September 14, 2023

From podcast: https://bengreenfieldlife.com/podcast/ross-pelton-rapamycin/

[00:00:00] Introduction

[00:01:38] Who is Ross Pelton?

[00:04:32] How was rapamycin discovered?

[00:09:28] mTOR and autophagy

[00:15:55] Who should take rapamycin?

[00:17:29] What is mTOR syndrome?

[00:20:02] Could the rapamycin success be due to its anti-fungal effect? 

[00:23:01] mTOR and excess muscle loss

[00:34:30] The price of rapamycin and how to get it

[00:41:22] Ross’s daily routine

[00:46:50] How to take care of your gut microbiome?

[00:58:10] Ross’s course

[01:02:31] End of Podcast

[01:03:02] Legal Disclaimer

Ben:  My name is Ben Greenfield. And, on this episode of the Ben Greenfield Life podcast.

Ross:  Most people have a total misunderstanding of probiotic bacteria in what they do and how they function. The job of your probiotic bacteria is to digest components in your food and break them down and produce secondary molecules that we call postbiotic metabolites, and that these smaller metabolites that the probiotic bacteria produce that have a wide range of biological activity. So, it's not the probiotic bacteria themselves, it's the compounds that the probiotic bacteria produce these postbiotic metabolites that regulate not only your microbiome ecosystem but they get absorbed systemically and influence every single organ system in your body, especially your brain and your immune system. And, the problem, Ben, is that most people are not feeding their gut microbiome well. And, if you don't feed your probiotic bacteria well, they will not thrive and survive, they won't be able to produce the postbiotic metabolites that regulate your health. So, what are the types of foods that your probiotic bacteria require? They are dietary fibers and polyphenols.

Ben:  Faith, family, fitness, health, performance, nutrition, longevity, ancestral living, biohacking and a whole lot more. Welcome to the show.

Alright, folks. So, you've probably heard me talk about rapamycin a few times in the past several weeks if you've been listening to the podcast as any loyal podcast listeners should be. Anyways, it's because I've been taking a deep dive lately into this darling the anti-aging longevity sector. I had some reservations about rapamycin for the longest time. After reading the book written by today's podcast guest, I learned a ton about it. The book is called “Rapamycin, mTOR, Autophagy, and treating mTOR Syndrome.” If you don't know what mTOR syndrome is, don't worry, we'll clear that up. And, my guest is Ross Pelton.

Ross is extremely intelligent when it comes to all things related to anti-aging and longevity. He's a pharmacist. He's a nutritionist. He's an author of this fantastic book and some other titles. This book, again, is called “Rapamycin.” And, he's a health educator and he has a lot of knowledge as well in the microbiome and in drug-induced nutrient depletions. He was actually named as one of the top 50 most influential pharmacists in the United States and runs a fantastic website social media profile and is a really great follow. So, I'll link to all his stuff if you go to the shownotes over at BenGreenfieldLife.com/Rapamycin. And, if you don't know how rapamycin is spelled, we'll tell you right now because you want to know. You're going to see it all over the place in the next 10 years I guarantee. BenGreenfieldLife.com/Rapamycin, it's R-A-P-A-M-Y-C-I-N. 

Ross, welcome to the show, man.

Ross:  Ben, great to be here.

Ben:  Yeah. I've been looking forward to this interview and I think even alluded to it on a few other podcasts. And, one thing I have to ask you before we jump in, I was actually in preparation for our show today listening to an interview with a guy who's in the longevity sector down in, I believe he's in New Zealand. I don't have it pulled up in front of me right now, you might know who this guy is. And, it was a whole podcast episode about rapamycin and the longevity-enhancing benefits of rapamycin. They got to the end of the interview and the interviewer said, “Well, do you take it?” And, he's like, “No, no, no, no, no, no, not yet.” And so, I suppose I should just lead this interview off rather than waiting to the end to ask you. Do you actually take rapamycin?

Ross:  Absolutely. Been taking it for about two and a half years now.

Ben:  Okay. Yeah, me too, except for about two and a half weeks now. So, I'm a little bit behind you and we'll get into why, of course. But, before we start, I think the story of rapamycin is very interesting, this whole idea of Easter Island and the soil and I believe a Rapa Nui is the name of the island or something. Can you tell that story?

Ross:  Sure, you bet. So, back in the 1960s, a group of Canadian scientists made a scientific expedition to Easter Island. And, the goal of that expedition was to look for potential sources for new antibiotic and anti-fungal drugs. They took a lot of soil samples around Easter Island. And, when they got back to their labs and started looking at things, one of the soil samples had a compound that's produced by a strain of streptomyces bacteria. So, one of the things I like to emphasize, Ben, is this is something that's naturally produced in nature by a strain of soil bacteria. It's not some weird molecule that the pharmaceutical companies have produced that's never been seen on planet Earth or in any human's body before, but this compound that is produced by this strain of soil bacteria was named rapamycin after the indigenous people's name for Easter Island, which is Rapa Nui. So, that's how it got its name.

And interestingly, they started to develop rapamycin as an anti-fungal drug and then they discovered that it suppresses the immune system. So, all this research came to a screaming halt. But then, in September of 1999, the FDA approved rapamycin for people that get kidney transplants because people who get an organ transplant need to be on immune suppressive drugs for the rest of their life. So, that was the way that rapamycin got its original FDA approval.

Well, samples of rapamycin were sent off to the National Cancer Institute and they went crazy over it. They discovered that rapamycin is the first example of an entirely new class of chemotherapy drugs. Most chemotherapy drugs are called cytotoxic. They kill rapidly dividing cells like the tumor cell, but they also cause a lot of side effects because there's other cells in your body that divide rapidly like the epithelial cells that lie in your gastrointestinal tract and liver cells and bone marrow and so forth. So, that's where all the side effects come from.

It turns out that rapamycin is not cytotoxic, it's cytostatic. It stops the cancer growth but it doesn't have all these side effects. So, in the early 2000s, rapamycin got FDA approval for treating two different types of solid tumor cancers. These FDA approvals, Ben, have been an impediment to getting rapamycin accepted as a life extension drug because most functional medicine docs and health-oriented physicians are not going to write a prescription for a life extension enthusiast for chemotherapy or some something that suppresses the immune system or something generally a cancer drug.

But, Joan Mannick is a scientist that worked for one of the big multinational drug companies in Novartis, and she had the enviable position of being able to research anything she wanted. And, she was interested in aging, she decided to research rapamycin and she devised a really interesting clinical trial that really changed the landscape for rapamycin and opened up the floodgates for our understanding of it as a literal revolution, a real breakthrough in life extension therapy. So, Joan Mannick's trials, she selected elderly people, age 64 and older, divided them into four groups of people. One is a placebo group and then the three other groups took a different dose of a rapalog, a rapamycin-type drug that has exactly the same effects of rapamycin. One group took 0.5 milligrams every single day. The second group took 5 milligrams once a week. Third group took 20 milligrams once a week and they took their dose or the placebo for 12 weeks. And then, there was a two-week washout period and then she subjected all these participants to the seasonal flu vaccine. And then, she did blood work and measured how their immune system responded to this challenge of the flu vaccine. It turned out that the people taking 5 milligrams once a week, that was a sweet spot. These people got a 20% boost to their immune system.

Ben:  Now, just for comparison's sake, how much would people be taking if they were using it as an immunosuppressant or as a cancer chemotherapy agent?

Ross:  You bet. So, if you're taking it for chemotherapy or for immunosuppression, you take it every single day.

Ben:  Same thing, 5 milligrams every single day or more than 5 milligrams?

Ross:  Different doses. It's not one set dose, the different doses. But, the difference is rather than taking daily, Joan Mannick's trial discovered and announced that if you take rapamycin episodically, in this case once a week, there's tremendous health benefits. So now, I want to kind of morph into an explanation of why taking it once a week provides such unique and important health benefits. And, to do that, Ben, I need to get into the other topics in the title of my book, “mTOR and Autophagy.” And, right at the beginning of my book, I say there are two main themes in my book; One is the drug rapamycin, which is a very interesting story in and of itself. 

But, to my way of thinking, mTOR and autophagy are a much more important topic in my book than just the drug rapamycin because this understanding of mTOR and autophagy has opened up a whole new understanding of cellular metabolism, of health, and the aging process.

So, let me break this down and describe these terms and what they mean. In 1994, David Sabatini discovered the mechanism of rapamycin. When rapamycin gets absorbed across the cellular membrane, it goes into a cell and it binds to an enzyme, and this is an enzyme that is a master sensor of when nutrients are available. And, when nutrients are available, this particular enzyme sends out signals to the cell that says “Use these nutrients to build and grow, make new proteins, make do enzymes build new cellular components.” And, because this is the enzyme that rapamycin binds to, David Sabatini named this enzyme mTOR, which stands for the mechanistic target of rapamycin. So, it's just the term that Sabatini gave to the target where mTOR binds to.

Ben:  I think a lot of people hear that term mTOR because it gets thrown around a lot these days. They don't even realize the R stands for rapamycin.

Ross:  Yeah, yeah. And, if you're looking in PubMed, there are thousands and thousands of published studies and articles on mTOR. And now, I need to discuss and explain the other side of the equation. So, I mentioned mTOR senses when nutrients are available. If there are no nutrients available, then a process of autophagy gets activated. And, Japanese scientist Yoshinori Osumi won the Nobel Prize in 2016 for his discovery of autophagy.

When no nutrients are available, autophagy is the process where cells are able to target old misfolded proteins and enzymes and cellular components and break them down and get them out of the cell for detoxifying the cell or they're reutilizing the components like the amino acids in misfolded proteins breaking them down to their amino acids and then reutilizing these amino acids to build healthy new proteins and healthy new enzymes and healthy new cellular components. So, autophagy is detoxification and it's also the rebuilding and the revitalization and the renewal of your body.

And, for hundreds and hundreds of thousands of years of evolutionary history, mTOR and autophagy were in balance. And, when I use the term “balance” in mTOR and autophagy, and when I say they're in balance, that doesn't mean equal parts. And, I use the analogy of the gut microbiome. A gut microbiome that's in balance is about 85 to 90% good bacteria and only 10 to 15% bad bacteria. That's a healthy balance in the gut microbiome.

Ben:  Right. It's not like it's a 50-50 split is what you're saying?

Ross:  Right. It's not a 50-50. When the good bacteria vastly outnumber the bad bacteria, the bad ones aren't causing problems. So, a balanced microbiome is vastly overpopulated by good bacteria.

So, back now to mTOR and autophagy. For hundreds and hundreds of thousands of years of human evolution, people did not get up in the morning and go to the kitchen and open the refrigerator and start making breakfast. Ancestral humans did not eat three meals a day. And, these days, we've got people eating breakfast, lunch, dinner, in between meal snacks, desserts, evening cocktails, relative to our ancestral humans. Relative to the way our bodies develop for hundreds and hundreds of thousands of years, these days people are eating all the time, which means nutrients are always available to the cell, mTOR is always getting expressed and autophagy is not getting expressed. 

So, this is a fundamental cellular mechanism that is out of balance for most people alive today. And, what's the effect of this? Well, these days, mankind is experiencing what I call an epidemic of epidemics. We've got an epidemic of heart disease and diabetes and obesity and inflammatory conditions and autism and all of these things are off the charts compared to where they were 50, 60, 70 years ago. Back in the 1960s when I was a kid growing up, none of these were epidemics.

Ben:  Yeah. But, at the same time, by the way, it is a lot more fun to watch than the National Football League because now the players are 400 pounds rather than being 250. The rampant societal anabolism has certainly had payoff in some cases in the case of something professional sports. and, it's kind of funny, I don't want to totally derail, and I think this is one reason why perhaps people who are still in a highly anabolic phase such as my own 15-year-old teenage boys, I'd never tell them to go take the rapamycin I'm currently taking because I kind of want them in a pretty pro-anabolic state for a lot of the time. But, I was explaining them last night at dinner actually this conversation came up, I told them, “Look, you see dad doing things like intermittent fasting, rapamycin, engagement in autophagy-related activities, cold thermogenesis, et cetera, but I started really focusing hardcore on those when I was about 35 to 40 years old because at this stage in my life, anabolism and fertility is not quite as important as longevity and autophagy.” So, I think some of this stuff, it's age-related context, right?

Ross:  You're right. And, you bring up a good point. Who should take rapamycin? And, when should you start taking it?

I'll first admit that we don't have all the answers. This is a very new field, but we do know these things. You would never give rapamycin to a child because mTOR senses when nutrients are available, it's a primary anabolic process. So, you don't want to inhibit anabolism or the building process in an infant. I don't think that teenagers or even young adults in their 20s and 30s should start taking rapamycin yet. And, a pregnant woman should never take it because you don't want to interfere with the building processes when the fetus is growing.

Ben:  Yeah.

Ross:  But, somewhere around late 30s, early 40s, 50s, that's when people can start to consider taking rapamycin. And again, we don't have all the answers, maybe a healthy exercising person at age 50 should think about taking it, but maybe an overweight obese person in their 30s would be beneficial to start taking it. We don't know the answers of these things.

Ben:  Yeah. Someone who's overweight or obese who might have an increased need for cellular autophagy might start taking it earlier in life. And, I actually do want to get back to the dosage and timing a little bit later. And, by the way, my dose right now is 5 milligrams once a week. My wife after hearing me talking twice in the past two weeks at dinner table conversations about rapamycin now started herself last week on 5 milligrams once a week. And, if you get my wife to take a supplement, that's pretty darn impressive. But, when I interrupted you, you were getting into this issue with excess societal anabolism and this constant pro-growth state. I assume that that's related to this mTOR overactivation syndrome that's part of the title of your book.

Ross: You bet. It is. In fact, I coined the term, “mTOR syndrome,” which is the constant over activation of mTOR and autophagy is not getting its due. It's the appropriate time for detoxification and rebuilding. And, aging is a comp complex process. There are many, many things that contribute to the aging process. But, I think this imbalance between mTOR and autophagy is a fundamental cellular mechanism that's out of balance in most people today and it's actionable. People can do something about this to improve their health. Rapamycin is not a magic bullet. If you've got bone-on-bone arthritis, rapamycin is not going to fix that. But, when you start taking rapamycin, every single cell in your body is going to start working better. You're going to get better detoxification, but more importantly, you're going to start to effectively rebuild and renew your body.

And, the analogy I like to use here, Ben, think about a car that has a flat tire. You can't change that tire. You can't put that new tire on until you take the old tire off. That's the same way it is with proteins and enzymes in the body. They're huge molecules consisting of hundreds and thousands of amino acids linked together in unique shapes and forms. But, over time, these proteins and these enzymes undergo stresses and it changes their structure, it changes their shape. And, when the shape of a protein or an enzyme changes, it loses its functionality but it still is in place. You can't get a new protein or enzyme to take its place and tell you detoxify and break down and get rid of that old protein.

So, that's what autophagy does. It's breaking down damaged cellular components, misfolded proteins and enzymes that are not functioning and rebuilding healthy new proteins and enzymes. So, it's really critical that people understand that autophagy is the number one process for detoxifying every cell in your body but it's also the rebuilding and the renewal of your body. And, people age faster when they don't activate autophagy and they're not getting this renewal process going on on a regular basis.

Ben:  Yeah. When you talk about the host of chronic degenerative diseases that are addressed by rapamycin metabolic syndrome, type 2 diabetes, neurological diseases like Parkinson's, MS, inflammatory conditions like rheumatoid arthritis, systemic lupus, macular degeneration, hearing loss, periodontal disease, cognitive decline, Alzheimer's disease, I mean, you treat each of these in your book with more justice than we could do on the podcast. I at least want to give a head nod to all these different conditions that rapamycin seems to prevent or treat. 

But, it got me thinking, this is something I don't know if you've ever been asked this, but you mentioned that originally even before it was used as a cancer chemotherapy agent or immunosuppressant that they were looking at it for its potential as an anti-fungal. How confident are you or other researchers that some of these systemic effects or these system-wide effects related to chronic disease are not necessarily to autophagy and mTOR inhibition but perhaps to controlling fungus, candida, yeast, things like that? Because I realized that's also a big concern in modern society of people consuming excess sugar, alcohol, et cetera. Have you ever thought about that?

Ross:  Sure, you bet. And, as I say, aging is a very complex process and there's a lot of things that people do; lifestyle and environmental factors that are contributing to aging. I mean, we know about environmental toxins, things like glyphosate, we're poisoning the planet, and sedentary lifestyles, and poor dietary choices. And so, there's lots of things that go into aging processes and there's a lot of things that people can do to slow down their aging process. I'm just saying that this mTOR-autophagy ratio is so critically fundamentally important to cellular metabolism. I think it's a one of the foundational concepts that is contributing to the poor health of mankind right now. And, this is such an important process that in the second edition of my book, Ben, I proposed the mTOR autophagy theory of aging to try to talk attention to this, to get more recognition of the significance and the importance of these two terms and what people need to do to balance these things. And, of course, one thing I want to emphasize for our viewers today, the natural way to balance mTOR and autophagy is fasting, intermittent fasting, condense your food window into a smaller period of time, so you go longer periods without nutrient intake. And, some people do the 16/8 protocol and some people do two days a week 24-hour fasting.

Anything you do to do some type of fasting is going to be very beneficial for your long-term health. I advocate doing virtually everything. I take rapamycin. I do intermittent fasting. I exercise. I have a fanatical adherence to a healthy diet. So, I recommend that people do all of these things.

Ben:  It's interesting because you still get some pushback on this. Now, we've already established the fact, I think, a little bit earlier that the use of rapamycin as an immunosuppressant or cancer chemotherapy agent is at volumes much higher than the amount this 5 milligrams-ish or so amount that's used every week or I've even seen in some cases 5 to 6 milligrams every two weeks. And so, that's no longer a concern of mine, the immunosuppression. 

However, I also get some pushback from people who I've been talking to about this that they're concerned about the loss of muscle mass or perhaps the potential triggering of almost like a sarcopenic, a muscle wasting type of state. If we're inhibiting mTOR too much and of course, we know that things like grip strength and muscle mass are protective and associated with decreased all-cause risk of mortality. 

So, how do you think about that question whether or not rapamycin could be excessively inhibiting mTOR and causing someone to say not gain muscle in response to exercise in the same way that metformin and other popular off-label drug for diabetes and blood glucose management seem to cause a little bit of an impairment in mitochondria and VO2 max? A lot of people weren't taking that, but what do you think about mTOR when it comes to excess muscle loss or inability to put on muscle?

Ross:  The key here is that when you take rapamycin, you partially inhibit mTOR which allows autophagy to get activated for a period of time. And, I've had a lot of discussions with a lot of bodybuilders and weight lifters. And, early on, probably two, three years ago, a lot of the weight lifters are saying, “I don't want to get into this, it's an inhibiting mTOR, is going to prevent my ability to build muscle mass.” But, it's really not the case, it's actually the opposite of that. You need to have periods of autophagy in order to effectively build new muscle mass when mTOR gets reactivated. You've got to get those old damaged proteins and enzymes out in order to build the new ones. And so, we find out that taking rapamycin is not detrimental to bodybuilders and people who are trying to increase their muscle mass and their strength, it actually is beneficial because you've got to have this period of autophagy in order for the mTOR process to work appropriately. And, when mTOR is always getting activated, when people are eating all the time and autophagy's not getting activated, it's kind of driving a race car with a pedal to the metal forever. You can't do that or you've got a sprinter who's really a good track and field performer but they can't run fast forever, you've got to have periods of rest, relaxation, and rejuvenation.

And, I like to compare autophagy to sleep. During the day, we're active all the time, that's the mTOR phase. We're taking in nutrients, but we think about sleep as a rest phase kind of like autophagy as a rest phase. But, sleep is not a rest phase in terms of nothing going on, there's a tremendous amount of activity going on during sleep. You activate the glymphatic system, which detoxifies your brain. And so, sleep is very important for detoxification and rebuilding and renewal of your body just like autophagy or at least there's a thread of a metaphor there that's similar. So, autophagy is just critically important for long-term health.

Ben:  Here's the way I've been thinking about it. I'd love to hear your feedback on this. I generally lift weights Monday through Friday. My weekends are primarily devoted towards things like frisbee golf and pickleball and walking and hiking and being with the family, and Sundays tends to be even more of a recovery day. So, based on that logic, I've actually been taking my rapamycin on Saturday morning because I figure, hey, if it's inhibiting mTOR, I know the half-life is closer to four days, but I think it's kind of against the wane in the system after around 48 hours, if I'm not mistaken. By consuming it prior to a couple of days of lighter activity and a couple of days for which mTOR activation is not as important to me as autophagy that I'm timing my rapamycin dosing in such a manner that if there were any risks to inadequate muscle response to a weight training workout, I'm kind of mitigating those by getting most that rapamycin out of my bloodstream before I start weight training again on Monday morning.

Ross: I'll give you a maybe on that. Nobody's done the studies. We just don't know all these things. And so, those are things that need to be researched. And, your theory there has got some validity to it but I just have to say nobody has really looked into this. We don't know the best timing for rapamycin. And so, we don't know if once a week is best, maybe once every 10 days is best, instead of 5 milligrams once a week, maybe 10 milligrams every other week is better. We really don't know the answers to these things. And, there's biochemical individuality. When we really dive into this, we'll probably find people have different methods or different capabilities of absorbing rapamycin, of metabolizing it, we'll be able to individualize doses at some time in the future, maybe five years or so. But, right now what we know is 5 or 6 milligrams once a week is extremely safe. In fact, I think that taking rapamycin appropriately once a week is safer than over-the-counter drugs like acetaminophen and ibuprofen, which I think they have far more potential side effects than rapamycin.

Acetaminophen is the number one cause of liver failure and liver transplants in the United States and you can buy it without a prescription. So, I think that people should have access to rapamycin. The upside is tremendous, the side effects are minimal. The most common side effect from rapamycin are these little aphthous ulcers, little mouth sores. Maybe 5% of people get those when they take rapamycin. They generally go away fairly quickly and don't reoccur. But, some people get elevated triglycerides, some people have a drop in their iron or the hemoglobin levels. These are minor side effects. Most people don't have these effects. I do encourage people to get a baseline set of labs before they start taking rapamycin, and then three months or so later get a second period of set of labs and do your comparisons, so you can kind of have a before and after look at. But, the side effects from rapamycin are very, very minimal, they're manageable. And, the upside is tremendous. Rapamycin, and to my way of thinking, is a revolution in life span increases. And, I like to emphasize, it's not just increasing life extension, it's increasing health span. 

Ben:  Yeah.

Ross:  In fact, back in the 1960s or so, a doctor by the name of James Freeze wrote a paper they got soundly criticized for, but now it's pretty well generally accepted. What we're trying to do with life extension and anti-aging is called rectangularization of the aging curve and the compression of morbidity. So, you age healthfully for a much longer period of time. And, at the very end of life, whether it's at 95 years or 127 years, wherever, your infirm years are very small at the very end of your life. And, that's what we're doing, that's what rapamycin does when you take it appropriately and exercise and healthy diet and all of the other things if you're taking metformin or any of the other AMPK inhibitors. This is all designed to actually slow down your aging process to get activity in autophagy so that you are balancing this mTOR autophagy ratio.

And so, when you talk about diet, Ben, for a long time people have always been concerned about the quantity, how much you eat; the quality, what's the quality of your food, are you drinking/eating organic foods and drinking filtered water. But, the thing that has been missed is the timing of food. And, that's what's addressed here in the mTOR autophagy ratio. Leaving more time without nutrient intake so autophagy gets activated to rebuild and revitalize your body and detoxify your body. So, it's not necessarily consuming less, it's just narrowing the window of your nutrient intake so you have more time to activate autophagy.

Ben:  Right, the metabolic effects and health benefits of a prime rib consumed at 1:00 a.m. is a lot different than prime rib consumed at say 10:00 a.m. after a weight training workout or something like that. I absolutely agree or any breakfast with a decent amount of protein used as a circadian rhythm management tool like a zeitgeber. Yeah, timing, that's a lot of Satchin Panda‘s research of course that food is not just about quality and quantity, it's also about timing. And, you're absolutely right when it comes to that.

Now, you mentioned about other agents that people take for longevity. I've been very impressed with peptide bioregulators. I've been very impressed with what I've seen on NAD, increasingly impressed with C60 and astaxanthin and there's a few others out there. But, when it comes to rapamycin in some of the digging around and discussions that I had leading up to this interview, I saw people doing a few other different stacks. I think one that came up repeatedly was, I don't know if I'm pronouncing this right, acarbose or something like that, like people taking acarbose with rapamycin. Are you familiar with this?

Ross: Yup, it's one of the blood sugar regulators and it's an AMPK activator. And, another one is metformin. And, they all have some benefits, but all the other life-extension drugs I'm aware of have significant individual benefits. Rapamycin and regulating the mTOR autophagy ratio is a fundamental mechanism. And so, I think all the diseases of aging are related to this imbalance of mTOR and autophagy. And, in animal models, every single age-related disease response rapamycin, metabolic diseases, cardiovascular diseases, neurological diseases, everything in animal models responds to rapamycin. They all have a slowing down of the process. Some of them actually reverse some of the processes. Cardiovascular disease in animals with rapamycin.

And, the research thus far in humans is certainly all encouraging. It takes a lot of money to get clinical trials going. There are a few clinical trials with rapamycin, but it's so safe for people to take. I think the downside of not taking rapamycin is much more detrimental than taking it. I guess I'm a proselytizer when it comes to rapamycin.

Ben:  But, I got to ask you, the wholesale price, do you talk about this in your book? Wholesale price to pharmacies for a bottle of a 102 milligram, I think it's called Sirolimus, I believe, is the brand name of rapamycin.

Ross:  Sirolimus is the brand name.

Ben:  Yeah. It's over $3,000. And, in many cases of course, if it's for longevity, that wouldn't be covered by insurance. So, I'm curious what your personal strategy is because I think you talk about in the book like you're paying something like a $20 copay or something like that. So, tell me about how you're getting your hands on this stuff.

Ross:  You bet. So, when I first got my prescription for rapamycin, I took it to my local pharmacy, Ashland Drug. Pharmacist looked up, he said, “It's available but I'm not going to order it for you, it's well over $3,000 for a bottle of 100 tablets.” My prescription is just going to get filled for a few tablets, so he's going to have a lot of money in his inventory tied up that's not turning over. So, I took it to the local chain drugstore and they don't have nearly the controls at independent retail pharmacies have. They ordered it for me and they fill it for me and I, for a long time for a couple of years, have gotten it filled for $ 20-a-month copay on my insurance program.

Ben:  About your Mom and Pop pharmacies along with the Soda Fountain and the [00:35:48] _____.

Ross:  Right.

Ben:  Yeah. And, I know the type you're talking about.

Now, I want a different route because you talk about this generic form called RapaPro, which is a product made by actually I think you can get it through this anti-aging systems website, which is interesting because I interviewed him, Phil Micans, about peptide bioregulators, and that's where I've been sending a lot of people, that same website, to get peptide bioregulators, which are a discussion for another day, but I also think are a fantastic life extension agent.

Ross:  Yeah, you bet.

Ben:  So, for me and my wife, we're taking 1-milligram tablets, five of those once a week, those boxes of RapaPro are, I believe, about 69.99. So, that means we're paying about 30 bucks a month each as a couple to take 5 milligrams, the dose we've been talking about rapamycin once a week. So, we are not talking about expensive supplement. I mean, that's pretty affordable. 

Ross:  Yup. I'm showing the box of RapaPro on the screen.

Ben:  Oh, yeah, you got it held up.

Ross: And, it's available from international anti-aging systems. They are a company that's been around for quite a number of years. They specialize in making hard-to-obtain life extension drugs available. A couple of years ago, they got interested in rapamycin and they contracted with an Indian pharmaceutical company to produce their generic proprietary brand of rapamycin that's called RapaPro. And, this Indian pharmaceutical company uses a new nanotechnology for the production of RapaPro. So, the particle size is extremely small, which means it has very good absorption. So, I got excited about this because, as you mentioned, Ben, the price is really reasonable. It's $69.95 for a box.

Ben:  Yeah, that's dirt cheap for supplement with this many systemic effects.

Ross: Yeah, 51-milligram tablets. And so, you're getting 100 tablets for 70 bucks roughly. It comes out if you're taking 5 or 6 milligrams once a week, it's about a two-month supply for 70 bucks about 35 dollars a month. That's a very reasonable price.

Ben:  Yeah. If people want to see the video of what the box looks like, if you go to BenGreenfieldLife.com/Rapamycin, R-A-P-A-M-Y-C-I-N, you can see Ross holding up the box here. But yeah, that's the exact boxes up in my pantry right now.

Ross:  Yeah. So, I did my due diligence, I started ordering RapaPro and I started doing my sirolimus blood test. And, this is another thing I want to talk about, Ben, because I'm strongly encouraging people who take rapamycin to get their plasma sirolimus blood test done to find out how well is absorbed and what their plasma levels are. So, when I started taking RapaPro, I did my blood test and I found it is very well absorbed, my plasma levels are right up there in the range where they should be. So, I just verified for myself that this is a really quality product, it just gets well-absorbed and for a very reasonable price. And so, a lot of people can't find a doctor who will write a rapamycin prescription for them. Many people don't have insurance programs that'll cover it. This is a way people can get rapamycin for a very reasonable price and International Anti-aging Systems. People have actually said that people use my discount code of Ross-10, they'll get a 10% discount on their initial order.

Ben:  There you go. I'll put that information in the shownotes for people. And, I'll link to interview with Phil Micans on peptide bioregulators as well.

Where are you getting the sirolimus tests?

Ross:  Okay, that's good point to bring up. So, the Sirolimus blood test is made available by LabCorp, big national company that does labs for all across the United States. So, I found out that Life Extension allows people to order the sirolimus blood test for $95.

Ben:  You mean the Life Extension Foundation?

Ross:  Yeah.

Ben:  Okay.

Ross:  Bill Faloon and his group. So, if you call Life Extension and order the sirolimus blood test, you pay them, they send you the order, you take the order at LabCorp and you get their blood draw. That's $95. The same blood test is available directly from LabCorp for $54, but that requires a physician's prescription. Well, I've educated my doctor about rapamycin, so I went to her and said, “I want to be getting my sirolimus blood test so I can check my absorption and availability.” She wrote out a prescription for the sirolimus blood test for me. And, I don't know if she put good for one year. So, I can now go to LabCorp anytime I want and get my blood tested. I was taking rapamycin for well over a year. And, when I did my blood test, the plasma levels were not nearly as high as I wanted them. So now, I've upped my dose to, I'm taking 10 to 12 milligrams once a week and the blood levels are up as high as I want them. But, that's why I'm encouraging people if you don't test, you don't know. And so, I really encourage people to do the blood test and check and make sure that they're getting adequate blood levels up in the levels that they want.

Ben:  And, you haven't had any muscle loss or any noticeable decrease in strength from doubling your dose once a week?

Ross:  I have not. The only thing I've lost is a little visceral abdominal fat.

Ben:  Well, you can't complain about that.

I'm just curious, when I talk to guys like you or, I don't know, this other guy I spoke with a few weeks ago, Bryan Johnson, who has this pretty extensive Blueprint protocol or Phil Micans or any of these other guys in the anti-aging sector, I kind of like to know anything else that you're doing. I mean, you mentioned you do some intermittent fasting. It sounds like you weight train. You take rapamycin. But, is there anything else in your protocol that you think is particularly effective or that you swear by whether it's supplementation or certain parts of your daily routine?

Ross:  I got a lot of things I can talk about. First of all, I just want to emphasize that number one on everybody's list should be a healthy diet. And, I'll say a few words about a healthy diet in just a couple minutes. Second thing is exercise. That's just got to be number one along with diet, diet and exercise number one and number two. 

In fact, on my website, I've got a study that I summarized a group of Italian scientists a number of years ago studied a fairly large group of elderly people between the ages of 94 and 105. And, they were trying to figure out what's the number one thing for healthy aging. And, they examine a huge number of parameters turns out the number one thing for healthy aging maintain your muscle mass. So, you have to do regular strength training or resistance training. Things like cycling and swimming and jogging, those are great aerobic exercises but you're not building muscle mass, so people need to understand the importance of doing strength training. And, I especially emphasize this for women because far more men do strength training than women and everybody needs to do it.

Ben:  Yeah.

Ross:  And, I think there's tremendous benefit for most people to boost their glutathione levels. Most people have low levels of glutathione levels for a variety of reasons, all age-related–

Ben:  Yeah. Although, Ross, I got to interrupt you real quick with a caveat. I mean, obviously, as you age, you see a remarkable decrease in glutathione, same thing with NAD, for example. But, many people not do well from a genetic standpoint. I have an entire podcast with Dr. Kashif Khan about this with supplementing with straight glutathione and instead need to take precursors like n-acetylcysteine or selenium because they can actually, I believe, it's excess methyl depletion that can occur with glutathione supplementation in someone who has poor glutathione absorption SNPs. So, just something to consider, I would recommend you listen to that podcast and make sure because I'm a guy who doesn't do as well with glutathione as I do with n-acetylcysteine, selenium, and some glutathione precursors.

Ross:  Those are all great precursors. I'm in favor of them, but when people take glutathione orally, it's not well-absorbed, it gets broken down and destroyed. Some of the liposomal delivery systems are a little more effective, but I happen to work for my day job. I'm the scientific director for a Dallas-based company named Essential Formulas and we have the sole rights to import a product from Europe called Reg'Activ is the brand name, R-E-G-apostrophe-A-C-T-I-V. And, these products contain a unique strain of probiotic bacteria called Lactobacillus fermentum, ME-3. And, we call it ME-3 for short. And, ME-3 synthesizes glutathione.

Ben:  Oh, interesting. So, that's the way that you're that you'd be bypassing any issues with exogenous supplementation. You're just getting your body to make more of its own.

Ross:  Exactly.

Ben:  I like that. I mean, I have to look into this.

Ross:  Human clinical trials showing tremendous benefits. So, this is a real breakthrough in my mind because people can naturally boost their glutathione levels on a daily basis.

Ben:  That is especially with the increasing difficulty securing N-acetylcysteine. I think this is great. I didn't know about this. I'll look into it.

Ross:  Yup, I'll send you stuff afterwards on all of this so that you can put that in the shownotes–

Ben:  Yeah, I'll put in the shownotes for people too, yeah. Yeah, perfect.

Ross:  And, next item on my life extension formula list is crystal-free coenzyme Q10. A lot of people know about coenzyme Q10, many people don't realize that the melting point of CoQ10 is 10 degrees higher than body temperature, which causes it to crystallize. When it crystallizes, it forms clumps. We cannot absorb clumps of CoQ10. It has to be single molecules in solution. And, if most of the CoQ10 products on the market have horrible rates of absorption, literally only 1 or 2%.

There's a company out of Denmark, Pharma Nord, that has a patented process for keeping their CoQ10 in solution. They've done clinical trials. They get three to 10 times higher plasma levels than most of the commercial products on the market. So, I'm a big proponent of crystal-free coenzyme Q10.

Ben:  And, that's very good information too if someone's on a statin because of the CoQ10 stripping properties of statin in the associated muscle soreness and mitochondrial deficits. I know a lot of people on statins are taking CoQ10, but I don't think many of them are aware of this temperature issue and the availability of crystal-free. So, I'll get more information from you and put this in the shownotes too. Okay, so that's super interesting yet crystal-free CoQ10 and Reg'Activ.

Ross: Yup. The information I send you on CoQ10, Ben, from Pharma Nord, they've agreed to give people and order it with a discount code that I have 20% discount. So, I'll send all that for your shownotes so that your viewers will be able to get a 20% discount on Pharma Nodes going to CoQ10.

Ben:  Okay.

Ross:  Next topic I'd to talk about, which I think is critically important, I am a microbiome guy. My company Essential Formulas‘ markets premium probiotics and I'm trying to re-educate the world about how the gastrointestinal tract and the gut microbiome really function. Most people have a total misunderstanding of probiotic bacteria in what they do and how they function. The job of your probiotic bacteria is to digest components in your food and break them down and produce secondary molecules that we call postbiotic metabolites and that these smaller metabolites that the probiotic bacteria produce that have a wide range of biological activity. So, it's not the probiotic bacteria themselves, it's the compounds that the probiotic bacteria produce, these postbiotic metabolites that regulate not only your microbiome ecosystem but they get absorbed systemically and influence every single organ system in your body especially your brain and your immune system. And, the problem, Ben, is that most people are not feeding their gut microbiome well. And, if you don't feed your probiotic bacteria well, they will not thrive and survive, they won't be able to produce the postbiotic metabolites that regulate your health. So, what are the types of foods that your probiotic bacteria require? They are dietary fibers and polyphenols. Those are the two primary food groups for your probiotic bacteria.

Ben:  Right. And, by the way, I want to emphasize, you didn't you didn't just say kefir, kombucha, yogurt, kimchi, sauerkraut, even though some of those have those fibers in them, you're specifically talking not necessarily about fermented products but the polyphenols and the fibers themselves whether fermented or unfermented.

Ross:  Exactly, you bet. I mean, fermented foods are great, but the fundamental mechanism of how the gut microbiome works is that probiotic bacteria digest and ferment dietary fibers and polyphenols to produce these postbiotic metabolites. Over 99.9% of the bacteria in your gastrointestinal tract reside in the colon. That's where all the action takes place. That's an anaerobic environment. And so, when we ingest dietary fibers and polyphenols, humans do not have the enzymes to digest dietary fibers so they pass totally through your digestive system. And, this similar situation with polyphenols, most of them are massively large molecules. We do not absorb most polyphenols efficiently, so they will also pass through your digestive tract. But, when these dietary fibers and polyphenols reach the colon, they are the food for your probiotic bacteria and that's when the bacteria will ferment these products, break them down, produce the smaller postbiotic metabolites that regulates your health. The problem, Ben, is that I've got multiple studies that report from 90 to 95% of American children and adults do not consume adequate amounts of dietary fibers and polyphenols. So, nobody's feeding their gut microbiome the way they should. And consequently, everybody has gut problems.

Now, take a little time to dive into what it means to have a dysregulated gut microbiome, what we call dysbiosis. Too many bad bacteria, not enough good bacteria. The reason bad bacteria are bad is because they produce compounds that are inflammatories. So, you get gut inflammation. And, when you have inflammation and gastrointestinal tract, that causes a substance called zonulin to be produced. And, I don't know if your listeners are familiar with zonulin but a physician by the name of Allesio Fasano who's a pediatrician at Harvard discovered zonulin, and I hope he wins the Nobel Prize. I think it's one of the most important health discoveries of all time paralleling mTOR and autophagy. But, zonulin gets expressed when you have gut inflammation and it degrades and breaks down the tight junctions in the epithelial cells and the lining of your gastrointestinal tract and creates leaky gut or intestinal permeability. And, that allows lipopolysaccharides to leak through into systemic circulation.

A quick explanation or definition of lipopolysaccharides, they are components of the cell walls of gram-negative bacteria in your intestinal tract. Everybody has them. They're supposed to stay in your gastrointestinal tract. But, if you have leaky gut, these lipopolysaccharides leak into your systemic circulation, they are highly inflammatory and they create systemic long-term chronic inflammation which accelerate your biological aging. So, it's critical for people to understand how to create and maintain a healthy microbiome with predominantly good bacteria. And, the way you do that is to feed your microbiome and your probiotic bacteria well. 

And, the key here, Ben, is that not just the quantity of dietary fibers and polyphenols, the thing that's important is the diversity. Most ecosystems are more functional and stronger and more resilient when they have a high level of diversity. And, the only way you can get a diverse microbiome with lots of different strains of probiotic bacteria is by consuming a wide diversity of different types of fiber-containing foods and polyphenols.

Ben:  I agree. I'm looking out my office window right now, and by the way, I've got right out in the garden there's rosemary and thyme, beyond that wild nettle, wild mint, dandelion, Oregon grape, and Oregon grape root. So, I do a lot of plant foraging and one reason for that, I make this fantastic wild plant pesto head nod, shameless plug for my cookbook, the recipes in my “Boundless Cookbook.” But, I go out of my way to eat a lot of these plant varietals.

I got to ask you though, when you look at these postbiotic metabolites producing the colon, are you primarily referring to short-chain fatty acids or things like butyrates?

Ross:  That's just one class of postbiotic metabolites. We're just at the tip of the iceberg of this understanding of how this microbiome works. In the future, we will probably discover that probiotic bacteria are capable of creating thousands of different postbiotic metabolites. We know that some of them have a wide range of anti-inflammatory activity. Some of them directly kill pathogens. One of the most important things that postbiotic metabolites do is regulate the acid-base balance in the gastrointestinal tract. A healthy microbiome has an acid-base level that's just slightly acidic. When you have a slightly acidic acid-base level in the gut microbiome, you support the growth and the proliferation of your probiotic bacteria, and it suppresses or inhibits the growth of bad bacteria. When people have dysbiosis, too many bad bacteria, not enough good bacteria, you become 10 to 100 times to alkaline. You have to get down to that slightly acidic condition to have a healthy microbiome to allow your good bacteria to proliferate.

And so, here's how you maintain this. You create this slightly acidic pH in the gut microbiome with postbiotic metabolites like short-chain fatty acids which are proprionic acidic lactic acid, and nucleic acids, and organic acids, and amino acids, and folic acids. Many of the different types of postbiotic metabolites are slightly acidic. And, that's how you create and maintain this slightly acidic pH that allows the good bacteria to thrive and it suppresses the growth of the bad bacteria.

Ben:  And, that all comes down to diversity of fiber and polyphenol sources it sounds like you're saying.

Ross:  Exactly, diversity, diversity, diversity. And so, many people think that just taking a probiotic–Americans think more is better. “My probiotics got 50 billion, mine's got 100 billions, mine's got 200 billion.” When you take high doses of a single or several strains of probiotic bacteria like that, you're working against balance and diversity. And, it's the same with prebiotics. Now, a lot of companies are putting some prebiotics in their formulation so they can get the term prebiotic on the label. A large amount of inulin, a large amount of fructooligosaccharides. That's just one as you're working against balance and diversity. So, I try to get people to understand the importance of meeting a little bit of as many different types of fruits and vegetables on a daily basis as you can to get this diversity of fibers and polyphenols. I want to encourage people to Google my eight-minute YouTube video. If they google Ross Salad Buzz on YouTube, I've got an eight-minute YouTube video that teaches people how to make a microbiome supporting salad. I call it Ross's Salad Buzz, B-U-Z-Z.

Ben:  Yeah, you sent me the video. I didn't watch it. Maybe I'll watch it during lunch today while I have a salad.

By the way, it's interesting. Two things. One, I should mention because I just interviewed Colleen Cutcliffe yesterday of this company called Pendulum that makes a blood sugar controlling probiotic that contains high levels of Akkermansia that they put inulin into, but I was pleased to hear her describe to me this secondary polyphenol supportive compound that they encourage people to take along with it. So, I don't want people to think just because a supplement that's inulin, it means it's bad, it just needs to be accompanied by their polyphenols.

The other thing that's interesting is that it's concerning to me unless it is for the purposes of a short-term immune-friendly diet for healing the gut and eliminating a host of diverse plant defense mechanisms from entering the gut that so many people these days are on, a very fibrant polyphenol pore carnivore diet or low fiber keto diet. I also think this is why many of the people I talk to follow that diet for some period of time wind up settling back into. In the case of a carnivore diet, some pretty significant fruits and avocado consumption. In the case of a low-fiber keto diet, a lot of them return back to a low fiber keto Mediterranean type of diet, rich in herbs and spices and polyphenols, which I think is an intelligent move. And again, I think there's a time and a place for an autoimmune-friendly diet, a short-term carnivore stent if you need to give the diet a break from plant defense compounds. But, long term, I think it's very important that people hear the message that you're sending, Ross, which is the importance of these gut postbiotics and the fact that you need diversity in polyphenols to get them.

We're running up kind of short on time, but you have that salad buzz video. You also have a course or something like that about these postbiotics that you're talking about, don't you?

Ross:  Yeah. I've got a booklet that I can make available to all of our viewers free of charge. This is a book that I wrote, Dr. Ohhira's probiotics and postbiotic metabolites. And, I'm the scientific director with Essential Formulas and we have the sole rights to import Dr. Ohhira's probiotics from Japan in the United States. This is a probiotic that's made in a multi-year fermentation process. They've got large 80-gallon fermentation vats in a sterile warehouse. They put in a wide range of Japanese fruits and vegetables and mushrooms and seaweeds and 12 starter strains of bacteria. The bacteria get to digest these foods for three to five years before they encapsulate the product. And, the final product has got over 500 of these postbiotic metabolites. So, this is the fastest way to institute positive changes in the gut microbiome because you're directly ingesting these postbiotic metabolites. When people take a commercial probiotic, even if those bacteria survive transit through the harsh acid in the stomach, when they reach the colon, those bacteria have to locate dietary fibers and polyphenols which most people aren't consuming enough of and then start the process of converting them into the postbiotic metabolites, which takes time. Take Dr. Ohhira's probiotics and you are directly ingesting over 500 of these postbiotic metabolites. So, you're directly getting anti-inflammatory activity, rebalancing the acid-base level, re-establishing gut-brain communication, balancing your immune system. So, there's nothing else in the world like Dr. Ohhira's probiotics which directly delivers these 500 postbiotic metabolites.

Ben:  Are you saying Dr. Hairs or Dr. Harris or Dr. Harrows?

Ross:  It's Dr. Ohhira, O-H-H-I-R-A.

Ben:  Oh, O-H-H-I-R-A. Okay, cool. 

Ross:  He was the visionary microbiologist that took him 10 years to develop the system. He was initially a Buddhist monk. And then, after he left the monastery, he became a landscape architect. He had a worldwide reputation as a landscape architect. And, in 1976, the country of Malaysia invited him to put a large freedom park and design the architectural design, which he did. 1980, he went back to Malaysia for the Grand Opening Ceremonies. He ingested some bad food and got violently ill. There was a shaman at these Grand Opening Ceremonies that saw Ohhira lying on the ground writhing in discomfort and vomiting. He pulled some black syrupy stuff out of his leather satchel and started spoon-feeding Ohhira with this stuff, cured him right away. 

And, he's a curious individual so he finds out the stuff the shaman gave him was made from locally fermented Malaysian fruits and vegetables. He takes it back to Japan. He plays around with it. He can't study it the way he wants to because he doesn't have the scientific education. So, at age 49 with a very successful landscape architect career with an international reputation, he walks away from that career, goes back to school, gets a degree in microbiology, and starts this whole process of developing Dr. Ohhira's probiotics.

Ben:  Wow. Well, this has been a wealth of information, Ross. And, I'm super happy I had you on the show. I didn't even know we're going to go this deep into the gut, but this is just as interesting to me as the rapamycin piece.

Ross:  It takes a gut, Ben.

Ben:  Yeah. Alright. Well, so BenGreenfieldLife.com/Rapamycin, R-A-P-A-M-Y-C-I-N. I'll have all the shownotes over there. I'll follow up with Ross to get links and everything else for all this stuff. And, in the meantime, you can also leave your questions, your comments and your feedback over there for Ross or for me. And, Ross, thank you so much for doing this, man.

Ross:  You bet, Ben. My website for people that want to know is NaturalPharmacist.net. And, to get a free copy of this book, go to NaturalPharmacist.net/OhhiraBook, O-H-H-I-R-A-B-O-O-K. Ben, love being with you.

Ben:  Cool, Thanks for doing this, Ross. Alright, folks, I'm Ben Greenfield with Ross Pelton, Natural Pharmacist, signing off from BenGreenfieldLife.com. Have an amazing week.

More than ever these days, people like you and me need a fresh entertaining, well-informed, and often outside-the-box approach to discovering the health, and happiness, and hope that we all crave. So, I hope I've been able to do that for you on this episode today. And, if you liked it or if you love what I'm up to, then please leave me a review on your preferred podcast listening channel wherever that might be, and just find the Ben Greenfield Life episode. Say something nice. Thanks so much. It means a lot.

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During our discussion, you'll discover:

-And much more…

Quantum Upgrade

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Resources from this episode:

– Ross Pelton:

• Rapamycin: Rapamycin, mTOR, Autophagy & Treating mTOR Syndrome by Ross Pelton
• Dr. Ohhira's Probiotics & Postbiotic Metabolites by Ross Pelton
• Essential Formulas
• Natural Pharmacist
• Quantum Upgrade

– Podcasts:

• The New Darlings Of The Anti-Aging Industry & The Russian’s Secret Age Reversal Weapon: Peptide Bioregulators With Phil Micans.
• A Step-By-Step Blueprint For Longevity: The Most Advanced Age Reversal Strategies Known To Humankind, With Bryan Johnson.
• Sleep Genetics (& 3 Ways To Crush A Good Night Of Sleep), Why You Get Depressed When You Get Bored, Personalized Exercise & Diet Based on Genetics & Much More With Kashif Khan Of The DNA Company.

– Other Resources:

• International Antiaging Systems (use code BGF15 to save 15%)
• NAC 
• Selenium
• Reg'Activ Essential ME-3
• Pharma Nord Crystal-Free CoQ10
• Pendulum
• Life Extension
• Sirolimus At LabCorp
• Sirolimus
• Boundless Cookbook by Ben Greenfield
• Bryan Johnson's Blueprint Protocol
• Joan Mannick
• Yoshinori Ohsumi

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Do you have questions, thoughts or feedback for Ross Pelton or me? Leave your comments below and one of us will reply!