Making Sense - Sam Harris - #328

00:00:00.000 Welcome to the Making Sense Podcast.

00:00:08.820 This is Sam Harris.

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00:00:46.220 Welcome to the Making Sense Podcast.

00:00:48.320 This is Sam Harris.

00:00:50.700 Today I'm speaking to my friend Peter Atiyah.

00:00:53.700 Peter is a doctor and the founder of Early Medical.

00:00:57.220 He received his medical degree from Stanford University, and then he trained at Johns Hopkins

00:01:02.660 in general surgery.

00:01:04.840 He also trained at the NIH as a surgical oncology fellow and at the National Cancer Institute.

00:01:11.020 And he's also the host of his own podcast, The Drive.

00:01:14.500 But today we focus on his new best-selling book.

00:01:18.080 The title is Outlive the Science and Art of Longevity.

00:01:21.660 And that really is our focus.

00:01:23.820 We talk about healthspan as opposed to mere lifespan, the lessons that can be learned from

00:01:30.420 centenarians and supercentenarians, diet and nutrition, including topics like sugar and

00:01:37.020 macronutrients, alcohol, fasting and time-restricted eating, exercise, heart disease, blood pressure,

00:01:45.940 cholesterol, cancer, brain health, metabolic disorders, proactive medical testing, medication

00:01:53.740 side effects, esoteric drugs like rapamycin, emotional health, and other topics.

00:02:00.800 The full conversation runs three hours, so it is a fairly comprehensive look at most of

00:02:08.340 the variables we might control to maximize the chances of living a long and healthy life.

00:02:13.380 And now I bring you Peter Atiyah.

00:02:21.900 I am here with Peter Atiyah.

00:02:23.760 Peter, thanks for joining me.

00:02:25.440 Yeah, Sam.

00:02:25.920 Thank you so much for having me.

00:02:27.260 So you have written this amazing book, which we are going to talk about.

00:02:31.860 The title is Outlive the Science and Art of Longevity.

00:02:36.020 And first of all, congratulations on the book.

00:02:37.860 It really appears to have been trumpeted from the ramparts everywhere, from Oprah on down,

00:02:44.200 and it's really getting out there.

00:02:45.600 So it's got to be gratifying because when you publish any book, to say nothing of a first

00:02:49.820 book, you really have no idea what's on the other side of that printing press.

00:02:54.760 And this is really about as good of an outcome as I can imagine.

00:02:59.560 So it's got to feel good.

00:03:01.500 It does.

00:03:01.880 Yeah, and I think this time a year ago, effective at least when we're recording this, was when

00:03:07.760 I really had the thing ripped out of my hands by the publisher.

00:03:11.900 And I remember sort of thinking to myself, like, I'm not happy about this.

00:03:17.980 It's not perfect, blah, blah, blah.

00:03:19.360 I'm sure the same thing that you've thought of many times as you've obviously written a

00:03:23.200 number of successful books.

00:03:24.180 But then I had this thought that sort of calmed me, which was, look, is it at the point now

00:03:29.320 where I will be proud if my kids read this in 20 years?

00:03:33.720 And if I can answer yes to that question, then the rest is sort of out of my hands.

00:03:37.980 And maybe people will hate it, and maybe people will find a bunch of mistakes in it, and all

00:03:42.080 of the sort of insecurities that I'm sure every author goes through.

00:03:45.000 But I know that once I kind of got to that point of saying, as long as my kids will one

00:03:49.480 day be proud of it, which I know it sounds a bit corny, it'll be okay.

00:03:53.240 And then I think the rest sort of took care of itself.

00:03:56.820 Yeah, well, it's quite a useful book, and it's a very candid book, too, which you really

00:04:01.920 go into your story in considerable depth.

00:04:05.100 Before we jump into the topics at hand, we're going to sort of track through your book.

00:04:10.180 Obviously, there's much more detail in the book, and I recommend people read it if they

00:04:13.940 want more detail on any of the topics we touch.

00:04:16.760 I should also say that you have a podcast, The Drive, which really goes into extraordinary

00:04:24.860 detail on all of the topics we'll touch and many others.

00:04:28.760 So if we're going to talk for 10 minutes about lipids for cardiovascular health, your podcast

00:04:35.760 probably has 10 hours on that topic.

00:04:38.800 I don't think I'm exaggerating.

00:04:40.300 I think you're underdoing it.

00:04:42.860 I think I have more than 10 podcasts on it.

00:04:46.080 Right, okay, so 30 hours, yeah.

00:04:48.120 Yeah.

00:04:48.480 Yeah, so there's quite a wilderness of detail awaiting anyone who wants to follow you into

00:04:54.940 it.

00:04:55.560 But before we jump into the topics, perhaps you can summarize your background and career

00:05:01.400 in medicine, because you've had a kind of an interesting story of how you have come to

00:05:07.960 emphasize the kinds of topics you have focused on.

00:05:12.140 Yeah, so I didn't want to go to medical school at any point during my life.

00:05:16.940 I was not a pre-med or anything like that.

00:05:18.460 In fact, I'd already sort of finished engineering when I had a change of heart, decided to go

00:05:23.080 back and do medicine.

00:05:24.660 And in medical school, like many others, I'm sure I was a little undecided about what to

00:05:28.140 do, always had an interest in oncology, and when I showed up in med school, kind of thought

00:05:33.360 I might do pediatric oncology.

00:05:35.480 But by the end of medical school, realized I had more of a surgical personality, and

00:05:40.780 so decided to do surgery with the plan to then go on and specialize in surgical oncology.

00:05:47.320 And after five years of my residency, for a number of reasons, some of which I write about

00:05:52.980 in the book, I just became quite frustrated with what I've later come to call medicine

00:05:58.860 2.0, although at the time, of course, I had no idea that that's what was really frustrating

00:06:02.720 me.

00:06:03.460 Then I just decided to kind of leave.

00:06:04.880 I sort of felt like the last 10 years had sort of been not a good use of my time, frankly.

00:06:11.200 And I wanted to go back and get another degree, probably an MBA, felt I already had enough

00:06:18.020 debt, and so instead I joined a company called McKinsey & Company, which is a consulting firm,

00:06:24.240 and sort of went down the path of corporate finance and risk there, which was very appealing

00:06:30.700 to me and to my sensibilities around quantitative things.

00:06:35.560 I missed my background in mathematics and was sort of happily marching along doing that

00:06:42.540 and sort of spent six years completely away from medicine until my own health became of

00:06:49.300 a high enough priority to me and a high enough interest that the endless pursuit of trying

00:06:55.780 to understand that better kind of gradually led me back into the notion of practicing medicine

00:07:01.040 again, but obviously doing it in a very different way, which is, you know, through this lens of

00:07:05.120 prevention as opposed to last-minute treatment.

00:07:08.080 Right, and you've gone very deep into topics like diet and nutrition and exercise, I mean,

00:07:15.240 more than the average physician, I would say, and we will cover that.

00:07:20.920 So let's start with what would be our first chapter here on the topic of longevity and really

00:07:28.640 health span, I think is your preferred word, because, you know, it's more than a matter of just not

00:07:33.940 dying. How do you think about the main causes of mortality and the main causes of reduced

00:07:40.660 health span? And maybe we should define health span at the outset here.

00:07:45.140 Yeah, so I think longevity is best explained, at least for me conceptually, I think of longevity

00:07:51.020 as a function of these two things, lifespan and health span. Lifespan being the easier to understand

00:07:58.460 because it's the binary one. It's the, you know, you're alive or you're dead, you're respiring or you're

00:08:02.220 not. And the current medical system is really focused mostly on lifespan. It's the metric that

00:08:08.480 gets measured and it's the metric, obviously, that therefore gets managed. Health span, which is

00:08:15.540 obviously not binary, is somewhat subjective as well, really speaks to quality of life. And while I think

00:08:23.280 that everybody intuitively gets that, certainly I'm sure if you ask a person, you know, would you want

00:08:30.520 to live to a hundred if the last 20 years of your life you were cognitively or physically

00:08:36.260 debilitated? I think most people would immediately say, no, not really. So very long, very long lifespan

00:08:44.360 in the absence of health span is not desirable. But similarly, wonderful health span with insufficient

00:08:50.420 lifespan is also undesirable. You know, Sam, if I said, you know, you're going to die at 60, but you're

00:08:55.520 going to be from now until 60, you're going to be as strong and cognitively sharp as you were in your

00:09:01.000 twenties. I still think we would view that as tragic as well. Your lifespan was cut short. So

00:09:05.640 what we're really trying to do is optimize both. But I think the biggest insight I've had in the past

00:09:12.180 five years is that if you focus relentlessly on health span, you get the lifespan benefits

00:09:18.120 typically along the way. If you do the reverse, that's not necessarily true.

00:09:24.300 So what can we learn from centenarians and I guess you call them super centenarians, people who live

00:09:31.520 to be a hundred and beyond and in many cases really thrive? I mean, it's almost like their health span

00:09:38.640 is extended by two decades or more with respect to the average population. What have we learned

00:09:47.100 from them and to what degree do you think they're the correct lens through which to look at the

00:09:53.400 goal here and the strategy and tactics we might use to extend longevity and health span?

00:10:00.940 Well, this is a question I've been interested in for about a decade. And there are two people who

00:10:06.020 have really done a lot of work on the centenarians, the offspring of centenarians, and even the

00:10:14.100 super centenarians, those who live to be 110 and beyond. And these two folks are both here in the

00:10:19.260 US. So one is a guy named Thomas Pearls at Boston University and the other is near Barzillai out to

00:10:24.360 Albert Einstein College in New York. Now, understandably, most of the work that Pearls

00:10:29.800 and Barzillai have put into this have been focused on kind of, you know, the more high tech side of the

00:10:35.980 question, which is, you know, what are the genes that are associated with this exceptional longevity?

00:10:43.520 Because it's pretty clear that it's a genetic benefit that's been bestowed on these very

00:10:49.800 infrequent individuals. In fact, from a behavioral standpoint, you know, it's kind of amusing to look

00:10:56.960 at the typical lifestyle of the average centenarian. You know, on average, they're more likely to smoke,

00:11:01.860 more likely to drink to excess, less likely to exercise, and more likely to have poor eating

00:11:07.240 habits. So it didn't take long for people to figure out that these guys were, you know, winning

00:11:12.900 the genetic lottery and not, you know, living like monks. And understandably, I think most of the effort

00:11:19.400 has been on what are those genes. I touch on that in the book. But for me, the big aha moment came

00:11:26.580 roughly 2014, when I was kind of reading a paper about centenarian mortality. And I realized that

00:11:34.220 if you look at the mortality tables of centenarians, it looks very similar to the mortality of the rest

00:11:41.020 of us. It just has a 20-year phase shift. And that might sound really obvious, but it's actually not,

00:11:46.780 right? Because what it says is, centenarians are just as likely to die from heart disease

00:11:51.960 eventually. They're just as likely to die from cancer eventually. And by the way, they're just

00:11:56.760 as likely to die from cancer once they get a cancer diagnosis as the rest of us. What this tells us is

00:12:02.800 that their superpower, which again is brought on genetically, is a delay in the onset of disease,

00:12:09.820 not in a resilience to a disease once they have it. I want to have a separate chapter here on

00:12:16.300 specific medications and supplements that might be derived from any insights we've had into the

00:12:22.700 genomes of centenarians and through other means. So things like rapamycin and metformin. But how do

00:12:30.400 you use what we've learned about centenarians so far in your thinking through the strategy and tactics

00:12:39.160 you employ in your medical practice and just personally? And perhaps you want to differentiate

00:12:45.500 between strategy and tactics and how you think about longevity?

00:12:50.400 Yeah. So I think that's a great way to lead into this, which is that insight, which as I say,

00:12:55.760 it sounds relatively so what-ish, I think for me was a real wake-up call. And it made me realize

00:13:02.580 that the only way one is going to somehow improve their longevity is to think about prevention through a

00:13:11.680 much longer lens. So we have to pretend that our coronary arteries at the age of 80, we need to

00:13:20.800 position them to look like they would otherwise look at 60. And the only way to do that is to think

00:13:27.280 about primordial prevention as opposed to just quote-unquote primary prevention. So let's use

00:13:32.380 coronary artery disease as an example of that because it is the most ubiquitous cause of death

00:13:37.580 in the United States globally for men and for women. It really is the great equalizer.

00:13:44.600 We know this from as early as the early 1970s, late 1960s, when they were doing autopsy studies on

00:13:51.140 young men who were dying in Vietnam, that even 18-year-old men have, while not gross evidence

00:14:00.640 of atherosclerosis, i.e. you wouldn't open up their coronary arteries and see clots. Histologically,

00:14:06.020 they already have the process embedded. So in other words, if you look under a microscope at

00:14:10.800 their coronary arteries, you'll see the foam cells, you know, the macrophages that have ingested

00:14:15.960 cholesterol that's been oxidized in the arterial wall. And you realize that that process is actually

00:14:21.480 beginning as we're children. And the slow burn of that process is such that for most people,

00:14:28.320 it doesn't become clinically relevant until you hit about 65. So about 50% of men who are going to

00:14:35.560 have a coronary event in their life will have it before the age of 65. And about a third of women

00:14:40.760 who will have a coronary event in their life will have it before the age of 65. So that gives you a

00:14:45.260 sense of the timescale. Well, if we want to prevent that, we can't really wait until you're 50.

00:14:50.840 That's effectively the point here. We have to take prevention much more seriously, and we have to

00:14:56.800 significantly bend the arc of the disease curve basically as soon as possible. And we do have

00:15:03.100 examples of this working already, right? So if you take children who are born with something called

00:15:08.120 familial hypercholesterolemia, which is a not terribly uncommon genetic disorder that results in unusually

00:15:15.720 high levels of cholesterol, these are indeed people who can have, you know, MIs, myocardial infarcts and

00:15:21.220 heart attack in their 20s. And these are kids that actually have to be medicated as youngsters. And

00:15:26.380 if you do that, and if you do it aggressively, these kids can go on to live normal lives.

00:15:31.320 Well, we'll have a separate chapter on heart health and, you know, cardiovascular disease

00:15:36.880 here. But let's talk about diet and nutrition. This is really the first stop in most people's

00:15:44.600 thinking with respect to how to prevent, you know, really all of the diseases of aging and to live a

00:15:51.120 healthy life. You know, I consider it one of the great scandals of medicine and science generally

00:15:56.380 that there's still any uncertainty about what constitutes a healthy human diet. I mean, it's

00:16:02.340 just amazing to me that there's such a diversity of opinion on this topic. I mean, there are people who

00:16:07.700 will tell you that whole grains and legumes are among the healthiest things you can eat. And there are

00:16:13.320 people who will tell you with equal confidence that they're just pure poison. And there are whole

00:16:19.120 diets marketed around these antithetical views. And, you know, so I had thought prior to this

00:16:24.960 conversation that the one totally uncontroversial point in nutrition now is that refined sugar is

00:16:32.260 generally bad for us. And maybe that's still the case. I mean, I think it's generally described as

00:16:37.580 the dietary equivalent of smoking. But right before getting on the mic with you, I think it was

00:16:44.960 yesterday, I stumbled upon this YouTuber who apparently spent 100 days on a diet consisting

00:16:51.960 of nothing but 2,000 calories of ice cream and 500 calories of protein powder, plus booze. And he lost

00:16:59.000 32 pounds and totally revamped his lipid profile. Obviously, that's just an N of one, and who knows if

00:17:05.680 it's true. But what do we absolutely know is true about diet and nutrition at this point? So let's

00:17:12.960 go through gradations of certainty here. What are you sure of with respect to diet and nutrition

00:17:20.140 that is generically applicable to more or less everyone who would listen to this? And what do you

00:17:27.180 think is just very likely to be true? And let's just track through with those two flags with respect to

00:17:34.380 our epistemic certainty as we touch the various topics. How should people think about diet and

00:17:42.120 nutrition here? And is there anything on this landscape that is the equivalent of a generic

00:17:48.780 certainty like it's not a good idea to smoke cigarettes, which I think is a piece of health

00:17:54.960 wisdom we have truly conquered at this point?

00:17:57.660 Yeah. I like the way you framed the question, Sam. And it's sort of funny because as you know,

00:18:03.400 you've read the book, there's like 17 chapters. Two of them are on nutrition. Three of them are on

00:18:07.560 exercise. Everything else gets one chapter, right? So clearly exercise and nutrition get a little extra

00:18:13.020 attention in part due, I suppose, to their complexity in the case of nutrition and the impact

00:18:18.820 in the case of exercise. However, during the first writing of the book, I was so annoyed by the

00:18:25.660 problem you describe that I very sort of cheekily sent my editor a one-page version of the nutrition

00:18:34.840 chapter. And I said, this is the chapter. And it was what you just said. It's like, here's what we

00:18:39.980 know. And it was like, I don't know, six bullet points. And I said, how about I just do this and

00:18:45.200 spare myself and the readers all of the crap that follows where I have to start getting into some

00:18:50.120 uncertainty. Needless to say, that didn't go over very well. But what I basically said is,

00:18:55.080 here's what we know. We know that when it comes to nutrition, too much and too little are problematic,

00:19:02.760 though generally on different timescales. Let's expand on that for a second. We've been around

00:19:07.700 for, you know, depending on where you want to draw the line in the sand of where we began as,

00:19:11.780 you know, homo sapiens versus, you know, previous forms. Let's just make it easy and say like

00:19:16.260 a couple hundred thousand years, right? And for most of that period of time, food has been

00:19:23.500 relatively scarce. So that's fact one. Fact two is, I would argue this, I think you would probably

00:19:29.300 agree, Sam. What separates us as humans from every other species on this planet is our brain. That's

00:19:36.140 the sort of, that's our superpower, right? It's certainly not how strong we are or how fast we are

00:19:41.520 or any other sort of physical power. It's, it's really, it's, it's, it's really our brains that

00:19:47.700 differentiate us. That brain is an insanely energetic organ. So roughly 25% of our caloric

00:19:56.320 need goes to servicing that organ that constitutes 2% of our mass. Therefore, the trick that allowed us

00:20:05.260 and only us to leapfrog out of the swamp ahead of every other species was the capacity to store

00:20:12.620 energy. And it's important to understand just how profound that is, right? If we couldn't store weeks

00:20:21.980 and weeks of energy, we wouldn't be here. Now we store most of that as fat. So obviously excess fat

00:20:29.580 gets stored as fat. Excess carbohydrate gets stored as fat beyond the paltry amount we can store as

00:20:34.760 glycogen, which is just a fancy word for the storage form of glucose. And in times of relatively

00:20:41.200 short fasts, we just break that fat down and use it as energy. And in relatively long periods of

00:20:47.240 fasts, we turn that fat into something called ketones and we use those as energies. But regardless,

00:20:52.500 we can go a relatively long time without food. By comparison, of course, a mouse can go like

00:20:57.680 two days without food before it dies. Even a lean person could go 20 or 30 days without eating.

00:21:05.120 So what's the price we pay for that superpower? Well, up until relatively recently, we've paid

00:21:12.100 no price for that superpower. It's only in the last hundred or so years where we have shifted from

00:21:19.480 hundreds of thousands of years of food scarcity to tragic food abundance. Are we starting to show

00:21:27.640 that actually the drawback of this remarkable capacity to store excess energy is X, Y, and Z.

00:21:34.880 And there are these metabolic consequences of doing so. Now, again, those are chronic problems,

00:21:41.340 not acute problems. And therefore, on a relatively long timescale, food scarcity or food shortage is

00:21:49.000 still a much greater evolutionary concern. In fact, you would argue the natural selection has really

00:21:54.020 no interest in the problem of overnutrition. But to go back to your question, what can I say

00:22:01.120 definitively? I can say that too much nutrition is going to be bad chronically. We'll go into more

00:22:05.760 detail. And too little nutrition is going to be bad acutely. That's fact one. Fact two is there are

00:22:15.080 certain amino acids and fatty acids that are absolutely essential for life. Meaning there are

00:22:24.040 certain types of foods, primarily in the form of fats and proteins, that we must consume in some

00:22:31.700 quantity from the outside world. And failure to do so will result in horrific consequences. So, you know,

00:22:39.620 not just general caloric malnourishment, but, you know, deficiencies in cartilage, bone, muscle, things

00:22:47.500 of that nature. There are also certain nutrients, you know, essential vitamins and minerals that are

00:22:53.000 absolutely essential for life. Everybody, of course, knows the story of the, you know, the sailors who were

00:22:58.160 not given enough vitamin C in their rations, develop scurvy, et cetera, things like that.

00:23:02.700 There are certain things that are toxic to us acutely. So, you know, we don't do very well with

00:23:09.000 certain types of bacteria. So, you know, E. coli in our food, relatively problematic. That's about where

00:23:15.560 it ends, Sam. That's, you know, that's about all I can tell you with capital T truth written all over

00:23:22.080 it. Meaning those are the things that are kind of universally true for which there's no ambiguity.

00:23:27.780 If we start to get into how many grams of protein a day do you need? Why is it that someone can eat

00:23:34.520 7,000 or pardon me, 2,000 calories of sugar per day and still lose weight? I mean, I have lots of

00:23:40.840 thoughts on those things and I hopefully have more insight on those things than maybe the average person

00:23:45.760 on Twitter, but we are definitely less able to reliably say things. And I guess that speaks to

00:23:54.320 another nature, another element of the problem, which is the human body has a remarkable dampening

00:24:00.160 factor quality when it comes to nutrition, right? So if you think of a system, like an engineering

00:24:05.680 system where you put inputs into it and then you get the outputs out, I think of the body as this

00:24:11.100 remarkable dampener where when you put things in, it sort of squashes the output. So it's very

00:24:19.620 difficult to, in the short term, discern how the input affected the output, right? So body weight is

00:24:26.180 an example. You know, what you ate the day before from a caloric standpoint, believe it or not, doesn't

00:24:32.840 have an enormous impact on your body weight the next day. That's probably more a function of water weight

00:24:37.920 and sodium than the actual weight of the food because most food comes with so much water in it.

00:24:45.560 So therefore, looking at your body weight five times a day is not really a good way to determine

00:24:52.320 energy balance. There's so many other movement systems in it. Furthermore, there's so much variability

00:24:59.040 in our system with how we process nutrients with respect to other variables, such as sleep. So we'll maybe

00:25:06.740 talk about sleep, but a poor night of sleep impacts insulin signaling more than most people would

00:25:13.680 appreciate. And certainly several nights of poor sleep would have an even bigger effect. And the

00:25:19.920 impact of that, i.e. insulin sensitivity on fuel partitioning, meaning how you store the nutrients

00:25:25.620 you consume them, and then how you go back to the energy well to draw them from storage is quite

00:25:30.740 significant, actually. So under two nearly identical circumstances, food-wise, two different nights

00:25:37.360 of sleep could also impact things. So all of these things make it very difficult to study the problem.

00:25:44.080 Yeah. Yeah. Well, so one point about evolution, and you actually make this in the book, I mean, evolution

00:25:49.880 can't see really anything we care about. And surprisingly to many people, it can't see

00:25:57.760 the variables that would determine our health span and longevity certainly past our 50s, right? I mean,

00:26:07.460 it just simply doesn't care about you living to a ripe old age and being able to swing kettlebells

00:26:14.200 into your 80s. It just cares about you spawning and maybe helping your children secure their spawning

00:26:23.080 period so that, you know, maybe there's a, you can be a young grandparent from the point of view of

00:26:28.600 evolution and still have some genetic utility. But after that, there's just no, evolution is blind to

00:26:36.620 what we care about. And so I guess I, I'm always hesitant to, when I hear of a diet that is using

00:26:44.560 our evolved environment as a reference point, so like, you know, like the paleo diet, right?

00:26:50.380 Where it seems to put a lot of stock in the 200,000 years that preceded the present moment.

00:26:58.040 I just, I'm wondering about the, how you view the limitations of the lessons we can draw

00:27:03.500 from that. It just seems to me that we're living in the, in the world of science fiction now. If we

00:27:09.460 care about living to 120 with anything like a modicum of health span, we're, you know, we have to figure

00:27:16.580 it out on the basis of principles that evolution has never anticipated.

00:27:21.480 Yeah, that's a very interesting question. And it's one I think a lot about, and you're,

00:27:25.620 you're absolutely right, by the way. In fact, I could just taking us back for a second, I could

00:27:29.020 point to a couple of genes that persisted because of, you know, evolutionary advantage that are a

00:27:38.340 distinct disadvantage today. So the LP little a phenotype, which has come, comes from the LPA gene

00:27:44.300 and the APOE4 gene. So these are both genes that are highly prevalent today and highly associated

00:27:50.740 with disease, cardiovascular disease and Alzheimer's disease, respectively. It might be tempting to ask

00:27:56.400 the question, why the heck do these genes exist? And we know that the APOE gene, the E4 isoform was the

00:28:03.580 original isoform. Well, I think the easiest answer is one, evolution doesn't care about Alzheimer's

00:28:09.060 disease because nobody's getting it before reproduction. But even two, it's that the APOE4

00:28:14.640 isoform offered protection in a world where infection ran rampant. And the same is probably

00:28:21.340 true of LPA. It certainly increased blood clotting, which would have been a huge advantage if you can

00:28:26.880 think about it, right? Hundreds of thousands of years ago, if not just a few hundred years ago,

00:28:31.180 to have more, you know, to have a greater likelihood of clotting in the event of a cut would

00:28:36.740 have been an enormous advantage. Today, it's not so much an advantage and all of the negative

00:28:41.080 consequences of all people really work against you. So with all that said, lots of examples of those

00:28:46.680 situations. When it comes to nutrition, I find it hard to make the case that any extreme diet is our

00:28:54.300 optimal diet. But I find myself relying on an evolutionary example here, which is we were

00:29:01.160 the most opportunistic omnivores around. So I can certainly make the case for extreme diets to treat

00:29:09.240 disease, meaning if a person has type 2 diabetes, then maybe some extreme diet or some sort of extreme

00:29:16.300 dietary restriction is the optimal diet. But I would certainly argue that if you don't have, you know,

00:29:24.360 if you're just starting from a place of health, I feel like one shouldn't have to be that restrictive.

00:29:30.160 Though maybe I find myself, you know, making this argument based on the fact that we have lots of

00:29:35.360 evidence that at least to certain age, and this of course is based on looking at the few remaining

00:29:42.440 hunter-gatherer societies that do still manage to make it into, you know, old age, consuming,

00:29:49.100 you know, basically opportunistic omnivore diets. So it's a little bit of evolution, but it's also a

00:29:54.620 little bit of looking at, you know, for example, you know, certain hunter-gatherers that still do

00:30:00.680 exist, for example, in Australia and Africa. Okay, so let's talk about macronutrients, right? We're

00:30:07.720 talking about fat, protein, and carbs. I guess to come back to the crazy example I started with of

00:30:13.880 the guy who ate nothing but ice cream or 2,000 calories of ice cream plus 500 calories of protein

00:30:20.800 powder and alcohol. So he sounded like he had fun, at least for the first week. The fact that it was

00:30:27.820 ice cream rather than Skittles makes me think that maybe there was, it's not quite as insane a story

00:30:35.800 as it might seem, because I remember the one time I tracked my blood glucose for, you know, 14 days,

00:30:44.620 I was actually surprised to find that ice cream, I assume because the sugar is being mediated by fat,

00:30:52.100 was not as a high glycemic load as many other things that were ostensibly much healthier that I

00:30:58.540 might eat, like a, I remember a vegetarian burrito just sent my blood sugar, you know, off the charts.

00:31:05.180 Whereas ice cream was pretty, you know, unspectacular. But in any case, so how do you think about

00:31:13.900 fat, protein, and carbs in general? What generically can you say about what most human beings most of

00:31:23.560 the time require on that front? And how can you extrapolate from those principles to what we might

00:31:32.060 assume is a, if not the perfect diet, at the very least, a very safe bet for a healthy one?

00:31:40.240 So I think about this in kind of a formulaic way that maybe takes a little bit of the romance out

00:31:45.880 of eating, which doesn't mean that I necessarily adhere to it with that rigor. But if I'm going to

00:31:51.020 think about this as an engineering problem, it's actually, I think, quite simple. So, but before I do

00:31:57.380 that, I think it's worth kind of addressing the, perhaps the mystery in the ice cream man. So let's

00:32:03.600 assume that this is correct. And I think that's not an assumption one should take lightly, right? So

00:32:08.900 I think the whole, you know, I did this on YouTube, therefore it's true, is one needs to have a healthy

00:32:15.380 degree of skepticism. And it would be more interesting to see that in a clinical trial. But let's just assume

00:32:20.920 there was a clinical trial that said we took, you know, 700 overweight people whose, you know,

00:32:29.700 whatever, average caloric intake in the run-in period was X, and we created a 25% caloric deficit

00:32:37.160 that consisted of what you just described. Do you think they're going to lose weight? My answer to

00:32:43.420 that question would be yes. I would be, I would, I would expect them to lose weight. In other words,

00:32:48.400 I think that the single greatest determinant of energy balance is indeed, or maybe a better way

00:32:55.960 to say this, the single greatest determinant of weight loss is going to be energy imbalance would

00:33:00.480 be maybe the most accurate way I could say that. So in other words, a caloric deficit,

00:33:05.080 no matter what you're eating. No matter what it's constituted by. That's right. So, so, so if we,

00:33:09.640 if we did another, you know, thought experiment and we said, look, we're going to, we're going to take,

00:33:14.120 you know, a thousand people who are all ostensibly overweight and let's just make it really elegant

00:33:19.340 and say that they're all basically genetically equivalent. So it's just like a bunch of mice

00:33:23.040 and they're, they're all coming in at 3,500 calories per day and their weight stable at 3,500

00:33:30.180 calories per day. We're going to divide them into two groups. And the first group is going to go on

00:33:36.480 a 2,800 calorie a day diet of junk food. The other group is going to go on a 4,000 calorie a day diet

00:33:45.180 of whole foods, right? The best, you know, whatever, come up with your favorite best diet.

00:33:51.380 There's no doubt in my mind that that group eating 4,000 calories per day is going to be heavier when

00:33:57.680 the trial is done than the other group. And by the way, they might also be less healthy at that big of

00:34:04.360 a gap, right? Because of something we should probably talk about, which is why is it that

00:34:10.120 excess energy is harmful? Because it's not the aesthetics, right? It's, it's, it's, it's not

00:34:16.220 because you lose your six pack that you're unhealthy. There's something going on that's much more

00:34:20.400 important to understand. So with all of that said, how do I, how do I think about the problem? I think

00:34:25.340 about the problem by saying, and there's really a fourth macronutrient, Sam, that we should at least

00:34:29.460 mention, which is alcohol. And the reason is alcohol is so calorically dense, right? So I think

00:34:34.460 most people know that, you know, carbs and proteins are roughly four kilocalories per gram. Fat is nine

00:34:41.440 calorie kilocalories per gram. Well, ethanol is seven. So one has to be mindful if they're in the

00:34:48.020 business of trying to lose weight of just mindlessly consuming alcohol for at least two reasons. The first

00:34:53.620 being the energetic reason. The second being, if you're anything like me, there's no greater way to

00:34:59.120 reduce my inhibition around food than to give me a couple of drinks. Yeah. So I start with protein

00:35:04.920 because protein is the most important in my view. And there's different ways to think about this,

00:35:12.100 but I would just start by saying that the RDA, the recommended dietary allowance is clearly

00:35:17.380 incorrect. And I go to great lengths in the book to kind of explain this. I've also written about this

00:35:21.420 elsewhere. I've got multiple podcasts on the topic. The RDA, which offers something to the tune of 0.5

00:35:28.780 grams of protein per kilogram of body weight or sort of 0.5 to 0.8, I think is the RDA. You know,

00:35:39.200 that's sort of what it takes to not have malnourishment. But if we want to really talk

00:35:44.800 about thriving, especially in people over 50, it's probably closer to 0.8 to one gram per pound of

00:35:52.960 body weight. So again, that's a huge difference, right? So if you take a person who weighs 175 pounds

00:36:00.140 or 80 kilos, the RDA would say that person can get away with 60 grams of protein. I'm arguing that

00:36:07.740 person should be between about 150 and 180. So it's a huge difference. And I'm certainly not saying this

00:36:13.720 alone. Some, you know, people much smarter than me would agree with that. So we start with that.

00:36:19.780 The next thing I'm thinking about in the formula is what is your carbohydrate tolerance?

00:36:26.860 So you mentioned a moment ago that you'd worn a glucose tracking device, I assume a continuous

00:36:31.980 glucose monitor for a couple of weeks. Yeah.

00:36:34.220 So I think those are really helpful tools to give people a sense of what I mean by carbohydrate

00:36:39.780 tolerance. Carbohydrates are also very important. And I unfortunately bear a tiny bit of responsibility

00:36:46.720 in a previous life for probably demonizing them too much. But the reality of it is, you know,

00:36:52.360 carbohydrates are important. They're our most abundant and quickest source of energy. So there's

00:36:58.240 nothing you can do to turn food source into ATP quicker than glucose. And it is the preferred

00:37:05.400 fuel of our brains. In fact, even in a state of total starvation, 40 days without food, which believe it

00:37:12.280 or not was actually studied by George Cahill at Harvard back in the 1960s, not a study to be

00:37:16.740 replicated. They had subjects that fasted for 40 days. They were still getting 50% of the energy

00:37:23.540 to their brain was coming from glucose. The other 50% was coming from ketones. If you ask where does

00:37:28.640 that glucose come from when you're starving, it's because making the ketones and breaking down the fat

00:37:34.220 to do so creates a byproduct that gets recycled into glucose called glycerol. But anyway, glucose is

00:37:40.200 important. The problem with glucose is too much of it chronically is harmful, not acutely. Acutely,

00:37:47.960 we are much more interested in protecting against the downside and not having enough of it. So

00:37:52.780 hypoglycemia is acutely fatal. Hyperglycemia is not outside of very extreme circumstances that can only

00:38:00.860 exist if you have type 1 diabetes. So the body, again, going back to kind of the evolutionary thing

00:38:06.780 we talked about earlier, isn't really working that hard to protect you from a blood glucose of 150

00:38:13.380 milligrams per deciliter, which is about 50% higher than normal. It doesn't truly care. However,

00:38:20.100 the effect of that over many years is devastating. It will destroy your kidneys. It will destroy your

00:38:25.360 heart. It will destroy anything in your body, including your brain, that has small blood vessels.

00:38:31.000 And that's why people with type 2 diabetes have twice the risk of most diseases, right? Cancer,

00:38:38.180 heart disease, Alzheimer's disease, et cetera. But that's not a huge difference, right? So we have

00:38:43.620 to figure out what's our limit. And I think there's sort of two ways to think about this. What's your

00:38:49.040 average blood glucose and how much variability is there in what you eat? And again, you can figure this

00:38:54.820 out using traditional biomarkers. You can figure this out using a continuous glucose monitor.

00:38:59.140 But basically, once you figure out how much protein you need, the next question is,

00:39:04.480 how much carbohydrate can you tolerate while keeping yourself in those parameters? And I offer

00:39:10.040 some suggestions for these, but I think if you're going to be really aggressive and have, if you want

00:39:14.780 sort of an A plus on your report card here, I would say having an average blood glucose below 100

00:39:20.080 milligrams per deciliter. So that takes into account all the peaks and valleys would be considered

00:39:24.540 excellent. And that would correspond to about a hemoglobin A1c of 5.0. Now, what determines that?

00:39:29.960 Well, your activity level, how much muscle mass you have, how insulin sensitive you are, how well you

00:39:34.620 sleep, how much hypercortisolemia is going on. Genetic factors certainly play a role in it. All of these

00:39:39.860 things will matter. And even for a given individual, they'll change. So when I was a cyclist, I could

00:39:47.100 consume 800 grams of carbohydrates a day and still be within that band. Today, it's much lower than that.

00:39:53.380 So you sort of have to know what that looks like. And then the final point is that fat makes up the

00:39:58.720 difference. And the total amount of fat that goes in as basically a plug is to determine where you

00:40:05.320 need to be on energy balance. So believe it or not, in a reasonably healthy diet, your appetite can

00:40:11.500 serve as a reasonable backstop for how much you need to eat. And by the way, going back to the funny

00:40:16.940 example you gave of the guy eating ice cream all day, one thing I'm always interested in, and I don't

00:40:21.540 know if the guy talked about this in his video, is what was his degree of satiation? You know,

00:40:26.940 in other words, when you're eating 2,000 calories of ice cream a day, what kind of cravings was he

00:40:32.240 having for other food? And was he satiated? Did he go to bed at night feeling like I'm full? Or did

00:40:37.720 he kind of go to bed starving because his body was actually demanding more, but he was kind of

00:40:42.320 capping it artificially? Did he comment on that?

00:40:45.260 I don't remember. I remember that the punchline was that he was ultimately quite miserable on this diet.

00:40:50.580 I mean, he was surprised to be as unhappy as he was despite the improvements in his weight and

00:40:58.000 lipid profile, but he was not having fun ultimately.

00:41:02.000 But there's another component to that, right? Which I think is, you know, I think you asked

00:41:07.180 earlier, like what would we agree on is universally true? Another way to ask that question is, if you

00:41:14.200 had all the experts in the room, could they agree on what is the driver of the modern epidemic of

00:41:19.500 obesity? So it's a different question, but they're related, right?

00:41:22.620 Yeah.

00:41:22.940 Well, why have we never had an answer to that? And I think the answer is that the nature of

00:41:27.980 science is that most people study one pathway or one vehicle. And in obesity, I think there are so

00:41:33.420 many that I think there are a dozen plausible explanations. And it may be that every individual

00:41:41.000 who's obese is, you know, their obesity may be driven by two or three of those as the dominant

00:41:48.380 drivers versus others. So for example, one theory of obesity is that our food is so much less

00:41:56.580 nutrient dense than it used to be. And there's, this is one thing I actually didn't write about

00:42:00.840 in the book that I really wanted to, but there simply wasn't enough room to get into nutrient

00:42:05.160 density and to talk about, for example, soil health and how soil health impacts plant health

00:42:10.520 and that how, how that impacts animal health, et cetera. But there's very little doubt that the,

00:42:14.860 that food today, whether it be spinach or beef or barley or whatever has fewer nutrients in it than

00:42:21.880 it did a hundred years ago. And the question is, are we intrinsically innately wired to seek a certain

00:42:29.720 volume of nutrient? And as the density of our food, nutrient density, our food goes down,

00:42:35.700 are we simply seeking more calories to meet our nutrient needs? That's, that's an argument.

00:42:40.820 There's another argument that says the same thing. We're hardwired to get a certain amount of protein,

00:42:44.420 but as our sources of protein are getting diluted, we're seeking out higher and higher caloric

00:42:50.460 volumes of food to meet the same protein requirements. Other theory of course, is that it's all driven by

00:42:57.380 palatability, the more palatable the food, the more likely we are to seek it out. So you get the idea

00:43:01.740 that there's multiple theories. It's also possible they're all kind of partially right.

00:43:06.460 So on this question of protein, I think in your book, you, you emphasize as you did here that as you

00:43:13.020 get older, it becomes even more important to focus on how much protein you're getting.

00:43:18.060 What are the prospects of getting sufficient protein as sufficient as to just defined by you,

00:43:23.180 something like a gram per pound of body weight. If you're a vegetarian or a vegan, I realize this is

00:43:33.260 dangerous territory with respect to getting put on the radar of the vegan mafia. But what are your

00:43:39.640 thoughts about cutting meat and even all animal protein out of one's diet and still getting the

00:43:47.160 requisite amount of protein as one gets older? I mean, I think it's still possible. It just gets

00:43:53.120 harder. There's, there's no question. It's a trade-off. What you're referring to is anabolic

00:43:56.900 resistance. And that kind of, you know, starts, yeah, roughly in your fifties, but, but certainly

00:44:02.440 increases probably non-linearly from there. And that's where you probably have to start getting

00:44:07.880 closer to that one gram per pound of body weight to maintain maximal muscle protein synthesis,

00:44:15.360 the process by which muscle gets broken down and rebuilt. And the reason this is so important is

00:44:22.780 that sarcopenia is an enormous problem of the elderly. Sarcopenia is the disorder of low muscle

00:44:29.400 mass. And with sarcopenia and frailty comes enormous mortality. I think this is actually kind

00:44:37.300 of the hidden epidemic of aging. You know, I do write about this, but I think I write about it a little

00:44:41.660 bit more in the exercise chapter, which is once a person reaches the age of 65, if they fall and

00:44:49.240 break their hip, and I can't imagine there's a person listening to us speak now, Sam, who doesn't

00:44:53.800 know somebody for whom that's happened, right? It's like, oh, my friend's mother or somebody, right?

00:44:59.580 I've literally talked to two patients in the last week who have had parents go through this.

00:45:04.760 So if you're over the age of 65, you fall and break your femoral neck or your femur.

00:45:09.040 There's a 15 to 30% chance you will be dead in the next 12 months. And if you don't die in the next

00:45:16.200 12 months, of those who survive, meaning of the 70 to 85% who survive, there's a 50% chance you will

00:45:24.120 have a full-scale reduction in your mobility for the remainder of your life. Meaning, if before this

00:45:29.900 incident you walked freely, you will forever be using a cane. If before this incident you were using

00:45:35.000 a cane, you will be in a walker, etc., etc., all the way down to a wheelchair. So accidental deaths

00:45:41.580 due to falling is the leading cause of accidental death for people over the age of 75 at a level

00:45:48.820 that exceeds even what we see for accidental overdoses for people under 65. And I think most

00:45:55.940 people are probably now aware that accidental death due to overdose has become the most common

00:46:03.060 cause of accidental death for people under 65, eclipsing even automotive accidents. So with

00:46:08.800 all of that said as the background, frailty and sarcopenia are an enormous problem. And not just

00:46:14.640 because of what they do showing up on death certificates, but because of how much they

00:46:19.840 rob people of healthspan. So even if it doesn't kill you, it can easily ruin the last decade of your

00:46:26.080 life. So with all that said, the antidote to this is to have as much muscle as possible,

00:46:31.820 to be as strong as possible, to be as fit as possible. I make this joke all the time,

00:46:37.460 but it's true. In the entire history, I mean, how many people have existed, Sam? Do we have a,

00:46:41.540 it's like, there's 8 billion now. How many billion were there before us? Isn't it about another?

00:46:45.560 I think it was about 110 billion. Okay. I'm willing to bet, and I don't know how we could

00:46:51.460 ever verify this, but my bet would be in the entire history of that 100 billion people,

00:46:56.660 I would bet that no one in the final days of their life said, I wish I had less muscle,

00:47:02.100 I wish I was less strong. It's simply not possible. So protein intake is an essential component of

00:47:09.900 maintaining muscle mass. And of course, resistance training is as well. So to your question,

00:47:16.640 can a person who morally or philosophically doesn't want to consume meat or who doesn't

00:47:21.440 want to consume animal protein still, you know, avoid sarcopenia? I think the answer is yes,

00:47:27.820 but they have to acknowledge that they're in for a harder ride, meaning they're going to have to work

00:47:32.740 harder at eating than maybe you or I do, if we're willing to consume meat and animal products.

00:47:37.880 Yeah. On this issue of sparing muscle mass, I mean, there's this, I guess, two questions. Well,

00:47:46.180 one actually has a potential, poses a potential puzzle with respect to evolution. So when you just

00:47:52.500 stop eating, when you start fasting and even start starving, and you rely on your fat stores,

00:47:59.820 as evolution has permitted, why doesn't that reliance spare muscle systematically until you lose

00:48:09.300 all your fat? Because my understanding is if you start fasting, there is some considerable risk that

00:48:16.300 you are going to be losing lean muscle mass during that fast. Why is that? It seems like evolution would

00:48:23.900 have recognized that more muscle is generally better for all sorts of things, and the fat store has been

00:48:31.480 put there for a reason to be utilized under just these circumstances. So why doesn't it just spare

00:48:38.080 muscle systematically? Yeah, it's a great question. So below a certain calorie threshold,

00:48:43.940 we will use protein for energy. So for example, if you went on a thousand calorie a day fast,

00:48:52.800 but that thousand calories was 250 grams of protein, right? So 250 grams of protein is about

00:48:58.940 a thousand calories. You'd lose weight, but you'd probably lose muscle as well. So why is that? Well,

00:49:07.180 first of all, the body does have a pretty remarkable tool to prevent the complete emaciation of muscle,

00:49:12.540 and that is ketosis. So earlier I mentioned glycogen, which is the storage form of glucose. So

00:49:17.960 we can store, I don't know, somebody your size or my size, Sam, we could probably store 400 grams

00:49:25.860 of carbohydrates. So you could probably put 300 grams of glucose into your muscles. So that's about

00:49:33.140 1200 calories, and you can put another hundred into your liver. And by itself, if you never made any

00:49:39.840 other tweak to the system, that's like a day's worth of energy. Obviously, lots of times when we

00:49:45.300 need to go more than a day without eating, as sort of our ancestors at least did. So what you don't

00:49:52.220 want to do at that point is immediately start tapping muscle. Because if you did, you would break

00:49:57.260 down muscle in a really rapid fashion. So in other words, if we broke down muscle for amino acids

00:50:02.440 and sent those amino acids to the liver to undergo a process called gluconeogenesis,

00:50:06.780 we would make glucose out of the muscle. I'd have to do the math on it. I've never done it, but

00:50:11.380 I think it would be just a matter of a week or so until you'd be completely broken down.

00:50:17.940 So while that is happening somewhat, it's more happening because we are not providing new amino

00:50:24.300 acids for the muscle protein synthesis. So we constantly break down muscle and replace it

00:50:30.900 partially with amino acids that we already have break broken off muscle and partially with new

00:50:36.880 amino acids that we're eating. So it's actually a very, the only way you can tease this out,

00:50:42.000 by the way, in research is to do labeled studies. So you give people amino acids that have

00:50:46.360 tracers on them, and then you can distinguish between how much of the muscle protein synthesis

00:50:50.740 is coming from the exogenous amino acids versus the endogenous amino acids,

00:50:56.900 and what you realize is it's actually a pool of both. So I don't know if I'm making sense to the

00:51:01.600 listener. I think you understand what I'm saying. But basically, in a form of starvation, you've taken

00:51:06.100 away half of your amino acid pool, which is the exogenous pool, and you're only able to then rely

00:51:12.720 on the endogenous pool for muscle protein synthesis. And that's why you will experience muscle wasting.

00:51:18.320 But that's far better because at least you're not using muscle to then make glucose via

00:51:25.800 gluconeogenesis. That would be a catastrophic problem. So I guess what your question is, is

00:51:30.140 why hasn't the body figured out a way to undergo muscle protein synthesis without exogenous amino

00:51:37.540 acids? But honestly, I think that's sort of like asking, why do we need food?

00:51:41.880 Mm-hmm. Mm-hmm. So yeah, let's touch this final topic under nutrition of fasting and time-restricted

00:51:50.180 eating, because I know you've experimented a lot with this personally, and many people are interested

00:51:55.480 in this as just a way of reducing caloric intake. I mean, just shrinking the time window in which you

00:52:03.480 eat as a strategy for not living with this, with a toxic surplus of calories. What are your thoughts

00:52:11.680 on this now? And I guess obviously it connects with a certain strand of research on the topic of

00:52:19.340 longevity, where caloric restriction has, I think, across every species in which it's been

00:52:26.420 looked at, shown to be correlated with longevity. How do you think about this now?

00:52:33.060 So I guess I would just sort of put this all in the context of the broader problem, right? So if the

00:52:37.340 problem is, what do you do in the case when an individual is overnourished, which I think is just

00:52:43.480 kind of a technical way to say, they have too much stored energy, and it is exceeding the point

00:52:50.560 of utility, and it's now, that energy is spilling over into other areas and causing problems. So that

00:52:56.140 fat is spilling into the space between their organs, it's getting into their muscles directly, it's

00:53:03.000 getting into their pancreas, and it's toxic, right? It's inflammatory, it increases insulin resistance,

00:53:08.860 which exacerbates the problem, all of these things. The solution to that is reduction of energy input,

00:53:15.740 right? So you have to create a caloric deficit in that situation. Broadly speaking, there are three

00:53:23.300 ways to do that. The first is to directly, day in and day out, minute by minute, think about reducing

00:53:30.620 intake. So that's the example, I think, of what we've just been talking about, right? It's like,

00:53:36.500 okay, I eat 3,000 calories a day, and I need to lose fat, I have to reduce that to 2,500,

00:53:42.980 I'm going to track those macros and count up to 2,500 calories a day. The other way to do it is

00:53:48.900 dietary restriction. Come up with a restrictive diet and focus on excluding as many things as possible.

00:53:56.640 And the more restrictive that diet, the more likely you are to achieve energy imbalance. So if you go on

00:54:03.020 the no lettuce diet, it's not going to be very restrictive, you're not going to lose weight.

00:54:06.500 But if you go on the potato-only diet, you almost assuredly will lose weight.

00:54:11.680 Now, the third strategy is what you're talking about, which is time restriction. Just create

00:54:15.460 a narrow enough window in which to eat, such that at some point, the window becomes narrow

00:54:21.760 enough that you're going to create an energy deficit. So calorie restriction is the direct

00:54:27.620 way to do it. Dietary and time restriction are the indirect ways to do it.

00:54:30.900 I was sort of, I would say, probably six, seven years ago of the view, because we really didn't

00:54:38.380 have the data at the time, that thought there was something beneficial to time restriction

00:54:43.500 beyond the caloric deficit. In other words, I believed that the act of not eating for 18

00:54:52.140 to 20 hours per day in and of itself brought a metabolic benefit independent of the caloric

00:54:59.300 deficit. I would say that that view has been refuted by at least two studies in the past

00:55:08.780 three years, two years, that have, when controlling for intake, demonstrated two things. The first is

00:55:17.460 that actually all of the benefits of time restricted feeding seem to come down to the reduction in

00:55:23.160 calories. But a more important finding has been that there may actually be a downside to time

00:55:30.500 restricted feeding, which is that many people are incapable of consuming sufficient enough protein

00:55:36.220 in that window. And while they do lose weight, they may disproportionately be losing muscle.

00:55:41.900 Interesting. Just to backtrack for a second, so the restriction of specific foods, do you think

00:55:50.360 there's any metabolic magic there where you hear someone who's on an all-meat diet, say, and they're

00:55:58.520 losing weight versus any other strategy? If you're emphasizing one macro over another, do you think

00:56:06.340 it isn't, at the end of the day, just a matter of calories in with respect to, you know, energy

00:56:13.520 balance? Is there metabolism working above the mere caloric physics that accounts for weight loss on

00:56:23.560 certain restricted diets? I don't think so. And I do think now we're clearly, if we go back to the way

00:56:30.400 you posed the questions at the outside of our discussion vis-a-vis nutrition, I think we are clearly in the

00:56:36.120 area where we need to have a lot of humility and just acknowledge we're now speaking in the

00:56:40.420 unknowns. But my intuition, based on the existing body of literature, is that from an energy balance

00:56:47.760 perspective, a calorie is a calorie. So I do not believe that we are, because the only way that it's

00:56:54.680 not is to say you are impacting energy expenditure. So does the body metabolize these calories different

00:57:02.960 from those calories? And the short answer, I guess, is yes, there's a little bit of that. So there's

00:57:07.240 something called the thermogenic effect of food, where we require more energy to energize, to break

00:57:13.300 down protein than we do carbohydrates and fats. And so there is a slight discount metabolically that

00:57:18.660 comes from that. Do I think that that is why a carnivore diet being basically, I don't know, it depends on

00:57:26.260 what kind of meat you consume. But a carnivore diet could easily be one-third protein, two-thirds fat

00:57:31.820 from a macro perspective. Do I think that that explains the profound weight loss that people

00:57:38.020 experience when they experience it on a carnivore diet? I don't think so. I think that really comes

00:57:43.400 down to just reduced intake. But this gets to an important point, right? Which is the point of satiety.

00:57:48.960 And this is the hardest thing to study because, you know, if you're doing a really well-controlled

00:57:55.800 study, you actually want to feed people prescribed amounts of food, thereby ignoring or negating the

00:58:02.600 benefits or disadvantages of a change in satiety. But in the real world, satiety might be the single

00:58:09.620 most important factor in determining long-term compliance, right? I don't believe that most people

00:58:16.620 can exist in a state of perpetual hunger, day in and day out. Clearly some people can, but I don't

00:58:23.100 think that's the norm. And therefore, whatever is at the root of the societal energy imbalance we have

00:58:30.420 must have at its basis something to do with satiety. Unless you believe people are just mindless eating

00:58:37.540 machines. And I'm just not sure I'm ready to fully concede that point yet. So...

00:58:41.740 Do you happen to know what the experience is of people who have taken the caloric restriction

00:58:45.720 principle to a proper extreme? I mean, I know there are food scientists and doctors and a few

00:58:52.880 other people who have decided that the data are in. We know what happens to mice. We know what happens

00:58:59.880 to yeast. If you dial down the calories to the absolute minimum maintenance level, you increase

00:59:09.100 lifespan by an enormous amount. And so there are people walking around, you know, I don't know what

00:59:14.280 their caloric ceiling is, maybe something like 1,500 calories. They're living on a diet that

00:59:21.440 abstemious for years at a stretch. Is their experience one of being perpetually hungry or do

00:59:27.760 they reset and experience kind of a normal level of satiety?

00:59:32.900 I haven't studied them. I know anecdotally a little bit just from... I have, you know, a couple of

00:59:38.780 colleagues who have even gone and spoken at their conferences because there are societies of CR

00:59:43.280 out there. There's caloric restriction societies of people who do exactly what you're describing.

00:59:47.420 You know, I think it's probably closer to 1,800 to 2,000 calories per day. But yes, I think it's an

00:59:53.040 interesting question. I mean, there's two interesting questions there, right? So at least two, right? So

00:59:56.560 one is, what is their subjective state of existence? Are they constantly thinking about food? I will say

01:00:03.060 this. I've definitely spoken to a lot of bodybuilders and that's about the amount of calories they're on

01:00:08.940 during a cutting phase. And Sam, I've never spoken to one of them who hasn't said that they don't want

01:00:16.120 to end their life during that phase. So now again, you could argue, well, they're only doing that for

01:00:21.940 12 weeks and maybe that's not long enough to acclimate. And they're also asking a lot of

01:00:26.840 themselves because they have to exercise during that period of time. So that's not an apples to

01:00:31.280 apples comparison. But that's question one. I think the more important question, in as much as

01:00:35.720 it's academically interesting, is does the draconian step that they're taking translate

01:00:40.560 to an improvement in lifespan and healthspan for the species of interest, which is humans?

01:00:47.140 So everything you said is true, right? We know that yeast and worms and fruit flies and rodents,

01:00:53.260 at least in a laboratory environment, will live longer under CR conditions. But we don't know if

01:00:59.440 that's true for humans who live in the real world. And as I devote probably half a chapter to in the

01:01:05.600 book, when I go through the NIH Wisconsin NIA experiment with rhesus monkeys, it turned out

01:01:12.180 to not even be clear that CR was beneficial there.

01:01:14.760 Yeah. You mentioned alcohol as a fourth macro here. I was going to ask you about it under

01:01:20.940 the heading of lifestyle, but maybe we'll just discuss it here. Maybe it's been 10, 15 years since

01:01:29.800 the emergence of a kind of cottage industry in hopeful articles about the health benefits of

01:01:36.620 alcohol, some of which I think in retrospect were sponsored by the alcohol industry. It's not to say

01:01:44.580 that a conflict of interest always proves that the science is bad, but what do we know about the

01:01:50.620 health impacts of alcohol? And perhaps we can boil it down to kind of a personal punchline. I mean,

01:01:57.040 just how is it that you approach this yourself personally? What have you decided is the risk

01:02:03.940 reward trade-off that you're comfortable with in your own life?

01:02:08.200 Yeah. I mean, I'll just give you my answer for me, but then I can sort of explain it or defend it or

01:02:12.860 explain why it might be illogical. So my view is I do continue to consume alcohol,

01:02:18.040 but I think from a risk standpoint. If you'd like to continue listening to this conversation,

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01:02:48.040 Thank you.

Making Sense - Sam Harris - August 02, 2023

#328 — Health & Longevity

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