A (4:40)

Thanks Stephanie. I'm so happy to be here. It's going to be a great show.

B (4:44)

It is. My audience very much knows that my opinion on fasting has evolved over time. I used to be very much like we all should be, fasting all the time and then, you know, kind of forgetting that I was a woman and some of the sex specific differences that exist between men and women and have evolved that opinion to, to softening, a softening of my, on my view, around fasting especially. And we'll get into the benefits for muscle preservation, bone preservation, et cetera. However, we do want to still acknowledge that there are, there are benefits to fasting. I just think that what often happens with women is that we go too hard, too much, too fast, and then there can be sort of a detrimental, you know, a maladaptive response, let's say, in, in the female body. So to start off our conversation, let's actually talk about the biology of fasting. So what is actually happening from a, you know, we can, we can talk about this in general terms for my light roast Betties, like, what's happening? And then we can get dark roast as well. For all of my Betties are like, tell me the mechanism. What is a sirtuin? Tell me about mtor, what's ampk? So let's talk about what, what is happening with fasting? Why are we, why did we even start paying attention to fasting in the first place?

A (6:01)

Yeah, absolutely. And it's a great question. I, of course, nerd out about fasting. This is literally what I spent my entire PhD in nutritional biochemistry studying. And it is exactly that same question. Fasting seems to have all of these really, really amazing impacts. So it is one of the few ways that we know of to reliably extend lifespan in animal models. But even beyond that, it's also been shown in both animal models and in clinical studies to help treat, prevent or delay most major diseases. And it does all of that without actually adding anything into the system. Right. So it's not this superfood or this wonder drug that's activating all these great pathways and all these great benefits. But somehow fasting is turning on this what I call longevity bio program that we all kind of have inside of us, but isn't ordinarily active. So what is happening in the body during a fast is essentially it's going completely from exogenous energy sources, food that we would be taking in, digesting, metabolizing, and using that for energy, to then relying completely on endogenous energy sources. So the fuel that we already have inside of our bodies, our stored carbohydrates, our stored protein, our stored fat. When that happens, you get this shift over from our typical metabolism, which is more of like a glucose carbohydrate state metabolism, over into a fat and ketone, ketone body production metabolism. So you get a holistic shift in the types of nutrients our cells have available to them and the types of Nutrients that they're actually utilizing to survive. And when you have that shift, you have this big change in how cells actually respond, how they function, and kind of that activation of that survival mode. So when we think about what that survival mode actually is and what its purpose is, you know, we can go back to kind of evolutionary states, right? So in a normal fed state, that's basically an evolutionary signal to our bodies that this is a great environment like rich in nutrients. We should be focusing on trying to get to the next generation, right? So you're going to be focusing more on reproduction, fertility, and less about survival, longevity maintenance. So in those states, our cells kind of like to run dirty, so to speak. So they're going to be producing all of the proteins that they want. They're going to be replicating all the DNA that they want. They're going to be, you know, producing as much waste mitochondrial damage as they want because they're not super concerned about what happens to this generation of cells. They're just like, ah, we have plenty of nutrients. If something goes wrong, I can just make a new one. So it's kind of a less effective way for the cells to run where they kind of produce more damage, produce more inflammation, are a bit more overreactive to things because they have the res to be able to do that in a fasting state. All of that gets flipped on its head. So instead of this big, you know, nutritional repletion state, instead your cells are getting this signal where it's like, oh, there's no food around. This would actually be a very bad place to have kids and raise the next generation, because if we can't even get enough nutrients, how are we going to take care of a kid at the same time? So you get this shift over to really survival, longevity maintenance, repair. A lot of these metabolic efficiency pathways that are happening to conserve energy. So you get processes being activated, like autophagy, right, which is our cellular recycling and cleanup protogram, where we're going to break down dysfunctional proteins, we're going to break down dysfunctional organelles, turn them into their constitutive parts, and then use those parts to build new parts that are more functional. So you're conserving energy that way, switching over from the glucose to the lip lipid and the ketone metabolism like we were talking about. You know, you're Getting activation of NAD and Sirtuins, you're downregulating MTOR, you're upregulating AMBK, you're upregulating PPARS, you're upregulating NRF2. So better protection against stress, which is like the antioxidant defenses of the body get up regulated, the cellular response elements get up regulated, membrane stability goes up. So this holistic shift from we don't really care about ourselves, we can just make a new one to all of a sudden, oh, okay. If something goes wrong, we don't have the energy to make a new cell. So we have to protect and maintain the ones we have to the best of our ability for as long as possible. And ultimately that's the longevity game, right? It's not about, you know, constant turnover and recycling and renewal of cells, but actually about maintenance, repair and protection of the ones that we already have. So that's kind of, you know, the big nutshell of what fasting is doing and why it's doing it.

B (11:04)

And what are some of the. Maybe let's explore as we're diving into this, some of the lengths of time of fasts as well, because there's a lot of, at least there was a lot of discussion around, well, there's time restricted eating, which is like a daily circadian style fast. There is pushing your fasting or your eating window rather later in the day so that you're prolonging the fast. There's an alternate, there's an. And every other day there's the 5, 2, there's the OMAD, there's 24, 36, 72. So talk to us about some of the different lengths of fasts and in terms of everything that you just described, when you're talking about the maintenance and the repair and the renewal, how long do what is happening at each of those stages and do we know if there's an ideal length of time for a fast in terms of maybe metabolites or upregulation or downregulation of pathways that we are going to see optimal, like why, why we're doing the fast in the first place is I'm assuming to reduce inflammation and as you said, like extend lifespan and improve metabolic processes. What is the point in time that we want to be aiming for where we're going to see the, you know, it's like the area under the curve, like we're seeing that sort of bell curve. Like we're not overdoing it, we're not underdoing it and we're getting maximal benefit from the time.

A (12:24)

Yeah, that's a great question and it's one that we are still really trying to figure out in the fasting research space. But there have been A lot of studies on, you know, various states, kind of like not an entirely through line of like from you know, hour zero all the way to five days of fasting, what happens at each individual hour. Right. But we do know some things. So basically the different styles of fasting, the most popular one is kind of that 168 style, right? Where you have a 16 hour fast with an 8 hour eating window. That really became popular probably around, you know, 2015, something like that. And you know, very rapidly it spread throughout the health and wellness space. There were a lot of studies that were done on it consequently. But from a biochemical perspective, a 16 hour fast is actually not long enough to really get you into a biological state of fasting. So like when we were talking about before that switch over from glucose metabolism to fat and ketone metabolism, that's only going to happen in your body after you have depleted your glycogen stores. So your stored carbohydrates, your stored glucose that you have in your body, that needs to be totally run through before your body will start moving over to fat metabolism and ketone body production as its primary fuel source. And that's not gonna happen until around 20 to 24 hours of zero food intake. That's depending on how, how much glycogen you had in your system before. Right. But that's the general rule of thumb. So to really get even into the early stages of, you know, this metabolic switch, these biochemical fasting processes, you know, you really have to fast for much longer than people think that they do. The 16:8 style of fasting has been shown in a lot of clinical studies to have great effects on, you know, transient metabolic markers. So like, you know, improving glucose levels, improving cholesterol levels, improving triglyceride levels, but nothing super significant at the cellular state and definitely not the things that we usually associate with fasting like autophagy and stem cell regeneration and these anti inflammatory effects and these longevity promoting effects like that. So from 16, 8 then we kind of go to, you know, a 24 hour fast, right? One meal a day or omad, another very common type of fasting and actually the type of fasting that I still do. And so that is, you know, you're getting to the point of glycogen depletion, you're getting to those initial stages of fasting and you're also minimizing the amount of time that you're spending in the postprandial state, which is essentially the post eating state, which, you know, has a lot of downsides associated with it because you're throwing a lot of metabolic chaos in the system. You have dietary inflammation, you have whatever's going on in your like intestines, bloating, all that, all that fun stuff and just really minimizing that and maximizing your kind of like rest recovery homeostasis state while getting into the actual biochemical fasting state. After that we kind of go to alternate day fasting that is eating normally one day fasting the next day, eating normally the next day, fasting the next day, rinse and repeat basically forever. This is the type of fasting that's been shown in the majority of studies to actually promote lifespan and promote it pretty significantly anywhere between you know, 60 or sorry, 30 to 60%. And that is independent of caloric restriction. So there is something really interesting that's specific to fasting that happens where even if you don't reduce overall calories, you still get this lifespan extension from just delaying when you're eating. And so that's really the state where we, you know, you're entering into the fasting state. You're in the fasting state long enough to activate these longevity like benefits, the autophagy, the anti inflammatory effects, the metabolic efficiency effects, the cardioprotective effects, all that fun stuff. And that's where we have the best data for lifespan extension. Then beyond that you kind of get into the multi day fasts. Multi day fasts are you know, even deeper state autophagy. This is where we see things that are like really great for cancer prevention, chemotherapy, things like that. We also see immune cell regeneration at around the 72 hour fasting mark. So that's basically as far as our knowledge goes right now, is that number one, unfortunately we have to go way deeper into fasting to get some of these benefits that we associate with fasting than you know, like a 16, 8 fast would normally give us. And we don't really have too much knowledge from a like peer review publication standpoint of what really happens in these like deeper stages of fasting where you go past around three or five days.

B (17:17)

Yeah and I would, you know, the 16, eight, I would sort of classify it as maybe it's good for glycemic control, it's good for weight, you know, it's good, you know, if you were, it's very difficult to get in all of your calories, let's say specifically protein, which I know we'll talk about in an eight hour eating window. Let's say it's very difficult for most people in one or two or Even three meals to sort of fit that all in because you're just so full. And I think that the 24 to 36 hour range, this is sort of where you said, this is where we're gonna start seeing ketone, that you know, the ketones are being produced as the primary fuel source. You've exhausted the stored glycogen somewhere around 2000 calories, ish, I guess in the liver. And then we start moving into fat oxidation as well. I would actually love to, I would love for you to maybe map out almost like the fasting signature, like what are, when we're looking at that 36 hour, let's say if that's sort of the gold standard, which is, I mean I'm going to tell you right now, that's a long time to fast.

A (18:18)

Exactly.

B (18:19)

And I actually want to talk about this from the lens of females and we'll get there in just a moment. But what are some of the specific like at the 36 hour mark, what are we seeing in terms of like the meta, like the plasma metabolites that are, that are, that are doing some of the things that you said like the immune system reprogramming, the ma. We'll talk about macrophages, I know we haven't gotten it in there quite yet, but some of the tissue level, like what are we seeing in the plasma at that 36 hour mark that is telling us, okay, this is working, this is reducing inflammation, this is doing all the things that you were describing.

A (18:50)

Yeah, absolutely. So this is what I spent my entire PhD doing is studying a 36 hour fast. So there is indeed a, a metabolic signature that happens when you get into the true biochemical fasting state. And there you're just gonna see, you're gonna see a really big drop in circulating glucose levels, you're gonna see a big rise in ketone levels. That's you know, classic standard like we were talking about before. We've also done comprehensive metabolomics looking at a before and after, from just like an overnight fast to a 36 hour fasted state. And we found that there were over 300 significantly elevated metabolites in a 36 hour fasted state versus a baseline state. And that those many of those 300 molecules were also uniquely upregulated during fasting. So those are kind of these like bioactive biochemical signals that are essentially telling the cells to kind of run the fasting program or run the longevity bio program that we were talking about before. And so those can be anti inflammatory molecules like endocannabinoids PEA and oea, sea ala, they can be more like autophagy promoters like spermidine. There's going to be a big increase in, you know, circulating NAD levels, cellular NAD levels, a lot of the NAD precursors as well. Nicotinamide, nicotinamide, ribos methyl nicotinamide. So you're really going to see this big shift from a baseline state to a 36 hour fasted state with a lot of unique molecules that are really only elevated during a fast, that are kind of activating a lot of these beneficial effects, especially at the cellular level that we think of when we think of fasting. And we have also done what's called ex vivo modeling. So basically we had people fast for 36 hours, looked at their before and afters, not only in their metabolites, but also in their plasma functionalities and their cellular functionalities. So when we had people fast for 36 hours, there were huge improvements to cellular antioxidant capacity, cellular anti inflammatory capacity, cellular cardioprotective ability and metabolic flexibility. In terms of what nutrients were they using, what was their preferred fuel source? Cellular protection was also really highly enhanced, cellular resilience to stressors as well. So it's really, really fascinating to look at what happens to cells after a 36 hour fast. Because we did this all in young healthy people, an equal proportion of men and women, and found that there were these like universal effects, basically taking already young healthy people and turning them into super people, which was really, really fascinating.

B (21:37)

Into super people. I like that. It's like a T shirt. I feel welcome to super people. I'm part of the super people. Exactly. Are you frustrated with losing muscle and gaining fat as you get older? Well, let me tell you, it's not your fault. Your body's enzyme production naturally declines with age, making it harder to break down protein from your food and then therefore building muscle. But there is hope. Mass Zymes from bio optimizers contains a potent digestive enzyme formula. Mass Zymes supercharges your protein digestion, increasing the amino acid absorption by an incredible 1200%. That means that you're going to get more from your protein. So that's more muscle building nutrition from every meal and you're going to experience faster recovery, less soreness and better workout results. Sign me up. Masimes isn't just for athletes. It can help anyone struggling with age related muscle loss and weight gain. By optimizing your digestion and your protein absorption, Mazzyme supports lean muscle maintenance and fat loss. Please go to buyoptimizers.com better and use code better at checkout to get 10% off your order. That's B I O P T I M I z e r-s.com better and make sure you use better at checkout. Your midlife lack of energy isn't a caffeine deficiency problem. It's a mitochondrial efficiency one. If you're finding your energy dips between meetings and workouts and those perimenopausal ups and downs, I want you to think more more about optimizing your energy production rather than having more coffee. Meet Troscriptions Just Blue. This is a precision dosed methylene blue buccal troche. And methylene blue works like a tiny electron shuttle for your mitochondria. It supports ATP production, which is the energy currency that our cells run on. And we are after cleaner, steadier energy and focus without the jitters. Early human brain imaging even shows that low dose methylene blue can improve attention and memory networks. Is exactly the circuits that suffer the most in midlife and that we lean on the most in our midlife transition. Each trochee is 16 milligrams and it's scored. So you can choose how much you can choose your dose. I would start with a quarter trochee and swallow it because you probably don't want a blue tongue. Or if you do, you can just let it melt on your mouth and in about 15 or 20 minutes you're going to feel that smooth energy lift and that mood lift as well. So one pack has up to 16 doses. This is a completely new way to optimize your health and I want you to give it a try@troscriptions.com better or just enter better at checkout for 10% off your first order, that's t R O S C R I p t I O-N-S.com better for 10% off your first order. Let's actually talk about NAD because this, this molecule gets a lot of attention. I had David Sinclair on the show, gosh, years ago at this point he was talking about nmn. He was talk nic nicotinamide riboside. I've had guests on the show over the years who have talked about this idea that NAD as a function of aging tends to degrade up to like 50% or more. By the time we're 50, we have about 50% of the amount of NAD that we had when we were, let's say 20. So you mentioned that over out of the 300 metabolites there was you Said a lot of, you said a lot of letters there. So we're going to get back to them. But Nadia. Yeah, so nad, I think that many of my listeners will recognize that molecule as being discussed on the show before. So talk about what that does. And then I, I actually want to put a little bit of a female spin on it because we know that estrogen also has an intimate relationship with nad. So I want to talk about this in the context of perimenopausal and menopausal women. When we start to see estrogen decline, how that can also amplify nad. So talk to us a little bit about NAD and if you can, some of the, you know, some of the, the like the NR and NMN and all the things that sort of come from it.

A (25:41)

Yeah, yeah, absolutely. So NAD plus is basically the main energy sensor molecule of our cells. So a high proportion of NAD versus nadh, which is kind of like its, its counterpart, basically signals to the cells. Hey, we do not have a lot of energy under typical circumstances. You know, NADH is the molecule that's actually used as part of the energy and when it gets used as part of the energy production process, it goes from NADH to just plain old nad. So as energy gets utilized you have this accumulation of NAD that sends the signal to your cells. We don't have a lot of energy around. Let's activate these caloric restriction and fasting like pathways. And so it does that through Sirtuins, Sirt, 1, 2, 3, et cetera. And what sirtuins are doing are they are histone deacetylases, so, or histone acetyltransferases. So basically what that means is that they are putting on or taking off these methylation patterns, these post translational modifications onto DNA sequences which helps them either be more expressed or less expressed. So NAD through the activation of sirtuins has a big impact on how our DNA is translated and transcribed into proteins, which ultimately has an impact on overall cellular functionality and what, how, how often we actually translate and transcribe DNA. And usually we're making it harder for us to translate and transcribe DNA so that we're not using as much of it as we should be. So that's kind of the role that NAD is really playing in the body. It's basically helping us to activate that kind of, of longevity bio program that we've been talking about through the activation of sirtuins and the consequent post translational modifications that happen in the DNA.

B (27:47)

Okay, so estrogen. So let's bring in the conversation around estrogen and nad because we know that one of the things that estrogen does at a molecular level is it helps with NAD salvage. Right? So it helps to preserve NAD. And, and so as women age in their 40s and 50s and beyond, obviously we become estrogen deficient, like where the trend is downward until we're menopausal and then we know it's about 1% of what we had. So that loss of estrogen is now gonna make women less efficient. We'll say at, at sustaining NAD pools. Right. Like during fasting. So does the, so when, when women, and this is maybe more of like a sex specific difference when women are fasting for the 36 hours, or if we need to fast for the 36 hours in order to see this upregulation of all these metabolites that you're talking about, isn't that going to, then, especially for women in midlife, influence, like our resilience, our energy, our capacity to repair because we don't have as much estrogen and therefore that capacity to preserve our NAD is also blunted.

A (29:00)

Yeah, that's a really great point and a really good question. And unfortunately I don't have like, you know, the best scientific answer because we don't do enough research on women and fasting. It's like, you know, a big problem in the entire scientific space, but especially in the fasting. In the fasting space. Typically when we do fasting research with women, it is more of that, you know, 16, 8 style, 5:2 style. And it's really more focused on weight loss specifically and not the longevity side of the coin. But what is interesting is typically what we see is that postmenopausal women tend to behave when fasting like just men essentially. So like they have very, very similar responses in the post postmenopausal side of the coin versus the premenopausal or the perimenopausal side of the coin. And that is very much has to do with like the influence of the hormonal cycle of the estrogens and cortisol that's happening. All the differences in how those things fluctuate between men and women. And that's much more, more apparent pre menopausal than postmenopausal. Postmenopausal. Yeah. It is very interesting to see that women tend to have, number one, an easier time fasting and then number two, from a biochemical lens, have very similar fasting responses as men do.

B (30:23)

Okay, so let's talk a little bit you mentioned cortisol. I kind of want to wade into like hormonal cross talk a little bit because with cortisol certainly fasting is going to elevate cortisol. Right? That's going to happen across the board, men and women, but women often, and you would be able to speak to the research certainly better than I. Women tend to show a greater HPA axis sensitivity. Right. So if the, in, in the absence of calories, let's say a woman's. And I would say this is probably also especially true for women in perimenopause. We're gonna see with a prolonged fast, like 36 hours, 24 hours, whatever sleep amp. Like this is going to amplify like sleep disruption, maybe even like more belly fat accumulation. Right. Because her cortisol is going up. So she's going to start and there's. There, there can be other contributing factors to that belly fat accumulation, but certainly elevated cortisol can contribute to that, mood swings, et cetera. So you mentioned that, I think just in passing that you sort of typically do the third. You're still doing like, you know, one a day eating or once every other day. Obviously you're not a woman, at least, I mean, you know, you're, you're male. So, so what do we think about with long term fasting and the impact a higher sensitivity to the HPA axis and therefore cortisol production can have on quality of life, things like her sleep and even just body composition as well.

A (31:44)

Yeah, absolutely. And that is a huge consideration, especially for premenopausal women. Right. You have the influence of all the hormones that are happening and also just like the cycle at which they are happening in. So even depending on where you're fasting at a certain point in your cycle, you are going to have different biochemical responses to what's happening. Right. When you like, you know, and we, we've done this study basically looking at the different, you know, stages of the menstrual cycle and how fasting can impact them. And what we found was essentially kind of what we described before. Like when you get to, you know, the, the big hormonal dip, right, where everything is kind of leveled out, that's where you see responses in women to fasting that are, to what we see in men. But then once you get like, you know, the influence of the hormones coming back again, especially as they kind of like ebb and flow within each other, then you see these differential effects that are happening. So there is definitely, you know, an impact of the menstrual cycle to the body. The body's response to fasting cortisol in and of itself is a really like, interesting one because cortisol is of course, you know, as we all know, like the stress hormone. Right. It's actually one of the ways that our body, you know, wakes us up in the morning is it starts to elev cortisol just as we get to being awake. And what that does is actually mobilize resources. So it's kind of like, okay, great, we're under stress. We need to start like using glute, glycogen to start using fat. Typically it's gonna be the glycogen, right, the stored glucose. That's what's really gonna, you know, kick the brain out of, out of rest and into wake. The problem with elevated cortisol over time is that like, yes, you're still putting your body in that stress state. So it's like we need to be utilizing energy, but then a stress state in the body essentially says we need to utilize energy, but also we need to store it as much as possible. So that's really why you get like a lot of, you know, a lot of anxiety production because it's like, keep mobilizing the glucose and then you get a lot of like belly fat storage because they're like, keep mobilizing the glucose, but also like, store as much fat as possible so that.

B (33:49)

Right, right.

A (33:50)

You know, like in these longer term times of stress, we still have energy to be able to, you know, move around and run away from things. The whole evolutionary process there. So, yeah, like, like the way that this all kind of interacts and interplays is really, really fascinating. And there's so much research that we still have to do to really figure out how it all works together.

B (34:09)

I have a couple more questions that like, I want to kind of double click if we can on a couple of different hormone, like a couple different systems, endocrine systems. And the one, the other one that I want to talk about, so the HPA axis for women seems to be more sensitive. The other area is thyroid. Right. So this is our master metabol, you know, master, you know, endocrine organ for metabolism when we're fasting. And this is where I almost feel like it's so sometimes it's so hard to be a woman. We want to get all these benefits, the longevity benefits and everything. But in order to do that, we are going to be sacrificing sleep, you know, and all the things that go up when we have the cortisol but thyroid also, fasting will also suppress or reduce T3, which is the active thyroid hormone. Right. So this can also, if you're fasting for a long time because you're like, God, I got to do it for 36 hours. Like that's going to compound fatigue and cold tolerance and your metabolism is gonna slow. And it's sort of like the cortisol story and the thyroid story for women, particularly in midlife. Like this is when we get diagnosed with Hashimoto's thyroiditis. And this is when we have, you know, this, some women will call it like thyro pause. Right. Where like the thyroid just stops working in midlife because the, just the chronic stress and strain is, is, is just too much. So we start to get sort of maladaptation there. So do we, do we think that extended fasting at least at that, you know, the, the research that your, that your body of work entails around that 36, 24 to 36 hours, let's say, is that, is it more harmful or helpful for women when we're thinking about some of these different hormonal sensitivities that we have?

A (35:46)

Sure, yeah, that's a great question. And that's another one where, you know, I don't have the best of answers from a scientific perspective because we weren't looking at thyroid hormones or thyroid function. We were really focused on, you know, cellular funct functionality maintenance and repair at more of like a generalized level.

B (36:01)

Right.

A (36:01)

So even, even in our research when we were looking at things, we didn't see, you know, big impacts on thyroid function or thyroid mechanics. But definitely from the research that has been done, it seems like fasting is beneficial for thyroid disorders and specifically Hashimoto's. I'm not entirely sure what the mechanism behind that is, but, but usually it has to do with Hashimoto's can also kind of be like a manifestation of autoimmune reactivity and like inflammatory disorders. Right. You have a lot of hormonal disruption that comes from that. Fasting is very anti inflammatory and very immune cell regulatory. So that could be a big impact that's happening there and kind of, you know, an undercurrent of all metabolic diseases, all cardiovascular diseases, all actually all any disease really is inflammation. So that's one of big ways that fasting can really help by kind of tamping down the immune system, getting to more of this like typical regulatory and homeostatic state rather than, you know, like we were talking about in the Fed state, you kind of get an overreactivity of immune cells because there's all these nutrients around. They're like, we can create all the inflammation we want. It's fine when you're in a fasting state. Immune cells then really switch that around and they're like, okay. We can only respond to real threats because that's all we have the energy for. So you get a lot less autoreact and that can be really beneficial for autoimmune diseases. Yeah, metabolic diseases.

B (37:33)

Hashimoto's like that improvement in central tolerance. Really?

A (37:38)

Yeah.

B (37:38)

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No mystery chemicals, just real food. And these chips don't only avoid all the bad stuff, they just taste incredible too. Snacking on Masa chips is nothing like eating regular chips. With Masa, you feel satisfied, light and energetic. There's no crash. And that gross, bloaty, sluggish feeling afterwards is not, not there. And because these chips are made with real food, they're more satiating. So you're not going to find yourself in the pantry again uncontrollably binging and still feeling hungry afterwards. My personal favorite of Masa is lime. And their sister company Vandy Crisps have a herb de Provence chip that will make you proclaim mom, that's class. If you are ready to give Masa or Vandy a try, use code better for 25% off your first order@masachips.com that's M A S A chips.com better for 25% off your first Order. Let's talk about muscle and bone. Maybe the, you know, the cornerstone of my life. It's like my professional degree is in that. What. Let's talk a little bit about, you know, whenever I would do any type of longer fast, I don't do them anymore, truthfully. But when I, when I did do a longer fast, I would always make sure that I was resistance training because I always wanted to provide some type of mechanical stimulus to the muscle. So what are. And, and maybe I'm sort of leading into this and talking a little bit about ampk and mtor because of this. These two, I mean, related pathways get a lot of attention when we say, oh, we're upregulating MTOR or we're down regulating or upregulating mpk, we're downregulating MTOR when we're fasting. And these pathways seem to be central to fasting in terms of all the benefits that you've talked about, you know, like the, you know, the improvement and you know, anti inflammatory, et cetera. When we're thinking about fasting, male or female, how can we think about preserving lean muscle tissue, specifically muscle. And then I also, I have a follow on question around bones and collagen and ligaments, et cetera. But let's start with the muscle story first because the long term fasting, at least for me, feels like it is counterintuitive to preservation of muscle tissue, especially if you're not resistance training. And we know as much as I, you know, people who listen to the show maybe are sick, maybe sick, maybe not. If you're still listening of me talking about the importance of training for women because you are literally in a race against time to preserve the tissue that you have. So talk to us a little bit about what happens to muscle when we're fasting, how we can preserve it, if we know if there's any known mechanism and describe those mechanisms as well.

A (40:49)

Absolutely. So what happens to muscle during a fast, you know, is dependent upon the length of the fast. But you know, let's go into the deeper stages of fasting like we were talking about, like 36 hours and beyond. So at 36 hours and beyond, this is kind of a major, a major reason why the muscle question comes up in a normal state. We're using glucose as our primary fuel source because that is actually what our brain and our cells perform when we switch over to a fasting state. We're going to go into ketone body metabolism, which comes from the breakdown of adipose tissue and fat cells. Right. So that's where the ketone bodies are actually coming from. They're being created from fat. And most of your cells will be fine to use ketone bodies. They'll be like, okay, great, we're just switching over from one thing to another. Not a big deal. Your brain, on the other hand, is what's called an obligate glucose consumer. So that means that no matter what, you have to have a, at least of the brain's fuel coming from glucose. But in a fasted state, we have run through all of our body's stored glucose. Right. That's why we're using the ketones. So what the body will do in order to keep providing glucose into the system so that the brain can keep operating is that it will start breaking down protein and using it for gluconeogenesis, so creating glucose from protein. And that can end up being a problem, especially in the deeper stages of fasting. Because where is that protein going to come from? From initially, it's going to come from organ mass, specifically liver and kidneys. That's where the body will first pull from. So when you're doing more of the, how do I even say it, the shorter, longer fasts, right, like 36 hours, 48 hours, that's where you're going to see. Okay, yes, there is protein that's being mobilized, but it's coming from organs and less from muscle. As you get to the deeper states of fasting, muscle itself is very energetically in a efficient, right. Especially if we are not utilizing it. So then the body starts pulling proteins from muscle because it's like it's a kind of a two in one for them. They're getting the protein to create the glucose while also decreasing the overall energy needs of the body. So as you get into the deeper stages of fasting, that's where you're really going to have to start being concerned about muscle loss and protein utilization that way. The best way to prevent that though is that like what you already said, Stephanie, basically like doing the strength training, specifically focusing on resistance training, not doing cardio. That's another big one when you're fasting. So that can be very helpful for, you know, mobilizing fat. But also at the same time, you know, long state cardio and not like, you know, sprinting or hit, but something like endurance, cardio. Catabolic. Yeah, it's catabolic, yeah. So you're just going to kind of be feeding the beast. So yeah, the strength training is really helpful because your body operates essentially off of a use it or lose it principle. Right. Your body won't start catabolizing your muscle muscle if it thinks that it's necessary to your survival. Right. So if you are doing strength training when you're doing the fast, that's going to be sending a signal from the mechanical stress from the use of the muscles that like, hey, we actually need these to, you know, stay alive, keep going. So it will pull more protein from organ mass rather than muscle mass because it knows that it needs it. So that's really the best way to prevent, you know, muscle wasting in these longer term stages of fast fasting.

B (44:13)

That's still terrifying though. I have to say, like, it's like, okay, how do I prevent it from going into my liver? Like, I don't. I would like to not. I'd like to preserve my liver.

A (44:22)

That is okay as well. This is the nice thing. Like, the body is very smart. It pulls from the liver initially because we can regenerate liver cells, right? Like, we're, we're very, very good. The liver is a very regenerative organ. So it pulls from there because it's like, if I take it, it's okay, I can put it back. It's not that hard. Muscle, not as much. Right. Because in order for muscle cells to grow, you all of like, you know, the physical tearing, the micro tears, the actual mechanical stress of, of working out and exercising. Your liver can just like go up and down as your cells want it to, as your body wants it to. It doesn't require an external input.

B (45:00)

Okay, that makes me feel a little better.

A (45:01)

Yeah.

B (45:03)

How do I get my liver back? What do I have to do for that? Let's talk about bone then. Because I, you know, bone, when you're fasting for a long period of time, I'm assuming that you're going to have more bone turnover. So again, like the sprinting and the weight training like that, you know, your, your bones are essentially scales. Like, they're always measuring how much impact is being levied onto them. So if you're jumping, if you're sprinting something that's higher impact, you're probably going to be able to maintain that balance of bone resorption to bone, you know, bony turnover. What are some, what are some, what are some ways that we can prevent. If we are thinking about a longer fast, how can we preserve our bone density as well? Another big concern for women in midlife.

A (45:44)

Yeah, absolutely. So the reason why bone density is a problem during fasting is actually, you know, the same reason why muscle wasting is a problem to a certain extent. So when we switch over from glucose metabolism to ketone metabolism, ketones are actually fairly acidic. So they have a, you know, they have a net negative charge that's applying this like, acidic pressure to the blood. Blood does not like to exist anywhere outside of its preferred PH range, which is like 7.4. So like, oh, just a little bit, A little bit basic. So when the ketone bodies come in, in, they start acidifying the blood and your body doesn't like that. So what does it do? It says, okay, I've got all these, you know, negative ions around the acidic portion. I need to go get something with a positive ion so that I can counteract that and make things neutral. Where does that come from? It comes from calcium in the bones. So as ketone body production increases, you get blood acidification, which means that your body goes and pulls calcium out of bones literally to buffer your blood so that it doesn't get too acidic to the point where you function. You get ketoacidosis, you fall into a coma. So, you know, your body is like, ah, I, I don't have any good options here, so I'll take the one that doesn't involve me immediately dying. And the best way to, the best way to, you know, maintain the, the bone density because you're going to have, you're going to have some loss. There's just no way around it. Strength training will definitely help that. But you, you know, like we said, we need to buffer the blood so we're going to pull from calcium. But yeah, doing the strength training, same thing we said before, that use it or lose it principle. So you are applying the mechanical stress that actually stimulates osteoblast activity, which is the cells that put more mass onto the bone. The osteoclasts are the ones that take mass away from the bone. It's kind of like the cycle of bone turnover and resorption and rebuilding and regrowth. So yeah, fasting is going to stimulate osteoclast activity, strength training is going to stimulate osteoblast activity. So you can kind of create a balance there.

B (47:49)

All right, so I want to actually come back to some of the metabolites that we were talking about. We talked about nad talking about nicotinamide, you mentioned. I said there's a bit of a letter salad there. You said PEA and oea. Yeah, let's talk a little bit about each of those. And I would like to, if we can, maybe even relate them back to some of the things that we've been talking around, around, you know, muscle loss and bone loss, sometimes like chronic pain and inflammation. Talk to us about OEA and PEA and what your, what your, what the literature or what you, what you found in your research around those metabolites being amplified in the fasting process.

A (48:23)

Yeah, absolutely. So what we found was, you know, of that list of 300 metabolites that were highly elevated during a fast, we basically screened through those molecules, molecules looking for ones that had some kind of literature, evidence already of having bioactivity. So whether that was creating anti inflammatory effects, antioxidant effects, autophagy, what have you from that list of 300. We were able to identify around two dozen candidates that could have been responsible for activating all these beneficial cellular effects that we were seeing during a fast. And so we screened through those molecules and eventually found this combination of four of them, pea, oea, nicotinamide and spermidine, that when we combine them together, put them on human cells, they could recreate all of these benefits that we were seeing during fasting. Those same anti inflammatory effects, antioxidant effects, cardioprotective effects, metabolic effects. And what was even cooler was that when we took those four molecules and did a lifespan extension analysis in CF elegans, we were able to extend their lifespan by 96% just through supplementation with these molecules. So we.

B (49:34)

This is 36 hours.

A (49:36)

Yeah, this is 36 hours, correct. Okay, okay, yeah, yeah. This was, this is all, all of this was from a 36 hour fast.

B (49:42)

And C. Elegans, for those of you listening, this is, we're talking about worms.

A (49:45)

Yeah, little nematodes. Yeah. So they typically live around, you know, a month. And so they're a really good model for longevity. Very good high throughput way to identify candidate molecul that could have lifespan extension ability. And what was really fascinating was that we looked at each of those molecules individually as well as in combination and found that each one individually could extend lifespan to a certain extent. You know, anywhere between, you know, 5%, 10% up to around like 26% for the individual molecules. But it's when we combine them all together that we got this 96% lifespan extension. So there's really this synergistic effect activating these complementary pathways between these four molecules. Molecules that are really kind of recreating that bio program of fasting and giving us that, you know, lifespan extension and those beneficial cellular effects.

B (50:38)

Well, I'll come back to spermidine in a minute, but I just. My question as you're talking about this, so 96% is incredibly impressive, right? We know that it's in worms. So what is the. How does that translate into, you know, from a nematode? How does that translate into mammals? How does that even like M. Is it like if it goes 96, is there like a step down or a step up for mice and then from mice to humans? Like how can we extrapolate 96% from C. Elegans into humans?

A (51:10)

Yeah, it's a great, great question. And there's not like, you know, an easy peasy, like, oh, just plug it into this equation and you can get it. Because there's, you know, A lot of steps along the way. Typically how longevity research is conducted is, you know, you start off in the smaller organisms, you make your discoveries there. And like the Drosophila, the fruit flies or the C. Elegans, the nematodes and you're like okay, cool. I found that can extend lifespan here. So yeah, then let's try and apply it to mice and then let's try and apply it to you know, dogs or let's try and apply it to primates and then let's try and apply it to humans. So it's this big kind of bottom up approach too. And the problem with that is along the way you get things that of course, you know, this worked in worms but it didn't work in mice or this worked in worms and mice, but then it didn't translate up into the higher organisms. What's cool about what we were doing was that we are kind of flipping that on its head. So we are start from human research, identifying these things that have these impacts on human cells that are part of like the human fasting bio program and then you know, kind of confirming that they can work in C. Elegans. So we're taking this top down approach so that we know anything that we find, anything that we discover is going to be immediately applicable to human health. Because it comes from human health, human research. So I couldn't give you an exact like okay, 96% in C. Elegans equals X in humans.

B (52:36)

30% in humans.

A (52:37)

Yeah, exactly. But I can tell you we have done so taking that, taking that four ingredient fasting memetic combination. We did a, an eight week study where we looked, you know, just the before and after of someone just like taking those four molecules. The mimeo formulation, M I M I O the mimeo formulation and they sort saw that they could get a two and a half year reduction in biological age in just eight weeks before and after taking the supplement.

B (53:09)

And that was based on what markers?

A (53:11)

So that's based on DNA methylation. So you're using the, the trueme. Yeah, methylation patterns.

B (53:18)

So two and a half years decrease in biological age. Unfortunately not chronological age in humans. You can reduce the biological age in humans. That is, that is very important. Impressive. Okay, well let's talk about the, let's talk about these molecules. Like I, I, you know I, I have a couple of there, I think there I pulled up an rct, it might still be pen, I think it's still pre print. But let, let's talk about pea, oea spermidine. My audience has heard of before. So talk to us. And then nicotinamide. So talk to us about that particular combination and then the dosage of, of each one. Right. So if it's like, okay, I have spermidine, do I need to take like one. What do I need to take a gram milligram? Like, what do I need to be taking? So talk to us about each of those questions, components, and then how much of each to get to make that synergistic effect of all four of them in the mimeo formulation that you were describing?

A (54:02)

Yeah, absolutely. So to go with just like what the molecules are, what they do. Pea, that is palmitoy ethanolamide. It's involved in the endocannabinoid system, so simulates through CB1, CB2, TRPV receptors and is also a PPAR alpha activator, and also simulates through Cox 1 and 2. And for the immune system. But wait, there's more. Yeah, pea. I love pea. It's just like, it's this, it's a such an amazing molecule. It's basically the body's rest, relax and recover molecule. So it has.

B (54:34)

Which is good for chronic pain.

A (54:35)

It is, right?

B (54:36)

It's also for chronic pain for. Yes, okay.

A (54:38)

Yes, absolutely. It has anti inflammatory effects. It has mood and cognition enhancement effects. It has antidepressant effects. It has, yeah, it. And it has pain relief effects. So kind of like your body's natural CBD or your body's natural ibuprofen works through very similar mechanisms there. After that, we have oea, that's oleoylethanolamide. So PEA and OEA come kind of like from the same family in that endocannabinoid system. But OEA is actually involved in the gut brain axis where it stimulates satiety and suppresses appetite. And what's really interesting about OEA is that for a very long time, people thought that OEA was only elevated after eating. Right? So it's produced by intestinal cells signals through the vagrant afferent nerves to the brain that says, okay, we have, we are full, we can stop. What we found was that during a 36 hour fast, yes, OEA is elevated in the fed state, but it's even more highly elevated in this 36 hour fasted state. And we think that that's actually an evolutionary adaptation to fasting. Basically, it doesn't do your body any good if it is searching for food to be doubled over in hunger pangs. Right. Like it needs to focus on finding those berries or hunting down that gazelle or Whatever it is. So OEA is kind of like your body's natur, natural appetite suppressant during fasting so that you can actually stay focused on problem solving and finding food, getting the food.

B (56:07)

Yeah, good.

A (56:08)

Yeah, exactly.

B (56:09)

And then actually just before you go on to the next one, I had just had a question with, does it work like, is it the same mechanism as GLP1? So like OEA, can you compare and contrast the two there it is a.

A (56:20)

Little bit, it is a little bit different. So OEA does work in the same way as GLP1s as that like it's excreted from intestinal cells or ordinarily then signals to the vacant afferent nerves and has that kind of appetite suppression effect. Where it's different is that OEA also has a big impact on cellular metabolism and not just brain signaling. So OEA is also a PPAR alpha activator. And so that is a big thing during fasting. That switches us over from on a cellular perspective, from the glucose metabolism to lipid metabolism, fat oxidation and things like that. So yes, they both have these, you know, satiety enhancing appetite suppressors effects. But GLP1 is much more short lived than OEA is, you know, when it's naturally occurring, not the semi glutide. So those are kind of crazy. But yeah, oea OEA will stick around longer and it will go around in circulation and help to holistically promote that metabolic switch.

B (57:18)

Fantastic. Okay, so now talk to us about spermidine. We've been talking about nicotinamide a little bit, but tell us about the spermidine.

A (57:24)

Yeah, spermidine is essentially most well known for enhancing cellular attacks, autophagy. And we're still not entirely clear on the mechanism of how sperminine does that. We know that it like kind of skirts around mtor so it actually ends up inhibiting an inhibitor of autophagy. But that whole mechanism is still kind of up in the air. But that's what spermidine is most well known to do, like activating that autophagic pathway that happens during fasting, which of course like we talked about, is that cellular cleanup and recycling part of the metabolic efficiency processes and it's been shown in clinical stud have a pretty like interesting impact on longevity as well as cognition and cognitive decline specifically. So when you look at the studies of spermidine and longevity, what we see is that an intake of 30mg of spermidine or more is highly correlated with, you know, increased lifespan and increased health span in humans. So though that's, that's really significant because the average American intake of spermidine is around 8 milligrams per day. So we're like pretty robustly missing that mark. And yeah, that's kind of what spermidine is doing in this equation is kind of having those longevity promotion effects of the autophagy and creating that more holistic metabolic efficiency system alongside the PEA and the oea.

B (58:53)

And so when we're taking these four molecules, like when you were looking at this in human trials, where we were taking the nicotinamide, the spermidine, the oea, the pen together, is the thought that these can now replace fasting so we don't have to go for this extended 36 hour. I mean, I know 36 hours is the gold standard, but I'm going to be honest with you.

A (59:13)

Yeah, no, yeah.

B (59:14)

With my training schedule, like, I just can't go every other day eating. So is the thinking then that when we supplement with these compounds in the mimeo formula, and you can talk a little bit about that, certainly as well, is the idea then that we can still get the benefits of fasting without having to fast? Is that kind of what the whole idea is?

A (59:34)

Yeah, that's exactly right. The whole point of mimeo and this whole formulation is so that you can get the benefits of fasting without having to fast. And that is for many reasons. Right, like what you were saying, who wants to do a 36 hour fast? Right. We found that these molecules are, you know, uniquely elevated during these longer stages of fasting, specifically a 36 hour fast. So it can be a great way to kind of recreate fasting at the molecular level, you know, activate all these same cellular pathways, get those same benefits, but without actually having to fast. And we've proven that out in three different clinical studies at this point, basically showing that this formulation together. And you asked about the actual, the actual concentrations in the doses.

B (60:17)

Yeah, yes, before.

A (60:18)

Yeah. So what we're using right now is 600 milligrams of pea, but we're also using ultra micronized pea, which is the most bioavailable form. And it's about, you know, four to six times more bioavailable than ordinary pea. And one of the few companies in the US that actually is using that, that form of the product OEA, we have 400 milligrams, spermidine, we have 8 milligrams. And then nicotinamide, we have 250 milligrams. And that formulation we've tested in the three different clinical studies. And what we've found there is essentially our original pilot study that we did, we had people come in, eat a standardized breakfast alongside a placebo case control, then looked at their cellular functionalities, their plasma functionalities, like we did in the original fasting study. Then we had those same people come back after a washout period, eat that same standardized breakfast, but then just with supplementation with mimeo. And what we saw there was that when people ate the meal with the placebo, there's this big loss of cellular and plasma functionality, which is really typical of the postprandial state, right? So you got all this metabolic chaos coming into the system, flooding things through shifting focus away from maintenance, protection and repair to digestion, metabolism and absorption. And then there's a lot of dietary inflammation that comes along with that because, you know, foreign molecules going into the body creates an immune response. So you really kind of throw the system at a homeostasis. And that's what we saw. Their plasma became pro inflammatory, it became less antioxidant, it became less cardioprotective, less metabolic flexibility. But when they had that same meal, but with supplementation with mimeo, we were able to not only prevent all of that loss of function, but then actually add gains of function on top of that. That mimicked what we saw during a fast. So instead of being pro inflammatory, their plasma became anti inflammatory and antioxidant and cardioprotective, and they had much better metabolic flexibility. And then we talked about before our second clinical study, a clinical case study with Mount Sinai, looking at eight weeks worth of supplementation with the mimeo formula. That's where we saw the two and a half year reduction in biological age, but then also a lot of improvements across metabolic markers. We saw a 50% increase in testosterone levels, we saw improved glucose levels, improved HbA1c levels, improved insulin levels, better cholesterol levels, better triglyceride levels. So like really all these major metabolic, hormonal and longevity effects of fasting just in that really short eight week period of time. And then our last clinical study that we just completed a couple months ago, randomized double blind, placebo controlled studies. So gold, gold standard looking at the impacts of eight weeks of mimeo on an older population. 50% men, 50% women. What we saw there was that eight weeks of mimeo supplementation has this really profound effect on hunger control. So that's, you know, most likely coming from the oea, although pea has these effects as well. But way improved cravings control, less distractions from cravings throughout the day. More of eating only when hungry, more feeling fuller, faster, staying fuller, longer sleep satiety as well as just decreased overall daily hunger. And that kind of like kept going down over time. So we feel like if they, if we went past eight weeks we'd get even bigger effects there. But just like we saw in the previous study, we also saw these great impacts on metabolic health. So improved glucose levels, improved cholesterol levels, less inflammation, less LDL cholesterol, specifically less LDL particle number which is an even, you know, better CBD risk marker and then less overall cellular stress as well. So again, so like what mimeo is really doing for you is it's recreating what your body would naturally produce during a 36 hour fast to activate all of these fasting like pathways and give you the same metabolic longevity, anti inflammatory, antioxidant effects of fasting without actually having having to fast.

B (64:29)

Fantastic. So you're seeing some of these metabolic markers like the cholesterol efflux, the ldl, I'm assuming glucose control and then the noise that you describe, right, like the hunger, the cravings, eating when hungry, like that subjective food noise. Proving as well, don't be fooled by the frigid temperatures. Keeping hydrated in the wintertime is super important. In colder temperatures we sweat more due to a higher metabolic demand of trying to maintain a core body body temperature. We lose more fluids and electrolytes through our urine, we lose more water through respiration and just general breathing. And our skin dries out in the wintertime as well. We are a ski family and over this winter we have been using Elementi's Chocolate Medley. The chocolate chai is absolutely incredible with some boiling water, a splash of milk and my kids love the chocolate mint with some hot water. This is our apres ski. We cozy up with Element Hot after hours on our cross country trails. Now for a limited time you too can get the Elemente Chocolate Medley and enjoy them hot as I have been doing with this exclusive insider bundle for you. When you buy three boxes of any flavor it doesn't have to be the chocolate, it can be any of the flavors that they offer. You are going to get the fourth box free. If you head over to DrinkElement.com Dr. Estima, you'll see that exclusive offer at the bottom of the page. That's D R I n k lmnt.com d r e S T I M A and tell me which of the chocolate melody you love the best. Was there any discussion or any inquiry into muscle joints cartilage again Coming back to that, like chronic pain, like a lot of women in midlife and in menopause, really, like we start to see, you know, just with the day degradation, like with, with estrogen being gone, we see connective tissue degradation, we see joint degradation, we do see sarcopenia as well because women are not training enough and all the things is there, was there any inquiry into looking at either preservation of or improvement of the quality of muscle tissue or bone or joints?

A (66:42)

Yeah, not in the studies that we have done so far like these, the eight week studies that we've done. We're really focusing on the cellular health elements of it and the metabolic elements of it. That was, is kind of, you know, what we have to, what we have to cordon ourselves in on. You know, unfortunately, you know, as a.

B (66:59)

Scientist, you gotta start somewhere.

A (66:59)

Oh yeah, exactly. As a scientist I'm just like, I wanna do all the things, but yes, you have to, you have to start somewhere. So yeah, we didn't get a chance to look at all of that in our studies. But I can tell you from other studies with pea, specifically, right, Talking about joint discomfort, talking about exercise performance, talking about, you know, muscle muscle maintenance. PEA has been shown to be incredibly good for all of those things, but especially, especially the pain management portion of it. So the anti inflammatory effects and then also the signaling through Cox 1 and 2 and the endocannabinoid system in general has very similar effects to ibuprofen. And there have actually been studies of PEA stacked directly against aspirin and ibuprofen, showing that PEA actually has a greater effect size than either of those at, you know, the same concentration concentrations. So like really natural, effective pain relief, especially for nerve pain. It seems like PEA is great for fibromyalgia, diabetic neuropathy and then also menstrual pain as well. There have been a few studies with PEA for menstrual pain.

B (68:07)

So with fasting, you know, if we're trying to, if we're saying, okay, in order to maximize the benefits, like that 32 hour mark with mimeo, is it this? How do we, is it something that we take every day? Do we take it every other, other day? What's the best, what's sort of the best protocol that you've been able to look at in the research in terms of how to maximize these benefits? And then the other question is, is there any tolerance? Do we know that? If, is there any habituation that happens with taking supplements all the time? So how do we take it and do we, is it do we cycle it? Do we take it consistently? Like what's the best, what's best practice?

A (68:41)

Yeah. So it's designed as a daily supplement. So just every day, constant use. That's what all of our clinical studies have done. Just people taking, you know, the single dose of the, of the formulation once a day for those eight week periods of time and not altering their diet or lifestyle in any other way. So we can still see these really great fasting like benefits even when people are just normally eating. How I take Mimeo is actually as a fasting enhancer. So we, I do the one meal a day style and what I will do is I'll start my day with some mimeo and some green tea and that will kind of carry me through the whole day. I'll work out in a fasted state and then have like this big reward meal at the end of it. Right. So I'm kind of trying to do my best to maximize the impact of both fasting and eating. So I eat after my fasted workout because you know, my, my body's primed to take up all of that, get that MTOR signaling, kind of like promote the pro, the anabolic progress pathways in that very short dense period of time. And then I can transition back, back into fasting for the, you know, the longevity and the cellular health benefits. And Mimeo is really helping me to achieve more of those benefits than I would otherwise because you know, Even in a 24 hour fast, I'm not getting to the point of a 36 hour fast where these molecules are really highly elevated. So Mimeo helps make my fasts not only easier but ultimately more effective. Effective.

B (70:17)

Yeah. And I, you know, one of the reasons why I wanted to have you on the podcast was like I started off in the beginning of this conversation saying like I've really softened my view on fasting, particularly for women. It can, I feel, I mean just very transparently and honestly I think that aggressive fasting 30 and I would include 36 hours, 72 hours for women when the, for women in midlife who are trying to preserve muscle and bone. It's almost like we want all the benefits that the 36 hour, you know, the anti inflammatory, the longevity benefits, the cellular renewal, we want all of those things. But it seems to have for women come at such a high cost. So the HPA that we're talking about, the thyroid, the muscle, the bone. So I'm very interested in the science that you're presenting today around this idea that hey, you can like, like you can have your cake and eat it too, like you could, you can get a lot of these benefits from these, these four compounds that you've extracted and combine them together in the way that you have and you can still continue to train heavy and make sure that you're getting your protein and all the resistance training that is in my opinion just essential for women. So for people who are not, who cannot do a 36 hour fast or not willing to do a 36 hour fast, such as myself, I think that Mimeo actually provides a nice, what would be the word? Like it fills in the, that gap for that cellular renewal that I'm not getting because I'm not fasting and I can still continue to do the things that I want. I can still continue to eat the protein and all the, in the calories and all the things. And still, I mean, obviously I'm not like gorging on, you know, like Haagen Dazs or whatever, but I'm, I'm still like, I'm having my Whole Foods and all the things, but I still can get some of the, the cellular renewal benefits and potentially the longevity benefits as a woman who has a much more sensitive hormonal environment than maybe Amanda's. And then again, like thinking about bone preservation, like when we lose estrogen, man, like bone preservation, muscle preservation, like these things become extraordinarily more difficult for women, which is why I was very excited when I heard about your formulation and the science that you were doing and why I wanted to have you on the show. So and the other thing, the actually the other thing I'll say is for a lot of women in, in menopause, I sort of have lovingly nicknamed it like the menopause munchies. Like again, as we lose, lose estrogen, we tend to get more snacky, like we just want to eat. So reducing that food noise, it seems like through the OEA compound as a, maybe a mild appetite suppressant. Not the semaglutide, the tirzepatides, the monger. Like none of that very, like you said, it is one option for people, but it maybe this is a gentler way to dampen some of that food noise and that rumination that can happen for women around food in general.

A (73:03)

Yeah, absolutely. And that seems to be what we have seen in all of the clinical studies, like really great appetite suppression. We hear this from consumers all the time too, that Mimeo really helps them, you know, fast longer than they have before or you know, we've had customer testimonials where it's like I just had a baby. I was trying to lose the baby weight. Like mimeo really, really helped me. I had all these cravings that I didn't have before and it like kind of just helped like reduce them down or. Yeah, like I just like started a caloric restriction diet and it's always been hard for me. I started taking mimeo and now things seem easy. So like, you know, I'm, I'm really, really excited especially about the metabolic side of things and that like, you know, we were saying, I think it's really interesting and really fascinating that fasting activates this longevity bio program. Right. But then there are also the downsides that come with fasting. And so if we can use science to tease out, okay, well, what are the beneficial things versus what are the negative things, things, and then just like take all the beneficial things. That's just a wonderful feat of human biohacking. So I'm really excited about the research that we've done. Yeah, exactly. And I think, and that was that, that was the goal.

B (74:12)

What would be like if you had like the, I know you were like, I'm a scientist and I want to do all the studies. Like what is your next, if you had like unlimited resources, all the IRBs were like, everything is, everything is approved, you have unlimited grants. What's the next couple of studies that you would like to look at in terms of some of these compounds maybe and some of the effects that you can replicate with fasting?

A (74:31)

Yeah, definitely. I would do a larger scale, longer term study than the one that we, that we've already done just with the current formulation. I think that, you know, just looking at it in different use cases, different indications could be really, really useful and effective. And it just help, you know, helps stack on top of all the science that we've already done. What I am really excited, excited about though is twofold. Number one, you know, we described that list of 300 metabolites that are elevated during fasting. You know, we got to screen through about two dozen of those, but that leaves, you know, 275 more that don't have any, you know, literature on them yet. So that's kind of like this blue ocean of these molecules that are all involved in fasting and all elevated in fasting, but we don't really know what they, they do yet. So screening through those molecules on the back end, finding new cellular functionalities for them, you know, new synergistic combinations, ways that we can improve the fasting formula to make it even more effective. Give it more benefits, make it even better at recreating that holistic longevity bio program. I'm really, really excited about that. And then in the like, more distant future where really excited about taking this biomimetic approach that we applied to fasting and then looking at it in other interesting regenerative states of the body. So like what happens in the body during exercise, what happens in the body during sleep, what happens in the body during cold exposure or meditation. You know, look at, look at those data sets and see if we can find more of these biomimetic formulations that can mimic these benefits of these states. But you know, without having to do the cold plunge or you know, like giving you like a nice 8 hour restful sleep metabolomic profile or spending 2.

B (76:19)

Hours in the gym.

A (76:21)

Right, exactly.

B (76:22)

If you can do exercise in a bottle or sleep in a bottle and fat, well, I mean you have fasting in a bottle now. I think that, yeah, that's gonna, that's gonna be the trifecta for sure. Dr. Rhodes, this has been absolutely phenomenal. Tell people where they can find, if people want to try the mimeo formulation, tell us where we can find it. We'll, obviously we'll make sure that these are all in the show notes as well for people to check out, but just give some. Tell people where they can find you and more about mimu.

A (76:47)

Yeah, absolutely. If they're interested in me specifically, I have a TikTok channel. You can look at me scream about nutrition into my bathroom mirror, as is classic TikTok style. That's at that nutrition doctor. That nutrition doctor. And then if you're interested in mimeo, all the research that we've done, all the clinical studies, that's also up on our website@mimeohealth.com m I m I o health.com and then socials are the same at Mimeo Health.

B (77:16)

What does mimeo mean?

A (77:17)

Ah, so mimeo is a combination of mimic and biology smashed together. So yeah, that kind of gets at our whole underlying biomimetic approach.

B (77:28)

Love it. All right, Dr. Rose, this has been so fascinating. Thank you so much for. I mean we, we went on a, we went on a little bit of a nerd safari today. This is a little bit what we like to call dark roast Betty. Really, really appreciate your time time, your attention, your focus and yeah, fasting in a bottle. I'm, I'm, I'm in, I'm into it.

A (77:46)

Yeah, it's the same here. Thanks so much for having me. This is such a good time.

B (77:50)

What's up, Betty? Welcome to the after party where I tell you what I really think of this episode and the after party aptly named after menopause because that is what we are all going towards. We're all going to get invited to the after party at some point. All right? So in case it wasn't abundantly clear, like my poor, my poor guest, in case it wasn't abundantly clear, I am not a big fan of long term fats. I, if I go back into the, into the show notes or even just, even the timestamps, how many times I told him I'm not a fan of long term fasts. He was very gracious. He was like, yep, yep, totally get it. I don't want to fast for a long time, however, because I. It's all about those gains, baby. Right? Like I want to preserve my muscle, my joints, my bones, all the things my brain trained my organs. But you know, you just can't deny that there are benefits to fasting, right? So he went through really, really eloquently went through like the fed state versus the fasted state, where in the fed state, you know, we're growing, it's like more, you know, we're running a bit more dirty because we just know that we can replace things because lots of food, but in a fasted state, you know, it's upregulating maintenance and repair and autophagy and all those things for longevity. So you just, you can't deny that there are benefits to fasting. I just don't want to do it because I'm very active. I want to lift weights, I want to selectively build. Right. Stay in a selectively anabolic state with muscle and bone. I really like the research that him and his company have conducted around supplementing with some of the, some of the metabolites that are upregulated during fasting so that we can actually, you know, benefit from it but still continue to make those gains. With a Z, of course. So I really appreciated that. Overall, I think that the conversation, conversation where I think we need more research, certainly with fasting and just generally women's health is, hey, what is the impact on women, right? So I was bringing up a lot of the, like, what about the thyroid and what about the HPA axis and cortisol and what about this? What about that? And you know, I think that we can extrapolate and make some really good hypotheses about what happened to women, but we don't know definitively yet. And I think Chris or Dr. Rose was very, very honest and trans transparent with that as well. I really loved the little nerd safari we did on OEA and pea. Pea I've known about this for a while in terms of chronic pain. So he'd mentioned fibromyalgia as a way to mitigate chronic joint pain and ligaments and, and so PEA is a compound that I have been familiar with for many, many years, but very happy to see it kind of coming back into the spotlight in the context of something that is upregulated when we are fasting for a time, long, long period of time to help with chronic pain. A lot of, a lot of people who fast for a long period of time because of its anti inflammatory effects will report things like less pain, less chronic pain, less systemic pain. And then the other thing I thought was really interesting was OEA and food noise. So this is. Again I mentioned this towards the end of the conversation, but a lot of women in perimenopause and menopause have a lot of these like this, this food noise, like this rumination. It's like I've eaten but I just, my face is in the pantry because I'm looking for a snack. And so I regulating that is a very promising area of research in the context of, as I said, food noise, appetite and hunger control as well. Because in midlife so many women will say like my waist is disappearing. And we slowly see them becoming more sedentary, consuming more calories and just getting hungrier and hungrier and hungrier. So a lot of women will feel powerless. So the 400 milligrams of supplementation with OEA he was talking about in the middle meal formulation, really super, like super cool conversation there. I really loved that. And then the whole nicotinamide convo and nad loved that as well and how estrogen kind of plays into that too. So estrogen as we lose it, particularly in perimenopause, makes us less resilient to fasting. So it's like okay, if I want to fast and I, well, I wanted the benefits of fasting, but I don't actually want to fast. How can I replace that? And these compounds seem to do, do that. So really, really enjoyed that. I'm curious about you in terms of like what are you going to take away from this conversation? Are you going to fast maybe, perhaps. Are you going to think about maybe supplementing with a fasting mimetic like the mimeo formulation that Dr. Rhodes was talking about? Let me know in the comment section wherever you are listening to it. I am always looking at the comments and the feedback that we get for the show show. It helps us program future programming and just let us know how the the content is landing with you. So until next time, I bid you adieu and we'll see you soon. All right, all right. I hope you enjoyed today's episode and I must give you the obligatory legal and medical disclaimer here. This podcast, Better with Dr. Stephanie is for general information only and the advice recommendations we discuss do not replace medicine, chiropractic or any other primary health care provider's advice, treatment or care in the consumption of this podcast. There is no doctor patient relationship that has been formed and the use and implementation of the information discussed are at the sole discretion of the listener. The information and opinions shared on this podcast are not intended to be a substitute for primary care diagnosis or treatment. In other words, guys, be smart about this. Take it with a grain of salt. Take this information to your primary healthcare provider and have a discussion with him or her to make the best choice. That is for you. Remember, I am a doctor, but I am not your doctor and these conversations are meant for educational purposes only.