In short · Summary by AI
Dr. Scott Kanoski, a USC neurobiologist, explains how GLP-1 hormones and drugs suppress appetite via gut-to-brain vagal signaling, and how diet, including sugar, artificial sweeteners, and heat-processed foods, can affect hippocampal memory in animal models, sometimes via the gut microbiome. He stresses that most evidence is preclinical, that human data are limited, and that a healthy, nutrient-dense diet, exercise, and gut health are the best-supported ways to protect brain function.
- GLP-1 is an incretin hormone released from the intestines after eating and also made in the brainstem; GLP-1 drugs like Ozempic and Wegovy raise levels far above natural ones and mainly suppress appetite, with nausea and vomiting as common side effects.
- Whether newer GLP-1 drugs reach the brain is still unclear; much of their appetite effect likely works through vagus nerve signaling that tells the brain when enough food has been eaten.
- No large clinical trials have tested microdosing GLP-1 drugs, so reports of cognitive or energy benefits remain anecdotal.
- Artificial sweeteners' effects on appetite and metabolism are contested; Kanoski's rodent study found juvenile exposure to stevia, Ace-K, or saccharin was linked to later memory impairments and altered insulin response.
- Memory of recent meals strongly influences later eating, shown in studies where priming people to recall a pizza lunch reduced cookie intake.
- In rodents, a high-sugar or junk-food diet during development impaired hippocampal memory that persisted after switching to healthy food, and a heat-processed high-AGE diet did so too, with a gut bacterium (Lactococcus) linked to rescue.
- Acetylcholine release in the hippocampus rises during eating and stays elevated after meals, possibly helping the brain remember food locations and outcomes, though this response was absent with taste alone.
- Kanoski notes that evidence on food and dementia is largely correlational or from transgenic animal models, and that diets, exercise, and vagus nerve stimulation are being explored, but no proven treatment exists.
- 0:00Sugar and junk food effects
- 1:21Introducing Dr. Kanoski and GLP-1
- 3:18What GLP-1 is and does
- 5:10Side effects and microdosing
- 8:10GLP-1 receptors and brain reach
- 10:37Sponsor break
- 13:30How GLP-1 suppresses hunger
- 19:05Artificial sweeteners debate
- 26:34Memory and food choices
- 34:04Diet, memory, and hippocampus
- 36:49Heat-processed AGE diet study
- 44:10Diet, exercise, and dementia
- 50:22Vagus nerve and Alzheimer's
- 54:59Gut-brain-hippocampus connection
- 59:35Nutrition, processed food, and GLP-1s
- 1:13:26Vagal signaling and acetylcholine
- 1:25:16Gut microbiome and brain health
- 1:43:34Reward, dopamine, and food cravings
- 1:53:25Food industry and policy influence
- 1:57:02Oxytocin and food intake
Sugar and junk food effects
0:00When I started studying how diet impacts neurocognition and memory function, the first model we were studying was a high sugar model. The animals basically had ad libitum access to a sugar solution about the same percentage of calories as a soft drink that we consume, and otherwise they had healthy food and water.
0:19And with this model, the animals show hippocampal-dependent memory deficits when they're older, and these seem to persist later into life even though they're not consuming the sugar anymore. There may be a role for the microbiome. There's some changes in the bacteria in the gut from the sugar model that that may have a functional connection to the memory impairments.
0:38We've also looked at models where the animals are consuming like a total junk food diet. So, we give them chocolate peanut butter cups, ruffled potato chips, rodent high-fat high-sugar diet. They show these memory impairments that last even after you switch them to a healthy diet. >> Welcome to the Huberman Lab Podcast, where we discuss science [music] and science-based tools for everyday life.
1:04>> [music] >> I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Scott Kanoski. Dr. Scott Kanoski is a professor of human and evolutionary biology and neurobiology at the University of Southern California. His lab studies how hunger and memory interact and how the mind and body impact appetite, body weight regulation, food craving and choice.
Introducing Dr. Kanoski and GLP-1
1:28Dr. Kanoski's lab also studies how different types of nutrients impact brain development and brain function later in life. Today we discuss many topics including GLP drugs, how they work, how they impact hunger, and how they impact things like longevity, cognition, and drives in general. As you'll soon see, Dr.
1:46Scott Kanoski is an encyclopedia of useful information about how your brain and body control your relationship to food. And today he shares that knowledge with you in a clear, unbiased, and in many cases a actionable way. It's a conversation about the interactions that occur between your brain and body involving hormones, neurotransmitters, your memory, and your experiences that I'm confident will powerfully inform how you think about food, your food choices, and nutrition in general.
2:13Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost to consumer information about science and science-related tools to the general public. In keeping with that theme, today's episode does include sponsors.
2:29And now for my conversation with Dr. Scott Kanoski. Dr. Scott Kanoski, welcome. >> Thank you. Pleasure to be here. Thanks for the invitation. >> You work on a topic that people experience every day, which is hunger, feeding, and hopefully satiety. But we also have this obesity epidemic, which seems to be partially mitigated by the GLP drugs.
2:53But there's a lot to this whole thing that we call hunger and food and appetite and weight and all of that. And today you'll educate us about all of it. But to start things off, because it's on everybody's mind, what are the GLPs? What is this glucagon-like peptide 1 in its natural form in the body? And then perhaps we can talk about the drugs that increase their levels because either everyone's taking one of these now, coming off of one of these now, thinking about taking one, hates the
What GLP-1 is and does
3:23idea that anyone's taking them, or is has someone that they know is taking one. So, GLPs are here. >> In its natural form, it's an incretin hormone. So, it's secreted from the distal intestines around food ingestion. So, there's a little bit of secretion before the the meal actually starts. Then there's additional secretion during the meal, and this gets into circulation.
3:46There's also a source of GLP-1 that's produced in the brain in the brain stem nucleus tractus solitarius. There's a a population of neurons that make GLP-1 and then extensively send GLP-1 message throughout the brain. >> What do those do? Are they related to hunger as well? >> The peripheral GLP-1 and the central GLP-1 have very similar effects.
4:07So, they they're involved in hunger suppression, but they seem to be operating independently. So, there doesn't seem to be a strong connection between the peripheral GLP-1 physiological system and and the neurons that make GLP-1 in the brain. But, they they do both have appetite suppressing effects. >> But, presumably they're doing other things as well, right?
4:28>> Uh yeah, they're they're helping to regulate blood glucose levels to to stimulate insulin secretion when when there's high levels of glucose present in the blood. In fact, the first application of of GLP-1 based drugs was for diabetes treatment, not for obesity. But, because they also suppress appetite and food intake, which leads to body weight loss, um now they're they're probably more widely known for their for their weight loss capacity in present day.
4:54But, they started off as as diabetes treatment. >> My understanding is that the GLP-1 drugs, so Ozempic, Wegovy, and on and on, that they increase levels of GLP-1 thousandfold more than we ever experience naturally. >> Super physiological, for sure. >> Is there anything known about the potential downside to that?
Side effects and microdosing
5:13Um or upside? >> Well, I mean, most of what we know is is an upside. I mean, the people have been taking GLP-1 based drugs for for over a decade now and and the clinical trials support the efficacy of these drugs. The the There are side effects, nausea and and emesis, emesis being vomiting, uh the most common side effects, and this can lead to discontinuation in a lot of people.
5:37They kind of tolerate it for a certain period of time and then at some point uh discontinue the treatment. Um so, if there's any primary limitation of these drugs, it's trying to to mitigate those side effects and to to have more long-term efficacy beyond the initial weight loss. >> I hear that some people nowadays are taking far less than they are prescribed, so a microdosing, a term borrowed obviously from the psychedelics community, in order to offset some of the um side effects, still get some
6:08appetite suppression, and perhaps also reduce their cost cuz some of these are quite expensive, although many are moving to generic forms. Are there any animal and or human data that you're aware of on microdosing, or is this just a natural experiment that people are doing? >> I'm not aware of any any data on that.
6:23I Placebos are are very effective, so there could be some of that involved. I'm I'm old-fashioned and I like to see the large clinical trials, uh, you know, randomized controlled clinical trials before I I start to believe something's actually working, and we just don't have those studies to date on on microdosing.
6:46>> Seems like they probably won't be done. I mean, there's like not really an incentive for the the drug companies anyway to do it. Like people people taking less, buying less seems like not a good reason to start >> Studies are so expensive to to conduct that it it's unlikely that anyone's doing that right now or that they won't in the near future.
7:02So, we're we're we're kind of left with anecdotal reports in that zone. >> I also hear about some non-weight loss related benefits of the GLPs. In fact, I know people who are of healthy body weight who are taking quote-unquote microdoses or even full doses in order to glean what they claim are some of the benefits on cognition, on energy.
7:21A friend who is diagnosed with chronic fatigue syndrome has been microdosing it, and she loves the effects. She's working with a physician, obviously. She doesn't like the appetite suppression because she's already very lean and a little not underweight, but close to it, so but it speaks to the possibility that taking or elevating levels of GLP-1 could be beneficial for things unrelated to the weight loss.
7:47>> Absolutely. The The receptor for GLP-1 is not exclusively expressed in regions of the brain that control appetite and food intake and and glucose regulation. They're pretty densely expressed throughout the brain. And this is uh including regions that are in the the reward circuitry in the brain, the mesostriatal pathway.
8:05Um there's receptors in the midbrain VTA, the the striatum, nucleus accumbens. One of my favorite brain regions is the hippocampus, which has a lot of GLP-1 receptors. So there's definitely possibility of of applications for these drugs or or different GLP-1 receptor agonist for substance abuse disorder and and potentially even memory disorders and and dementia.
GLP-1 receptors and brain reach
8:30>> Interesting. >> And there's a lot of certainly preclinical data to support that. >> Mhm. >> Um [clears throat] the the clinical data are just ongoing and and starting to come out now. And part of the idea with the applications of GLP-1 receptor agonist to things other than appetite suppression has to do with uh the the capacity of these drugs to get into the brain.
8:51>> Mhm. >> Um this is somewhat of a controversial topic uh in our field of research. The first generation of GLP-1 drugs, so 2005 to 2012, we collected some preclinical evidence in rodents suggesting that uh a large part of the mechanism of action for food intake suppression was through brain action.
9:11So the drugs would get into the brain, activate receptors. Whether these newer generation GLP-1 drugs like Ozempic, Wegovy uh are getting into the brain is less clear. >> Really? >> Again, controversial. So some some studies will mostly preclinical, exclusively preclinical, will tag the the peptides with a fluorescent molecule and try to look at where it accumulates in the brain.
9:35And you see a lot of it clump into the what's called the circumventricular organs where there's no blood-brain barrier protecting the brain from from the circulation. Um so there's a school of thought that these drugs are acting primarily in those circumventricular organs, but those studies are are tricky because fluorescent molecules fade.
9:53And the brain has auto-fluorescent signal. So we we could be missing something with those fluorescent studies. There's um better ways to do this, but it's expensive and complicated where you radio-label the peptides with like carbon 14 and you can actually determine if it's getting into the brain and where.
10:13Those studies, Elizabeth Rhea, Bill Banks, and colleagues at University of Washington are starting to do some of those and it looks like some of the early generation of GLP-1 drugs readily get into the brain and some of the newer ones less clear. Maybe it takes a little bit longer, but the jury's still out.
10:30>> [clears throat] >> Um where where they're getting into the brain is not something we have a clear understanding of at this point. >> I'd like to take a quick break to acknowledge our sponsor, Our Place. Our Place makes my favorite pots, pans, and other cookware. Surprisingly, toxic compounds such as PFASs or forever chemicals are still found in 80% of nonstick pans, as well as utensils, appliances, and countless other kitchen products.
Sponsor break
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13:17Again, that's helixsleep.com/huberman to get up to 27% off. I'm sort of veering us toward reward and reinforcement and memory because even though those are those are topics that come up in the context of drug seeking, of pleasure seeking, and on and on. In the context of food, you know, what we consider rewarding and what we crave are very closely related.
How GLP-1 suppresses hunger
13:42And memory for what we think is going to soothe us is also or satisfy us at the level of food is also seems to be a strong component. I know you've worked in these areas, but as a way of of getting directly there, I'm very curious how the GLP's are actually suppressing hunger. If let's assume that it doesn't get into the brain, that these drugs aren't getting into the brain.
14:05So, if I take a full dose or a microdose of of a GLP-1 drug, what is the sensation that people report? I've I've never actually taken one, so I don't know. >> Okay. So, it but I hear like presumably it's satiety. It but is that mean fullness? Um people will talk about reducing food noise in air quotes.
14:25What is this at the level of biology? >> So, the GLP-1 normal physiological GLP-1 that that we secrete in the body likely has a paracrine mechanism of action. >> Could you describe paracrine? >> Yeah. So, the the vagus nerve innervates our our GI tract. And there's receptors for GLP-1 on the terminal.
14:44So, right where the nerve is contacting the gastrointestinal tract, there's GLP-1 receptors. And this paracrine mechanism is where the GLP-1 is released from these L cells in the intestines and immediately act on nearby receptors that are expressed on on the vagus nerve. So, that's one mechanism through which GLP-1, both the the GLP-1 drugs as well as our physiological GLP-1, may be producing this this feeling of satiation.
15:13So, the vagus nerve communicates a lot of within meal signals that contribute to us stopping eating, right? At some point we get full. This process is called satiation. GLP-1 is a big player in that in that process. Not exclusively through the vagus nerve, but but probably largely through the vagus nerve through this paracrine mode of action.
15:34So, this sends a signal to the brainstem that's the the first site in the brain where the vagus nerve signals to that the animal's had enough food at this point. The the stomach's starting to expand. There's nutrients entering the intestines, and there's uh sort of a symphony of signals that that some act through the vagus nerve, some don't, but eventually lead to this feeling of fullness and meal termination.
15:58And and GLP-1 is one instrument in that symphony. >> Does it turn off the desire for for food as well? Like people will talk about less food noise. And I know many people who are taking these drugs, some of whom are really bullish about also exercising, some who aren't. So, we'll get to that a little later, but um they all talk about reduced food noise, which tells me that before there was noise.
16:24And I don't know because I haven't asked them whether they were aware of that noise. So, I'm trying to imagine having never taken one of these what that noise is. I mean, when I see blueberries, I want to eat them. >> Mhm. >> But when I see bread or a steak or something, I may or may not want to eat them depending on when I ate last, time of day, this kind of thing.
16:43So, what is food noise? >> I am not someone who experiences food noise either. So, it is a bit of a a strange idea to me. Um but I've certainly heard, same as you, anecdotal evidence of people who are taking GLP-1 based drugs and are saying that, "Wow, it really really canceled the food noise." Whether that's based on receptor binding in the brain in higher-order brain regions that that are involved in in memory and cognition, hippocampus, prefrontal cortex, we don't know.
17:16Um again, I think that's that's one of the big gaps in this field is understanding where the drugs are acting. Are they getting to these regions in the brain that that are involved in higher order cognitive processes that may mediate the food noise or is this basically just a gut vagus satiation mechanism.
17:37There's a lot to uncover in that area still. >> What's the evidence that the vagus nerve is crucial for the action of GLP-1s in suppressing hunger? >> If you do a selective lesion to the the sensory vagus nerve as it comes up from the GI tract to the brain and then inject GLP-1, it's not effective in in reducing food intake.
18:00>> Okay. >> The [clears throat] native GLP-1, not a long-acting GLP-1 drug cuz that's a that's a different story. They're in circulation longer, can get into the brain. But if you inject the the short half-life native GLP-1 and the animals have a sensory lesion of the vagus nerve, they don't show the the food intake reduction.
18:17This is work from Wolfgang Langhans in in Zurich and his colleagues. They also knock down using short hairpin RNA interference so you can dial down the expression of GLP-1 on the vagus nerve. And those animals should have a phenotype, right? So they >> They eat more. >> Yeah. They I believe it's larger meals.
18:39>> Got you. So that's all consistent that our body is telling our brain when we've had enough. >> Because of fullness of the gut and the presence of enough nutrients have come in. I was going to get to this later, but I think now's the appropriate time given what you just said. Artificial sweeteners and low-calorie sweeteners are a really big topic online.
19:03There's some in my yerba >> I have some as well. Yeah. >> Stevia, right? So it'd be a low-calorie, quote unquote, natural sweetener, although there's some manufacturing to take it from a plant to like a a drink or a food, but uh different than like sucralose, etc. Um of course. There seems to be three camps.
Artificial sweeteners debate
19:20One is the camp that believes that these things are terrible, that they alter blood glucose, they mess up the microbiome, and that they um maybe even cause brain cancer. I mean, that People have made that argument about aspartame. Um I'm not in that camp, but you you will see people arguing this. The second group seems to be the ones that just say, "Look, this is not It's a non-issue that these are inert in reasonable quantities of consumption."
19:48And then there's a third group, which I think is a quite a few people that kind of wonder, like, "Well, it's {quote} human-made, and like maybe this stuff isn't good. What is the evidence, the the research on consumption of Let's lump them for right now low-calorie artificial sweeteners on development of appetite, development of the brain, development of the system that you work on, and what does it tell us?"
20:17>> This is a very controversial topic. >> Good. >> And I don't think we have definitive answers in any of to support any of those three camps. So, when we consume sweet taste, we have what's called a There's a cephalic phase response, where we're releasing insulin before the nutrients actually get through the GI tract, just from the the simple taste of sugar in the mouth.
20:40Uh so, this is part of our metabolism, right? If you if this was a sugary drink, uh you take a sip, you would have some insulin being released to kind of prepare the body, prepare the physiology for that perturbation in blood glucose levels. And there is some evidence in preclinical animal models that if you disrupt the relationship between sweet taste in the mouth and the caloric consequences of consuming something, that you can have perturbations in in appetite uh in in glucose regulation
21:12kind of like you're tricking the wisdom of the body, right? So, sweet taste means calories are coming. Oh, wait, but now it now it doesn't. And there's not a lot of definitive evidence in humans. There's been randomized clinical trials generally I won't I won't get into all that, but there's no definitive evidence from the clinical trials in humans that it's good for or or bad for weight loss.
21:35There's some evidence in either direction in the preclinical animal model world. There's some evidence that if you give animals habitual exposure to artificial sweeteners that this will will disrupt their capacity to metabolize sweet taste later on and can potentially lead to increased appetite and and weight gain.
21:57>> Interesting. So, this is early life daily exposure to artificial sweeteners. >> Yeah, so we we've done one study in my lab and I can speak more confidently about that. >> Please. >> We had animals who were in the juvenile adolescent stage of development. This is the period of life in which we we've studied a lot in in my laboratory in terms of dietary factors on adult cognitive processes.
22:20And we gave the animals a little bit of artificial sweeteners to consume each day and we kept it within the FDA's acceptable daily intake levels. So, this wasn't necessarily a sledgehammer. It might be something equivalent of six of these a day, something like that. And they consumed it voluntarily. We didn't put it in the drinking water.
22:39This was something they liked. They would just get their daily dose and and carry on. And when the animals were adults, we then tested neurocognitive and metabolic effects of having that exposure during development. So, at this point they're no longer getting the the sweeteners. They're just consuming healthy rodent chow and water.
22:59And in this case we we found that the animals had some memory impairments, which was an unexpected finding. We don't really know the mechanism for that. Um but they also had some glucose regulatory um changes as well. So, if you infuse glucose and and bypass the mouth, there's a insulin spike and the animals that have this exposure showed a larger insulin spike.
23:20They also showed changes in the sweet taste receptor expression on the tongue. Um so, we we found some changes. So, this is not not like whopping sledgehammer effects, but it at least in that model with with rodents consuming artificial sweeteners daily during that developmental stage, there is potentially some impact on on neurocognitive and metaca- metabolic processes when they're adults.
23:47>> Interesting. >> caveat is this is a rodent model. >> Sure. >> Um but we did use three different sweeteners and it didn't seem to matter which one we used. >> Do you recall which those >> Uh yeah, we had stevia, >> Mhm. >> uh Ace-K, >> Mhm. >> and uh saccharin. Saccharin's not one that's common in uh human beverages and foods these days, but it's one that that rodent's like quite a bit.
24:09So, a lot of the rodent model artificial sweetener literature is based on saccharin. >> Mhm. Okay. Thank thanks for clarifying why I always wondered. When I was growing up, saccharin was always on the table in restaurants. Um Sweet'N Low. >> Yeah. I think it's one of them. I don't remember. >> And uh nowadays, stevia, aspartame, and sucralose seem far more common.
24:29Uh I realize it's one study. Thank you for clarifying that it's a preclinical meaning an- animal study. You mentioned before that you can find data that support the use of low-calorie and artificial sweeteners for weight loss as well as studies that contradict that. Is there any work that you're aware of that's going to try and reconcile this because I feel like they are everywhere now.
24:50And I don't demonize them, obviously. Not. I'm drinking one right now. Uh but what's your thought on these? Do you mean do you actively avoid them? I mean you've had a few sips of your drink. Um, so apparently you don't avoid them entirely, but do would you, given the state of the evidence, uh, recommend people take a step back for young kids consuming artificial sweeteners?
25:11Or you you don't have to give a recommendation, but if >> Yeah, I I don't think we have the evidence for for recommendations this point. The literature's all over the place. Um, and and like you were alluding to a a minute ago, I don't think that this is going to be solved anytime soon. There's not going to be a randomized clinical trial that's going to figure this out.
25:29>> Mhm. >> You know, there's some evidence that if you replace habitual sweetened beverage consumption with habitual artificial sweetened beverage consumption that that could have some beneficial effects on weight loss, but again, there's no reliable uh, trend line where you can say this this is good or bad.
25:45So, I don't know which of the three camps that that puts me in, but I consume Coke Zero uh, regularly. >> Yeah, it's good Yeah, it tastes great. >> great. >> It tastes great. Yeah, so I guess then the takeaway in my mind is if people will have to decide whether they want to be in the experimental or the control group given what given what they know.
26:06>> Right. Right. >> Uh, which is kind of the best scenario. People can know that the state of evidence is mixed >> Yeah. >> and somewhat unclear, and then they can place themselves >> you know, driven by preclinical models, so that it's always that [clears throat] that asterisks caveat. >> So, the memory system >> Yeah.
26:22>> in the context of food. I'm fascinated by this because I I happen to love what most people consider healthy foods, maybe to an unhealthy level. But, I realize that some people have this relationship to certain foods where they just accept that it that food, however unhealthy, just needs to be a part of their life in some way.
Memory and food choices
26:42It's kind of interesting. It's kind of how I feel about caffeine. And I wonder if that's memory based. You know, if if there's some association early in life or later in life and the food provides something beyond just comfort, what is the evidence that our memory of a food experience can play an important role in how we frame that food in our behavior?
27:06>> Our memory of eating occasions can have a powerful effect on how much we eat subsequently. Um let me just give you a a couple examples. So, in one study from uh Suzanne Higgs and colleagues, they would have people consume a pizza lunch. And then they would have them come in a few hours later, and then they would prime them to really think about the memory of that pizza lunch in one group.
27:30Uh another group was primed to think about something else. I don't remember exactly what the other experimental condition was, but not that lunch. And there might have been a third control group that would had no priming. And they were given they call them uh biscuits in the UK, but we we call them cookies.
27:44They were given a a biscuit cookie taste test, and they would look at whether that memory priming had an effect on how much they ate at the at the cookie taste test. And if they were primed to remember the lunch they had just consumed, they consumed fewer of these biscuits or cookies. So, in in general, the the memory of recent eating will contribute to eating less at the subsequent eating occasion.
28:09There's another interesting study by Jeff Brunstrom and colleagues, where they had um I think it was tomato soup. So, it was a bowl that had a peristaltic pump that was either putting more soup into the bowl or pulling it out, but the uh the participants were not aware that that was happening. So, they saw a certain volume of of soup, and they consumed the whole bowl, but that could have been a mismatch.
28:34It could be that they're seeing 300 and they're consuming 500 ml, or they're seeing 500, but they're actually pulling the soup out, so they're consuming 300. So, this is a way to manipulate the memory of the meal. How much did you think that you you consumed? >> So it's sort of a magic bowl of soup. I'm continuing to to eat soup but the levels are not going down.
28:55>> They're Yeah, the or that or that or they're going down more than they would just by consuming it. And if you ask them to rate their hunger right after consuming the soup, it didn't matter what they saw. It was based on how much they actually consumed, right? So that that's sort of the the wisdom of the body.
29:09Uh but then a couple hours later that that flips and their hunger ratings are more driven by what they saw, what they think they consumed versus what they actually consumed. >> Interesting. >> Yeah. >> In fact, really to me really interesting because you said like the wisdom of the body piece is great.
29:26Like you eat until till you're full, till you're satiated. But then you said the memory of how much one thought they consumed impacts what you eat >> Uh I don't think this study actually had them eating after that. This was a self-reported hunger rating. >> Got it. >> But you know, presumably [clears throat] it could extend how much you would eat at a subsequent meal.
29:48>> So so much of it seems psychological. >> Yeah. >> They you know, I I think we've all experienced like when we're really really busy. I know there's some people who just seem to eat a lot more during stress and some people like their appetite just shuts off. They forget to eat is what we say, you know, or they're too busy to eat.
30:02Um is there any indication that people bend into one or the other category? Like people that forget to eat or people who eat when stressed? >> So we we study how eating impacts memory systems. >> Mhm. >> Um we mammals when we evolved, we didn't have food readily available, right? You had to compete for for food resources in a very complicated environment.
30:25And a lot of the systems that are traditionally studied for their role in metabolism and appetite and satiation control actually have uh beneficial effects on promoting memories. And our view is that that makes sense because when an animal encountered nutrients, this is a very important event for that animal.
30:48It it would be advantageous to remember what was consumed, what were the consequences of that consumption, can I find this food down the road in the future and trying to remember where where the food was located. So we think that these systems that are responding to nutrients when we eat are actually promoting memory function.
31:12Potentially, this is a system that evolved because of how important it would have been to remember these these eating occasions. These days maybe less so in modern human environments, you can find a cafe, you don't need to remember exactly where everything is, it's relatively easy to get food, but we think that these these satiation systems are very much tuned in into the memory systems in the brain and and our focus has been on the hippocampus.
31:39>> I'm guessing that your students probably ask you this from time to time, which is, you know, when and what and how much should they eat in order to optimize brain function? That dreadful word optimize, not one I particularly like, but I feel like it's highly individual. I'm most focused when I haven't eaten in a while, up to a point, then I'm thinking about food all the time.
31:59I guess that's food noise. And then if I eat something and I don't eat too much, I'm good, but if I eat just a bit too much, then I'm sleepy. Like it seems like energy and focus and memory and learning, I mean all this is it's kind of a narrow bridge to walk. >> Yeah, and as you pointed out, I think there's a lot of individual differences in this.
32:17I always ask my undergraduate class, "How do you guys eat?" You know, I'm I'm traditionally three meals a day, but some of them graze all day, never eat a proper meal, some of them eat one meal a day, and I'd like to assume that many of these individuals sort of fall into what's a sort of a natural eating pattern for them as opposed to being something that's forced on them by their schedule and course demand.
32:38But yeah, I don't think there's one recipe for when should you eat, how many times a day, how much and what's the distance between eating and some kind of mental activity or cognitive demand. >> Yeah, it seems like it's worth doing some self-experimentation for people to you know, I mean the my read of the the data on intermittent fasting is that it's one effective way to lose weight, but people can also lose weight by just eating fewer than maintenance calories across three or even more
33:10meals. Like I think for so many years we got excited that like there was going to be this magic solution to eating and weight maintenance, but >> One of the godfathers of obesity research is George Bray. He was asked and it was a chapter in a book, but he was talking about what's the right diet. I mean this is when this was written it was Atkins diet and all Mediterranean diet and all these different diets and his perspective one that I for the most part share is that the best diet is one
33:38that you can stick to and that's going to be a different approach for for different people. >> Let's talk more about the memory system cuz I'm I'm intrigued by this. So you study not how memory impacts food intake, but how food intake impacts memory. >> I would say we're on both sides of that. >> Okay.
33:53So let's talk about how food impacts memory. If I want my memory system to be as robust as possible, what should I avoid? Right? We can talk about what to do, but what what what clearly should one avoid besides alcohol, head injuries, you know, opiates and methamphetamine. I think we all agree on that those are bad for memory.
Diet, memory, and hippocampus
34:14>> When I started studying how diet impacts neurocognition and memory function, we were working with adult animals and we were using what we refer to as a Western diet. So this is a diet that maybe 35% of calories from fat, uh, coming from sugar, and and a lot of that simple sugar, so, you know, simple sugar carbohydrates, not not complex starch carbohydrates.
34:40And that in animal models can lead to hippocampal-dependent memory impairments. If the animals are on this diet for even even like a week, but generally studies take a a few months. And the hippocampal-dependent memory processes seem to be more susceptible to the negative impacts of these diet than other kinds of memories that don't rely on the hippocampus.
35:01So, the hippocampus is somewhat of a canary in the coal mine. And when I started my lab at here in Los Angeles, um, we were looking at, um, development. So, shifting away from adult models and looking at if you give animals individual components of a diet during the juvenile adolescent phase of development, is there a a longer-term impact on their memory systems?
35:24And the first model we were studying was a high-sugar model. Um, so, the animals basically had ad libitum access to a sugar solution about the same percentage of calories as a as a soft drink that we consume. And otherwise, they had healthy food and water. And with this model, the animals show hippocampal-dependent memory deficits when they're older.
35:51And these seem to persist later into life even though they're not consuming the sugar anymore. So, we we had a few studies with that model. Um, there may be a role for the microbiome. There's some changes in in the bacteria in the gut from the sugar model that that may have a functional connection to the memory impairments.
36:10We've also looked at models where the animals are consuming like a total junk food diet to try to look at at mechanisms. Um, but again, it's the same kind of thing. So, if the animals consume a junk food diet, so, we give them chocolate peanut butter cups, uh, ruffled potato chips, uh, rodent high-fat, high-sugar diet, they show these memory impairments that last even after you switch them to a healthy diet.
36:35That's not to say that we couldn't reverse these memory impairments with some kind of other intervention other than just putting them back on a healthy diet. Um, but at least in rodents and during this developmental window, these kinds of foods have a long-term impact on neurocognition. We have a preprint which is, um, not a peer-reviewed publication yet.
Heat-processed AGE diet study
36:54It's sort of in in the process of becoming that, hopefully someday. Where we were trying to look at food processing from a mechanistic individual variable perspective. So, in food processing is a term we all hear. Ultra-processed foods. The way this is studied in humans is there's this NOVA classification system where you have four different categories of food processing where the ultra-processed food is basically just, you know, shitty food and then uh, the the other end of the extreme is,
37:24you know, perfect raw vegetables and completely unprocessed food. And that's not really mechanistic in terms of what types of processing matter. Cuz food processing, there's a lot of processes that happen to to food in modernized food industry. So, we wanted to try to take it one variable at a time. And we ended up heat treating the food.
37:49So, this is an otherwise healthy food and we baked it for an hour at at a high degree high temperature. And the idea behind this is that it induces something called the Maillard reaction. The Maillard is used in cooking because it enhances the flavor of food. So, this is something that we do for a reason.
38:04Um, this is a chemical reaction that happens depending upon the the nutrient composition, the pH, a lot of factors. But when you heat treat food, you can get this this Maillard reaction. >> Do you want to just describe the the subjective experience of it? Like, if I took a carrot >> Yeah. >> and I just ate it.
38:22Most people know what that tastes like, but my if I took that carrot and I um sliced it and basted it with some uh butter, maybe a little bit of olive oil, some salt, and I stuck it in the oven and um cooked it until it was soft, it'd come out it has almost like a meat like quality to it. Tastes um that um it's a little tangy but savory.
38:44Um is that that's what you're referring to? >> Yeah. Yeah, I mean the the actual flavor components that are result of the Maillard reaction are not not well understood. So we we can't point to certain flavonoids and say that oh this is it's making it taste like this. But in general you know, if you if you bake a casserole, it's going to taste better than before you baked it, right?
39:06>> Yeah. Lord knows. >> So we were trying to to create this chemical reaction in otherwise healthy food. And what happens when you heat this food up is there's chemical byproducts of this process. They're called advanced glycation end products. >> Mhm. >> The acronym is AGE, ages. And these chemicals are actually in our normal physiology.
39:26So we have AGEs circulating. We have receptors for AGEs. It's the RAGE receptor, which is pretty cool name for a receptor. And this system is is generally associated with diabetes and aging and things that we don't think are uh great great things. And when you heat food, depending upon the chemical composition of the food, the temperature, et cetera, you get these AGEs that are introduced into the food itself.
39:54So we're basically looking at if animals consume this AGE-enriched diet, as what we were calling it, during development, is there an impact on on cognitive processes when they're adults? And it it turns out again, just the caveat this is unpublished work, but a preprint, is that we we see memory impairments with this AGE-enriched diet.
40:15Uh we think that there may be a role for the microbiome. There was a population of bacteria that was eliminated through the heat treatment process, and when we reintroduced it to the animals, uh, we were able to reverse these memory impairments. >> When you say memory impairments, could you describe the type of of memory impairment?
40:35And and um, I'm not trying to review your paper, but the are these big effects? I mean, they're obviously statistically significant or you wouldn't be describing them the way you are, but just to frame in our minds, uh, are I mean, are these animals, can they remember where something was placed and come back to it later?
40:50Uh, or is it sort of like getting into challenges with higher order memory? >> We We use a a variety of memory procedures in our lab. Some of the more common ones is we have a a maze actually about the size of this table, where there's holes on on the edge of the maze, and the animals are using visual spatial cues surrounding the maze to remember where things are located.
41:11This is a hippocampal dependent type of spatial learning and memory, and we've done different versions of this, but generally they're trying to remember where food was consumed. So, they crawl into a little tunnel, they eat a meal, and then the next day we ask them do they remember where that tunnel is.
41:26We also do memory tasks that do not involve food, where the animals are placed in an arena, and they have to remember which objects they've seen and which locations before. It's kind of like a, okay, I've seen this object before, but if I haven't seen it in this new location, the animal will preferentially investigate that object.
41:48Um, these are just some of the examples of hippocampal dependent memory tests that we use. Um, in terms of effect size, it That's That's a little bit tricky. I mean, it I'm not saying that it's the equivalent of having a lesion to that brain region, but in some of these memory tests, you you have above chance performance, and then you have not that.
42:11And generally we see that the control treatments will have above chance performance giving us some indication that the animals remember above chance where that food was located or which object they've seen in which location. And with some [snorts] of these diet manipulations the animals are performing basically a chance.
42:26So they're not showing us any evidence that they remember where they got the food from before. >> I'd like to take a quick break and acknowledge our sponsor AG1. I'm excited to share that AG1 has just launched their newest formulation AG1 Pro. AG1 Pro takes the clinically backed AG1 formula which is a blend of vitamins, minerals, probiotics, and adaptogens and adds three important new ingredients: creatine monohydrate, calcium HMB, and zinc carnosine.
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43:31AG1 is giving away a free bottle of omega-3 coenzyme Q10 with your first subscription. Again, go to drinkAG1.com/huberman to get a free bottle of omega-3 coenzyme Q10 with your first AG1 subscription. I don't want to make too much of the findings nor do I want to place you in the position of feeling like you have to, but I'm I'm intrigued by this result because for the last five years or so there's been this unofficial naming of Alzheimer's-like dementias type 3 diabetes which I I drives certain
44:05physicians and neurologists absolutely bonkers because that's not an official diagnosis term, but I think we do on the other hand now well appreciate that diet impacts the brain and that really disrupted metabolic function like chronically elevated insulin due to elevated blood glucose from either food intake or otherwise is problematic for the brain.
Diet, exercise, and dementia
44:32And as a consequence a lot of people in the spheres that I find myself in these days are trying to offset their potential memory loss in the future or even treat the memory loss of their parents or spouse by saying, "Hey, look, at a minimum we can control food intake." Might not be a cure, but you know, some are trying ketogenic diets for instance.
44:54Some are trying to manage blood glucose using metformin or berberine, neither of which I do, I should be clear. Um some are taking even more aggressive measures. And now there's this the discussion about the GOPs is like maybe these will improve longevity of brain function or improve memory. So I don't think it's too much of a leap to just chop it up around this topic and just with the caveat that you're not talking about specific data, what are your thoughts on this?
45:23This notion that maybe some major component of age-related dementia, maybe even Alzheimer's is earlier in life or current food intake related. >> Yeah, I there's pretty strong evidence from prospective studies. I mean, they're correlations, but from prospective studies showing that midlife dietary patterns and metabolic status can be associated with an increased risk of dementia later in life including visceral adiposity.
45:50So the the connections appear to be there. Um in animal models we have transgenic models of of Alzheimer's where animals have gene mutations that lead them to at a later point in their life develop symptoms that are analogous to to human Alzheimer's. And in the preclinical world, there's evidence that consuming a Western diet, so again, a high percentage of calories from fat and simple sugars can exacerbate that pathology, can essentially lead the animals to develop the the symptoms of that Alzheimer's in this
46:28transgenic model earlier than they would if they were consuming a healthy diet. So the the connections are are there. I think it's more prospective than something you can deal with once symptoms arise. I don't think that I think it's it's more important to have a healthy dietary pattern throughout life as opposed to once there's a problem, you know, switching switching at that point.
46:52>> Yeah, so it's sort of the and here I am heavily uh joking {slash} stereotyping sort of like, were you raised in West Los Angeles where everyone's talking about eating healthy all the time. It's like a major topic of focus. Are you from an area like um an area of the country where nutrition isn't prioritized or are you sort of like most people where grew up eating some healthy foods with a mix of some ice cream and pizza and and a little bit of alcohol for most, you know, like I mean, most people are in
47:29this kind of mishmash. And yet we see people with Alzheimer's who are dealing with metabolic dysfunction. And we see people who get Alzheimer's who otherwise look healthy. I mean, I don't see how we can draw a one-to-one correlation >> definitely can't. Yeah. Yeah, there there's correlations, but it's it's not a direct line.
47:49>> It seems these days that people just feel really good talking about the fact that exercise is one of the few things we can do to maintain or improve brain function. I'm not aware of any studies showing that exercise actually makes people smarter. I think it places the body and brain in a position to go learn and get smarter or to hold on to what they've got.
48:11But the question that I can't seem to find an answer to is are the positive effects of exercise on cognition and memory, are they the consequence of improved metabolic function, end of story? Or is there something else there? >> I think the answer's probably both. >> Mhm. >> Um getting back to this this diet model in rodents where we have a a western diet, there is some evidence that exercise can reverse those those memory deficits.
48:37And in part that's happening through changes in the brain. >> Interesting. So for the animals that were fed an an unhealthy diet, let's just call it, and then later are put on a healthy diet and exhibit these long-standing memory deficits, if they exercise they can rescue those deficits. >> That's been shown in in rats, yeah.
48:56>> Interesting. And I recall, I never worked in this area, but that one could um do a memory test where you actually have the animals swim >> Morris water maze. >> So does the exercise have to be related to the memory task itself or can they just run on a wheel and that rescues their memory? >> Well, there's treadmill models and there's wheel running models of exercise in rodents.
49:19One of the reasons that we don't use the the procedure you were talking about is it's it's stressful for the animal. >> Mhm. >> They don't like being thrown into water and and there's a physical demand, you know, to swim and so we we try to avoid that particular task where the the exercise capacity of the animal has any >> Mhm.
49:37>> any input at at all into their performance. >> What we're talking about here sits right at the edge of like where modern brain health and longevity care is at. It's like on the one hand we're talking about like what one eats, whether one exercises, and brain function. But to my knowledge, there's nothing else known about Alzheimer's that tells us to do something specific.
50:04Besides also trying to be a lifelong learner and social connection. Okay, those are critical, too, obviously. But there's tons of stuff it seems that can impair the system. But we actually have in hand very few things besides exercise, quality nutrition, social connection, and an ongoing curiosity to try and maintain brain function.
Vagus nerve and Alzheimer's
50:21I realize this isn't your specific area of focus, but when you look out on the landscape of dementia and Alzheimer's research, preclinical or in humans, what Like you've spent some time in the hippocampus as a researcher. What Like do you think we're going to get to the place where what we call Alzheimer's is is a reflection of a bunch of bad choices plus some genetic preloading of the system, um some susceptibility that might be heightened in some people, or do you think there's really a a disease that
50:52that is independent of all that? >> We haven't come very far in terms of finding effective treatments for Alzheimer's, as I'm sure you know, and one thing that that we've been doing in my lab is to try to think outside of the box and try to think about how the gut might be connect connecting to this pathology as opposed to just looking at what chemical processes are are changing in the brain.
51:16One example of that is we've done some work with with the vagus nerve. I think I I mentioned earlier, and if you lesion the vagus nerve that as it's coming out of the gut, the gastrointestinal innervating components of the nerve, animals show hippocampal-dependent memory impairments. So there's a connection between the the vagus nerve and the hippocampus, and we're interested in trying to understand is that connection relevant to Alzheimer's and dementia pathology.
51:47We don't know yet. There was one study in a population in Taiwan that in the 1980s, maybe a little bit into 90s, people would get vagotomies. So, they would get a truncal vagus nerve lesion for stomach ulcers. That was a somewhat common treatment at the time. >> Medicine loves to start with a sledgehammer.
52:09>> Start with a sledgehammer. >> ulcers, let's give you a vagotomy. Let's cut off the nerve. Let's cut your Let's cut Let's cut the major connection between the brain and body. >> And it was effective for that. >> Yeah. >> Um but what's what's interesting is we have in other countries, not so much the US, they they have impeccable medical records that are kept for decades.
52:25And you can look at, okay, if an individual had a truncal vagotomy for stomach ulcer, what's the probability of developing dementia later on? And there there does seem to be in one small study a positive correlation. So, there may be some risk factor for vagotomy in humans in developing Alzheimer's of some kind of some kind of pathology later on.
52:50We're interested in looking at that in in a different cohort in the Swedish national registry, looking at whether we can kind of dig in a little bit deeper and and find out whether there's any risk in humans of having vagus nerve disruption and Alzheimer's pathology. In animals, we can study this a little bit more directly.
53:12So, we have a transgenic uh Alzheimer's model in a rat. So, they basically develop the the amyloid and tau pathology in the hippocampus in an age-dependent fashion. So, when they're older, pretty pretty decent model as far as these things go. And we have devices that are called vagal nerve stimulation devices.
53:33And we can implant them. Um there's different kinds of VNS devices. The one that we're working with it relies on mechanical distension and contraction of the stomach. >> Mhm. >> So, it's basically sutured to the stomach and it only sends a stimulation electrical stimulation to the nerve when the animals are eating cuz that's when you get the natural expansion and contraction of the stomach.
53:54And we're interested in knowing whether these devices can I don't want to say uh eliminate the Alzheimer's pathology, but potentially improve the outcome in these animals. That's something that that's ongoing. Right now, we have shown that these devices can rescue the memory impairments from an unhealthy diet.
54:13So, we we think there's some kind of functional benefits potentially of vagal nerve stimulation in in models of memory impairment, um but still in the baby stages of of trying to figure that out. >> I can make up a simplistic story in my mind that I'm sure is only partially true if at all, but uh it goes something like this, that the memory systems of the brain, which clearly involve the hippocampus, that's un- not debated, evolved first to keep us alive as opposed to make us remember,
54:47you know, sweet memories from >> Yeah. >> first junior high school dance cuz that was really awesome. I'm just kidding. The uh And that nothing is more fundamental to survival than our ability to keep ourselves nourished and hydrated from day to day so that a huge component of our hippocampal function is is nested in our guts' ability to communicate with our brain, "Hey, these nutrients came in at this timing and this amount in the context of a bunch of other things."
Gut-brain-hippocampus connection
55:17Like, I feel like most neuroscientists would agree and you work on the system. So, I think am I on solid ground there? >> Yeah, I mean, and not just the vagus nerve, either. We said the vagus nerve, but also if you look at at hormones that are involved in appetite and metabolism that they get into the brain, like insulin and ghrelin.
55:37There's a lot of receptors for these hormones in the hippocampus. So that seems to be an alternative pathway through which the hippocampus is getting insight into the the metabolic state of the animal through these circulating humoral signals like leptin is another one that that gets into the brain from circulation.
55:53It's really receiving the the the neural connection from the vagus nerve but also the humoral sort of longer-term energy status connection from these hormones. Um it's similar in many ways to the hypothalamus in terms of the receptors that are expressed there and of course the hypothalamus is the classic feeding center in the brain that's where these AGRP POMC neurons are that I I know you've discussed previously.
56:20That's the traditional feeding center but um we've been for a number of years now been making a case that hey the hippocampus is really important for this too. And [clears throat] feeding, eating, appetite is not a reflexive response. It's very complicated. It's a it's a very complex decision that has to be made when an animal decides whether to forage where to forage, you know, what to eat.
56:44Um these are not not simple behaviors. So it it to me it makes a lot of sense that these complex behaviors are not exclusively being mediated by these brain substrates that are thought to to control more basic homeostatic regulatory processes like the brainstem and hypothalamus but you also have these higher-order inputs that are um very much tuned into this behavior as well.
57:10>> So here's the model I'm sort of simplistic model I'm coming up with in my head that the the hypothalamus has these switches. Find food, eat, >> Yeah. >> stop eating, etc. And we pretty much know what those switches are, the location of the neurons and so on because of the work of you and excellent colleagues in the field.
57:30And then there's this other system that we've been talking about that's a major topic of focus, this body-to-brain vagus-to-hippocampus kind of uh memory system. And it's so interesting that you know, when an animal or a human doesn't eat well, meaning enough macronutrient, sure, most people are getting enough macronutrients at least in this country.
57:52I realize there are exceptions. But But not enough micronutrients, not enough of the essential fatty acids, the vitamins and minerals, the protein relative to the calories they're taking in. When that ratio is skewed in the wrong direction, then the memory system suffers. And so, if we adhere to the adage, use it or lose it, right?
58:10I I kind of getting this picture after all these years in neuroscience that like our brain develops and our parents and we do as well as we can. We don't control everything at the beginning and then we do the as well as we can then we sort of land in this early stage of adulthood of like mid-20s, 30s, and then our goal is to hold on to what we have and improve on it if we can, right?
58:31I mean, that's there's nothing, you know, new about the statement I just made. But that the gut is constantly updating like the body is getting what it needs. Therefore, if you're a neuron in the hippocampus, you can basically stay functional and alive. Otherwise, it sounds like neurons start cashing out.
58:51They might not die entirely, but I mean, this it's a different picture of nutrition that I think is so important. And I think it fits well with what we're learning about dementia and Alzheimer's that there is this blood sugar, but also nutrient-related aspect to it. So, if this system from the body to the brain is is really a core feature of keeping memory online and maybe even making it better without feeling the need to make specific recommendations, how do you personally think about this in the
59:23context of your own food intake? Is it like, okay, eat well but not too much? We know that, but what what do you think about doing that could keep the system robust? Because presumably you want to do that. I realize and I want to be very clear, I'm not asking you to make recommendations, but you're you're more versed in this perhaps than anyone ever I've spoken to about this body-brain connection as it relates to memory and food intake.
Nutrition, processed food, and GLP-1s
59:45So, I'm just curious where your mind is at and bracket it as many times as many caveats as you need to feel comfortable, but I'm curious what and I'm certain many other people are curious. >> I don't make specific recommendations about what people should or shouldn't eat, but I do share our results with with people who have kids who may be thinking about, you know, what what do I feed my kid?
1:00:08And I always make the very important caveat that we're studying rodents. We think are a good model for for memory systems, for for energy metabolism. They are a good model for humans, but it's a very important caveat. That said, there is evidence in humans that supports some of what we're doing in rodents.
1:00:25So, for example, um Dick Stevenson and colleagues did some studies in healthy adults. So, this is undergrad students age approximate and looked at their habitual dietary patterns and then how well they did on hippocampal dependent memory tasks. So, these otherwise healthy adults are not diabetic, really just normal healthy young adults.
1:00:46There was connections between habitual sugar consumption and saturated fatty acid consumption and how well they did on these memory tasks. That's not to say that these can't easily be reversed by consuming a healthier diet, but I do think it it's worth looking into what we know in humans, which is very little because humans um unfortunately aren't that good at reporting what they actually eat.
1:01:09This is a major limitation in doing these kinds of studies with rodents we control of what they eat, we measure it, we have 100% at near 100% accuracy of what they're eating and how much. >> Even with phones nowadays where all they have to do is take a picture. >> improved it. Yeah. >> Is it that they lie or they're just too lazy or they >> I I don't I don't want to say it's that, but I it the it's just not an accurate process to date.
1:01:33I I think having the the apps involved are going to make it a little bit better. There's [clears throat and snorts] caveats with both the animal model research because the rats and and the human research because we don't have a lot of control about what they're eating and how accurate their reporting is.
1:01:46But that said, there there does seem to be evidence in humans to support what we're doing in in rats. So, I I guess it not making precise dietary recommendations, but excess sugar not good. Excess saturated fatty acids not good. >> I wonder why um we've gotten so good at process creating {quote} highly processed or even partially processed food that's designed to taste really, really good.
1:02:19>> Yeah. >> So, people consume more of it independent of its micronutrient and and other value. Why can't we engineer foods that have robust amounts of micronutrients? Like I just think this would be a great thing. And parents want their kids to be healthy and adults want to be healthy. I don't think anyone wants to feel sick.
1:02:38So, >> provided um it was safe, I would love to eat a bowl of blueberries that had like 10 times as many polyphenols. I I would pay more for those blueberries. I don't know how much more. I guess it would kind of depend. But >> it seems that the engineering can be used to push the quality of food in either direction.
1:02:58And I don't understand why this isn't happening. And people will say, "Oh, because they just want you to buy more and more." Okay, that's true, but you can still keep food tasting good, very good in fact. So, why aren't people engineering better, more nutritious food? >> As as you're alluding to, I think the the technology is there.
1:03:15I think it's just the the sea change hasn't happened in terms of where the demand is, where the production is. I'd like to think that a sea change is possible. I mean, the the food industry is over 60% of calories that not maybe not you or I, but like many people consume come from ultra-processed foods in in the US.
1:03:41So, that that's a lot, over 60% and that's a direct product of largely the the food industry producing these kinds of foods. What you're saying sounds great. Like, if there's a sea change in demand or or some other top-down regulatory change in the food industry, yeah, I think I think that's certainly a optimistic perspective.
1:04:01>> people aren't eating enough fruits and vegetables, if you can spike an otherwise unhealthy diet with like two pieces of fruit a day and one vegetable, which is not what, you know, sufficient, but if you overload those with more micronutrients, it just seems so straightforward to do. >> Yeah. I mean, clearly the ultra-processed food industry has hacked the get people to desire more piece as well as the marketing piece to drive it through like cartoons and clever marketing and celebrity marketing and
1:04:29this kind of thing. It just seems obvious to me now. There's also an issue and I'd love your thoughts on this in the in the science field itself. I mean, years ago I used to occasionally come across an article in my journal of neuroscience, which you know, back then I think still now is a respectable journal.
1:04:43Um It would be like, "Blueberry intake correlated with improved cognition in rats." You'd occasionally see that, but I noticed that that kind of work got pushed aside and there seems to be more of an emphasis on finding relationships between the bad stuff and deficits. And I which I think is essential, but I >> And I'm guilty I'm very very much guilty of that, too.
1:05:04>> Well, and and I know I think it's important work, but I feel like loss of function and sort of well, gain of function is It's of a loaded term now, but it just means like things that push things in the potentially in the other direction. >> of the problem with what you're getting at in the preclinical world is a standard rodent diet is a very healthy, right?
1:05:21This is like 10 to 15% of calories from fat, the the carbohydrate source is complex carbohydrates. So we're we're kind of starting with the incredibly healthy baseline. That's not to say there's not more room for looking at certain extracts, supplementation, and whether they can have beneficial effects, but with the standard rodent diet the animals are they're not showing memory impairments on that.
1:05:47Does that make sense? It's sort of easier to make something go wrong than to take an already healthy baseline and and improve upon it. >> Yeah. I mean, I think it's I'm not going to blame science for this, but I feel like in some ways that's what led to this proliferation of like diet books and this is the way to you know, make your brain healthy, this is the way because there was just there was a lot of empty space for people to step in and there didn't need to be any kind of
1:06:12formal structure that they had to obey. So in some sense it's like the landscape was perfect for that. >> Lacking a strong scientific literature in this area, anything goes, right? >> Right. Right, cuz I think by now we all know what we shouldn't do. >> Yeah. And we and most >> many people try not to.
1:06:28I There's also I've been reading about this that with the the advent of the GLPs, we're we are entering perhaps the first time in nearly 75 years where we might start to see thiamine deficiencies and micronutrient deficiencies in a like fully modernized culture because people aren't eating enough and when they are eating they're saying, "Oh, you know, I'll just have like a little bit of this donut, I'll have a little bit of this salad."
1:06:54And you know, salad most places doesn't actually provide that in nutrients. Probably the salads that you make or that you can buy at a really good market, you know, but if you look at like most salads there's like a couple people pieces of iceberg lettuce, like slices of cucumber, tomato. Like that's not That's not what we're talking about when we're talking about getting sufficient fiber and vitamins and minerals, right?
1:07:15So, it could be that we end up with a large population of people who are kind of skinny fat because of the loss of muscle with the GLP's if they're not exercising plus micronutrient deficient. And in terms of hippocampal function, it seems like that would be maybe as bad as as obesity. >> That's not a concern that I have, but part of the reason for that is that people don't take in general, they don't take these GLP-1 drugs for a long period of time.
1:07:45A a majority uh will discontinue treatment within 2 years of starting. >> Because of the side effects or cost? >> Because of the side effects. Another reason for discontinuation in in elderly populations, um there's lean mass loss, which is um I'm not saying that the GLP-1 drugs preferentially uh reduce lean mass.
1:08:04I'm not saying that at all, but there's when you lose weight, you lose both fat and lean mass. So, that's another common use for discontinuation, but people just aren't staying on these drugs long enough to really have I mean, to my knowledge, there's never been micronutrient deficiency issues in any of the clinical trials, which that's most of what we know is from those clinical trials.
1:08:26>> Those are about a year or two as I recall. >> Um but those trials are done in individuals and everything's controlled. >> Mhm. >> Uh the diabetic and or obese. >> Mhm. >> Now, it's it's a whole new world out there where where people can get their hands on these that that don't need them. Um so, I think there are a lot of potential issues with GLP-1 based drug use in lean individuals that we just don't have any grasp on because we haven't We haven't done those clinical trials and probably won't.
1:08:55>> It's almost like a perfect storm like in in a country, the United States, where healthy eating has never been a theme, if I'm honest. >> Yeah. >> You know, it's just not. As a somebody who has a a parent from South America, it's like like the foods they champion are healthy foods. Overabundance of meat, admittedly, in Argentina, but like the idea is like people from Eastern Europe will talk about like their their comfort foods are often very healthy.
1:09:19They have a lot of nutrients in them, like South of France and in Scandinavia. And Americans will roll their eyes. They're like, "Oh, you know, this is it, you know." But it it's a reality that, you know, fried chicken, pizza, cotton candy, hot dogs, apple pie. These are like the American corn. These are the These are the American foods.
1:09:39>> Yeah. >> And so, in the absence of a complete revision of how we think about food and health, I feel like what's needed more than ever is people need to be educated on what to eat to keep their brain healthy. Like it's the one of the most common questions I get. And I end up having to revert to like all the other like exercise, sleep, and all the other stuff, like you can give answers, protein, fruits, vegetables, but my observation is that some people will do that, and many, many
1:10:07people are just they're looking for a pill or a solution, and the GLP seem to have provided a solution, at least to the weight piece. >> Yeah. >> But I'm it doesn't seem that they've provided a solution to the nutrient piece. And that has me concerned, frankly. >> Any weight loss program is should have some nutrient and physical activity components embedded in that program, right?
1:10:28Like simply taking a pill is not the optimal way to to lose weight. And the clinical trials where we have data from, there is nutritional guidelines and and physical activity guidelines embedded within those trials. >> They are having them exercise. >> Uh typi- most of them, yeah. I can't I can't say every single one, but yeah.
1:10:48>> I mean, this is one of the most common sets of questions that I get around the the issues we're talking about today, just incidentally, like uh should I be taking GLPs? Like what about, you know, what should I eat when I'm taking a GLP, you know, can I microdose it, can I go off it, what about the muscle loss, like, you know, it's like, I think this is the going to be a major theme for the next 5 to 10 years.
1:11:09And that's in adults, so to say nothing of the the questions about kids and GLPs. I don't know that there are any data on GLPs drugs in younger populations. I'm sure there are, but I'm not aware of them. >> I'm not deeply familiar with them, but I believe that uh semaglutide may be FDA approved in some populations of teenagers, but I don't remember the specific parameters for that.
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1:12:54>> Let's say that you had a enormous vault of funds to do research on anything in this system or any other system for that matter. Have you ever played that experiment? It's just too painful to think about given today's >> It's it's a little painful to >> Well, well, if if >> Unless you're unless you're offering the vault.
1:13:11>> No, but if you could do any experiment here like didn't have to write a grant to do it and you felt like what would that experiment need like what what do you think is really needed in this field to start to really connect the dots or or just that you think would be a fun and entertaining experiment cuz let's face it scientists like to do experiments also for fun.
Vagal signaling and acetylcholine
1:13:31>> In many ways I'm lucky that we are doing some of those experiments now. Like the example I gave earlier with the the vagus nerve stimulation device in this transgenic Alzheimer's model it that's what I want to be doing. Just try to think about how how the gut might be not just connected to the pathology, but potentially understanding that connection can lead to novel treatments that haven't really been considered or or applied before.
1:13:55We are working on what I would like to be working on which is in some ways it's a a benefit of the the NIH funding model that you have flexibility in what you study. Of course you you put a proposal in and it's reviewed and if you're lucky enough to get the funding, you're you're doing a lot of what you intended to do, but you're you're able to have a little bit of flexibility and oh, we found this unexpected uh result, so we're going to go with this this direction with it.
1:14:20Um so I yeah, I'm very fortunate to be doing what I want to be doing in in the lab these days. >> I'd like to know more about the nature of the signal from the vagus to the hippocampus. I mean, these days most people who've heard of vagus think about it as a calming pathway. They've heard about humming or long exhale breathing which is a different branch of the vagus.
1:14:40So that's that's all still true about calming the body, but my understanding is that the ascending the from the body up to brain, vagal connections are mostly um excitatory. They are mostly about creating more arousal in the brain, not more calm. And I think that confuses a lot of people, but my friends who do neurosurgery tell me that if a patient is, you know, maybe drifting under a bit, you could do vagal stimulation to make them more alert again.
1:15:08So, clearly there's something there. So, I'm curious what the nature of the signal from the gut to the brain is. Is it like we have food, we have nutrients, and that's sort of a bunch of gates. Like if you have enough fatty acids, enough protein, enough um glucose, then three gates have to be open, and then boom, there's a signal.
1:15:28Cuz the the gut >> Yeah. >> I think even for neuroscientists, we tend to forget that the gut doesn't go, "Hey, we just ate this amazing lentil soup." It's just the lentil soup has an effect, and then electrical currents get sent up. And the signals in my mind are kind of crude. And so, is it that then a bunch of excitation is released in the hippocampus, and now you can keep the neurons alive cuz excitation is good for neurons.
1:15:52>> So, the excitation >> like kind of the picture? >> It's not one common signal, right? So, there's there's mechanoreceptors in the stomach, and they're picking up on distension of the stomach when when food is in the stomach, and that that's a vagal signal, but that's distinct from chemoreceptors in the in the intestines.
1:16:09So, you get this um sort of different timing of different signals as the meal is being It's not as if there's just this unified electrical signal that's coming to the brain, and and these um the neurons of the vagus nerve in the nodose ganglia, they express different receptors. They're very heterogeneous.
1:16:27It's They're not all the same kind of neuron responding to the same thing. Mhm. We don't know a lot about you know, what the signal is when it gets to the brainstem, but we do know that there's there's many different things that are contributing to that that signaling pathway. I so, I don't think about it as just one unified "Hey, we've eaten."
1:16:43It's it's very nuanced. >> So, it's a song, not a gong. >> Yeah, exactly. We've identified how this information gets to the hippocampus. So, from the brainstem, there's an input to the medial septum, and then there's a acetylcholine producing neurons in the medial septum are then innervating the hippocampus.
1:17:03So, it's kind of a a three-tier uh pathway through which the gut at least from the vagus this information's getting to the hippocampus. So, acetylcholine is the currency that we've been studying most recently in this gut-brain-hippocampus axis. >> Interesting. Maybe we could drill into that a little bit because we had Michael Kilgard on the podcast who If people haven't seen that, he trained with the Mike Merzenich, kind of like one of the granddaddy modern granddaddies of of
1:17:31adult neuroplasticity and the the data on increasing acetylcholine and the effects on adult plasticity s- to me still, after all these years having spent so much time in that literature, are still kind of jaw-dropping. Like, if you get acetylcholine levels in the brain acutely elevated, you ungate incredible plasticity, which is not to say people should go do use nicotine.
1:17:57And by the way, if you're thinking about using nicotine, folks, if you use nicotine every day, you actually blunt the system. You reset the threshold. This is why it's technically only a cognitive enhancer if used every once in a while. So, like, I just want to put that out there cuz otherwise people will be looking up how to spike the system.
1:18:15>> But, I'm really interested. So, what is the acetylcholine doing for the hippocampus when the gut sends this song of "Hey, we've got these nutrients." It like what is the nature of that signal? >> So, using uh fiber photometry >> Mhm. >> recording, we can look at the activity of neuromodulators like acetylcholine when the animals are awake and doing something like eating a meal.
1:18:40>> Cool. >> And what we found is if you if you track the acetylcholine release into the hippocampus when the animals are actively eating, so they're holding food, they're chewing it, they're swallowing the acetylcholine levels are ramping up when that's happening. >> Mhm. >> And then when they stop, take a break, look around a little bit starts to ramp down.
1:18:59>> Mhm. >> And it kind of jigsaw is like this throughout the meal but one important finding is at the end of the meal the the baseline levels are higher than they were at the beginning. >> Mhm. >> So it's it's like a a staircase in some ways. It's kind of like up, down, up, down, but then eventually it's it's higher.
1:19:15We think that that elevated postprandial level of acetylcholine hippocampus is to allow the animals to remember what what the hell's going on, you know, like just ate this meal, where am I? Can I get back here and do this again? >> That's definitely how I felt when I went to Portland some years ago and I had the best croissant I've ever had in my entire life including it in comparison to France.
1:19:37>> Yeah. >> And I have a memory map of how to find that place assuming it's still there. >> Oh, he is. >> It's it's >> was that good, it's probably still there. >> that good and um I don't consume that many croissants especially not these days but like yeah, there's really something to it like when you get awesome taste, awesome hopefully nutrients also it's like you collect your prior experiences leading to that and I can see why that would be important for survival reasons but I could also see
1:20:05why if this system was hijacked by highly processed foods that um why we're so in trouble nowadays. >> And we we see the the same with the animal eating healthy food versus like a high-fat, high-sugar diet. We see the same acetylcholine profile. >> Mhm. >> So this really does have an analog to like TikTok scrolling versus reading a a chapter in a challenging book or interesting story.
1:20:30>> Yeah, what one thing that you said that made me think of something you mentioned the taste and the nutrient. We don't see this with with taste alone. So if the animals consume stevia, a non-nutritive sweetener, we don't see that the acetylcholine release patterns in the hippocampus. So it is We haven't done it the other way around where we infuse the nutrients without taste.
1:20:48That's something that's in our queue to do in the near future. But I My guess is what is that you need the combination of of taste and post oral nutrient sensing to drive this this vagal acetylcholine signaling the hippocampus. >> How much is being done to really parse the the character of the signal from the body to the brain.
1:21:11You know, the body-brain connection some years ago was considered really hippy-dippy. And now everyone talks about it and the vagus is the superhighway champion of this body-brain thing. We talk about it in the context of breathing, meditation, trauma therapy, psychedelic therapies, learning. >> Mhm.
1:21:30>> Now food intake and I get really excited when there's a repeating theme coming through on this podcast when I sit down with experts like yourself. And I I'm wondering, especially as a person coming from the visual system where we can describe, like okay, when a human sees a bar of light at this orientation of this intensity, we can trace the whole cascade now.
1:21:50That's a sensory system. This is a sensory system. Do we know what the nature of the signals are? >> But unlike the visual system, the interoceptive awareness is a very messy process. You know, it's it's not a precise process. We we can discriminate between I'm extremely hungry or I'm extremely full.
1:22:08But in between that, this is very much unlike the visual system. The these sensory inputs coming in are they're some neural, they're some endocrine. It's like a a a symphony of chaos in some ways. I don't think we're ever going to get to the precise level of at least I mean I shouldn't say ever but in the near future of really understanding the nature of that signal.
1:22:33Um the gestalt of that signal. >> [clears throat] >> One thing I I since I've been talking about the hippocampus a lot, it seems to be where this interoceptive awareness is being processed in the brain. So give you an example, if you take a a human who's densely amnesic who has damage to uh bilateral damage to the medial temporal lobe including the hippocampus.
1:22:57And these individuals have episodic memory impairment. So their their memory span is, you know, between 10, 30, 40 seconds depending upon the individual and you have them eating food, they'll consume a meal. Uh experimenter goes away, comes back with another meal. They'll eat the next meal. And this will happen even a third time.
1:23:18They don't remember eating the meal, but what's always fascinated me about this study and studies like this, uh I think Paul Rozin did the first one, is that if you ask them to rate their hunger and satiety level like on a scale of 0 to 10, they will be a seven out of 10 after eating three meals in a row.
1:23:37So of course they're getting this gut feedback to the brain. They're probably even feeling full, but they don't know how to interpret that signal. The hippocampus is needed to understand what that that signal means. And there's analogous studies in rodents. Like if you do a lesion to the hippocampus, a normal animal learn that a high level of energy restriction is different from not being food restricted.
1:24:02Like they can use that as a cue to predict something's about to happen like a foot shock or a food pellets coming. If you lesion the hippocampus, they they can't do that. So it's um interoceptive agnosia. They seem to be unaware of what this interoceptive signaling means even if they're detecting it at the sensory level, it doesn't doesn't mean what it's supposed to mean.
1:24:22Doesn't allow them to appropriately guide their behavior based on that that signal or symphony of signals to do the appropriate action. >> It seems that some people have so much interoceptive awareness and other people do not. And I I wonder how that relates to uh food intake. You know, we've hosted world-class choreographers on here and athletes.
1:24:46And what I always think of the people who move for a living as being really in tune with their body. And obviously they are, but then there's the rest of the population where we're not really trained to think about how our body feels in the context of daily living. We just kind of like live. >> When it comes to interoceptive awareness of hunger versus fullness, that can be impaired with with a high-fat, high-sugar diet as well.
1:25:11So, that's that's a a process that is plastic and susceptible to what we eat. >> I'm editorializing here again, but I feel like so much of the challenge in being a or the task, rather, of um being healthy um these days, especially in the United States, is trying to figure out like what the fundamental healthy baseline was or is.
Gut microbiome and brain health
1:25:36And trying to get to that because clearly processed foods, but also just the nature of life, like you even said it earlier, like three meals a day for you, some people it's one meal a day, like they all can work, and that's great. That's also part of the challenge is people figuring out what works for them.
1:25:56>> Yeah. >> And we don't really have like one system that our our brain-body connection is optimized for, we're built for. And I'm guessing that's because we went through periods of feast and famine what as we evolved. We need the system to be dynamic. >> Yeah, feast and famine and also physical activity as it relates to our our daily lives.
1:26:16So, you and I are physically active, but here we are sitting down. >> Yeah, we sit and talk for a >> Yeah, we sit and talk a lot, stare at screens. >> To me, it I chuckle sometimes that a lot of what we're doing for health nowadays is about moving the outdoors inside. So, it's like people are there like red light and their gyms and their you we bring plants inside and we you know, and hydrate.
1:26:35What's that? >> Are these real >> They are real. We have We have someone come by and Yeah, they do a really good job taking care of them despite the black walls. >> Yeah. >> They get their light. There's this idea that like there's a proper way that we're trying to get back to. But I like to think about human evolution sort of from where we are now and kind of like it's the front edge leading forward.
1:26:51And it seems again that we're really focused nowadays as a culture as a health culture on trying to figure out like what's the bad stuff that we didn't know was bad. And what's the bad stuff that hijacked us that we didn't realize hijacked us, whether it's highly processed food or whether it's uh uh >> advanced glycation >> end products content or like and we we have always like process of error correction.
1:27:14Like we sort of stumble forward and then we kind of get pulled back. Error correction, keep going. I mean, these are the issues that people really wonder about like what should I eat to keep my memory? I guess the question what shouldn't I eat, what shouldn't I do is far easier to answer. But the omega-3 fatty acids seem to have a pretty decent literature.
1:27:36>> Yeah. >> Uh there's a woman, forgive me, I'm forgetting the name. I will put in the show note caption who is a laboratory up at UC Santa Barbara who's looked at um supplementation with omega-3s during pregnancy and brain size and function in uh human offspring. Um it seems like the omega-3s, the polyphenols, enough protein, it seems like those are critical.
1:27:57>> Yeah, there's a few players that are established. You you've hit on on the main ones, yeah. >> What is your read of the omega-3 literature in terms of uh like if you get Have you done experiments where you give it animals enhanced levels of omega-3? >> We have not done that. No, the in my lab we're focused more on what's what's bad, you know, what what's not optimal for brain development.
1:28:15And the only interventions that we've done is either replace a bacteria population in the gut or to just simply switch to a healthy diet. So, we we I'm aware of of those studies, but we haven't modeled that in in our lab. >> Tell me about the microbiome studies. >> Sure. Um so, we we basically had I'm not a microbiologist, so I just want to leave with that.
1:28:42My background is psychology, so I got into the microbiome um largely by accident and and curiosity about 10 years ago, and we found that in this early life excessive sugar model that we were using in rats years ago, the microbiome was completely different. So, if you do like a principal coordinate analysis, you kind of see the the overall pattern of the bacterial population, the animals getting the sugar were just ex- tremely different.
1:29:09And that could be for a lot of things. It could be from the sugar, or it could be these animals are consuming a lot of their calories from the sugar, so they're getting less fiber and and and less um nutrients that are in the chow. That aside, there's definitely a a change that's happening. And we looked at individual populations, can we correlate the abundance of this population with the animal's memory performance in one of these memory tests that I described earlier?
1:29:37And in one case, we had a population of Parabacteroides that was elevated in the sugar group. I think maybe twofold, enough that it was significant and noticeable, and it was negatively correlated with uh memory performance. So, then we in a separate study, we did an antibiotic treatment to kind of wipe out the bacterial population a little bit, not completely eliminate.
1:29:59And then in that state, we enriched this population into the gut, and the animals showed memory impairments even though they had never consumed sugar. So, we were able to kind of replicate and in many cases the memory impairments were more severe when we enrich this population, but it was enriched maybe eightfold and more than what you were getting from the sugar.
1:30:23So, that's an example where we found a population that seemed to be uh negatively impacting the performance. In the preprint paper that I mentioned earlier where we have this heat-treated age-enriched diet model, we found another population. This one's Lactococcus. It's a lactic acid-producing bacteria that was completely eliminated when we heat-treated the diet.
1:30:44And in this case its performance was positively correlated with memory performance and we were able to rescue the memory impairments by enriching that population. So, these are the kinds of things that we can do with with microbiome studies. There's of course fecal transplant. Um we haven't done much of this, but a lot of people have in the field where you you just transplant the fecal and cecal content from one group of animals to another and in that case you can kind of replicate um some of the
1:31:14behaviors sim- simply by doing that, but in that case you're changing everything. It's not just a single bacterial population. So, we we've looked more at can we identify bacteria that seems to be changed by the diet and correlated with what we're looking at and then can we replicate or reverse something by by putting it in.
1:31:33>> Very cool. I I'm excited to read the preprint and see the paper come to publication, full fruition. Because for a long time when I talk to my colleagues about microbio- who work on the microbiome, I go, "Okay, well, which bacteria are beneficial?" And they go, "Diversity." I go, "I get it. Which ones are most beneficial?"
1:31:51And I realize in this case you did a rescue, so you had a diet, just to summarize in case people miss anything, like although you described it beautifully, a diet that leads to some memory impairments. This is the diet associated with these Maillard uh high-heat reactions. You can rescue some or all of the deficit by replacing a single bacteria.
1:32:09That doesn't mean that increasing that bacteria to super-physiological levels will increase memory linearly, but um so this is offsetting damage. Uh what we call rescue or um used to be called gain of function, but now people run ran with that term in different directions. Not a popular term. >> And I've been just kind of obsessed with like, "Okay, I get it.
1:32:30You like gut microbiome diversity, but which bacteria are the ones that we want?" And it's very, very difficult for anyone, experts in that field, to give me a a clean answer. And I think it's because they just don't know. >> yeah, I think that's it. I don't think there is a clean answer and and part of the reason for that is in 2012, that's when the approximately when the human microbiome project ended.
1:32:53And before that point, we didn't really have an idea about the genetic makeup of the bacterial population in the human gut. Mhm. So, if you go pre-2012, this was not really a a field of research. In fact, if you did a a PubMed hit, so PubMed is the database for biomedical publications, 10 years ago, you might have pulled up 7,000 hits.
1:33:15>> Mhm. >> Today, 250,000. It's just such a new field of biomedical research that we don't we don't have these answers. And yeah, you can find some bacterial populations that as I've just described a few, that seem to be bad in one context or or good in a different context, but then it it can be completely flipped in a different study with a different treatment.
1:33:38>> Mhm. >> And the abundance of one population's going to affect the abundance of you know, hundreds, if not thousands, of other populations. But it's just such a complicated thing. And it's such a new field of research that um I don't think you can say with clarity like, "Here are the good bacteria and here are the bad bacteria.
1:33:58We're not even close to that. >> Yeah, the throwaway answer right now is diversity. It reminds me of the '90s. Well enough to remember, it was like exercise. It was like, "Well, what kind of exercise?" And people said, "Well, weight training isn't good because muscles will turn to fat after you stop."
1:34:15So, cardiovascular exercise. You say, "What form?" And now it's very nuanced. It's like some combination of high-intensity interval training, longer slower training, resistance. Like, now we have answers because there's been 20-plus years or 30-plus years of really good studies and people attacking it seriously.
1:34:30I I've got a family member who right now is taking a very high dose spectrum of antibiotics because they unfortunately had a sepsis-type situation, and they they are very sharp in the mind ordinarily, and they were saying they're really struggling to think. Like, really struggling to think. And so, they're trying to repopulate their gut bacteria with you know, the I'm a big proponent based on Sonnenburg's work of low-sugar fermented foods.
1:34:57So, sauerkraut, kimchi, kefir, you know, all these incredible foods that we know really support the gut microbiome. And so, they're doing that and feeling better, but of course they're destroying their gut microbiome intentionally every day at the same time. And I said, "If you can just get through this period, defeat the infection, you're going to experience such a robust return, but it's a slow system."
1:35:16Like, this isn't the kind of thing where you take a pill and you feel better. The gut microbacteria take As my understanding is it can take weeks or months to really build up a quote-unquote healthy gut microbiome. It's not something you just do overnight or with one meal. >> No, it's not, and it's very plastic dynamic system.
1:35:32Like, it With with some exceptions, there's um Have you heard of C C. diff? >> No. >> So, this is a like a intestinal issue where generally from people in a hospital who are taking antibiotics, antibiotics deplete bacteria, and they'll deplete good and bad bad bacteria. And with C. diff, there's bacteria that normally keep this C-diff in check and with C-diff there's a lot of this bacteria which leads to sort of violent GI distress and can even lead to death.
1:36:04And there's an FDA approved fecal transplant procedure for this specific syndrome. So and I believe it's it's typically with a single transplant >> Amazing. >> is enough to correct this in in a high percentage of individuals. >> Amazing. >> So there there's you know there's a bright future for this. I don't think we're there yet.
1:36:24I mean to my knowledge that's the only FDA approved. >> Mhm. >> There could be others but that's the one I'm aware of. Fecal transplant or targeted bacterial treatment. Um but I think it's just such a new field of research. We're We're definitely in the baby stages of understanding this complex relationship.
1:36:42>> I was a little bit dismayed when I heard early on that your ideal gut microbiome is really a step the upper threshold of that is established in the first three years of life and I thought there's no way my parents got this exactly right. But then we learned that it's a little bit like the way learning and neuroplasticity was discussed.
1:37:00It used to be considered that okay up until your teens early 20s that was the opportunity for wiring the brain a particular way and then it's locked in and we know that that's not true at all. And so there's great plasticity if you will to the system which I find immensely reassuring. >> diet is a huge and probiotics these are are This is how you change the that plasticity.
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1:38:48To learn more, visit functionhealth.com/huberman and use the code Huberman for a $50 credit towards your membership. Again, that's functionhealth.com/huberman. Yeah, I I now think about the gut so differently than I did even a couple of years ago based on conversations like this. Like there's the vagal pathways, which we don't know the time scales they work on, but they can be relatively fast.
1:39:11And then there's the gut microbiome. I I think about the gut like gut health as and its relationship to general health, including brain health, as I need to give my gut my my bacteria the things they need so that they can create the things that my brain and body need. So, it's just like raw materials.
1:39:32>> Mhm. >> Short-chain fatty acids leading to neurotransmitter neuromodulator production like serotonin. I just need to give them what they need. And no, this isn't a a a you know a product endorsement because my observation is that it comes mainly from these low sugar fermented foods, getting enough fiber, um and not stressing too much cuz stress can also impair the gut microbiome.
1:39:54And then getting enough sleep. And so maybe at the end of the day it really is all about supporting the gut microbiome. Guessing there are other things, too. It seems that important. And I think I'm it's only really sinking in for me just how important it is. And as a child of the born in '75, like the '90s were just terrible for this.
1:40:12It was like low fat. I guess there was some emphasis on fiber. >> period as well, yeah. >> Yeah, it was it was the advent of margarines and processed foods really came in. >> Olestra, the the fat substitute. >> I never never had an Olestra chip. I wasn't interested in the the the leakage. Yeah, that's it.
1:40:27That was enough of a barrier. Um We'll move to reinforcement in a moment, but you reminded me of the '90s when the the fen-phen drugs were released, uh fenfluramine. These were supposed to be blockbuster drugs kind of like the GLP-1s, but they were basically stimulants, right? And then people started having heart attacks.
1:40:49Is that what is that what >> Sympathomimetics, yeah. There was some cardiovascular outcomes that uh were unwanted and led to the discontinuation of that. And then the uh the obesity drug market was dormant for many, many years until around 2010 and beyond when we um it wasn't just GLP-1 drugs. There was a few other ones that have kind of fallen out of favor because the GLP-1 drugs are the most effective, but yeah, there was a a period of time and probably largely due to the fen-phen
1:41:17issue where pharmaceutical companies were not interested in developing obesity drugs. But at this point 40 over 40% of US adults are obese. It's hard to >> Over 40%? >> Over 40%. >> That's unbelievable. >> So it's it's uh it's not something that can be ignored now. In the '90s wasn't 40%? >> Yeah. >> Might have been 20 then?
1:41:38>> Yeah. I mean, it's hard for people to remember and I'm not being disparaging of anyone uh but just by recollection like in junior high school or high school, there were probably a few kids in my class that were, you know, visibly quite overweight. Maybe a couple that were a bit overweight, but it was rare.
1:41:58You just didn't see it. >> Yeah. >> And then there would be these television shows about people who were they used to call it's not a kind term, but they would call morbidly obese, you know, and they'd remove them from a building with a crane or something. It'll be like Geraldo would do an episode and so you were aware that it happened, but it was really like these extremes of pathology.
1:42:16Um you just didn't really see very very lots of very very overweight people. >> then type 2 diabetes was called adult-onset diabetes and for reasons you're getting at, it's now not called that because we we get, you know, not high percentage, but a noticeable percentage of of children and and certainly teenagers who develop type 2 diabetes.
1:42:38>> Do you think it was all the highly processed food industry? >> I I I don't want to say anything was all, but it certainly contributed, yeah. >> Mhm. >> And I I didn't I grew up with an ad-lib access to Mountain Dew and uh >> Yeah. >> Yeah, it was just a different time. >> Yeah, school lunches used to be like a sandwich with maybe a bag of chips or a cookie.
1:43:01Like it was one or the other. You had to pick, you know, and soda wasn't really or you could get soda, but it was more like a treat. >> My high school we had an a la carte lunch, so you could buy like a pretzel with nacho cheese dip. You could just buy whatever you wanted. It wasn't There was no standardized here's a healthy meal.
1:43:20>> So, lunches changed so fast, but it looks like the error correction is coming in and hopefully not only in the form of GLP-1s. I mean, one of the reasons I do this podcast is to try and take, you know, showcase serious scientists and clinicians who are like extolling the the virtues of eating well, uh healthily for people of all ages.
Reward, dopamine, and food cravings
1:43:38But, all right, re- I've alluded to it so many times now, it's almost seems like a like I'm teasing it, but here we are. Reward reinforcement, uh enticement. Most people are familiar with the word dopamine. They think of it as pleasure. Most people, thanks to Anna Lembke's book Dopamine Nation, now and the book The Molecule of More, uh which is also excellent, I um in my opinion, that dopamine is about craving, wanting, motivation, >> Mhm.
1:44:03>> um at least as much and probably more than it is about pleasure. >> That's true. Yeah. >> So, in the context of food and food intake and nutrient intake and memory, uh what is the role of the reinforcement pathway? Um what you and I call the mesolimbic reward pathway. >> This system, which should it the most basic description of it would be a a mid-midbrain ventral tegmental area to the nucleus accumbens.
1:44:29So, that's kind of the the classic mesostriatal dopamine projection. And this system is engaged by palatable foods. So, like liquid sucrose, um a high-fat sucrose combination. But, there's a little bit more to it than that. So, you can get the system engaged by a bland-tasting healthy food when an animal's food restricted.
1:44:56Or you can get the the system engaged by by water when an animal's water restricted. Or um even a sodium-deplete animal will show a a dopamine release in this pathway to to sodium consumption. >> [snorts] >> So, it's it's it's very much dependent upon the the animal's state. >> Mhm. >> That said, palatable foods tend to tickle that pathway more so than what we consider to be more healthy and and bland foods.
1:45:24>> Okay. >> And then, [clears throat] of course, um substances of abuse tap into the same system, um, albeit to a different degree, but it it's definitely a common brain currency for for things that we enjoy. >> So, when I hear you say that if we are food restricted or we just haven't we're very hungry, it doesn't have to be fasting, that, um, bland foods can activate the dopamine reward pathway, a reinforcement pathway, excuse me.
1:45:50I'm trying to be even more careful with that language. I wonder whether eating highly palatable foods or or even just sweet foods changes our threshold for what we consider reinforcing and and and rewarding. I try to eat healthy and I notice that I really love and crave blueberries and, uh, I keep mentioning them, but that and other foods, but if I eat healthy foods and I like the way they taste, I find that I crave those foods and I don't tend to crave other foods, presumably because I'm sated.
1:46:22I'm not I'm not excessively hungry. But, is there a way that we can recalibrate this system? It seems there is. >> I think so. I mean, the examples you're saying make make a lot of sense and and individuals who consume a lot of sugar who stop consuming it or or consume much less, they they change their preference, you know, something that they normally would have enjoyed is now too sweet.
1:46:43So, there's a lot of plasticity in terms of what we want to eat and [clears throat] that's based largely on what what we choose to eat. We can we can we can change that. As you've described. Like, you probably weren't craving blueberries when you were 12, maybe. >> I mean, I've always liked fruit, but I liked other stuff, too.
1:47:03And I it's not like I actively avoid ice creams and things like that. But, I but I feel like it's different with food than it is with other reinforcing substances because if somebody who really craves alcohol, who really craves stimulants is deprived of those and then gets a small amount of it, I don't know that they say, "Oh, that just I didn't like that experience."
1:47:25Usually, it's like they really like that experience. But here, it seems we can rewire the the circuitry toward healthier choices, and maybe even to the point where what used to be rewarding is now aversive. And that is how I feel about like the other day I had a sip of a milkshake expecting it to be like delicious.
1:47:42And I was like, "Ah." Like I felt like it was like it was so unbelievably sweet. I felt like I needed a mouth cleanser afterwards. And but there was a time when I really enjoyed a vanilla milkshake. And I bet if I kept drinking that vanilla milkshake, I would start to enjoy it again. Yeah. So, I'm not sure people understand the plasticity of the system.
1:48:04So, is it about the amount of dopamine? Is the Is the threat like the upper threshold set by the most potent things like speed, milkshakes, you know, and banana split? And then if you don't eat those, so you don't consume those or or take those substances, then then you can get to that same high threshold with healthy choices, or is it that the the lower threshold just starts to become the upper threshold?
1:48:31>> I don't think those those careful studies haven't haven't really been done. I mean, there's ways to to measure with PET dopamine a proxy of dopamine binding in the human brain. In animals, we have really nice tools. I mentioned the acetylcholine sensors with fiber photometry. We also use dopamine sensors in my lab.
1:48:48So, we we can record dopamine release again, when the animals are awake and and doing things. We haven't looked at The question you're getting at is how plastic is that system? Um the most uh extreme example of the plasticity of that system is with like a conditioned taste aversion, right? So, if you have an animal who Normally, they consume sucrose, they will get uh dopamine release in that pathway either when exposed to a cue that predicts that sucrose is forthcoming or the actual
1:49:21consumption of the sucrose. But then if you subsequently treat the animal or train the animal that that sucrose consumption is associated with um malaise. >> So inject like a a compound that makes the animals uncomfortable for a few minutes, they attribute that feeling >> to consuming the sucrose. With that kind of training, you will eliminate that dopamine response that you see uh to sucrose.
1:49:45So that's just the most extreme example of the plasticity of this system. >> Humans have tried to use the aversion approach to learning. Basically giving people things that make them feel sick or electrically shocking them to try and rewire everything from uh and these are not ethical studies, but people in the in the old days like the '60s and '70s, they tried to use this to like conversion therapy, right?
1:50:08For for uh sexual orientation. Obviously terrible. Um and fortunately that's illegal uh now, but the but I'm not aware of any like really good studies showing that people will quit smoking if they're like electrically shocked when they pick up a cigarette. My my understanding of these studies, maybe this is not true, but I I was told by somebody who worked in this general area that people uh basically just figure out how to endure the shock.
1:50:34Like that's how rewarding nicotine is. And it I I wonder if there's something going on with the processed food um aspect too because I don't know that people really enjoy those foods. I feel like there is when we hear that they're addictive, I don't know that that's the proper word, but they are impairing people's health, but there seems to be this thing where people get into this kind of like it's not pleasure, it's not a hedonia, but it's this kind of like mind I don't want to say mindless, but there's
1:51:07there's some no man's land of eating and consuming not getting the thing they're looking for. That looks a lot like addiction. That looks like chronic drug use. But it's not like they're getting high off the food. >> Yeah, I mean it's tricky making the the comparisons because yeah, there's a common currency in the brain for substance of abuse and and palatable foods.
1:51:30But you have to eat every day, you know? Like this isn't it's not a a choice. Like you And there's a lot of controversy in in whether there can be an addiction to food and I don't know where I'm going to take a side on either uh either side of that one, but if you look at the the DSM criteria for substance abuse or addiction you can make an argument that there is food addiction based on those criteria, but that doesn't mean that that it's the same thing.
1:51:58>> Yeah, continued use uh continued harm to self or others. Um yeah, inability to stop is a desire to desire to these kinds of things. Late last year, there was a really interesting set of videos that were authenticated. The discussion was should um food stamps be allowed to be used to uh purchase soda?
1:52:19And someone from the um American Heart Association was asked on this panel, "What do you think? Do you think soda is healthy?" And they And they did this incredible but really dismaying, in my in my opinion, tap dance around, "Well, you know, in the context of this and then of this and then I mean they they did everything they could to avoid answering the question, basically.
1:52:40>> Sugar lobby is very powerful. >> Yeah, so >> been historically. >> Are these health associations, like the American Heart Association, are they really like in bed with the sugar lobby? To me, that seems a little bit like a like a movie um that I'm hoping isn't real, but uh in the end they I think they took uh soda off the the list of things that could be purchased with these stamps.
1:52:59I I believe that's the outcome because there was enough social pressure because of social media and this just went wild. But is it really the case that our medical industry is in bed with the processed food industry? I mean, hospitals have some of the worst food in the world. Not Stanford Hospital, but I'm sure not USC Hospital.
1:53:17>> Definitely not USC. Definitely not Kaiser. >> But, but many hospitals you go in and the goal is to get people many calories for very little money and that's understandable why they feel they need to do that. Um, but you just go, "Oh my god, the the nutrition here is just dreadful and this is a hospital."
Food industry and policy influence
1:53:32So, my mind goes like it might be true. But, is it true? Do we know? >> It certainly seems possible. Um, I mean, I've as someone who's researched the negative impacts of sugar consumption, I've I've had a few brushes myself with with the sugar lobby early in my career. >> Have they you've had someone uh detailing your car?
1:53:53This kind of thing? >> to that level, no. >> Okay. All right. >> More of a public-facing statements, but um But, yeah, to the extent that that's influencing our policy, I don't know. >> So, you've had the sugar industry giving you basically. >> Yeah, early early in my career we had a it wasn't even published yet.
1:54:12It was from our early life sugar model that I talked about earlier where um, there was a press release. It wasn't through me trying to get it noticed. It would just got picked up for something and when you get pressed, that's when the sugar lobby, for lack of a better term, may have a forward public statement about that particular study.
1:54:35>> Yeah, exactly. And and generally it's not a a >> That's a great study. Um, kind of comment, but um >> That was a long time ago. >> Yeah. >> Don't worry, you're safe. Actually, by saying this here, you're actually safer now. Also, the world's changed. Nobody Nobody trusts big institutions anymore, especially medical-related institutions, which in many ways it is both good and bad.
1:54:56>> Right. >> Yeah. >> Because you know, you're a you know, god forbid someone has to a you want an excellent surgeon. Like you can't just like you can't just like health and wellness that, you know? But But the and on and on. But it's I do think we've experienced a tide change now. I think the the United States is really um on board that things need to change.
1:55:15In fact, this week we have an episode out with Michael Pollan who's written extensively about the food industry and plants and and health and he actually was very It was really remarkable. I'll provide a link to this that one segment in the caption for anyone who wants to see it. He He really said, he's like, in order to move the health of this country forward there it needs to be a bipartisan effort.
1:55:36Like, the fact that there's an emphasis on improving nutrition, but it really just focused on food dyes and he wasn't so thrilled about that. But then he actually tipped his hat to some of the things that the administration has been doing, but then also pointed out some of the things that they were doing like related to liberating the use of pesticides.
1:55:55That was not good. So, he has a very balanced view of this and I and he and is able to say we need to get away from the politics if we ever want to move forward and be a an actually healthy country. >> I think we still have a long ways to go. >> We do, but there's hope. >> There's hope. And you and I are young enough and our gut microbiomes hopefully are healthy enough that >> we will remember what we need to know moving forward.
1:56:17And And there's this whole other generation of young kids that grew up I'm I'm realizing like thinking about food, nutrition, exercise, sure through the firehose of social media where there's a lot of like bad information, too. But they many many of them think about taking really good care of themselves.
1:56:35And if they grew up in a home where that wasn't a priority, they think about it. And they're helping people and I like to think that things are changing. Before we wrap, I do have a question about oxytocin. >> Yeah. >> Most of us think of oxytocin as the love >> lovey-dovey >> lovey-dovey hormone neuromodulator.
1:56:54Educate us on the role of oxytocin in the context of food intake and nutrition. >> It's been known for quite some time that that oxytocin can reduce appetite and food intake. And through careful studies from Harvey Grill and others, we have identified the brainstem as being the the most robust target of oxytocin signaling to reduce food intake.
Oxytocin and food intake
1:57:20Um so oxytocin is uh released or created in the PVH in the hypothalamus, released into the circulation, but also there's projections from oxytocin producing neurons throughout the brain. And some of those neurons project to directly to the brainstem. And that system seems to be an important system for reducing food intake, mainly through the level of meal size, making meals size smaller.
1:57:46>> [clears throat] >> Increasing satiation. We had a a study recently where we were looking at its role in the hippocampus. And in this case, we found some results that were a little bit surprising, I should say. Um there's a phenomenon in in human humans that rodents also show. It's called the social facilitation of eating.
1:58:06So if you and I are if you're eating alone, you might eat less than if you're eating with a group of people. And if those people are familiar to you, you're going to eat more than if they were unfamiliar. So that's kind of the the um the gist of the phenomenon. And we can model this in rodents. And we found that that phenomenon requires oxytocin signaling in the hippocampus.
1:58:27So if you genetically turn down the signal, um the animals don't show that effect. So this is kind of a different role for oxytocin because under these conditions in this brain region, it's actually promoting intake in a social context. So I think it's it's really complicated, like most things in the brain are.
1:58:47Um but historically, the it's been a unit unidirection uh that oxytocin in the brain reduces food intake. But some of recent findings from our lab and others are saying, "Well, maybe yeah, but it might depend on the the social context, for example, and where the signal's getting to." >> Well, Scott, thank you so much for coming and sharing your mechanistic data.
1:59:08I love that you're highly mechanistic. Offline, I want to know the the literal organization of these cholinergic afferents to the hippocampus cuz I think that's more of a a fisheye auto question, but it's clear that you're studying a really, really important system for the health of all humans, and especially right now with the highly processed food thing, but also the GLP's, and also the this explosion of discoveries on the microbiome, and the positive explosion of people that are
1:59:38interested in doing what they can for their brain and bodily health. You're you're clearly in the right area, evidenced by the fact that I said if you had a vault what of money, what would you study? And you're like, "What I'm doing right now." So, you're clearly in in the right laboratory, which you run.
1:59:53So, thank you thank you for doing the work that you do, and it's not lost on me, and it shouldn't be lost on the audience that you do that work with taxpayer dollars. So, you're working on our behalf for our health. So, and you're very busy. So, thanks for coming here today. Appreciate you. >> Thank you very much.
2:00:06Appreciate it. It's been fun. >> Great. Next time bring your dog. >> I will. >> Awesome. Thank you for joining me for today's discussion with Dr. Scott Kanoski. To learn more about his work, please see the links in the show note caption. If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel.
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2:01:47Thank you once again for joining me for today's discussion with Dr. Scott Kanoski. And last, but certainly not least, thank you for your interest in science. >> [music]
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