus these days personally in my exercise regimen on high intensity very brief duration or very, very long duration, typically walks, like two to four hour walks. I have a bar bell approach. So it's kind of like my investing approach. But my physical training approach is very barbell-oriented. So it's either like these sprint-like demands, which could be, say, overhead squats are really fantastic for a whole host of reasons for preventing a lot of the physical maladies that plague people as they get older and then long two to four hour walks.
- Rhonda: Awesome.
- Tim: Humans have made a lot of evolutionary tradeoffs to be able to walk long distances. So I feel like maybe that's something we need to do more of. We've made so many compromises to be able to walk long distances. I find quality of life suggestively assessed a lot higher when you're doing long, steady-state walking.
- Rhonda: And it's also the meditative aspect of it. That's something that you get from walking long distances.
- Tim: For sure.
- Rhonda: Especially if you're in a calm and peaceful environment.
- Tim: Yeah. A lot of parks out there. Get outside.
- Rhonda: I'm interested to know. You do talk about meditation a lot and being mindful and how that's important for a lot of things and it's been shown to improve learning, memory, things like that. Have you ever tried floatation tank?
- Tim: I have.
- Rhonda: You have?
- Tim: I have. I've tried flotation tanks. I like floatation tanks. There is a new location, actually, in the city that I have not been to.
- Rhonda: Reboot Spa or something, I think is . . .
- Tim: Yeah, Reboot Spa, maybe Float Lab. I'm not sure exactly what the name is. I think it's Reboot. The only location that I had available to me beforehand was a real pain to get to from where I am kind of in the Noe Valley are. As a result, I went a handful of times, but could never make it a regular trek or didn't want to make a regular trek. But I could see using floatation tank for all sorts of different experiments, including potentially incorporating microdosing of various types. But do you use floatation tanks?
- Rhonda: I'm actually going to try it for the first time next week. So this new floatation tank place reached out to me, I think it's Reboot, and gave me some free passes and I'm like, "You know what? I'll do it. Let's get it a go." So I'm going to go next week.
- Tim: Cool. Don't shave the day before.
- Rhonda: Oh, okay. Yeah.
- Tim: You're basically in the Dead Sea. It's all salt. So you will be really unhappy.
- Rhonda: I'm excited.
- Tim: I wouldn't shave for a couple days beforehand.
- Rhonda: Just a couple not particularly health-related questions I just wanted to ask you before we close.
- Tim: Sure.
- Rhonda: One is in your books and also on your TV show, "The Tim Ferriss Experiment," you talk about doing some silly things that help people push past anxiety, like laying on the floor of a crowded place or going and ordering a cup of coffee and asking for a discount arbitrarily. So what do you think some of the positive benefits that can be reaped from that are and are there any specific fear-inducing things that you've engaged in that have given you benefits in your life?
- Tim: So I think the benefits of practicing discomfort is realizing repeatedly that the worst case is just isn't that bad. So becoming comfortable with increasing levels of discomfort, especially something that's ridiculous and has no real tangible downside other than embarrassment . . . and this comes back to my obsession with stoic philosophy. But if you were to look at, for instance, Cato, who is considered the perfect stoic for a period of time, he would wear a tunic that was an unusual color to train himself because he would get ridiculed for it, to train himself to be embarrassed about only those things which are truly worth being embarrassed about, clothing not being one of them. So going into, say, Starbucks or whatever and just kind of calmly sitting down and laying down on the floor for ten seconds, super awkward, people are going to think it's weird. Some people might take five steps back and kind of freak out. Then you get back up and be like, "I'm fine." It's a small way of inoculating yourself against succumbing to peer pressure about stupid things or holding off on making important decisions or having uncomfortable conversations because of this irrational fear of this massive downside that you've never actually thought about. So something like laying down, asking for a free coffee or asking for a discount is really just rehearsal for the things that happen outside of your control or the more important conversations so that you have a certain level of calmness and have repeatedly had the realization that the worst case scenario you're imagining is almost never that bad. So those are just training mechanisms.
- Rhonda: Yeah. So you're basically dealing with stress. You're inducing stress to deal with it better for the next time when there actually is a stressful situation. You're more calm.
- Tim: Yeah. Right. If you want to negotiate a raise with your boss, probably not the best to practice your negotiating in that first conversation. You should go to a state fair and like learn how to haggle. Take $100 and that's your tuition, that's your MBA in haggling. Don't be a jerk and negotiate with everybody and not buy anything. But it's like all right, you have $100 to spend. Your job is to get $300 worth of stuff for like $100 at a state fair. It's like go practice.
- Rhonda: That's a great suggestion. I've actually overcome . . . I had a lot of fear of public speaking. I would go into the mall and tell jokes to random people. I am not a comedian. I'm a scientist. I've been in a lab most of my life reading books. Social interaction is a little anxiety inducing for me. So I would do this and most of the time, people would laugh at my bad jokes and look at me like I'm insane. I'd still get that. I did get over that anxiety of having people think I'm crazy or just like that awkwardness of like talking to someone. Now I'm communicating science to people. So it worked for me.
- Tim: Yeah. And the baby steps that seem so ridiculous, like the telling of the jokes or asking for a free coffee, it's hard for some people to realize how much those experiences transfer because they're like, "When am I ever going to have to ask for free coffee?" It's like you're missing the point. The point is to subject yourself to the same types of fear and discomfort that you will experience in a million other circumstances and to overcome that in a very sort of rehearsed way. For instance, for me, in the dating episode, the dating game episode of the TV show, Neil Strauss, who wrote "The Game," forced me to do cold approaches at the Ferry Building here in San Francisco, which was like my ultimate nightmare. It brought back like every stressful sweaty palm miserable situation from like eighth and ninth grade.
- Rhonda: It's giving me sweaty palms thinking about it.
- Tim: Yeah, I mean it's just so bad. But I enjoy like every week, it's like plan something out that is going to force you to do something potentially funny, right, that is going to be stress-inducing. Just figure out what that is and go do it. Maybe it's getting a milk crate and a hat and going out and try to busk without getting arrested, but trying to busk and be a shitty dancer and make $5. That's your goal. You have an hour to make $5 being a shitty dancer or being a terrible mime or whatever it is. The more you practice that type of thing . . . I'm going to disappear from camera for a second. I have this. I don't even know how to pronounce his name, which I'm embarrassed by, but this quote is, "Life shrinks or expands in proportion to one's courage." If you can pronounce that, you've got me beat, A-N-A-I-S, with a umlaut over the I, N-I-N. So this is something that I have reminders like this in front of me constantly so that I realize that very rarely are the things we're afraid of worth being afraid of. To overcome that, you just have to practice.
- Rhonda: Most of the time we're not.
- Tim: It's very hard to think your way out of something you didn't think your way into. So if you're afraid of asking for a discount on coffee, that's not really a rational fear. It's just not. The way you overcome that is not by sitting down and drawing out a decision tree, although that stuff can help, like fear setting, this exercise I do a lot can be very helpful. You go out and just try it. That's how you overcome these irrational reptilian fears.
- Rhonda: Absolutely. Like you said, next time you have that fear, you're more calm, you're thinking more clearly. I'm sure if they were to do MRIs of people before they do the sort of microdosing themselves to this type of fear, then after when they're in a difficult situation, they may see that their amygdala isn't as hyperactive or something like that where you're really training your brain.
- Tim: The mediation, you mentioned that, the meditation helps a lot. The meditation helps you to not overreact. I'm a very like aggressive, bull in a china shop kind of guy. So the mediation is particularly helpful for me. Let's say you ask for a discount on the coffee and the guy is like, "Who the fuck do you think you are?" My instinct would be like, "Who the fuck . . . " and instead to be like, "Hmm . . . that's a good question. Give me a second." And then to calmly respond, get a laugh, and then the guy gives you the discount. Like having that composure to have a delay between the immediate like . . .
- Rhonda: That impulse.
- Tim: . . . is really, really helpful in almost every circumstance. And if people are looking to get started with mediation, it can be a super nebulous . . . people can get very sanctimonious about their meditative stuff. Just think about it as bringing your attention back to one thing. Get distracted, you bring it back .You get distracted, you bring it back to any number of things. That translates a lot to productivity and being effective throughout the day so you're not like, "Oh my god, I just spent two hours on Facebook. What the hell happened?" to avoid that kind of experience. Just get an app like Calm or Headspace and start doing like 10 minutes a day.
- Rhonda: Headspace, all right. I'm going to try it. I'd like to get more into the mediation.
- Tim: It's super, super helpful. It just trains you to be able to calmly kind of come back to what you're supposed to be doing or what you want to be doing. You do that 10 minutes a day. Especially when you get like five or seven days straight, it's amazing how something that neurologically or cognitively just clicks. After five or seven days of doing it consistently, I do it first thing in the morning.
- Rhonda: You do Headspace?
- Tim: I do transcendental meditation.
- Rhonda: Transcendental.
- Tim: So I just kind of sit there and focus on my breathing. Like I did that before you guys got here.
- Rhonda: How long?
- Tim: If you do that every morning for five to seven days, it's really profound how much more calmly effective you are. And I've never been a big woo-woo meditation guys. I'm just like, "Eh . . . I'll just have a cup of coffee. It will do me twice as good." Not true. Ten minutes in the morning will make you calmly efficient. You'll get 50% more done if you do that every day for a week.
- Rhonda: Ten minutes is not a lot of time.
- Tim: It's not a lot. My magic number for me is 20 minutes. But don't start there because it's too much to start with. Start with whatever you're going to do, baby steps. Start with whatever you're going to actually do. If it's three minutes, make it's three minutes. If it's 30 seconds, then make it 30 seconds. But use an app like Headspace with guided mediation makes it a lot easier. Just commit to doing it for a week or two. Then it becomes self-perpetuating. You'll see the positive effects. But yeah, I think mediation, sometimes mindfulness practice plus practicing humiliation, super potent, valuable combination. Quite frankly, the practicing humiliation, and nine times out of 10 you don't end up being humiliated, it's just fun. It's a good way to get laughs. You can do it with your friends too.
- Rhonda: Exactly. Well, Tim, this has been great. I've got one last question I'm dying to ask you and then we'll close. So I did read on, I think it was your Reddit Ask Me Anything, you talked about how you were interested in recruiting Hollywood talent, whether it's directors or actors, etc. coupled with your interest in fiction writing, it leads me to believe that you're writing the next "Matrix" or something cool, totally hoping to blow your cover here. Are you writing a cool . . . ? Is this . . . ?
- Tim: I am working on some screenplay stuff. Yeah.
- Rhonda: Awesome. I hope it's science fiction.
- Tim: Yeah. Whether it will be cool or not is to be determined. One of the main reasons I'm spending more time in Hollywood and spending more time with people who are good at, whether it's screenwriting, directing, fill in the blank is because I want to start to absorb the gestalt understand of how that whole machine and ecosystem functions but I also want to get to know people who are like the good guys and the good gals, the people who are not only really good at what they do, but the cool people I can be friends with for 10-15 years. So I'm spending more time down there. I'm not in a rush. I'd rather do it right than do it quickly.
- Rhonda: That doesn't surprise me.
- Tim: Yeah. So I'm taking time. Honestly, for screenwriting, for books, for blogs, for podcasting, whatever, the power, for those people who have a direct audience is growing by the day. So making a movie the way I would like to make a movie I think will just get easier. Six months from now it will be easier than it is today. A year from now it will be much easier than it is today. Two year from now it will be even easier than it is today. That's very exciting.
- Rhonda: Just like science.
- Tim: Just like science.
- Rhonda: Very exciting, Tim. I really enjoy talking to you as always.
- Tim: Likewise.
- Rhonda: Thanks a lot for coming on the podcast.
- Tim: My pleasure.
- Rhonda: Most people know where to find you. You're pretty famous. But for those that don't, where can they find you?
- Tim: They can find me at FourHourWorkWeek.com all spelled out and there are a million ways to misspell that, which is like in retrospect, oops on me. But four as in the number four, hour, H-hour, not O-U-R, FourHourWorkWeek.com. On Twitter, @TFerriss with two R's and two S's. Facebook, I put up a lot of videos, like Q&As and stuff on Facebook. That's just Facebook.com/TimFerriss, two R's and two S's.
- Rhonda: Awesome, Tim.
- Tim: Yeah.
- Rhonda: Thanks a lot for doing this.
- Tim: My pleasure. Thanks for having me.
- Rhonda: I look forward to talking to you again.
- Tim: Yeah. Until next time.
- Rhonda: All right. Awesome.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
Amyloid-beta (a-beta or amyloid-beta 42)
A toxic 42 amino acid peptide that aggregates and forms plaques in the brain with age. Amyloid-beta is associated with Alzheimer's disease, a progressive neurodegenerative disease that can occur in middle or old age and is the most common cause of dementia. Heat shock proteins have been shown to inhibit the early aggregation of amyloid beta 42 and reduce amyloid beta plaque toxicity  .
Apolipoprotein E (ApoE)
A lipoprotein produced in the liver and the brain. In the brain, ApoE transports fatty acids and cholesterol to neurons. In the bloodstream, it binds and transports cholesterol, bringing it to tissues and recycling it back to the liver. Approximately 25% of people carry a genetic variant of this lipoprotein called ApoE4, which is associated with higher circulating levels of LDL cholesterol and a 2- to 3-fold increased risk of developing Alzheimer's disease.
A chemical produced in the liver via the breakdown of fatty acids. Beta-hydroxybutyrate is a type of ketone body. It can be used to produce energy inside the mitochondria and acts as a signaling molecule that alters gene expression by inhibiting a class of enzymes known as histone deacetylases.
Branched-Chain Amino Acids (BCAAs)
An amino acid having aliphatic side-chains with a branch (a central carbon atom bound to three or more carbon atoms). Among the proteinogenic amino acids, there are three BCAAs: leucine, isoleucine and valine.
Play or music or otherwise perform for voluntary donations in the street or in subways.
Bacteria that are beneficial or at least not harmful to the host, in contrast to pathogenic bacteria where the host derives no benefit and is actively harmed from the relationship. Roughly 100 trillion commensal bacteria live in the human gut. The term commensal comes from Latin and literally means “eating at the same table.”
A broad category of small proteins (~5-20 kDa) that are important in cell signaling. Cytokines are short-lived proteins that are released by cells to regulate the function of other cells. Sources of cytokines include macrophages, B lymphocytes, mast cells, endothelial cells, fibroblasts, and various stromal cells. Types of cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.
An unhealthy change in the normal bacterial ecology of a part of body, e.g., the intestines or the oral cavity.
Beneficial stress that can be psychological, physical (e.g. exercise), or biochemical (hormesis) in nature.
Hemoglobin A1C (Glycated Hemoglobin)
A blood test that measures the amount of glycated hemoglobin in a person’s red blood cells. The hemoglobin A1c test is often used to assess long-term blood glucose control in people with diabetes. Glycation is a chemical process in which a sugar molecule bonds to a lipid or protein molecule, such as hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases in a predictable way. In diabetes mellitus, higher amounts of glycated hemoglobin, indicating poorer control of blood glucose levels, have been associated with cardiovascular disease, nephropathy, neuropathy, and retinopathy. Also known as HbA1c.
Biological responses to low-dose exposures to toxins or other stressors such as exercise, heat, cold, fasting, and xenohormetics. Hormetic responses are generally favorable and elicit a wide array of protective mechanisms. Examples of xenohormetic substances include plant polyphenols – molecules that plants produce in response to stress. Some evidence suggests plant polyphenols may have longevity-conferring effects when consumed in the diet.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
A broad term that describes periods of voluntary abstention from food and (non-water) drinks, lasting several hours to days. Depending on the length of the fasting period and a variety of other factors, intermittent fasting may promote certain beneficial metabolic processes, such as the increased production of ketones due to the use of stored fat as an energy source. The phrase “intermittent fasting” may refer to any of the following:
- Time-restricted eating
- Alternate-day fasting
- Periodic fasting (multi-day)
A diet that causes the body to oxidize fat to produce ketones for energy. A ketogenic diet is low in carbohydrates and high in proteins and fats. For many years, the ketogenic diet has been used in the clinical setting to reduce seizures in children. It is currently being investigated for the treatment of traumatic brain injury, Alzheimer's disease, weight loss, and cancer.
Molecules (often simply called “ketones”) produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. There are three types of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. Ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
Long-term meditation is a practice where an individual trains the mind or induces a mode of consciousness designed to promote relaxation, build internal energy or develop a desired mental state. It can range from 20 minutes to an indefinite amount of time. Long-term meditation is associated with increased gray matter density in the brain stem.
A drug commonly used for the treatment of type 2 diabetes. Metformin is in a class of antihyperglycemic drugs called biguanides. It works by decreasing gluconeogenesis in the liver, reducing the amount of sugar absorbed in the gut, and increasing insulin sensitivity. A growing body of evidence suggests that metformin may prevent genomic instability by scavenging reactive oxygen species, increasing the activities of antioxidant enzymes, inhibiting macrophage recruitment and inflammatory responses, and stimulating DNA damage responses and DNA repair. 
 Najafi, Masoud, et al. "Metformin: Prevention of genomic instability and cancer: A review." Mutation Research/Genetic Toxicology and Environmental Mutagenesis 827 (2018): 1-8.
Methylene tetrahydrofolate reductase (MTHFR)
A gene coding for an enzyme that converts homocysteine into methionine; a critical step in the methyl cycle. Natural variation in this gene is common among healthy people, however, some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer’s disease and other forms of dementia, colon cancer, and acute leukemia.
The collection of genomes of the microorganisms in a given niche. The human microbiome plays key roles in development, immunity, and nutrition. Dysfunction of the microbiome is associated with the pathology of several conditions, including obesity, depression, and autoimmune disorders such as type 1 diabetes, rheumatoid arthritis, muscular dystrophy, multiple sclerosis, and fibromyalgia.
A mucopolysaccharide or glycoprotein that is the chief constituent of mucus secreted by the epithelial cells lining the gut in order to produce a barrier preventing infection by microorganisms inhabiting the gut.
A result of oxidative metabolism, which causes damage to DNA, lipids, proteins, mitochondria, and the cell. Oxidative stress occurs through the process of oxidative phosphorylation (the generation of energy) in mitochondria. It can also result from the generation of hypochlorite during immune activation.
Reactive Oxygen Species (ROS)
Oxygen-containing chemically-reactive molecules generated by oxidative phosphorylation and immune activation. ROS can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.
A related byproduct, reactive nitrogen species, is also produced naturally by the immune system. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.
The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from ROS (oxidative stress) and RNS (nitrosative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.
The loss of skeletal muscle tissue with age. Sarcopenia is one of the most important causes of functional decline and loss of independence in older adults.
The condition or process of deterioration that occurs with age. Cells that acquire enough damage can become senescent, which means they are not metabolically active and do not serve a function. Senescent cells often release inflammatory cytokines, which can then lead to the damage of neighboring healthy cells.
Sex-Hormone Binding Globulin (SHBG)
A glycoprotein that binds to sex hormones, and is produced mostly by the liver. Testosterone and estradiol circulate in the bloodstream bound mostly to SHBG. Only around 1-2% is unbound or "free", and thus biological active. The relative binding affinity of various sex steroids for SHBG is dihydrotestosterone (DHT) > testosterone: androstenediol> estradiol> estrone.
A rhizomatous herbaceous perennial plant of the ginger family that grows wild in the forests of South and Southeast Asia. Turmeric’s strong antioxidant and anti-inflammatory properties are attributed to its high concentration of curcumin. After being boiled and dried out, turmeric has a golden-orange color.
Type 2 diabetes
A metabolic disorder characterized by high blood sugar and insulin resistance. Type 2 diabetes is a progressive condition and is typically associated with overweight and low physical activity. Common symptoms include increased thirst, frequent urination, unexplained weight loss, increased hunger, fatigue, and impaired healing. Long-term complications from poorly controlled type 2 diabetes include heart disease, stroke, diabetic retinopathy (and subsequent blindness), kidney failure, and diminished peripheral blood flow which may lead to amputations.
A pituitary hormone that acts to promote the retention of water by the kidneys and increase blood pressure.
A potent water-soluble antioxidant found in citrus fruits. Vitamin C is an essential nutrient involved in tissue repair, neurotransmission, and immune system function. Also known as ascorbic acid.
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