Auto-transcribed and lightly edited for readability; speaker labels added by LIV3. Timestamps follow the Libsyn player above. The views expressed are the speakers' own. Individual experiences described in the conversation are anecdotal, are not typical results, and have not been evaluated by the FDA.

00:00 Cold open: what signal are we sending?

00:00Chris:if our only perception of it is either high fructose corn syrup, which is bad, or it's fruit, which is good, it's like there is so much under the surface that really is important to understand. And I think the simplest way to say it is that if the body is using it as a conservation signal, is that what I want to be telling my body? Do I want to be saying like store fat for the winter? Because that's effectively what it's doing. That doesn't sound like most people's goals.

00:25 Welcome to Biohackher

00:25Azra:Hello, and welcome to the Biohackher podcast. I'm Azra Alagic, your host and founder of Biohackher. I'm an integrated nutrition health coach specializing in longevity for women, a health and wellness journalist, writer, corporate consultant, and a biohacking advocate. Biohackher is a space where we can explore ways to optimize our health to live well longer, whether it's through improving our nutrition, exercising, cryotherapy, supplementation, technology, and more. I'll be bringing you information and interviews with the best longevity experts to help you

01:11Azra:understand what you can do to optimize your health, prevent disease, and slow down or even reverse the symptoms of aging by taking control of your unique bio-individuality. Want to know more? Let's dive in. Hey Chris, welcome to the Biohackher podcast. So great to have you here.

01:33 What are we getting wrong about fructose?

01:33Azra:You specialize in metabolism and metabolic resets. Most people think that fructose simply means sugar and fruit. What are we getting wrong about fructose?

01:48Chris:I think that it's been largely ignored and the latest research as of maybe a couple months ago, it seems to be getting closer to reclassifying it as a signal. So it's of course a calorie, but it's less a calorie and more a signal that that particular paper suggested that it regulates metabolic health and disease. So under that lens, suddenly this little half of table sugar that we encounter many, many, many times a day becomes highly relevant.

02:14Azra:So in what way does it become relevant to women in particular, do you think?

02:27Chris:Well, it effectively seems to be sending a conservation signal to your cells. So biochemistry gets complex, we can talk about it, but basically it is telling your mitochondria to slow down. And in doing so, kind of creating a bottleneck where it's like the cell isn't going to be making as much energy and it won't be fueling as much energy, which means that fuel will start building up. Basically the cell tells the body, I'm starving, so go eat more because it's not making energy. And then we go and eat more, but then the cell can't use that energy. So this little bottleneck right at the center of the entire equation becomes highly relevant to even our experience. We have cravings, we're always tired. It does this with inflammation. So then we start feeling sore and then we start gaining weight and the whole problem becomes a loop and we don't know where it's coming from effectively.

03:17 The ancient survival switch and eco mode

03:17Azra:I'm sure a lot of women would relate to that, that it would resonate with them. You describe fructose as an ancient survival switch. What does that actually mean biologically and why would something that once helped humans survive now potentially work against us, do you think?

03:32Chris:I think that's a very important question and I want to be very clear that I don't think that we should villainize fructose. I think we just need to understand it because as you mentioned earlier, it's in fruit and we don't view fruit as bad for us. We largely think of it as good for us, but again, there's nuance there. But effectively, what we need to start thinking about it as is a conservation program and conservation is highly beneficial usually. It's like in our car, if we put our car into eco mode, we get to stretch the resources a little bit further. We do that by down regulating how fast our engine will perform so that it can keep our fuel level a little bit more intact as we try and go the distance. This is arguing that the same process

04:22Chris:is available to us in our body. If you think about animals, they largely would benefit from this because the natural world is a difficult place to live. We've got resources that are suddenly available and suddenly not, whether it's food or water or even oxygen at times. And if we had the ability to enter a conserving state, then it would help us to survive a little longer, even if that just happens to be winter time. Unfortunately, if this program is activated with fructose and we like to eat it because, of course, any animal would benefit from trying to eat a conservation signal, then we've entered into a problem with our modern diet where we're

05:07Chris:activating the signal relentlessly through many, many different nodes throughout the entire modern diet. And suddenly we don't have the ebb and flow that the natural world provides where it's like, this is to help us with scarcity. Suddenly we have nothing but abundance all the time.

05:25 Fasting, a three-day water fast, and energy regulation

05:25Azra:And in the biohacking world, that's something that's often flagged, I think, from a longevity perspective that we tend to eat too much. And so there's a lot of schools of thought out there around intermittent fasting and how that can support metabolic shifts. I've actually just completed a three-day water fast.

05:43Chris:Hey, here we go.

05:44Azra:Yeah, so this is my first day eating again after three-day water fast. What are your thoughts on the role that intermittent fasting can play in metabolic shifts? It's 3 p.m. today and I don't think I've had anything to eat yet.

05:57Chris:I think it's highly beneficial largely. I think there's nuance there and I think we have to think of it from the sense of energy regulation, which is really what fructose is all about too. It's like if we're sending a signal that there's a lot of energy, then our cells are going to try to store it or our body's going to think, hey, I've got a season of plenty. This is great. I should probably take advantage of that. And so when we fast, our body seems to appreciate that largely. It speeds up its metabolism. Our human growth hormone increases. I think it maxes out about three days like you probably are experiencing right now. You probably have this amazing mental clarity and all this going on, right?

06:46Azra:Totally. It's been amazing that the cognitive clarity that I have is next level as a result of the water fast that I've been on. Especially yesterday, I found it. It peaked on day three. So today's day four. I'm eating again, but day three, I was on fire.

07:04Chris:Yeah, that's amazing. You have to be somewhat careful. I mean, I remember there's this one account I read about. Back in the 70s, there was this severely overweight man. I think his name was Anthony Barbieri, if I remember right. And he had a medically supervised fast that lasted 382 days, I believe. It was insane. I'm reading this. I'm like, that can't be right.

07:32Azra:As in nothing?

07:34Chris:Nothing at all. I suppose. No caloric intake, effectively. And amazingly, he did very well. He basically lived the rest of his life at a normal weight and did okay. I imagine coming off of that fast was quite the challenge. I do not recommend that whatsoever. But in contrast, I've also read that Gandhi also fasted, but at a certain point, his body fat was so low that he almost didn't survive like a three-day fast. And so it really seems to activate the usage of fat stores through ketosis. But if you don't have that, then it becomes a problem. But it just kind of shows me that our body is highly resilient. And this is not inherently a bad thing. Not eating is not

08:26Chris:inherently a bad thing. It might actually be a good thing. It might activate certain things that allow us to actually feel great. And I think in many ways, just circling this back to fructose, these are all part of a number of different programs that'll run inside of us that allow us to use resources or spend resources or conserve resources so that we can basically, it's trying to manage our energy levels effectively, like our cellular energy levels.

08:54 Food culture and having your cake too

08:54Azra:And I think we're in a society now or certainly here in Australia where the concept of not eating is not something that's very prevalent in our society. It's something that is relished. It's something that's very much within our common culture, going out, having lots of food together. It's something that's been positioned, I think, socially as something that should be celebrated. And I wonder whether we're overestimating how important food is to us biologically.

09:26Chris:I think that's probably true. On the other hand, I consider myself a foodie. I love good food. And I think what we need to basically get to is a place where we can sort of have our cake and eat it too, where we love life and we love all of the benefits that come with whole foods and using them in creative ways with all the different cultures that have influenced that over the recent decades, but also appreciating that it is a tool for our biology and we have to respect how those tools work. And so then, I don't know, I remember you probably saw Ratatouille years ago and I believe it was the villain Anton Ego. I love that, his line where

10:14Chris:if I don't love it, I don't swallow. And I love that. It's like, it cracks me up. I think that we need to get to a place where we appreciate the good things but we understand their place.

10:25Azra:Yeah. And we don't eat just for the sake of eating either because we don't necessarily

10:31 Endogenous fructose: how the body makes its own

10:31Azra:need to be eating all the time. I suppose it was just around that point out. One of the most surprising parts of your work, I think, is that we don't necessarily have to eat fructose for our bodies to make it. How does endogenous fructose production happen?

10:44Chris:I love this part because it really opens up the entire conversation. So the body makes its own fructose through a pathway called the polyol pathway and effectively what happens there is it uses a spike in glucose levels to convert glucose into sorbitol and then sorbitol into fructose. And so it's starting to appear that the issues that we blame on glucose, like we wear glucose monitors and we watch our glucose levels, that high glucose in itself is not seemingly problematic. And that is starting to be recognized when you inhibit fructose metabolism because the metabolic

11:29Chris:endpoints that we would otherwise attribute to high glucose levels suddenly drop off quite significantly. So it seems that it's, I think of it this way where it's like we don't often blame our car for underperforming because we have too much fuel in the tank. The problem is usually under the hood. It's with the engine. And so by that argument, this is kind of a funny way to think of it. But the problem with the fuel could be when the fuel goes bad because you simply have too much of it. And effectively, that seems to be what's happening. If it's converting into fructose and then the fructose is sending a conserving dial down signal to your engines in your cells, then suddenly that's where you're going to start to see the problem come out. So then we have to start asking how does the body make fructose? Well, it does it with high glucose

12:18Chris:levels. And so then high glycemic carbs become highly relevant to the story. We don't want those glucose spikes. It also does so through dehydration because osmolality allows the body to manufacture fructose as well. It still depends on carbs. It still depends on glucose, but it kind of piggybacks onto that. So then that means that dehydration, high salt levels, or alcohol all contribute as well because they all influence the osmolality of our blood. And so suddenly it starts to look like, hey, we talk about this stuff all the time. The other side of it is that stress signals can do this as well. It's particularly dehydration is a stress, but also hypoxia is a stress. And we're all probably well aware that when we start

13:06Chris:gaining weight, we start getting sleep apnea. Now we don't have sufficient oxygen levels. That's also going to be activating the same endogenous fructose pathway. And suddenly it's like, okay, we've got carbs, we've got salty foods, we've got dehydration, we've got even umami foods play a role in this because I'll get to that later, but it has to do with the uric acid levels. We've got alcohol. We've got all of the things that come with chronic obesity because chronic obesity means you have high glycogen, which makes you dehydrated. You have weight on the chest, which gives you sleep apnea. You've got high glucose levels basically persistently. So suddenly you become a fructose generating machine. And no wonder people get

13:53Chris:locked into a place where even though they're eating really well, they can't break out of that

13:59 A signal, not a villain

13:59Chris:self-perpetuating fructose generation.

14:04Azra:Because everything you've just described is probably relatable to a lot of people out there. There are a lot of people out there that are consuming alcohol, that are experiencing stress, that are consuming carbs. How do we help people understand that this needs to be shifted in order to improve their health moving forward?

14:23Chris:That's what I'm trying to achieve with even a show like this because fructose is largely misunderstood. I mean, we could talk about fruit again, but like if our only perception of it is either high fructose corn syrup, which is bad, or it's fruit, which is good, it's like there is so much under the surface that really is important to understand. And I think the simplest way to say it is that if the body is using it as a conservation signal, is that what I want to be telling my body? Do I want to be saying like store fat for the winter? Because that's effectively what it's doing. That doesn't sound like most people's goals. But it also takes the binary nature out of it. It's not saying that it's villainous, it's just saying that it's a signal. And

15:09Chris:understanding how so many different parts of our environment and our food and our own personal history influence that, it really starts to inform so much of our experience.

15:21Azra:I mean, like I love fruit. And here in Australia, we're very, very fortunate to have access to lots of beautiful fruit. And indeed, here on my farm here, I have mango trees and I know mangoes are high fructose and that's one of my favorite fruit. But I think that this concept that fructose is bad for you, a lot of people would struggle with that because of their love for fruit. But even the concept that the body naturally makes it as well, is probably a bit of a revelation to people. So do you think it's a balance?

15:54Chris:I do. I think that we have entered a period of history where we've hacked our food system to the point where we are overexposed. And there's sort of no going back, like you can't legislate that. You can't say stop doing it. And even trying to think of it as a restriction thing, it's like, okay, I'm not going to eat sugar, I'm not going to drink alcohol, I'm going to watch my hydration levels, I'm going to go low-carb. It's like, okay, same story that we've been talking about encircling for decades, right? So I think that we need a slightly different approach. I think it's important to talk about fruit as well, because fruit is healthy, but it's also so nuanced. So like, do you want to dive into that for two seconds?

16:38 Fruit in context: ripening, juice, dried fruit, and fermentation

16:38Azra:Yeah, let's do that. How do you go?

16:39Chris:Okay, so fruit is different from vegetables, right? Vegetables, they don't really ripen. They just kind of begin and end the same state. The carrot is this big and then it's this big, but it's sort of, it's delicious regardless. Fruit goes through a very different process where initially it starts off as dull and fibrous and fairly unpalatable. It's not sweet, it's bitter, it's hard, it doesn't smell good yet, all of those things. But as it ripens, the plant is basically trying to create a point where it wants animals to come and eat that fruit so that it can distribute its seeds. It's part of its reproduction. And so when the time is right, that fruit transforms. It goes from all of those basically fat burning compounds, full of polyphenols,

17:29Chris:full of fiber, all of that, into replacing much of that with what we now understand is a survival signal. So it ripens with color, with smell, it's soft, it's juicy, it's sweet, of course, and suddenly the animal wants to eat it and sometimes will eat great quantities of it. And that works great for the animal now because it typically will ripen later in the season, usually ahead of winter time or the dry season or whatever it might happen to be. And so it kind of matches the biology of the animal where it's like, I want to conserve. And no wonder we have a preference for that kind of a food then because when the opportunity is available in preparation of winter, that makes a lot of sense too. So then if we were to take

18:16Chris:this to the end state, if you were to juice that fruit, you then remove the fiber from it and you get a stronger bolus of fructose. Or if you were to dry that fruit, you take the water out of it and you again, get a much stronger bolus of fructose. And typically that allows you to eat far more than you would otherwise. Like you can have a juice that will be full of like, I don't know, four apples and otherwise eating four apples in a single seating is much more challenging. Or 15 apricots or what might have ever happened to be, right? And if you take that to the very, very end state where it begins to ferment, then you suddenly see the alcohol argument start to enter the equation where it's like the survival signal spikes to a higher level where it's like, not only do you get the fructose, now you get the dehydration signal with

19:04Chris:it so that hopefully your body will use this urgency moment to try to take advantage of it. And if you look at the literature, the literature basically makes it very clear that the farther you go away from an unripe fruit to a processed fruit, the more metabolic risk appears. Now that is not to say that fruit is bad, rather fruit is very nuanced because it's starting with all of these fat burning signals. It just slowly removes more and more and more of them as we get closer to what is what, like dried fruit is effectively candy at a certain point, right? So the nuance is there. And I think that's super important, especially as you start to see how this kind of argument works in the natural world. There is a natural flow to the purpose of all of

19:51Chris:this, including our taste preferences. Like if we like sweet food, we like salty food, we like savory food, we don't like bitter food, we don't like sour food as much. And it's those few signals that we like that activate the fructose pathways, whether it's through dietary or endogenous, it's the other ones that don't. So suddenly it's like, maybe this is where even our taste preferences are coming from. And that can be so varied as you've just outlined.

20:23 Seasonal eating, keto, and paleo

20:23Azra:And I'm curious about the seasonal concept of eating as well, because is that something that we should be zoning in on, do you think?

20:33Chris:I think that there's a role to play there. I don't know that restriction is a great answer to this. So like saying, I'm not going to eat in the winter. I'm sorry, I'm not going to do that. Right, exactly. So I think that there's a seasonality to this whole thing for sure. But it more seems to be in what local food is available. I mean, the whole locavore movement seems to be kind of onto something. But I hope it's becoming apparent that so many of our good ideas are valid by this. This is just almost saying let's look a level up and try and figure out, this seems to be connecting so many. Think about it, like a ketogenic diet means that you're probably not eating sugar or carbohydrates, which means that whether it's dietary or endogenous fructose, you've kind of avoided the signal. So yeah,

21:21Chris:that makes sense. No wonder it works so well. And so many other things, of course, we're going to try and drink more water. We appreciate the role. We start to see that salt has a role in vascular problems. It kind of explains a different layer of so many things that we already are well informed on.

21:36Azra:What are your thoughts on the paleo diet?

21:42Chris:Much the same. I think that living in such a way is going to be a far cleaner way of avoiding much of the harms of the modern food system. I think so much of the modern food system has altered our exposure to fructose. And you can even trace it through history. Gout we've known about for centuries, but what was that other than access? It's the same as today. They would have access to food and alcohol and all the sugar, which most people didn't have access to. And then they started complaining about metabolic disease like Gout. That makes perfect sense from this perspective. And then if you look at in the 1850s, that's basically when the tariffs on sugar changed and it became widely available. And you can almost look at our consumption of sugar as a

22:30Chris:lagging, a leading indicator of the problems with metabolic health. Like we started reporting challenges with that as our consumption increased. And then you add the last hundred years and we've got supermarkets that allow us to eat whatever we want. We've got processed foods that have layered on high glycemic carbs and salt and of course sugar. And then we invented high fructose corn syrup, which basically is a higher bioavailability version of sugar. It's liquid, it's a higher concentration of fructose, and it's just more of the same thing. So it's like we've increasingly layered and stressed ourselves out because we could. We liked eating all of those things. And because they were delicious, we all think it's a great

23:17Chris:thing, but we didn't really understand the consequences. And I still think we're just starting to.

23:21 Ultra-processed foods and why restrictive diets are hard to sustain

23:21Azra:Yeah, I agree with you. And I think processed foods has significantly contributed to the state of metabolic health issues in a lot of countries. When we look at ultra-processed foods in particular, they are so high in sugar or fructose or hidden corn syrups and so on. If we were to just eliminate ultra-processed foods, do you think that there'd be a better balance metabolically for a lot of people by just doing that?

23:50Chris:Absolutely. I think that there's so many different ways that we can hit this with strategy. The challenge is that the body seems, I think that what it makes sense to pay attention to is how your body feels. Because if you do have cravings, like not just preference, no one's going to take away our preference for how delicious a piece of fruit is. But what's interesting is that many people that go on a highly restrictive sugar-free diet actually find that their preference for sweetness changes, where it's like they can't really palate added sugar that well, but fruit suddenly is amazing. So it's like there's this calibration that seems to happen, and that's even been studied a little bit. But I think that trying to accomplish all of this with a restrictive diet becomes highly challenging.

24:38Azra:Well, I think a lot of people don't find it sustainable because of a variety of reasons. There are so many variables that would contribute to a person's inability to sustain that sort of approach, I suppose. But it comes down to, I think, mindset and motivation as well, plus the educational understanding of how this can contribute to somebody's health and whether that's a care factor for them as well. Some people are quite happy to just continue with bad habits.

25:05 Taste versus craving: what the rodent research separated

25:05Chris:I do agree, but I mean, we know very well that restrictive diets don't work. I think that there's an interesting piece of the research that's important to understand why, because many people that attempt a restrictive diet are highly disciplined. They work great at their jobs. They go to the gym every morning, blah, blah, blah. They exercise discipline in many areas of their life, but suddenly they can't avoid grabbing a cookie when it tempts them, right? Some of the research has separated our taste preferences from a biological craving. And it's interesting to kind of understand how that works. So like in rodent models, one track removed the taste receptors so they couldn't really taste sweet, but they still

25:52Chris:consumed fructose. They still consumed sugary sources because there was something deeper that was driving it. And that source seems to be coming from primarily the liver or this entire signal. On the other hand, they also did a different track that inhibited fructokinase, so fructose metabolism, but left the taste receptors on. And they also ate fructose, but not as much. So it was like, there's like a taste driver that's just the sweet reward thing, but there's also a deeper effectively energy alarm that seems to be happening where it's like the body is saying or the cells are saying, I don't have enough energy, go get more, because we're almost in an emergency state here. And so that seems to be what we're identifying

26:40Chris:as food noise and cravings. And like when people are going on GLP-1s and suddenly that starts backing off a little bit, it's like, hey, I don't have to like reach for the cereal at nine o'clock at night. Like I'm okay. And so that kind of separation seems to be very fascinating where it's like we do have an underlying driver that's a biological thing that we probably won't be able to fight very well. You can't really fight biology.

27:07 Fructokinase, ATP, and uric acid inside the cell

27:07Azra:No, I think it's a really interesting point. I just want to take a little step back. Fructokinase, can you explain what that is and what happens in the cell once fructose metabolism is switched on?

27:23Chris:Certainly. So fructose, whether it's made by the body or it's eaten, is metabolized using fructokinase. It's also known as ketohexokinase or KHK. And what that does is it basically in the process of metabolizing fructose in your cells, it grabs a phosphate out of ATP and effectively degrades ATP into eventually uric acid. And so within the cell, now you have an inflammatory signal of uric acid that will also eventually restructure your mitochondria into a lower performance state. So it actually causes mitochondrial fission so that the mitochondria don't work as well. It doesn't kill the cell. It basically just downshifts it because if it were to kill the cell, then you would basically

28:12Chris:start running into like a self-consuming problem where your muscle is going to start degrading all these different things. But rather what it does by just kind of downshifting it is it eventually sends a signal to the brain that we need to eat more. And so then that's what we do. And that allows kind of this entire loop to start happening where it's like we eat more, we are exposed to more fructose, we pull another phosphate out of the pool, and suddenly it just compounds the problem little by little by little, which also explains why fructose, the research on fructose can seem contradictory. Like you can have a study that says like a high amount of fructose with 30 days didn't really do much, but then you do a high amount of fructose over six months. And it's like everything goes wrong. It's like it is a major problem. And it seems to be that it's because

29:01Chris:it requires time and pressure where it's like eventually it will cause the system to start losing its ability to recover. It's sort of like this time between challenges concept where it's like I can handle a challenge, great. And then I'm going to have a time to recover and I can handle another challenge. But if those challenges come in quick succession, you start losing your ability to respond and recover from each challenge and it slowly degrades. And that seems to be what's happening with fructose.

29:37 A healthy diet with the pathway still switched on

29:37Azra:Could someone be eating what they consider a relatively healthy diet, but still have that pathway chronically activated?

29:42Chris:It does seem to, but it sort of depends on what you classify it as. Because if you see it like a slow drip, then yeah, it can be very challenging. Sugar is everywhere, and it's really hard to avoid. And it seems to be even when we do really avoid it, people kind of experience it with social pressure where I'm fine midweek, but then I go out on the weekend and it's like everyone's having a drink and we're all eating whatever we want. And you get a hard time if you're the one being the poor sport and not participating. Exactly. And so it's weird, even within families, it's hard to live that way. There's many communities that try to hardline sugar and say, I'm not going to eat it. And the problems come quickly because it seems like it's an addiction

30:32Chris:where within like two or three days, suddenly it's like, I can't handle it. I have to have it. And because it acts that way, we kind of just see sugar as addictive, but that doesn't seem to be

30:43 Sugar as fuel plus signal: why cutting it can raise cravings at first

30:43Chris:actually how it's working. If you think of it this way, if sugar is part glucose, which is fuel and part fructose, which is signal, then when you remove both, which is sugar, I am telling my cell to speed up because I'm removing the fructose and I'm taking away its fuel. And so no wonder we get even worse cravings in the short term because we're speeding up the system while taking away what it needs. And so I would suggest that if someone wants to take like a sugar free diet as one of the possible ways of handling this, then increase your complex carbohydrates in the short term. Try to compensate for the glucose you're pulling out of the system. It'll make that little adjustment time easier to balance. And then later, once your cells are kind

31:30Chris:of like you've got that homeostasis again where things are running fast and you can start pulling back on the glucose and maybe a low carb diet will help you to lose weight too. But anyway,

31:40Azra:It's a good thought because a lot of people struggle with trying to avoid sugar. It's so prevalent in so many of our foods and hidden in so many different types of foods like sauces and so on. But we do tend to like it as we've discussed here as well today. And I think that a lot of people struggle to avoid it. So trying to find that balance, as you've just described, and finding an alternative or replacement. I know that's what I've done is that I've tried to find alternatives to having sugar. So opting for things like honey or maple syrup or something like that instead. But that has fruit taste in it as well, right? So it's like, are you replacing one bad thing for another? I suppose there's no

32:25Azra:question to you when we do something like that.

32:31Chris:It does. It does happen. I mean, you took like this from a different perspective. Many people with an alcohol dependency. It's well documented that when they go dry, they start eating sugar like crazy. And when you start thinking of this as like an alarm system with multiple redundancies, because that's what a good alarm system should do, it makes a lot of sense where it's like, it's not going to let you break out of this very easily. It's trying to help you. It's trying to help you conserve for the winter effectively. And so then it becomes a very big challenge. And moderation in itself, it's hard to get there, but I highly recommend it. I think every little bit helps.

33:12 Perimenopause, menopause, estrogen, and uric acid

33:12Azra:What about women in perimenopause and menopause? We often see increasing visceral fat and worsening insulin sensitivity at that age. Do we know whether fructose metabolism plays a role or is the evidence not there yet?

33:29Chris:I think there's some evidence. I think it could use more research. When women get to that age with their estrogen levels dropping in particular, what they lose is the advantage that estrogen levels have on uric acid clearance. And as we already discussed, uric acid plays a very big role in this because it's basically uric acid that is causing an inflammation signal that's downshifting your mitochondria. So in the same way as umami foods that are high in uric acid are also problematic without necessarily the fructose part being part of the equation, it seems to be very relevant where it's like because we can't clear that uric acid out as much, we start losing the advantage that would come from that clearance where you keep your cells at a higher efficiency level. And so it makes a lot of sense

34:19Chris:why women would start struggling with that as their hormones start shifting.

34:23Azra:Yeah, I did wonder about it because I'm wondering whether fructose metabolism might explain why some women are saying I'm eating exactly the same thing as what I used to, and yet I'm still gaining weight around my middle section of my body. I just wonder, I mean, I know that hormones play a role but...

34:44Chris:Yeah, of course. But it does seem that the hormone influence on how the body responds to that food, the signal that comes from the food, does seem highly relevant for sure.

34:55 Cellular energy as a common thread in chronic disease

34:55Azra:You also argue that cellular energy may be a common thread running through chronic disease. How strong is the evidence for that idea and where does hypothesis and established science actually begin?

35:09Chris:There is quite a lot of evidence that suggests it plays a very big role. We appreciate that mitochondria play a big role, that word is becoming more and more known in biohacker circles. And it's interesting because there is research that suggests an energetic model of metabolic dysfunction as well. I believe it was Dr. Wallace that hypothesized on that about 11 years ago or so or something like that. Anyway, it does seem to be there as a central focus of a preclinical state of metabolic dysfunction. So whether it's Alzheimer's disease, there's certainly evidence of mitochondrial dysfunction and effectively low cellular energy. There's inflammation, there's insulin resistance,

35:54Chris:that's all there. The same kind of signature appears in fatty liver, in vascular dysfunction, in whether it's like cognitive, metabolic, vascular, or even cancer models, energy plays a really big role. Even in cancer, cancer is an interesting one because cancer is so highly unique. Basically, every cancer has its own genetic signature which is why it's so hard to target. But Dr. Warburg, like 100 years ago or so, basically identified that cellular energy shifts in cancer cells. And it's like one of the only things that we can identify and recognize that makes cancer cells different from other cells. And so it's like, that's interesting. Why would energy change in cancer cells? And so if energy becomes this common

36:45Chris:question across metabolic disease, it starts begging the question of what's dragging it? Because inflammation will drag it, so it becomes part of the equation, but then what's causing inflammation? Or insulin resistance is part of this, but is insulin resistance the adaptation or the cause? And I would argue it's an adaptation. Because if you think about a bottlenecked cell where the energy conversion is not happening, if you were to shove more and more energy through that funnel, it would bust the whole thing. And that's accurate because if we were to insert too much substrate into the cell, the cell would die. And so is insulin resistance pushing back and saying, I can't handle it anymore? There's too much trying to go on here anyway? That kind of logic starts to hold up. And then at the center of all of this

37:34Chris:seems to be energy. It's like if energy is failing in the cell, that's fine for a single cell. It's okay for a few. But as we start scaling it to the entire tissue, it's no wonder that maybe the fragile energy, these like poorly inefficient cells are going to start seeing organ dysfunction and system dysfunction.

37:59Azra:Yeah. And so the role that fructose plays in contributing to chronic disease, I know that when we look at alternative treatments for cancer patients, there are a number of clinics out there that promote a real clean eating diet. So really cutting out fructose, cutting out sugar, obviously cutting out processed foods, keeping it super, super clean. What role do you think that fructose plays in contributing to those chronic diseases? Is it something that needs to be examined more, do you think?

38:26Chris:The research suggests it's a causal role. That doesn't mean it's the only cause. But if fructose is directly causing this state of poor cellular energy, of inflammation, of effectively causing insulin resistance, then it plays a very big role. And to me it's like no wonder that regardless of any of those dysfunctions, the doctors will almost universally say cutting sugar would probably be a good idea. This seems to identify why that plays such a big role and why clean eating, which might mean lowering your high glycemic carbs and lowering all the endogenous ways that fructose might play a role in this. All of those seem to become relevant to the conversation, just slightly below the surface.

39:10 Do continuous glucose monitors help?

39:10Azra:I'd like to explore some tactical approaches that we can help support our listeners if they are curious and wanting to maybe look at trying to shift their metabolism and trying to improve their diet. We've mentioned continuous glucose monitors, so CGMs. What role do you think they play in managing glucose levels and really in terms of looking at what fructose does within the body? Can CGM support that or not?

39:41Chris:I think it's a good signal, but I think it's a bit of a muddy one. I don't think we have enough data saying this level of glucose will cause fructose metabolism to occur. I think it's just in general we don't want to be spiking our glucose too hard. Like a big plate of pasta, we sort of already know that that's not probably going to be good for me. I think if we are careful, if we're moderate how we eat carbs, if we're trying to eat fiber and protein first to kind of slow the glucose spike, I think that all of that does help for sure. I think what is likely to be the first step if we're taking a dietary approach is to try to moderate the intake of sugar. In the short term, I would say try to increase your

40:27Chris:complex carbohydrates just to compensate for the alarm signal that's going to happen when you try to do that. I think that that will make the pressure a lot easier. But if you look at this, I'd say that a keto diet is the most natural way to plug this hole. If you do that, then you're probably not going to eat sugar and you're probably going to restrict your carbs. But that becomes problematic because trying to say live in ketosis for the rest of your life, we're very close to it, is a very big ask. So that's why I say like, this is the dietary conversation and I think there's so many layers to it. We got to drink more water. We got to make sure our sleep quality is good. There's so many layers. It sort of becomes the same conversation that we've had for many, many years. Do all of it, whatever you can. But I also believe that

41:17Chris:there's a slightly more direct way to give you a bit of assistance in this path. And that's where my focus has turned over the last few years because looking at the enzymes behind how fructose does its work becomes highly interesting. If there's so many pathways to activate it, but this is the one thing that does it, then that's the one thing I want to try to see if we can influence.

41:41 Fructokinase as the linchpin

41:41Azra:And so flush that out a bit more for us. What's that direct way that you're alluding to there?

41:55Chris:So the enzyme that allows fructose to slow the cell is fructokinase. And we've talked about it briefly already. That is the linchpin in the whole system. If we don't have fructokinase, then we aren't pulling a phosphate out of the pool. We aren't allowing our ATP regeneration to collapse. We aren't stressing our mitochondria with inflammation. It's sort of where all of this hinges on. And so the cool thing is there that you can have fructose coming from any one of those inputs and all of that complexity of dietary approach. And if this is where you're safeguarding, then hopefully you're taking pressure off the system in general. And so then fructokinase has kind of become my focus because it seems to be the biggest lever that we can hopefully try to figure out how to influence.

42:41 Pharmaceutical trials and the botanical path

42:41Azra:So is there a way to inhibit that yet?

42:49Chris:The research on this is interesting. And there are trials that have been done by Pfizer and Eli Lilly and others. And they're finding highly interesting results from it. So there are pharmaceuticals on tracks here. I don't know when they're going to come. And I know that there's a lot of business decisions that will come from that kind of a thing. So my interest in doing this was I think the research is super fascinating. I didn't know how to action it for myself. I was like, okay, this is all interesting stuff. I think this looks like the key, but I don't know what to do with it. And so it was a couple of years actually later that I found in the research, of course, these labs also do assays on a number of botanicals to see what compounds are worth researching to take a pharmaceutical track. And so I discovered that there was one in particular

43:35Chris:that has good evidence in mouse models and in petri dishes of human tissue, like liver cells in particular. And it's also on the shelf. And I was like, hey, I can buy that from Amazon. And I started experimenting with it. And the cool part was it started to mirror what people experience when they take a really, really strong, restrictive approach to controlling all of this with like a sugar-free diet and cutting all the signals that way. And I was like, wow, that's really cool. And that was already, I don't know, three or four years ago when we're seeing more and more and more and more confirmation, not only in all of this amazing science around fructose, but in that this application of trying to influence these pathways seems to be

44:27Chris:valid and at least worth some self-experimentation.

44:36 GLP-1s, peptides, and the engine problem

44:36Azra:So are we talking GLP1s here? Are we talking peptides? I know retatrutide is one that's...

44:42Chris:None of them. No, no, no, it's a completely different class, but it's interesting because I think those are all fantastic. I don't want to take away from them whatsoever. But what's interesting about them, even with Reta, people are reporting drop-in cravings, but not a simultaneous change in energy. And so it begs the question where are we influencing the metabolic engine or just a further downstream state of it where we're basically turning the hunger signal off? And I think that also explains why people on those peptides consistently regain the weight when they come off of them. It's very well-documented. Basically, it's like my argument with the logic there is that

45:28Chris:we are reducing the amount of fuel in the tank, which takes pressure off the system, but we're not actually changing the engine problem, the gummed up eco mode conserving engine. And so what this is suggesting is if that engine problem is coming from exposure to fructose metabolism and we interrupt fructose metabolism, then we should feel a simultaneous change in energy and cravings because the energy restores and the cell stops signaling an emergency state so that the cravings turn off. And the cool thing is that when people take a restrictive sugar-free diet, they report that typically around three weeks, three or four. It's really consistent. It also

46:16Chris:depends on your own metabolic state, like how fast you personally recover. So there's variability, obviously, but it's fairly consistent that as soon as the cellular energy seems to recover, it's available phosphate and can then start processing energy faster with a mitochondria, then that entire signal starts dialing back. The other cool part is that people that are using luteolin to inhibit as a potential fructokinase inhibitor, they report the same thing. Even on the same timeline, sometimes even sooner. So it's like if the argument is that fructose is causing that state, if we can buffer against it, if we can push back on that whatsoever,

47:02Chris:then maybe we'll be able to see a simultaneous change in energy and cravings. That's pretty cool. It's turning out.

47:08 What is luteolin?

47:08Azra:Yeah. For those that don't understand what it is, can you explain what luteolin is?

47:12Chris:So luteolin is a plant flavonoid. It's found in parsley and thyme and celery leaves and green peppers and wild artichokes and a whole many, many foods that we eat. We've been eating it for thousands of years. We've used it as a yellow dye in antiquity. It is just, it's been quietly part of the human experience for a very long time. That being said, it seems to be highly safe as well. Most polyphenols are very well tolerated. Quercetin is probably one of the bigger ones right now and most people recognize, hey, it's really good for me. I take it every day. So that's the classification. It's just not highly known because it hasn't been highly

47:57Chris:bioavailable. So it doesn't easily survive the gut. And because of that, even though it's really well researched in the laboratory, it's typically been through injection. And the potential in the lab, if you're to look it up on PubMed, it's crazy. It's like, yeah, it has benefits for cognition, for inflammation, for metabolic disease, for hormone regulation. It's like the whole thing. It's like, okay, that's interesting. So the challenge has been how do we make it bioavailable? And in recent couple years, liposomal formulations seem to solve that largely, where now it can survive the digestive tract and be delivered to the cells where it needs to do its good work. And so it's kind of exciting because it's like, it does seem to be pulling on

48:47Chris:this unified system of perhaps how our cells are losing their little energy capacity.

48:55 Is it safe to slow this pathway? Essential fructosuria

48:55Azra:It's fascinating. I wonder though, were they interfering with metabolic pathways, whether there's a downside to that? Because-

49:03Chris:That's a very good question.

49:04Azra:We don't know really, do we?

49:06Chris:Not too well. However, we're seeing good results from those pharmaceutical trials, like basically no adverse effects. And there's a very interesting natural experiment, because there are humans that don't have that enzyme. They're really hard to find. But basically, they're identified by having a weird amount of fructose in their urine. And so the condition is called essential fructosuria. And effectively, it only shows up on a blood test, or on a urine test, I should say. And these people are almost entirely recognized for having no metabolic issues, which is really interesting because it's like, okay, so if their bodies are not creating this conservation signal, then maybe the cascading

49:51Chris:effect on cellular energy and then the pathological endpoints of chronic disease are just not occurring because it's protecting them against metabolic disease. They are very typically skinny, they have a little bit more hard time gaining weight, and they don't get sick. It's like, that's interesting. And of course, luteolin in particular, it just seems to be healthy. No one seems to be reporting any issues as far as using it as a supplement for decades, even though it's not overly popular. We need more research on it. But it does seem that the body has alternative ways of ridding the body of fructose, which is why those people would pee it out. They basically just don't process it, which is really kind of cool. It also suggests that the side effect, if we were to call it that,

50:39Chris:is that you'll have a harder time surviving famine. And it's like, I think I'm okay. I think I'll be good that way, right? Because essentially, that's the process that it seems to be doing is it's allowing the body to enter a conserving state. And it's like, okay, that could be bad if I was an animal that had to deal with the challenges of the natural world, but I don't live in that world anymore. And so it does seem to be like, unless we suddenly find ourselves in a post-apocalyptic situation where we need a survival signal, then we're okay for now.

51:17 Three everyday signals worth paying attention to

51:17Azra:Well, and certainly in history, there have been situations where there have been famines across the world. So it's not like it could never happen. If a woman listening wants to know whether fructose metabolism could be affecting her, what biomarker should she be testing,

51:37Chris:I think the better biomarkers are the ones that we can observe at this moment. I think that uric acid will play a role in that. I think high glucose levels are important, all the things we've already talked about. But I think what is probably the most useful signal today is, do I have cravings? Am I fatigued? And do I feel inflamed? Because those are all core parts of this entire process, where it's like, if I need a nap every afternoon, that's not normal. I mean, it sort of is, but it shouldn't be.

52:05Azra:Some cultures it is, I suppose.

52:08Chris:Sure, but some people feel like they get exhausted, right? And we eat, and then an hour later, we're hungry again. That's not normal either. It shouldn't be. You just sent a signal to your body that fuel is available. So why is it screaming at you that it's not? So I think that those experiential things are probably the strongest indicator that this is worth looking at. If you have cravings, if you feel inflamed and chronic pain, and if you have low energy levels, all of those things are a pretty strong light that maybe this is worth looking at.

52:46 What we may look back on in ten years

52:46Azra:And finally, what's one piece of conventional metabolic health advice you think we'll look back on in 10 years' time and realize that we had it fundamentally wrong?

52:54Chris:I do believe understanding this is a big one. I think that our understanding of fructose has been largely missing. And I think that the researchers behind this probably will eventually be found to deserve Nobel Prizes, because it's going to fundamentally shift our understanding of metabolism. And I do think that interventions with fructokinase will eventually be seen as probably the best way to push back against the modern diet. I don't think that we're going to be taking en masse, like a removal of sugar from our diet. Our grandma loves to bake us a pie. We can't blame this all on big corporations that are trying to make profits off of us. I think that it's just part of who we are. It's part of our taste preferences. It's biological.

53:42Chris:And so I think that finding a way to kind of have our cake and eat it too, in a way, will be the most natural way to push back where it's like I can moderate in the way that feels natural and I'll be protected in the meantime. And so again, that's why I'm focused on this particular enzyme. I think that it holds the most promise. And ultimately, that's why we've developed a supplement that has a compound that most people have never heard of. Like luteolin is not something that people have heard of, but it seems to have the most promise for pulling on something so fundamentally interesting to our biology.

54:19 Where to find Chris and LIV3

54:19Azra:Look, it's been absolutely fascinating to do a deep dive with you into all things fructose. If people want to learn more, where can they get ahold of you? Or indeed, if people can order the supplement, where could they order it from?

54:34Chris:Yeah, our website is liv3health.com. And we developed, we only have one product. It's a supplement that is designed as closely as we can at this moment, I'll say, to hopefully influence these pathways. It does not treat disease. It couldn't. It's a supplement. But we hope that it can help to buffer against fructose metabolism. And it's exciting to see the reports coming from our customers about how much it mirrors what a really restrictive lifestyle can do. So it's liv3health.com. My YouTube channel is just starting out, but it's called The Fructose Model. And because this has such potential with this web across

55:20Chris:everything with metabolism, it's a really fascinating kind of thing to dive into. I talk about every sort of metabolic issue and dysfunction and our observational experience on there to hopefully try to uncover as much of this as we can. It's quite a puzzle and it's really cool to kind of see how it's resolving.

55:42Azra:Yeah, it will be really interesting to see how you go with it all. Chris, thanks so much. It was an absolute delight to have a chat to you today.

55:47Chris:Thank you. It was really great to be here. Really appreciate it.

55:54 Closing

55:54Azra:Well, that's a wrap for today's podcast. Thank you for tuning in. And if you'd like to learn more about biohacking, go ahead and sign up on my website at www.biohack-her.com to get a free copy of my five top biohacks to get you kick started. While you're there, you can also check out my blog page for more tips on biohacking. If you'd like to subscribe to this podcast, you can do so on Apple, Spotify, and Google Play. Let us know if there's anyone you'd like us to talk to in particular and we'll endeavor to get them on the podcast. Until next time, remember to live well longer.