Hi everyone, welcome to Crowdcast number 40. A few reminders before we dive into everything. First, I see a lot of people have submitted questions in the chat area, and just as a reminder, if you're gonna— if you're submitting a question, please submit it. If you look at the bottom of the toolbar, the bottom of the screen, there's a toolbar at the bottom that says Ask a Question. You have to click on that tab and then enter your question in that area. The chat is for me when I'm live with you guys and I'm gonna answer some live chat questions. So the reason I say that is because as I start the Q&A, if I have to scroll if I have to scroll up to the top of the chat, then I'll miss all the live chat questions.

And so I end up not addressing most of these questions in the chat box right here that have already been submitted. So please, please, please submit the questions in the Ask a Question section. Otherwise, it's challenging for me to get to those questions. So for those of you that are new, typically what I'm doing is Each Q&A, I've beforehand, I've gone through the ask a question section. I've looked at the questions and I choose the questions based on upvotes. I choose them based on interest and perhaps something that I haven't answered before or something that requires a deep dive that I'm particularly interested in. For example, this Q&A, we're going to do a really, really Big deep dive on rapamycin.

So, we also catalog these questions and we have— some of you may have noticed some team members have been emailing you back with maybe a science reference or a sentence or two about the question that you submitted if I have not answered it on the live Q&A yet. Also, you guys have asked and we delivered. We sent out a— we have a summary of the topics discussed in every Q&A that I have done so far. So the past 39 Q&As, you guys can search through them. You can click on clickable links that'll take you to a time point in the YouTube video. You can find that on your dashboard. If you miss that email, you can always log into your dashboard at foundmyfitness.com/dashboard. Dashboard, log into your account, and you will find the summary of topics discussed in my Q&As on your dashboard.

So I know I've gotten a lot of positive feedback. People are pretty excited about that. This time around, I do a variety of Q&As. Sometimes I will go deep, deep, deep into more than one topic. So some Q&As can go really deep on just a few questions. Other Q&As, I go a little more topical and I just answer a lot of different questions. So I do both types of Q&As. This time around, it's more of a deep dive type of Q&A, so there won't be as many rapid-fire questions this time around. But that again, it changes each time. And so, so it's not always just me answering a few questions very, very deep. It just so happened that Some of the questions that were submitted this time required a deep analysis to kind of get to the bottom of it. So that's what we're going to do this time.

I'll start off by saying that some of the top questions, voted questions, I guess, they're actually— I'm going to be getting to them next month. So ApoE4, there was a question about ApoE4, we'll get to next month. Hyperbaric oxygen is another one we're doing next month, and CoQ10. as well. So those will be coming next month in the Q&A. But this time around, I'm going to go ahead and start off with the rapamycin question. I have here that Arturo and Lydia submitted it. But in fact, I've had many, many, many people submitting questions about rapamycin. And for those of you that are unfamiliar with the term rapamycin, you're about to become familiar with it. So why do we care about rapamycin? So rapamycin is— it's a drug that has been shown to extend lifespan in multiple animal organisms.

Everything from lower organisms like worms and flies, which, I mean, interesting, but okay, like something that's going to extend the lifespan of a worm, why do I really care about that, right? Probably more relevant, it's been shown to extend the lifespan of rodents, lab rodents specifically, so lab mice. And its name, rapamycin, actually it was discovered because it acts on a protein called the mechanistic target of rapamycin, or mTOR, as commonly known. Many of you know about mTOR, have heard of it at least. And so rapamycin, and we're going to get into this a little bit more about exactly what it does with mTOR, but essentially is an inhibitor of mTOR. And like I said, it's been shown to extend the lifespan of many animals, animal models.

And so that's where the interest has come from, generally speaking. It was first isolated for its antifungal properties back in 1972 from soil bacteria. It was found on the Rapa Nui Island. That's how it got its name, rapamycin. And it was found to extend the life of worms and in mice. So mechanisms looking at rapamycin's action found that it inhibited this mTOR protein, the mechanistic target of rapamycin protein. And that was sort of the big finding. So what is mTOR, right? So if rapamycin is inhibiting mTOR and it's specifically Specifically, not just full stop inhibiting it. We'll get into the details of that. But what does mTOR do? For those of you that may have heard mTOR but like don't really know exactly what it is, it's a protein kinase actually.

And what that means is basically protein kinases, they are proteins that will transfer phosphate groups from energy like ATP. They take ATP, adenosine triphosphate, they take the phosphate off that energy. Currency, and they transfer it to other proteins inside your cells. And this allows your that protein to do a function. So it's really involved in a lot of growth pathways, in survival pathways, protein synthesis. And this is probably where most of you are familiar with it. It's essential for protein synthesis, and this is in many different tissues, but probably the most well-known and most relevant, I think, to application is muscle, skeletal muscle. So you need mTOR activation in skeletal muscle to make new proteins. So that is important for muscle hypertrophy.

It is important for staving off muscle atrophy. So very relevant for aging. The mTOR protein, there's 2 complexes of it. So there's an mTOR1 or mTORC1 complex and an mTORC2 complex. So 2 complexes that make up this mTOR protein that you generally hear about when you hear the word mTOR. There's actually 2 components to it. And the main function of the first component, mTORC1, is to regulate protein synthesis and cell growth. And this is required for development. So it's very important during, you know, childhood and adolescent development. It's required for just normal maintenance and also repair. So anytime you're injured, You have to make new proteins. So obviously, again, skeletal muscle is what we we comes to mind because protein synthesis is very critical for skeletal muscle, right?

So mTORC1 is critical for that component—the protein synthesis component of skeletal muscle. It is sensitive to nutrients like amino acids, particularly leucine. So leucine is a major major activator of mTORC1. And also glucose and oxygen act as energy sensors also. It is activated by a variety of other things like insulin, other hormones like sex hormones like estrogen can activate mTORC1. Even reactive oxygen species can activate mTORC1. So there's definitely some other activators. We usually think about amino acids and leucine. It is a major, major, major activator of mTORC1. mTORC2 is involved in the regulation of cellular metabolism.

It plays a very important role in normal cells, but also in cancer cells through its association with what's called the ribosome, which is where protein synthesis occurs. mTORC2 is regulated by growth factors like insulin, IGF-1, another growth factor called VEGF, and other growth factors. During development, mTOR is essential for growth. It's essential for wound healing. It's essential for muscle hypertrophy. I'm saying during development, muscle hypertrophy is also something that's relevant throughout adult life as well. But mTOR activation is important. Protein synthesis, having your children eat essential amino acids, particularly ones that are high in leucine like eggs, Egg whites are a great source of leucine.

And there's also been randomized controlled trials showing that if you feed kids eggs, they grow taller in length. So mTOR, very important for growth and development. Again, anything that's good for normal cells, you can always find cancer cells will find a way to hijack it and use it to its advantage. MTORC, because it is a grow, grow, grow, very strong grow signal, right? Cancer cells like mTORC as well. And so mTORC, you know, cancer is sort of the big, I would say, the double-edged sword here with respect to mTORC activation. Exercise. So during physical activity, we, you know, when you're doing, let's say, resistance training, stress is applied to muscle.

And ultimately, the stress that you apply to your muscle from whatever training you're doing will facilitate muscle hypertrophy or the growth, right? So like for when you're, when you're using your bicep muscle and you pick up a dumbbell, the muscle fibers contract and basically this suspends normal protein synthesis while you're doing that actual contraction. So when you're actually doing a heavy, when you're doing any type of lifting, Yeah. That is stopping muscle protein synthesis. But following the exercise, during the rest period, there's an explosion of protein synthesis. So it really kind of— it's almost like a hormetic response where you have this counter-response that is greater than the initial low-level stressor to counter it.

And it's like so robust that you have this very strong antioxidant effect. The same goes with muscle protein synthesis. When you are doing resistance training, you're stopping protein synthesis in your muscles. And then during the rest period, when you're done applying that force to your muscles, your muscles try to make up for that lack of protein synthesis. And so they explode and they do a high level of it. This happens through mTOR. So, yeah. It's it's really important that mTOR you know is activated for for that reason. mTORC2 specifically is essential for that rapid muscle protein synthesis that occurs in response to resistance training.

Now mTORC1 is the one that is really it's activated by resistance training as well, but it's very strongly activated by nutrients and again it's the leucine. that's really activating mTORC1. So the combination of someone that is doing resistance training and taking in a protein that's high in leucine, you're getting maximal activation of muscle protein synthesis through both of the mTORC complexes. And so, for example, when you have people that are using, you know, as Stuart said, branched-chain amino acid supplements, really the only thing that's important there is the actual leucine. I mean, you could do without the other branched-chain amino acids in that mixture.

But that's why, because you can actually use that in combination with resistance training to improve upon muscle hypertrophy with both the complexes. When you have someone that is not physically active, let's say an older grandparent who is much more sedentary, then they're really not getting that mTORC2 component of muscle protein synthesis. They're not getting the resistance training. But they can still get the leucine. They can still get the mTORC1 activation, and that does make a difference in muscle protein synthesis, and it does make a difference in helping the balance between hypertrophy and atrophy and sort of staving off the atrophy. You can also activate mTORC by other things, glutamine, sugar as well, but leucine is really the most robust thing that will activate the mTORC1.

: On the other hand, obviously, maintaining muscle mass is, you know, it's very important for health and for longevity. And, you know, this is where, if you're thinking about this now, okay, we talked all about mTORC1, mTORC2, what it's doing. Where does rapamycin— like, how is rapamycin going to become a longevity drug if it's inhibiting the thing that's so critical for health, which is maintaining muscle mass. So really only mTORC1 is, I would say, sensitive to rapamycin. You can suppress mTORC2 as well by chronic exposure. And also some tissues are a little more sensitive than others. And I don't know all the tissues off the top of my head. But mTOR— rapamycin strongly inhibits mTORC1, which is the nutrient-sensing part of the mTOR complex. This is the amino acid sensing part, right?

So that is something to keep in mind. And we're going to get into studies that involve humans that are, you know, doing resistance training and looking at muscle mass to talk about that. But you can kind of see how— where I'm getting where I'm getting at with respect to you know mTOR people always think about mTOR like I want to inhibit mTOR mTOR is bad mTOR is bad it can be bad but it can also be really good and context matters and so when does it become bad well it becomes bad in the case of cancer right when you have cancer when you have precancerous cells and you are allowing the survival of them, kind of similar to IGF-1 in a way, which is also very sensitive to amino acids and proteins, and proteins activate IGF-1, and IGF-1 is a very important growth factor for muscle growth.

It's— or maintenance and repair of muscle. It's very important for our neurons, and you want some IGF-1, but again, it's like that thing that you don't want it when you have cancer. So let's talk about some of the longevity research. I would say that about 20 years ago, it was found— rapamycin was found to extend the lifespan of worms. It's been, you know, lots of studies have been done since then. To date, there's really very few clinical trials investigating rapamycin outside of— so I'm gonna talk about some trials with rapamycin on healthy people, but there are a variety of trials that have also been done on people with a disease. And so we are working on a topic page on rapamycin, should be done this month.

I would say that, you know, I'm not going to go into every detail, but you can find more information on our topic page when that is up, and we will send you guys an email, of course, when that happens. So, let's talk about some of the preclinical investigations. I talked about the worms. Later, it was found to extend the lifespan of multiple different genetic backgrounds in animals. It's believed to slow aging by mTOR inhibition. And I'm saying slowing aging, but we'll talk a little bit more about that, exactly what it's doing in mice that... Helps them live longer. Increased autophagy is one mechanism. You know, when you are inhibiting protein synthesis, when you're changing the nutrient sensing pathways, then you are basically sending a signal like, oh, there's no food around.

It's almost like mimicking in some ways can kind of mimic fasting. And by the way, like fasting is not something that you would want to do all the time, right? Like you could not— you can Lose muscle mass if you are not getting enough protein. And so, you know, fasting, you know, you obviously— it should be combined with making sure when you're eating that you're getting enough protein, right? So there's always the other, the flip side of that. So let's talk about some of the rodent studies. There was one that looked at lifespan extension. Treatment began at about 270 days in rodents. So this is about 9 months of age. I would say that's about midlife. So most rodents will live to be between 26 to 30 months. 2 years is about an average lifespan for a lab mouse.

A lab mouse is about, I would say about 2 years is the average life expectancy. So some mice were given rapamycin at about 9 months of age and others were given at about 20 months of age. So that's definitely older age for those animals. Okay. Both groups experienced an increase in what's called maximal lifespan. So they lived actually even beyond the 30 months, which would be, you know, the maximal lifespan. Mean lifespan also increased for females. Mean lifespan really refers to— it's kind of— a good way to think of it would be healthspan. So you're basically, on average, the female mice lived longer because they were, you know, dying less, which we'll find out they're actually dying less of cancer. I'll talk about that in a minute.

So, the mean lifespan increased by 15% for females and 16% and 7% against— it was 3 different testing facilities that participated in the studies. So, oftentimes, there's different genetic backgrounds and differences like that. For the animals that were— for the life expectancy at 600 days, that was the maximum life expectancy, it increased by 45%, 48%, and 22%. But, this was only for females. The mean lifespan increased for males by 5%, 8%, and 15%. This was, again, against 3 different facilities that were doing this. The maximum— the life expectancy at 600 days, so the maximum lifespan increased. It was much lower than what females saw, the 16%, 23%, and one site found 52%. So there's a lot of variation there. It seems to be a little more robust in females than in males.

There have been some follow-up studies that have shown oral rapamycin given to mice at 9 months at various concentrations that basically only maximal and medium lifespan were affected in females. And the male mice only experienced a benefit, a lifespan benefit, when they were given the 2 higher doses. So, lower-dose rapamycin did not have an effect on male— on the lifespan of male mice. Some additional studies, there are different age ranges starting at, you know, early youth, so 2 months of age, all the way up to 24 months and different doses. So there was an increase in lifespan as large as 58% or even 100% in some studies, but again, giving a very high dose, while other studies found no increase in lifespan at all.

So it seems as though protocol, the dose, the timing, and the genetic background all make a difference in whether or not there is a lifespan extension. I think another important layer of interpretation to add is, and this is very important in my opinion, the natural occurrence of cancer in mice, and particularly, you know, because mTOR plays a major role in cancer. That is, you know, inhibiting mTOR is going to lower it's going to help lower the cancer risk. 70% of a common strain of wild-type mice that are used in, like, almost all research, 70% of mice die from cancer. So these mice aren't dying from diseases like humans or cardiovascular disease, respiratory illnesses, you know, they're not. And the types of cancer they're dying from are also very different than humans.

So humans, often we're getting solid tumors. The mice are dying from lymphomas and hematopoietic sort of types of cancers. So, it's a very— mouse biology is very different from human biology in that respect with, you know, the role of mTOR. So, mTOR plays a major role in determining, like, the lifespan of of lab mice because they are dying of cancer. And mTOR plays a major role in cancer. And if you inhibit mTOR, you're going to extend their lifespan. And I'll talk a little bit more why it's, like, it's a little bit unclear. So the propensity of cancer for humans varies, right? So some humans experience a much lower cancer rate than others. Certainly, we experience a lower cancer rate than mice.

But humans have higher cancer rates than some other animals like elephants, which, like, barely ever get cancer. You know, so I think it's important to keep in mind here when we're thinking about lifespan extension in lab mice, what that means, how it's extending their lifespan. There have been some studies that have found a greater risk of infection with rapamycin despite lower cancer rates in these mice. They have a higher risk of infection. And I think that's very relevant and important for humans because... Humans, we are not living in a sterile environment. Okay, these lab mice are in a sterile environment. They're shielded from a lot of infectious diseases. When humans get an infectious disease, particularly in older age, this leads to the disease and disuse event.

Basically, you go into the hospital and you become like immobile, right? You're sedentary and you don't move around and everything just goes downhill from that. You start to lose muscle mass rapidly. You don't ever gain it back like you could before that event. And so I think it's an important difference to point out when you're thinking about rapamycin. Should I take it? Is it going to extend my lifespan? Because it extended the lifespan of these lab mice. But again, lab mice are almost all dying of cancer, and they are living in a sterile environment, and the rapamycin can suppress and make them more susceptible to infectious disease. I think it's a very important context. So let's talk a little bit about lifespan extension and slowing biological aging.

So following some of these rapamycin studies, it was unclear whether the lifespan extension was due to a mere delay in death, especially death from cancer or other preventable causes, like, you know, slowing the rate of actual biological aging. If rapamycin merely delays the death due to cancer in older animals, then you wouldn't expect to see a benefit in younger animals. I mean, maybe, but I don't know that that's necessarily true because you could slow cancer initiation as well. There was a literature review, an earlier literature review that summarized a lot of available preclinical evidence and found rapamycin stimulates locomotor behavior and improved learning and memory across multiple strains. in younger mice.

Rapamycin reduced T helper cell while increasing pro-inflammatory gamma delta T cells. Rapamycin exaggerated age-related bone loss but increased the strength of tendons. Rapamycin increased red blood cell counts. And now you'll find something contradictory in humans. And rapamycin reduced endometrial neoplasms in female mice. but caused testicular degeneration in male mice. Cardiovascular findings, there was not a consistent benefit. So it's not all peachy, right? Then newer review kind of went on and added to some of that preclinical data, summarizing that rapamycin could actually reduce cardiac hypertrophy and fibrosis. And there were cancer findings. So rapamycin reduced the growth of multiple types of cancer, including human cancers that were transplanted into animals.

So animal, like, mice are not coming down with carcinomas and breast cancer and pancreatic cancer. You have to, like, give them a human, you know, tumor transplant, and then it grows in them. But rapamycin, once that happens, rapamycin would slow the growth. No surprise there. I mean, mTOR, if you already have cancer, mTOR activation would help the cancer grow. There were some Alzheimer's disease findings in mice that improved— rapamycin improved cognition, it reduced amyloid beta and tau burden. It seemed to help with some Parkinson's disease. It reduced inflammation and improved motor function. And, again, some more improved cognition. Functions, reduced anxiety, some more immune function. So some studies found beneficial immune changes.

And again, others found that it increased susceptibility to infection, and it also can be an immunosuppressant. So it might also just depend on the dose. That might be what's a defining factor. It, you know, again, there's just— it's hard to translate these things from mice to humans. Particularly because we know of the importance of mTOR and actual, like, strength training and eating enough protein for muscle mass and maintaining muscle mass. There's some non-mouse models, rapamycin studies. So, there's the dog study with Matt Kaeberlein. So, for many reasons, dogs are an excellent model for human aging because they inhabit environments very similar to ours and they consume diets that do sometimes contain human food or very similar to human food.

So there was a study, 24 middle-aged healthy dogs received either a placebo or a non-immunosuppressive dose. That's important, okay? So this was a lower— this was not a dose that could suppress the immune system of the dog. So a non-immunosuppressive dose of rapamycin, they were given 3 times per week for 10 weeks. And there were 2 different doses tested. And at the start of the treatment, the dog's age ranged from 6.6 to about 12.7 years. Dogs live on average between 10 to 13 years depending on the breed. So the dogs that were given the rapamycin, basically there was some improved heart endpoints. So there was improved fractional shortening, ejection fraction, the E/A ratio, which is a marker of function of the left ventricle of the heart.

The dogs were monitored for normal blood parameters. Rapamycin caused no significant adverse effects, although the mean corpuscular volume was decreased. So that means that dogs had smaller red blood cells than before the treatment. And this is something you'll find in human studies as well. So this is a side effect that is already noted In the in the rapamycin literature, honestly, my opinion: I look at that data and I think big deal. Like exercise and sauna have major robust effects on cardiovascular health, including left ventricular function that's been shown with sauna and cardiovascular exercise.

I am not sure that take a person who is You know, doing aerobic exercise, doing resistance training, doing the sauna, that's physically active and healthy, you know, I don't know that they would benefit from rapamycin. That's my opinion so far. I might be convinced otherwise. So far, I'm just not convinced of the mouse data, which I don't— I think, you know, now maybe mTOR, maybe rapamycin used as a cancer treatment, that's a different story. As a prophylactic, quote-unquote, longevity drug, I'm not seeing that yet. I'm not seeing that it's going to do anything better for humans that exercise and healthy lifestyle factors like sauna are going to do.

And, in fact, if people start just willy-nilly doing it themselves, they could even run into danger because rapamycin can have negative effects. Particularly when you're taking certain doses. So there's another ongoing study in non-human primates, marmosets, and so far, sirolimus is given to them either at 3 weeks or 14 months. It's really a safety and effects on longevity study. So they're 5— they're actually, they were 5 to 9 years old. They were given rapamycin for either 3 weeks or 14 months. Sorry, in case I confused you, but the marmosets' age was 5 to 9 years old beginning in the study. They typically have an average lifespan of about 5 to 7 years.

So some of them are already in, you know, older life when they were given the rapamycin, but they can have a maximum lifespan of up to 16.5 years. So some marmosets can live really long. I want to go into some of the clinical studies that I mentioned. I would say, you know, it's used, it is used, rapamycin is used. There's a lot of analogs, and I'm not going to, like, get into all those. That'll be on the topic page. But it is used with, you know, as a multipurpose drug with anti-cancer, immunomodulatory, and metabolism-altering effects. It became FDA-approved as a pharmaceutical drug for a small number of diseases back in 1999. And since then, there's been a lot of clinical research looking at rapamycin or analogs, mTOR inhibitors, you know, for a variety of different diseases.

Research investigating the use of mTOR inhibitors and rapamycin in extending longevity in humans is really in its early stages. There's no FDA approval. I think that there's, in my opinion, I am not convinced that rapamycin is, like, a great longevity drug for humans. It seems to be a pretty cool one for mice that are all dying of cancer and living in a sterile environment and aren't using the sauna and exercising and doing resistance training and all of the above, yada, yada, yada, right? So I'm just going to go in, you know, it's definitely used for preventing rejection of organ and tissue transplants. Like, there are a lot of uses for rapamycin, and it's being used in the clinical arena for a variety of different diseases. And, you know, there's uses for it.

I just want to talk about a few clinical studies, and I will have a graph on our topics page that covers the literature of other studies. But so there was some studies looking at generally healthy adults older than 70, and there are 25 generally healthy adults older than 70. They were given a rapamycin dose of 1 milligram. So this was probably on the lower end of some— compared to some of the other studies, which I'm going to talk about in a minute. And it was a feasibility study. There were no major effects on health, cognitive performance, physical performance, or immunity, but participants did have decrements in hemoglobin, hematocrit, red blood cell volume, and other erythrocyte measures.

Again, things were going down, they were smaller in size, so I would say that was— you know, that's something to take note, right? Now, another study was done. This is a small study in young adults that were 25 years old, about 8 of them, and they were given 1 dose of rapamycin, just once, much higher doses, 16 milligrams of rapamycin. And so, because rapamycin inhibits mTORC1, which is basically sensitive to leucine, what happened was muscle protein synthesis was blocked, in fact. So, basically, they were fed essential amino acids, and typically, the protein synthesis goes up by 60%. So, that's what happened, I think, in the placebo group. But when rapamycin was given, it completely blocked that protein synthesis increase.

So, there was no protein synthesis benefit in muscle from eating essential amino acids when a high dose of rapamycin was taken. And then there was another study, again, on 15 healthy young men who were also given a relatively high dose, 12 milligrams of rapamycin. And, again, I mentioned that mTORC2 is mostly responsible for the exercise-induced muscle protein synthesis that occurs. you know, from resistance training, that was blocked by a higher dose of rapamycin by about 40%. So usually, there's a 40% increase in muscle protein synthesis following resistance training. When those young men took rapamycin at 12 milligrams, that didn't occur. So they didn't have that muscle protein boost. And another study was done prior to exercise training.

And again, mTORC stimulation, mTORC1 stimulation was blocked. And so there was not full muscle protein synthesis following exercise and resistance training. So even though— and I couldn't find the dose on that one, but even though mTORC2 is supposed to not be sensitive to rapamycin, again, it's probably dependent on the dose. And I don't know to what extent muscle tissue, the mTORC2 is sensitive to rapamycin, but that may also be a factor, but certainly dose, certainly dose would be a factor. So some of these studies were really kind of testing high doses on the high end. And then again, there's a variety of other clinical studies that I'm not going to talk about, but you can read in the topic page.

My conclusions, and I think this is what everyone was waiting for, I really had to do a deep dive to come up with conclusions. In fact, it was so deep that it's a topic page now. And I wasn't planning on doing a topic page, but there we have it. A lot of information that my team and I gathered on rapamycin. I personally am not convinced that rapamycin is going to do much beneficial for humans, physically active humans that are healthy and physically active. Doesn't mean it doesn't have benefits, or maybe someone who's overweight and sedentary. And, you know, I'm talking about people that are physically active, healthy, actively looking for everything they can do to improve their healthspan.

I don't think that rapamycin on top of the physical activity and sauna use and everything else is necessarily the way to go. I think that many lifestyle factors, aerobic exercise, Resistance training being the top, followed by sauna, good sleep, whole foods diet with micronutrients, avoiding processed foods that are high in refined sugar, taking, you know, like a robust dose of omega-3. I think these are immensely beneficial for cardiovascular health, which is one of the major killers, you know, cardiovascular disease is a major killer in— it's number one in most developed countries, and overall health.

And with respect to the cancer, you know, I think the exercise, frankly, has been shown as one of the best lifestyle factors and strongest lifestyle factors that can prevent cancer and even, in some cases, treat, help as an adjunct treatment with cancer. So, again, I think there are things that can be done that, in our diet and lifestyle, that are just as good, if not better, than rapamycin. And I think that— Yeah. Frankly, you know, I would honestly be stunned if rapamycin had similar lifespan-extending effects in humans like it does in sterile environment lab mice that are dying, you know, mostly of blood cancers. So, I think people that are really interested in extending, certainly, maximum human lifespan, what the way and the road to that is going to be gene therapy.

And it's absolutely... Possible and probably going to happen in our lifetime. In fact, sooner than we think. So there you have it. I'm certainly not— I'm not going out there trying to get rapamycin. I certainly wouldn't suggest anyone else either. So I'm looking to see in the chat if there are any— if there were any questions related to rapamycin. But I do see some Other questions that people were submitting. There was a question about ubiquinol, and we are actually going to do a deep dive on that next month, and we have a topic page coming on that as well. So CoQ10, as it's referred to, it is an enzyme that we actually have inside of our cells. It's involved in mitochondrial function, energy production. There are 2 forms of it. You can take it exogenously, of CoQ10.

There's ubiquinone and ubiquinol. Ubiquinol is the reduced form, and ubiquinone is the oxidized form. The reduced form, ubiquinol, is much more bioavailable than the oxidized form. So you can get more bang for your buck. At a lower dose. However, many nutraceutical companies have figured this out and they've decided because it's more bioavailable, they're going to raise the price. And so, so you're going to pay more for the ubiquinol than you are the ubiquinone, but you have to take less of it. So I don't know, maybe it just evens out in the end. I, you know, I've never really done a head-to-head comparison, but, um, but there you have it. And in the chat, I'm sorry if I butcher your name.

Elias is mentioning on my latest tweet, Instagram reel that I did, I mentioned a new study that came out on coffee consumption and being associated with basically longer lifespan and improved cardiovascular health. So it was 2 to 3 cups of coffee, and it was both ground coffee, instant coffee, and even decaf coffee with ground coffee having the most robust effects on lowering all-cause mortality. And Elias is saying that coffee gives him anxiety and dehydrates him, messes with his sleep. So he's wondering if there is a way to do it without hurting himself. So first of all, yes, there are many different genetic SNPs that regulate. In fact, we have this in our genetic report.

If you have a 23andMe test you have done or AncestryDNA test you have done, you guys have unlimited genetic report uses you can use. We haven't updated it in a while. We will be updating it again in the future, but we have on there some genes. So there's SNPs in genes that change the function somewhat. Some people, when they drink coffee, they get more anxiety, and other people, when they drink coffee, They're very, very sensitive to sleep disruption. And we actually have that data in our genetic report, so you might want to take a look at that. But to get to the point of the question, you know, it's because the decaf coffee also had some, you know, had similar effects on longevity and lowering the risk of cardiovascular disease. Now, ground coffee had the most robust.

Ground coffee has the highest polyphenol content. So there's been studies comparing polyphenol content in ground coffee versus instant coffee and decaffeinated coffee. And both instant and decaffeinated are somewhat processed a lot, like more than just ground coffee is, right? And so some of the processing, you know, polyphenols are, they are, you know, subject to degradation and, you know, sensitive to certain heating processes to some degree. And so what I think, I think that polyphenols are probably largely responsible because, again, it wasn't the caffeine because decaf also had it. And so the question is, okay, well, what are other sources of polyphenols?

Well, one, decaf coffee may not give people anxiety and may not disrupt sleep because With the SNPs that I was referring to, it really comes down to sensitivity to caffeine, not coffee. We oftentimes synonymously use those words interchangeably, but there is coffee that is decaffeinated and has very, very, very, very little caffeine. So trying a decaf coffee would be my first. If it were me, that's what I would do. I would say, oh, I'm going to try decaf coffee, which still does contain polyphenols. But there are a variety of other foods that have polyphenols, and there's also supplements, and we're going to talk about a few today, actually.

So, you know, we have a polyphenol topic page you can look at, but anthocyanins from blueberries and blackberries are one, and that's been shown to improve cognition. There's cocoa polyphenols as well. CocoaVia is another one. So I do think there's other possibilities. There haven't been long, large, large, large studies like the one I posted yesterday because, I mean, There's so much interest in coffee. I mean, so many people drink coffee, right? And so, and we've talked a lot about coffee in these Q&As. In fact, if you go back to the PDF I mentioned at the start of this Q&A, you'll find I've talked about different methods. I've talked about espresso versus ground coffee and how espresso has benefits as well. We've talked about filtering our coffee versus not filtering it.

And And so all that stuff can be found in our previous Q&As. And we have, again, lists of those in that PDF we made that you can find on your dashboard. So go to the dashboard, foundmyfitness.com/dashboard. And then you can look into all those things about espresso and different types of filtering and all that, that you may be interested in. So I'm going to move on to another Let's see. There was a question about bone density, and this is also very relevant to aging. We've talked about bone density before in the Q&As. You know, we've talked about specific studies or certain— a certain supplement someone asked about. So, again, you can go back and you can search those— the PDF for bone density and then find all the Q&As and what specifically we've talked about in the past.

So generally speaking, bone density is very similar to muscle mass in that it is hard to increase in older adulthood. It really peaks around the 20s and 30s, much like muscle mass, and it slowly decreases over time. And of course, bone density and maintaining it is important for— much like muscle mass, it's important for preventing frailty, right? That frailty risk. And that is something that really starts to hit us certainly in the 7th and 8th decade of life, you know, even earlier in the 6th decade of life as well. And so the best things that you can do to actually increase both muscle mass and bone density is exercise, and weight-bearing resistance exercise are really factors that can help. Really help build and stave off the decrease of bone density as we age.

And so, again, just another really important reason why weight training is so critical for improving our healthspan. There are lifestyle factors that decrease bone density. So having greater than 3 alcoholic beverages a day can decrease bone density, smoking, being underweight. Rapid, rapid weight loss, low calcium intake. 1,000 milligrams per day is what we're supposed to be taking in for calcium. And if you're not meeting that requirement, then supplementation is also an option. Vitamin D deficiency also really accelerates bone mineral density decreases. And vitamin D is really maximizing your absorption of calcium. It increases the absorption anywhere between 40% to 60%.

So you could be taking in all the calcium that you want, but if you're vitamin D deficient, it's like a very inefficient process and you are not absorbing your full amount of dietary calcium. So vitamin D is also extremely important for bone mineral density. There are common medications that also decrease bone mineral density. Anything that's going to block sex hormones like testosterone and estrogen. And then a variety of other, like, proton pump inhibitors can do it as well, and some other medications. I would say— so we're going to talk about, like, again, exercise is the most effective, I would say, lifestyle factor that— one of the most effective lifestyle factors that can improve bone mineral density. So there was 97 randomized controlled trials that were analyzed in a meta-analysis.

And there was a variety of different exercise interventions, which is kind of why I like this study. There was aerobic exercise, there was resistance training, there was combined both aerobic and resistance. There was mind-body exercise. So this is like tai chi, yoga, dance. And it was found that like there's these different exercises interestingly affect different areas of the bone mineral density, different areas in the body. So the mind-body exercise, the yoga, the tai chi, the dance, was optimal for lumbar spine and femoral neck bone mineral density. Resistance exercise was optimal for hip bone mineral density. Aerobic resistance combined— and combined with some like mind-body, so like, you know, also doing some yoga or dance was the best for lumbar spine bone mineral density.

And then all exercise interventions affected the femoral neck bone mineral density, and aerobic and resistance exercise combined really was good for total hip bone mineral density. So it really seems like aerobic resistance is affecting the bone mineral density in the hips, and the mind-body is really lumbar spine, which kind of makes sense. You're doing a lot more of the spine stuff with with the mind-body types of exercises. And resistance, again, is hip. So I thought that was— I think that's kind of interesting to know the different regions that the different types of exercise affected. There was a meta-analysis that also found that resistance training in combination with creatine supplementation, it improved both upper and lower body strength. It increased fat-free mass.

It increased muscular endurance, but it also increased bone mineral density. So at least there does seem to be a few studies showing that creatine supplementation in combination with resistance training can slow age-related muscular decline and perhaps even bone mineral density decline. There's another— and you can find this, by the way, you can find those studies, that meta-analysis on creatine and resistance training on our creatine topic page at foundmyfitness.com/topics or just click on the topics in the toolbar section. So we also have a hydrolyzed collagen topic page.

And there is— there have been some studies looking at hydrolyzed collagen in combination with calcium and vitamin D may slow bone loss, and particularly in postmenopausal women where bone mineral density losses are exaggerated, right? Once women stop making as much estrogen, it really affects bone mineral density. So 5 grams of hydrolyzed collagen powder or a placebo, and basically the women were then given calcium. They were given about 0.8 grams of calcium and about 800 IUs of vitamin D depending on their body weight. And they had statistically significant increases in bone mineral density of the spine and increases in the femoral neck and the placebo group compared to placebo groups. So they were— they had much larger increases.

So that— I thought that was interesting, well, because calcium and vitamin D I knew, but it was interesting that they added the hydrolyzed collagen powder. And I think I should have mentioned that both the placebo— the placebo had the calcium and vitamin D, but they didn't have the hydrolyzed collagen powder. They had maltodextrin. And so they did experience increases in bone mineral density, probably largely because they were getting calcium and vitamin D. But the hydrolyzed collagen powder on top of the calcium and vitamin D was even better. So that I thought was interesting.

There was— and there was another hydrolyzed collagen, vitamin D, calcium trial, again, looking at the 2 groups that were either given 500 milligrams of calcium and then a very low vitamin D supplement containing only 200 IUs. And then they were given 5 grams of either hydrolyzed collagen or a placebo. And again, bone mineral density was increased in the one taking the hydrolyzed collagen powder. So interesting that maybe— and there's another study that found hydrolyzed collagen powder by itself did not affect— there was no effects on bone health. So there's something that maybe, you know, factored in that the hydrolyzed collagen is adding to the calcium and vitamin D, but it absolutely seems to require the calcium and vitamin D. So it's not just a hydrolyzed collagen by itself.

There's some interesting studies on— I would say not a ton of literature on ginseng. I just thought I would bring it up. There's 3 grams of ginseng per day that increased osteocalcin and And basically, it's basically showing that it's affecting bone resorption and bone formation. And so, the ginseng seemed to help with that so that basically you're not losing as much bone mineral density. But really, it's just one study. So, I mean, I wouldn't just go out and start taking ginseng, but I wanted to mention it. And the same goes for a mixed tocoferol. So, this is Yeah. I've talked a lot about the possible dangers in high-dose alpha-tocopherol, and high dose being like 1,000 IUs a day.

But even to some degree, 400 IUs a day, I think people taking 400 IUs a day should go with a mixed tocopherol because if you just take a high dose of alpha-tocopherol, there's 8 different types of vitamin E that we get from our diet. There's 4 different tocopherols and then there's 4 different what are called tocotrienols. And one of the different types of tocopherol called gamma-tocopherol is a— it's more of a— it modulates inflammation, dampens inflammation. And alpha— too much alpha-tocopherol, dietary alpha-tocopherol— actually, I should say supplemental, not dietary— can inhibit gamma-tocopherol. And so it's nice when you're taking it, you want to get a mixed variety. And there are supplements out there that do mixed varieties.

And I should say that the most recent NHANES study that came out— NHANES are like the big nutritional surveys that are done to look at micronutrient deficiencies and insufficiencies in the US populations. And the most recent one that was published, 2017, I think it was, They're always like years behind because it takes years and years and years to like aggregate and analyze all this data. But 75% of people in the United States do not get enough vitamin E from their food. In other words, they're insufficient in vitamin E. And vitamin E is important. I mean, it is an important micronutrient. And so, I don't know that it's— again, if you're taking a multivitamin, you are getting— you're getting the RDA. And so you're going to meet that requirement, right?

But a lot of people aren't getting it from their food. So there was a double-blind randomized placebo-controlled trial that showed 400 IUs of a mixed tocopherol per day was able to change the bone resorption biomarkers quite significantly. And so, and this was in postmenopausal women. So basically, it's possible that mixed tocopherol supplementation in postmenopausal women may help with preventing bone loss by stopping the resorptive activity, which is something that ginseng was also doing. So I thought that was interesting as well, just to mention. But I think that that's it for my bone mineral density. I kind of did— I went deep in that. I I went deep because I think it's really an important component of aging, of healthy aging. I'm a woman. I'm not postmenopausal.

I'm not, you know, premenopausal. I mean, I'm not perimenopausal yet, but one day, you know, that will be me. And so, doing these, you know, these lifestyle, making sure that I'm implementing all the lifestyle factors that are robustly known to affect bone mineral density, I think, is a good idea. So there was another question about apigenin and what I think about taking apigenin for helping with sleep or helping stay asleep. I think this question came up, maybe some influencers had talked about it. We covered this before in Crowdcast number 29. I will say, so apigenin is a flavonoid. It is found in certain fruits and vegetables, including chamomile tea. There is really, there's just very little data on, like, making a strong claim.

I hope no one made a strong claim because there's very little data on it. And it's kind of like when I just said the ginseng, I'm mentioning it, but I'm not necessarily saying that going out and taking ginseng is really going to do anything. I just thought it was interesting. We really need more data, right? Whereas the other things, there was meta-analyses on them, right? There was multiple, multiple studies. So there have been some— there actually have not been any clinical studies evaluating apigenin's ability to improve sleep. There are studies on apigenin-rich foods like chamomile tea, which is the big one.

And so there's like one cross-sectional study showing it helps with sleep chamomile tea can help with sleep quality, and even compared to placebo, or even chamomile can improve sleep quality relative to placebo. There's really a lack of evidence on apigenin supplements. In fact, I haven't even, like, I don't even know what supplement manufacturers are making it. Of course, it's another concern. But I would, I would stick to eating foods that are rich in apigenin, which I'll talk about, but— and mostly chamomile tea. Chamomile tea would be a great thing to drink at night before bed. And there is some evidence with chamomile tea. So that would make more sense. Other food sources are grapefruit, parsley, onions, oranges, rice, wheat sprouts, and again, chamomile being a major source.

There's also the parsley. Parsley is a really big source of it as well. And celery is a good source of apigenin as well. So celery is also a major source of it. So those are the food sources and the chamomile tea would be the one that I think if anyone that wants to experiment, I wouldn't go out and get an apigenin supplement. I just don't. There's just no evidence on it. And again, it could be like clover leaf or something. Like, I don't even know what, you know, you don't know what you're getting with some of these types of flavonoid supplements if you're not finding a reputable source. Not to mention, again, it's like there's just no data on apigenin supplementation. So I'm not sure I would start supplementing with it. The next question is about urolithin A, and Ernest submitted it.

He says, urolithin A seems to have a lot going going for it, but eating pomegranate may not be effective unless we have the proper microbiome to convert it to urolithin A. So what are some ways we can help our microbiome capable of this conversion? So for those of you going, what is urolithin A? Urolithin A is a gut microbiome-derived natural compound. It's referred to these days as a postbiotic, right? So prebiotics are fermentable fibers that our gut bacteria use, right, to make a variety of different beneficial compounds or just to help feed and fuel making more beneficial bacteria. Then there's probiotics. You can take actual bacterial species, right? You can supplement with them. You can eat foods that have probiotics that have been fermented, right? And then there's postbiotics.

And postbiotics are compounds that are essentially made by the bacteria in your gut. And you can find these as supplements as well, different types of postbiotics. Urolithin A is one. And Urolithin A is There is a supplement. I think there's just one I know of. They may have a patent on it or something. MitoPure makes it. It's extremely expensive. I bought a 1-month supply or 2. I think it's like you have to buy 2 months. They force you to buy a 2-month supply. It was ridiculously expensive. I didn't notice anything. I felt like I was taking a placebo. There was nothing that I noticed from taking it. And as I dive into this, you're going to probably figure out why that is. So urolithin A is a gut microbiome-derived compound.

Only 40% of people naturally convert the dietary precursors of it, which are different types of flavonoids and polyphenols and stuff that then are converted into urolithin A. There's been a variety of studies showing that urolithin A can improve cognition, it can improve endurance in humans, it can improve mitochondrial biomarkers of mitochondrial function in humans. So, and then there's tons of preclinical data as well. There's been a lot of preclinical data looking at mechanism. And so urolithin A increases mitophagy. So mitophagy is a type of autophagy that is very specific to mitochondria. And what it is, is it's the clearance, and most often it's a selective clearance of damaged mitochondria.

And oftentimes it'll be followed by, particularly if you're doing— if you're a physically active person, mitochondrial biogenesis. And so it's kind of this cool way or cool hack to out with the old, in with the new, right? You're getting rid of old damaged mitochondria through mitophagy, which also, you know, when you're fasting, you can also increase mitophagy as well. But urolithin A is a pretty powerful inducer of mitophagy. And so the idea is, oh, you take some urolithin A and combine it with exercise, and maybe you're going to have, like, you know, younger, healthier mitochondria, right? Okay. So let's talk about the compounds needed to make urolithin A. So there's a— this does happen in the human gut and there's 2 steps.

So the first step, you have a certain type of bacteria that degrades the tannin and there's different types of strains, Lactobacillus planetarium, Lactobacillus paraplanetarium, and Lactobacillus pentosis. They convert what are called ellagitannins into ellagic acid. So the ellagitannins converted into the ellagic acid then get converted into the urolithin A. And ellagitannins are really high, extremely high in pomegranate. In fact, it is like the best source of ellagitannins. There are other sources of ellagitannins. So, um, Other types of fruits, particularly berries: strawberries, grapes, blackberries, raspberries, cranberries, pomegranate, of course, as I mentioned, and then guava and pecans also have ellagitannins, and walnuts, walnuts as well.

So there have been some preclinical studies that have fed ellagitannins, high ellagitannin-containing food like the ones I just mentioned, all those berries. And, you know, they were able to basically help convert the ellagitannin into eventually the urolithin A. There was one study that at least showed that 4-day supplementation with raspberries didn't change the bacterial profile in a way. So eating those foods, eating the strawberries, eating the pomegranate, eating the— Yeah. Eating the source of the ellagitannins, what it does is actually increases the species of bacteria that can convert ellagitannins into ultimately your urolithin A. And so the idea is, is that, well, maybe you don't have much of the bacteria that can do that, but if you eat more of the foods that contain these ellagitannins, that will help bloom that bacterial number in the gut.

And so that has been shown to happen. It's not always the case, but 4 days may not have been enough. I would imagine, you know, 4 days of eating raspberries, you'd have to probably be a lot more consistent to affect the— statistically significantly affect. the bacterial number in the gut. So that is one way to increase your lithin A production is just eating more of the foods that have the ellagitannins that can convert it because that itself does seem to affect the bacterial number. The other thing is the food matrix. So it seems as though the food matrix may be beneficial as opposed to just Even just drinking the juice or taking a supplement, which doesn't surprise me at all.

Having that food matrix, so like eating the pomegranate and actually even having the fiber, the fiber is sort of part of the food matrix and pomegranate arils are very high in fiber. The ellagitannins are also the tannins, you know, the the pith part, the white part, if you take— if you're peeling the pomegranate and it's like underneath the skin, that bitter-tasting part, eat that. That's like what really has the ellagitannins. And that probably will both increase the bacterial number and it'll increase the precursor to make the urolithin A. So I think while there is some ellagitannins in the pomegranate juice and there's been a variety of studies showing benefits from pomegranate juice, Interesting.

Eating the food matrix, so again, having the arils and having that specifically that bitter-tasting part of the pomegranate is better than the juice with respect to bioavailability and also with respect to being able to increase the bacterial number in the gut so that you can even make urolithin A. And the fiber also affects it by slowing the transit time, which then allows the bacteria more exposure to it. So the fermentation process is happening and they're able to make, you know, it affects the bacterial number and it also affects the ability to make urolithin A, right? And there's a variety of, again, a variety of different type of species that are associated with high urolithin A producers versus low. One of them is Akkermansia muciniphila.

Which is a urolithin, a high urolithin producer. So people that have a lot of acromantia mucinophilia are able to produce more urolithin A from eating foods that contain it, like pomegranate. Well, guess what increases acromantia mucinophilia? Fish oil. Fish oil increases it. So again, another way you can increase some of these bacteria, supplementing with fish oil has been shown to increase Akkermansia muciniphila. So I thought that was also really interesting. And again, the pomegranate juice, there is benefits to that, but the food matrix is just— it's just much better in terms of bioavailability of urolithin A. So I think that sort of answers the question with respect to how to increase. I hope that helped. And really, I personally do not plan on buying that MitoPure again.

I thought it was so overpriced and I don't even— it doesn't have a food matrix. So I just, you know, I just don't know at the end of the day. I mean, maybe I'm wrong or maybe we can just start, you know, eating the pomegranate and taking our fish oil that increases the kind of bacteria that helps convert the ellagitannins ultimately into urolithin A. So, that's my thought. If we can, you know, be a little more frugal in what we're supplementing with, I mean, you just don't want to have 40 supplements, you know. I mean, you just got to like— there's a limit. Nick's asking my thoughts on PQQ. That was a supplement I used to take.

There have been a couple of studies showing that it can improve mitochondrial function or biomarkers of mitochondrial function and some Specifically, it improved cognition. And I don't remember what aspects of it off the top of my head, but it did, it had in human studies. And so that was something that I was supplementing with for a while and it just kind of fell through the cracks. So I do think that, you know, could be beneficial. Stephanie is saying in the chat, there are several scientists who have said they support Mitopure. And she's asking about my anecdote about can you even feel supplements in your body? So, you know, I'm sure there is some science behind the MitoPure. I don't know how robust. I didn't notice any changes. Like, for example, I've been supplementing with creatine.

I use a variety of, you know, heart rate max and my VO2 max and things that I'm doing when I'm doing my Peloton. And it's clear as day, creatine improves my endurance function, like my VO2 max, my— I mean, it is very clear that I am able to bike faster for longer periods of time. And I have data for that. I do not. I have not seen any data-driven improvements with Mitopure. Now, maybe I need to take it for X many months. Maybe 2 months wasn't enough. I don't know. And I certainly didn't measure any of my mitochondria. So perhaps there was something happening in my mitochondria. But the claim is that you're going to— it's going to improve endurance. That's the claim Mitopure makes, and that's the claim— You know, that's part of the science, right? That urolithin A was shown to improve.

I just didn't— there were no measurable improvements in my endurance when I was taking urolithin A versus my 5 grams of creatine a day. So, you know, again, I don't know. I guess I just don't know, you know, at the end of the day, I can't say with certainty That it's worth it. There's not enough studies on it. A lot of the supplements that I do think are staple, like omega-3, vitamin D, multivitamins, I think there's just— there's tons and tons and tons of evidence versus like 2 studies with, you know, the Mitopure. So, you know, again, it could be that we just lack the data and we'll get more data and we'll go, oh, we need this different dose for this amount of time. And Rhonda, you weren't doing that. And I was like, oh, okay. Well, then maybe I should do that.

But until I have those parameters, I'm just not going to waste my money on Mitopure. Okay. So another question was submitted by— and I found some interesting— this was an interesting learning experience for me. Margaret asked, she says, I've read that luteolin and quercetin are difficult to absorb and saw a claim that their pharmacokinetics are greatly improved in liposomal preparations using olive palmist oil. Is there any truth to this, or can you just take it with a fatty meal? So quercetin, we have a topic page on it. It's something that I usually— I don't— I have the supplement, and I was supplementing with it during COVID And I, you know, there could be an argument to supplement with it again. You know, there have been some effects with senescence, and it's anti-inflammatory.

It's found in a variety of foods. So, I drink buckwheat tea, which is a dietary source of it. I also eat capers. Both those food sources are high in quercetin. There's also apple, onions, tomatoes, broccoli, lettuce, black and green tea have it as well. So, it has antiviral properties. That was kind of like my major reason for taking it when COVID was a A little more scary to me, but I do have many bottles of it, and now that I have the information that I have, I might actually take it again. Let's get to the bioavailability. So it actually has a really low solubility. It's it's basically like one percent bioavailable in humans. That's like incredibly low. Liposomal formulations versus non-liposomal formulations.

So there is some evidence that basically it can increase— liposomal formulations can increase the stability of polyphenols, including and not limited to quercetin. It can improve the liver accumulation of it. So sort of like a slow-releasing reservoir in a way, so it like can prolong the half-life essentially. And there's better intracellular passages. So basically, liposomal formulations can get inside of cells better than non-liposomal formulations. So there have been some studies looking at dietary fat and how dietary fat can improve quercetin bioavailability. And this has been studied in a human crossover study.

Where a muffin containing about 15.4 grams of fat, so 30% of the energy was from fat, it was taken with a quercetin supplement and it increased the plasma quercetin levels by about 32%. Compare that to the muffin that was low fat, so it was instead of 30% of energy from fat, it was 1% of energy And basically, the absorption was 32% higher when the fat was taken with quercetin. And there was another study showing that the phytosome quercetin, so that is something that I think I did buy from Thorne, I believe. I have quercetin phytosome. And I did, at the time, I was just like, oh, this is probably better, but I didn't, I hadn't looked at all the data. And so, phytosome is much like liposome. It's just a little more distributed throughout the liposome.

And it dramatically increased the bioavailability. So, basically, while quercetin concentrations, if you look at the area below the curve. It's always below 10 nanograms per mL, but the phytosome basically made it concentrations of 100 nanograms per mL and up to even 170 maximum. So, significantly more quercetin in the bloodstream after a phytosome versus just a regular tablet. Big difference. And this is where the luteolin comes in because As far as I know, the only companies that are making luteolin supplements are— so Swanson has one and Life Extension has one, the Autophagy Renew, I think it's called, or Cellular Renew or something like that. And I don't think— I'm not sure if either of those have a fat source in them.

But yet again, So luteolin, it has been shown to have neuroanti-inflammatory effects. It's been shown to help improve, like, for example, with COVID-19, a small trial showed that luteolin supplementation helped people regain their lost sense of smell quicker than a placebo. And so there's a variety of studies that have showed anti-inflammatory effects, just all kinds of benefits. Particularly, I'm interested in the neuroinflammatory benefits in the brain. But it's one of those, again, it's one of those flavonoids that is dramatically improved from a basically liposome or even taking it with fat.

I think taking the supplement with a fatty meal seems to be sufficient because at the end of the day, if you can't find a reputable source of a phytosome or liposome luteolin or quercetin or whatever. Now, Thorn is pretty reputable. I don't have any affiliation with them, but they have the phytosomal quercetin, which I do have. I think taking it with a fatty meal, like I just mentioned, like this muffin with, like, you know, 30% of the energy coming from fat. So, like, what, you eat an avocado, you take your You know, it might even be something to do with a lot of these flavonoids, including, I wonder, the ellagitannins, which we just talked about.

It'd be really interesting if you, like, made a smoothie and you blended the pomegranate and the pith part that's a little bitter, add some raspberries, but add avocado as well. And I always add avocados to my smoothie, like my when I'm doing my blueberry kale smoothie. So the blueberry, the anthocyanins in there are— I think anthocyanins are also more bioavailable with the fat as well. So with the luteolin, the same thing. So basically, you're getting— if you're taking just normal luteolin without a phytosome or liposome, the area under the curve, like in your plasma, is about 1.97. When you do it with the liposome, it goes up to 10.7. So it's like tenfold higher almost, right? Pretty significant, I would say.

So to me, it kind of convinced me that I think that it's a good idea to take, certainly, at the very least, take these supplements with something that's like higher in fat, like an avocado. That would be the easiest, the lowest-hanging fruit thing to do, in my opinion. Nirvana is asking in the chat, what the best way to take a curcumin supplement? Again, I'm glad you asked. So lots of data on curcumin bioavailability as well being dramatically improved in phytosomal form. And again, so that is— it's a liposome. And what it's doing is it's bypassing some of the liver, your liver getting rid of things that are xenobiotics, right? Things that are not vitamins or minerals or something found in our body naturally. Liver sort of gets rid of it. It's like, oh, what's this?

This is not supposed to be here. So it slows that. So you're already kind of increasing the half-life of it in your bloodstream. And then the other thing the phytosome does is it really, it helps get it into your cells better. And so there's been a variety of studies looking at the curcumin phytosome, which is called Meriva, M-E-R-I-V-A. And that is what I take. I sometimes I take it on a daily basis. I if I like it helps with delayed onset muscle soreness for me, and there's some clinical evidence on that, and there's also some intervention studies.

I wouldn't say they're the greatest, like well-controlled studies, but helping showing it helps with like lowering inflammatory biomarkers in people with osteoarthritis, improving their walking distance, improving Walking gait and speed, and then there's some other studies looking at moriva, which is again curcumin phytosome, and pain relieving effects. That's another thing I will take it for. And so I don't often get headaches, but every once in a while, like you know, maybe I didn't drink as much water and I got too much heat stress, and so I was a little dehydrated. It helps me with with that as well. And there's been studies comparing directly moriva to ibuprofen and to Tylenol. And at a dose of, I think it was 1 to 2 grams, it had similar pain-relieving effect in people taking it.

So I do take a curcumin phytosome and it's called Meriva. I personally like— I've tried a couple of different brands and I really— something about the Thorne Meriva, I've— it's just, it works for me. But, you know, you guys can try, you know, other brands if you— you know, there's a variety of different— companies that make curcumin phytosome. Would phospholipid-rich foods be preferable for the absorption of luteolin and others compared to regular high-fat foods? It's possible, but I think that, you know, well, if you look at studies that are done, they usually aren't unless the phospholipid preparation contains the active component in it, which would be the phytosome, right? Most dietary studies are just doing a high-fat, a higher-fat meal.

So, you know, the question is, oh, well then do I have to supplement with, you know, sunflower lecithin or something with it? And I don't know, like, you know, maybe, but we don't— at least we know for a fact if you take a higher-fat meal that it's going to increase the absorption, right? So I tend to think that might just be something easier to do, or just go with the phytosome. So buy something that is a phytosome form like the quercetin, which comes in phytosome form, or the curcumin, which comes in phytosome form. With the luteolin, I don't think that it really comes in phytosome form. Although somebody can look up the Life Extension Cellular Renewal and tell me if there might be phospholipid in that. I just don't remember off the top of my head. So yeah, it's possible.

But again, eating a high-fat meal also has been shown to improve absorption. I do want to get to this last Okay. Well, there's another— there's a couple more questions, so I'll have to have some for next week because these were really deep dives. But this one we talked about last month. And so Margaret submitted a question, please discuss the GRAIL test gallery. Is the rate of false positives known? How often do we repeat it, etc.? So we talked a little bit about this briefly about a blood test. That it's called a liquid biopsy. And it's basically sampling and analysis of a non-solid biological tissue. So it's blood essentially. And tumor cells, they release genetic information into the blood. And that can be analyzed for cancer, gene changes, or it's called circulating tumor DNA.

So there's blood-based analytics for the detection of tumor cells or tumor DNA. And so this uses like a cell— it uses a— the GRAIL test, it's a multi-cancer early detection blood test. Now it's called early detection, but it's actually much better at detecting later stages, and it can detect some cancers, early stage, but not all. And so it uses cell-free DNA fragments that are more abundant than tumor DNA fragments on which other liquid biopsy tests rely. So there's other types of liquid biopsy tests that are done to detect DNA. And so this one is using— is detecting actual cellular fragments. And the detection is at a lower threshold than basically when you're doing some normal types of cancer screenings.

It also can detect abnormalities in methylation patterns, which also occurs with several types of cancer. The GRAIL test can detect up to 50 types of cancer. It's able to determine the tumor origin with about 87% accuracy. So last year, GRAIL reported that 44.6% of patients with a positive test result on Galleri actually had cancer. Galleri is the multi-cancer early detection test. However, in the latest analysis, the figure— there's a figure and it's called the positive predicted value. It's actually fallen to 38%. So this suggests that the diagnostic blood test is less accurate than previously reported.

And the decrease in the positive predictive value estimate means that there's a higher proportion of people, unfortunately, that underwent follow-up procedures despite actually being cancer-free. Most of the false positives, they're caught, they're usually caught. And subsequently, you know, if you test positive on a GRAIL test, You know, following up with classical diagnostic measures is extremely important before doing any type of invasive procedure. So I would say that based on their data, there was about almost 30% of participants that had false positives underwent an invasive procedure. That sounds very— it's kind of very unfortunate, in fact. That's a lot of people undergoing an invasive procedure for no reason. They didn't actually even have cancer.

The trial used blood samples that had about 50 times the higher rate of cancer than you would actually see in the real world. So 52% of cancer rate in blood bank samples versus about 1% cancer rate in the real world. So, so basically in a scenario that much more resembles the real world, the GRAIL test positive predictive value would be like 44% versus like 99% using the trial samples. So its negative predictive value would be about 99.5% versus like 68% using the trial samples. So I would say that detection of early cancer stages, while the test correctly identified about 55% of samples that were truly cancerous at any stage, including stage 4, test sensitivity was not as high for positive samples in early cancer stages.

And so, which is again, I, you know, the point of the GRAIL, in my opinion, is early early detection before other types of cancer screenings would even be able to detect it, right? So GRAIL sensitivity increased in a cancer stage dependent manner. So about 20%, it was— the GRAIL test sensitivity was about 20% for stage 1 cancers. It was about 45% for stage 2. Not too bad. I mean, if you're— so stage 1, it's, it's still like doing the GRAIL test it's only about 20% sensitive. So, you know, you're only going to be detecting it, you know, less than 1 in 4 times, right? 45% for stage 2 cancers. Sensitivity is 81% for stage 3 and 93% for stage 4. But I mean, by stage 4, that's quite late, of course. So I think there's some additional information with the GRAIL or with the Galleri test.

Gallery Grail test, the annual screening provides an opportunity to detect cancers more early, particularly, you know, stage stage two. I mean, stage one. I mean, if you're doing it every year, you may eventually then it may detect it. You know, because it's only got twenty percent sensitivity at this point. I you know, so it's obviously up to you know, it depends on a variety of family risk factors and lifestyle factors and all these underlying risk factors to determine the test interval, like whether or not it needs to be annual or. semiannual or once every 3 years or once every 2 years, I don't, depending on a lot of factors. It's not really intended to replace, I would say, normal guideline-recommended cancer screening tests.

So the United States Preventative Services Task Force, they recommend screening for lung cancer for high-risk smokers, breast, cervical, prostate, and colorectal cancers. So those are the ones that are recommended, you know, to have screening done. And using the Galleri test alongside those, such as like mammograms and colonoscopies, for example, probably would really increase the early cancer detection using— I think using them in combination in particular. Galleri may also find cancers missed during routine screening. So cancers in individuals who were like, you know, maybe non-adherent to current cancer screening tests, or, you know, there's a variety of reasons, basically. So Galleri may also help with, you know, things that are missed during routine cancer screenings.

So I think that ultimately, the Galleri is very interesting. And I certainly, I think I, you know, I personally want to try it. I'm quite young. I don't have a very significant family history of cancer. Like, it's not— like, that's not a really high risk in my family. But you heard me, like, the ability to detect stage 1 cancer, it's the, you know, sensitivity is quite low. Stage 2, it's a little better. So 50% sensitivity, you know, not too bad. Stage 3, even better. So I do see that there could be some benefit for doing a GRAIL test, particularly again with people that have family history, that have any type of underlying risk factor, right, that would warrant a cancer screening. So I have friends that had parents die of cancer young and they've done GRAIL.

So I think that would be a reason to do it. I'm hoping to have, again, I'm hoping to have Rick Klausner on the podcast to talk about this. He is the, you know, basically, GRAIL came out of his lab, his research. So there's a million questions that I would like to ask him about it. And I think that would be very enlightening if we could have a conversation with him. But that is it for this Crowdcast next month. We're going to talk about digestive enzymes and whether or not they are worth it or they have risks. We're going to talk about ApoE4. We're going to talk about ubiquinol supplementation. Do we need it? There was a rapid-fire question that I was going to also quickly answer, and it was from Lisa. And Lisa was asking about someone who has budget constraints.

Barring the actual like essentials like multivitamin, vitamin D, and omega-3 supplements, like those are the essentials. If you couldn't afford multiple things on top of that, what would I take? Would I take the sulforaphane by Brock or would I take the luteolin Autophagy Renew or would I take ubiquinol? And I think my answer really would come down to There's a variety of ways I personally would approach it because there are other ways to get the sulforaphane that are cheaper than broccoli. Broccoli is very expensive. I would probably opt for some moringa powder and broccoli sprouts because you could, you know, even— or you could take broccoli like twice a week. So it's not something that you really need to do every day. You know, I think there's some options.

So the moringa powder by Kuli Kuli. Or, you know, in combination with also having some broccoli sprouts or the broc a couple days a week. So you kind of maximize and it's like you have the supplement for much longer. Of course, refrigerated. And then I would get the ubiquinol. I do. I'm pretty convinced that ubiquinol is pretty awesome. But again, we're going to talk about more of that next month. So this was our deep dive Crowdcast. I went really deep into a lot of things. But I think that also understanding how things work and giving you guys a lot of information, particularly with rapamycin, there's been a lot of buzz. A lot of talking about it. And it's become quite popular, much like the metformin was for a while.

And so, I wanted to give you guys sort of a deep dive, non-biased, my opinion, and where I— what my personal conclusions so far, which could change, of course. But so far, what they are and what I'm looking forward to with real lifespan, maximum lifespan extension, is probably going to be with gene editing. Gene therapy, and certainly not with rapamycin. So remember to submit your questions for next month in the Ask a Question section. Be sure to go back and look at your dashboard, check out that Crowdcast summary of all the 39 Crowdcasts that we've done so far. And so you can look up previous questions and topics that we've covered for those of you that perhaps haven't been around that long. It's a really great resource.

And, um, and, and the chat questions, I like to, I like to see those when I'm here on the chat. And if you submit your questions there, oftentimes I won't get to them. So, um, I'm sorry if you are submitting your questions in the chat section early on and I'm not getting to them. So next time, please submit them in the right, the right area. That way I do see them. And, um, I hope you guys have a great month. Um, I'm going to be doing some fun, fun stuff actually For those of you that follow me on social media, I'm going to get on my Peloton right now, and then I'm going to do a post. And my post is going to be sort of piggybacking off of Joe Rogan's Sober October. I'm doing my own Sober October.

I am basically going to do some form of deliberate exercise every single day, whether that's a high-intensity workout or some resistance training or a run or just something deliberate that I'm doing every day. I'm going to be posting a lot of exercise-related studies. I think it's the best thing that you can do for your brain health, for your overall health. It's, like I said, better than rapamycin, better than any longevity drug. We can do it. It's easy. It's free. I mean, it's not something you have to pay for. I mean, you can do jumping jacks, push-ups, jump rope. I mean, it's like you can go for a run. You don't need to pay for it, right? So So look for that coming soon. I'm literally about to hop on my Peloton and then I'm going to do a real posting about it.

And I'm going to be giving you guys some exercise studies along the way. One I'm super, super into that also has to do with— it has to do with discipline. So my Sober October is discipline, right? I have to be disciplined to do a deliberate exercise workout every day. And I think that this ties into something that I'm super interested right now, which is grit. And I guess as a parent, I'm very interested in trying to foster grit in my child. And, you know, grit is really that combination of passion and perseverance. And I think that exercise and sticking with exercise and being disciplined and forcing yourself to do it every day is one great way to build grit. But more on that later. My favorite Peloton coach? Factor 8 is asking. I love Leanne Hainsby.

She's just like, I don't know, she pushes me. And then Ben, and then her beau, Ben Aldrich, I like him as well. I think those are my 2 faves. So I'm actually gonna go see her right now. Talk to you guys next month. Thank you so much for everything. Bye.