Gladden longevity — Episode #49

Steve Reiter: Welcome to the Gladden Longevity Podcast with Dr. Jeffrey Gladden, MD, FACC, founder and CEO of Gladden Longevity. On this show, we want to help you optimize your longevity, health, and human performance with impactful and actionable information by answering three questions: How good can we be? How do we make 100 the new 30? And how do we live well beyond 120?

I'm Steve Reiter and Dr. Gladden; it's 2023. January 2023.

Dr. Gladden: Happy New Year.

Steve Reiter: Happy New Year, my man. You are in Puerto Rico right now enjoying the beach and the sun and the waves and-

Dr. Gladden: True. All true. And the rainforest. All true.

Steve Reiter: So, I wanted to start this one by asking you, how was your 2022, overall?

Dr. Gladden: 2022 was a transformative year for me.

Steve Reiter: How so?

Dr. Gladden: Well, I'll say on a personal level, I went through a breakup in September of 2021, and I spent a year following that, kind of working on myself, answering the questions of what I was bringing to the table. How did I select this person? What are the growth areas for me? And I think that's something for the audience to take in, is that if something's not going well, it's easy for us to blame the other person or blame something else. But I took the responsibility of saying: “You know what? I think I have some areas to grow here too.”

Steve Reiter: Ooh, that's good.

Dr. Gladden: So, I basically threw myself into some seminars and some retreats and some things like that where I had an opportunity to dissect out some of those underlying psychological tendencies or some of that early imprinting that's still, that software that's still playing that kind of biases you in certain ways. And I was able to crack the code on a number of things, really, about four or five things that were kind of critical in that whole regard. And one of the final ones, well, maybe one of the first ones, was actually around feeling safe.

Steve Reiter: Yeah.

Dr. Gladden: Not feeling safe. We've talked about that.

Steve Reiter: We've talked about that on the podcast. So, for those that haven't listened to it, just talk a little bit about the importance and what it's done for you, personally, and how you've seen this for some of your patients that you've brought this concept to.

Dr. Gladden: Yeah, exactly. I think for me, it had to do with some financial things that went on between my parents and myself when I was in my twenties, and I was kind of on my own. All of a sudden, I was just on my own. And it kind of gave me a feeling of not being safe. And the other thing that it did was it drove me into a mindset of needing to make a living more than needing to make a life.

Steve Reiter: Ooh, ooh.

Dr. Gladden: And so... Right?

Steve Reiter: Yeah. Yeah.

Dr. Gladden: And so, understanding that any issues that I had around money were actually issues that I had around safety. And then being able to come to grips with that and then understanding that really it's safety that we're going for. And I find that many people don't feel safe. When they feel worried, when they feel anxious, when they're worried about a child or worried about their own future or whatever it is, they're, it all really devolves down to not feeling safe. And I think the same is true for depression too. It leads to this set of feelings of not feeling safe. So, being able to crack the code on how to give myself safety, how to scoop up little Jeff and make him safe, or connect to my spiritual reality of: No, this is really immutable. I really can't be changed or hurt by anything that happens.

So, giving yourself sort of safety in a psychological and kind of a metaphysical or spiritual sense was transformative. And then, I realized that I was focused on making a living as opposed to a life and some other insights I had along the way. Anyway, it was a very, very productive year for me. And actually, the weekend after, I had the insight about wanting to make a life as opposed to making a living. I met a woman that-

Steve Reiter: Here in Colorado.

Dr. Gladden: Yeah, in Colorado, right. In Boulder. And it was kind of like the universe was orchestrating. I mean, if I recounted it to you, it, I mean, the way that it happened, it was kind of like threading a needle from a thousand miles away for this to actually happen, but it happened. And we're here together in Puerto Rico now, and it's-

Steve Reiter: I'm so happy for you.

Dr. Gladden: It's become... Yeah, it was, but it's become the most phenomenal relationship of all time because we keep going into what I call ‘courageous conversations’ where the thing that you're wondering about, it's like, “I'm a little ambiguous about this. I'm not sure if I feel safe about it. I don't know what they think or how they feel, or they said something, but I'm not sure what that means.” So, kind of going at those things, it's like, and not in an aggressive way, but just in a take responsibility for yourself way of, “I'm just not really feeling safe about this. I need to understand this better.” And then having that reciprocated, those courageous conversations where you feel like, if I bring this up, it might risk the whole relationship, but you bring it up anyway, and then you find that when you work through that, you hit new levels of understanding and intimacy.

This whole idea of what is a relationship for, what's the goal of a relationship, right? Really, what's the goal? Is it companionship? No. For me, it's knowing and being known, loving and being loved. That's the goal. And to feel safe. That's heaven on earth, knowing and being known, loving and being loved. So, if you're going to do that, you've got to have these courageous conversations, which are always scary. It always feels like you're risking the whole relationship for whatever reason. But this idea of being courageous is a habit. And just like, you learn to swim by swimming, you learn to be courageous by couraging, so to speak. So, having these courageous conversations and building this relationship has been a phenomenal experience.

So, that's on the personal side. I would say on the Gladden Longevity side, moving into the new office space, decking it out with all the equipment, getting the testing dialed in, and all the different tricks and toys. And then moving into the whole Life Raft protocol, we're actually now we're focused on turning back the clock, using plasmapheresis, young plasma, and lots of different things. And now, with the whole transcriptomics project that we're working on and bringing to life right now, actually, we were testing it in 2022, and now it's coming to life. The last call I had before I jumped on here was on that very topic. And we're starting to actually unravel the Rubik's cube of aging, and we're using transcriptomics to be able to do that. So, I mean, 2022 was amazing. I think 2023 is going to be incredible because I think 2022 is really going to serve as a launchpad for 2023, quite honestly, so yeah.

Steve Reiter: And that's really in our conversations that you and I have had offline, pre-podcast, post-podcast. That's the way '22 was really looking to be for Gladden Longevity as a clinic was things were really starting to build, and '23 is looking like it's going to be a pretty awesome year for you guys. I'm super excited about what we have planned for the podcast and for the community, and we'll talk more about that once we're ready to unveil that, hopefully in the next month or two.

Dr. Gladden: And bringing forward the whole Age Hackers piece that we're working on that people are going to be excited about as well. And just lots of things. There's just been so much progress in 2022, and I think 2023 is really going to be incredible. I think people are going to see that we're going to have data that's showing that we're actually turning back the clock for people. And so, what could be more exciting than that? I think that's really quite wonderful. So, anyway-

Steve Reiter: So, it is January, and apparently, I've just found out as January has started that it's ‘Dry January’, and this has kind of become a thing where people abstain from alcohol. Many celebrities and influencers are doing this, and I've seen Dr. Daniel Amen talking about it on his Instagram feed. And so, what are your thoughts about ‘Dry January’?

Dr. Gladden: I think it really raises the question of: Why alcohol? And there are lots of studies that show that people that drink in a modest amount actually live longer. And so, to be a teetotaler is not necessarily a longevity move. Although I don't drink. I did take a sip of champagne on New Year's Day because I was at a restaurant here, and I got pulled into using a saber to open up a bottle of champagne as part of a ceremony, and I don't even drink. But all of a sudden, they're videoing me with this saber, like Napoleon Bonaparte opening up this bottle. And it's like, “okay”. So, anyway, I had a sip of champagne, but I'm really not a drinker. And the reason for me, not drinking is because I just sleep better. I feel so much better.

My runs are better; my workouts are better. My brain is sharper when I don't drink, and that's why I don't drink. I have nothing against alcohol. I used to enjoy alcohol. I used to enjoy dark beer, fine wine, whatever. I think there is a detox element, though. I think a lot of people, when they drink one drink a day becomes two drinks a day, becomes three drinks on the weekend, becomes four drinks on Saturday becomes... And I think all of a sudden, people find themselves getting caught up with more alcohol than they want, and there's a detox element. So, I think January, ‘Dry January’ is really about them detoxing.

It's a little bit like Lent. And so, is there value to that? I think there's some value to it, but really there's more value into asking yourself the question: “What's my relationship with alcohol? And what do I really want it to be? And why don't I just do that for the whole year? If I don't want to drink, why don't I not drink for the whole year? If I want to drink once a week and have a drink with whomever, then why don't I just do that?” But what we've seen over and over again, and I think you have too, is that sleep is really wrecked by alcohol. And so, if you wear a Whoop or Oura ring, right, either one or something else, you see that, and it's just not fun.

Steve Reiter: So, with those studies that talk about people who drink moderately live longer-

Dr. Gladden: Yep.

Steve Reiter: What's behind that? And I would assume that if you're taking care of all of these other things: eating right, sleeping well, exercising, getting good sunlight, doing the very basics of biohacking, if you will, that the benefits of alcohol really aren't that great, if you're doing all these other things, right?

Dr. Gladden: I would think that that's the case. But there are a lot of counterintuitive things that happen. There are a lot of counterintuitive things that are happening. We're going to talk about some of that here in just a minute when we talk about people dying sooner from intermittent fasting. It's kind of counterintuitive, but there's reasons for it. Alcohol does sort of thin the blood. It's a little bit of an anticoagulant. It also relaxes people, which can decrease stress, and it also can raise good cholesterol in the blood, HDL, if you have the right genotype. Now for certain genotypes it makes all your cholesterol numbers worse, and it makes brain function worse and some other things. So, I don't necessarily advocate that nobody ever drinks, but I think you just have to understand what your relationship with it is.

And I find that there are other people who, quite honestly, once they really confront it they, realize that they're alcoholics, and they didn't really admit it to themselves. And so, if you're an alcoholic or you've ever had a problem with alcohol, then not drinking is infinitely better than drinking. And that becomes kind of a line in the sand. So, there's a lot of things around alcohol, but if you're going to have a drink every now and then, I'm not going to say that you're killing yourself for doing it, that's for sure. The data would support otherwise, so I'm just giving you my personal take on it.

Steve Reiter: Yeah. All right. You mentioned intermittent fasting, and I had sent an article that the Daily Mail had published and was picked up by Drudge. That's where I saw it. “Intermittent fasting, the celeb favorite diet followed by Courtney Kardashian and Mark Wahlberg, may raise your risk of an early death by 30% study suggests.” That's the title. And before we recorded, you took a look at the article. You took a look at the study.

Dr. Gladden: Yep.

Steve Reiter: What are your thoughts?

Dr. Gladden: Yes. Well, the actual article is in the Journal of the Academy of Nutrition and Dietetics, and it says meal skipping and shorter meal intervals are associated with increased risk of all-cause and cardiovascular disease mortality among US adults, which is a pretty stunning thing. And they looked at 24,000 adults over the age of 40 between the years of 1999 and 2014, which means that they have had enough years to kind of follow up on these people since we're in 2023 now. But what was fascinating is that the people that ate one time a day had a significantly higher mortality. Let's see, participants eating one meal a day were 1.3, had a 1.3 times the risk for all-cause mortality and a 1.83 risk for cardiovascular mortality. The people that skipped breakfast had a 1.4 X risk for cardiovascular mortality. And so skipping lunch 1.12 for lunch and 1.16 for dinner.

So, it seemed like skipping breakfast was a bigger deal, and also, just eating one meal a day seemed to be the worst. Now, we have heard about all the longevity benefits of fasting, and so we know that fasting increases autophagy. We know that it increases cellular rejuvenation. It turns on genetics that re-lengthen telomeres, that reboot mitochondria. So, there's so many benefits to fasting. So, if there are so many benefits to fasting, why are people dying? And I think the flip side of it is that eating is actually, and I've talked about this in prior podcasts, that eating is actually a very stressful activity. And so, if you're only eating one meal a day, what happens is people tend to load their body with lots of nutrients and lots of calories all in one sitting, and that's a very stressful thing on the body.

It can overwhelm the body's ability to cope with it, and all of a sudden, things go out of whack for an hour or two or three, blood sugar spikes, protein levels go way up, and lipids in the blood go way up. All of a sudden, it's a very stressful thing for the body to deal with eating. So, I think my conclusion on this is that eating is actually very stressful. And if you're going to try to consolidate all of your food into one sitting, that's actually counterproductive. I don't actually think that fasting is a bad thing because we have information that fasting actually has a lot of longevity benefits. Walter Longo, with a 5-day fast-mimicking diet, they have great data on improvement in longevity. Calorie restriction has been shown to be universal in all mammals tested, something that improves longevity. But there again, in chronic calorie restriction, you don't have overeating.

What you have is you have fasting or low-calorie intake. And I think the thing that's sabotaging people with their intermittent fasting is that they may skip breakfast, they may skip lunch, but then, gosh, they eat a really big lunch. I'm going to have a salad, but that salad's going to have 3000 calories in it, then I'm going to have dinner, or I'm not going to have dinner, or I'm going to go the whole day and then just have dinner. And I also think the time of day that you're eating makes a big difference. We're probably better off eating in the morning and actually eating a lot less at night. So, if you were going to skip a meal, skipping, what was it? Skipping lunch was 1.12, and skipping dinner was 1.16. So, you're much better off to skip dinner, let's say, than you are skipping breakfast.

And I think people need to understand this that it's not that fasting is bad, that big bolus' of food is bad. So, maybe we need to get back to this idea of eating small meals, and maybe we need to eat three small meals if we're going to try to control our calories. Maybe that's a smoother way to not overstress the system. But then you want to have that window of time when you do become ketotic, let's say, where you do have the chance for autophagy. And I would be curious to see, quite honestly, if all the people that are trying to push themselves into keto, maybe we can look for a study on this, whether or not they're dying sooner or not, because that's another stress on the body. And I think what we want here is we want to treat the body well with these small hormetic stresses. But I think we've really underestimated what a stress eating a big meal is, and I think maybe that's the take-home message here.

Steve Reiter: So, for listeners, I would assume then what you're advocating is maybe a small healthy breakfast, a couple of eggs, the sprinkles.

Dr. Gladden: Hash browns, bacon, the usual stuff.

Steve Reiter: Maybe a smoothie in the late morning and then a good size lunch, but nothing over the top. And then what we had talked about on the 5-day mimicking fast podcast where we talked with, I believe it was, if I remember correctly, the CEO of ProLon, the fast mimicking diet episode where we have maybe a ProLon fast mimicking bar in the evening just to put something in your stomach. And I would assume that then that would be a healthier way to intermittent fast.

Dr. Gladden: I think decreasing what you take in dinner in the evening is a healthier way to eat because that's when we tend to overeat. If I'm going to reach for carbs, it's going to be then. If there's ice cream in the house, you're going to reach for it then; if there's a candy bar, you're going to reach for it then.

Steve Reiter: I'll fully admit, last night, that was me. I had a good breakfast, nice and healthy, and then for dinner, I had a nice bowl of brussel sprouts, but then I was super hungry, and I went to some stuff, some gluten-free cookies that I shouldn't have, and so...

Dr. Gladden: Yeah. No, we're all human. I'm not perfect, either. But I think the thing is that this idea of eating smaller meals is probably a really smart thing. And I do think that fasting is valuable, but maybe the way to do it is, instead of trying to intermittently fast every day, is to do a bigger fast one day where you maybe go 24 hours and just do a water fast or just drink some electrolytes or things like that. You do want to always stay well hydrated. However, we'll talk about that in a minute too.

Steve Reiter: Next.

Dr. Gladden: Right. And that's important too. Stay well hydrated. But I think we've probably missed the boat with intermittent fasting because we think that we're doing a good thing because we've skipped breakfast or skipped a meal, and yet we're overeating, overcompensating, and actually doing more harm than good.

Steve Reiter: This episode of the Gladden Longevity Podcast is brought to you by H2 Molecular Hydrogen in the Gladden Longevity Store.

Dr. Gladden: Yeah. Steve, you've heard us talk about this numerous times on the podcast in terms of the benefits of H2 and hydrogen water. We love it. It's really the best way to balance your entire redox system, so it really protects you from free radical damage. I take it every time I get it on a flight to protect me from radiation damage when I'm flying, and I use it to rejuvenate my brain in the afternoon. There are really two kinds of exercise. There's physical exercise, and taking H2 before or after that works great, but also there's a mental exercise, and I find that the H2 will bring your brain back when you're tired in the afternoon. So, I think it's the perfect thing for longevity and for performance, quite honestly.

Steve Reiter: And I talked to you about this that I found dropping one to two tablets in a glass water bottle right before bed. I've seen an overall bump in my deep sleep when I do so.

Dr. Gladden: Fascinating. Yeah.

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Dr. Gladden: Yeah. One of the other things that I use it for routinely is when I'm about to go on a mountain bike ride, and I will say this, that if I go on a long mountain bike ride, I will take one prior, I'll take one during, and I'll take one after. And some of the Iron Men that we've worked with have said that when they're doing an Iron Man, they'll take it three or four times throughout the race, and their comment is that it's taking out the old battery and putting in a new one. It really rejuvenates your body's ability to perform when you're doing a more extended athletic activity. So, think about that too. If you want to go do a longer hike or whatever else, take it with you.

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Steve Reiter: Well, we talked about the water article, and it was one that was published in the Daily Mail as well, very recently. “The Secret to Anti-aging. Drinking eight glasses of water every day can prolong your life up to 15 years and slash the risk of heart attack and strokes, a dementia study suggests.”

Dr. Gladden: What's interesting to me is this idea of drinking eight glasses of water. My grandmother used to tell me this. She used to be talking about her father, who was my great-grandfather who lived to be 96, or something like that. Actually, he was out swimming in a river at 92 and stuff like that with his friends. He was a character, apparently. But every summer, they would go out when it got warm enough and had to have their annual first swim in the river kind of thing in Marshall, Michigan. But she always said he drank eight glasses of water a day, and she was always drinking water. She lived to be 96, and her husband died at 97. And what's interesting to me is this idea of drinking eight glasses of water a day. So, is that a magic thing? Well, when you look at this study, what they actually determined is that it's the level of your serum sodium.

So, when you have your blood tested, and you get your electrolytes done, there's always a serum sodium, a potassium, a chloride, a CO2, a BUN, it's called, which is blood urea nitrogen, and creatinine, which is basically released from muscles and is filtered by your kidneys and gives you an idea of kidney function. But the sodium, the serum sodium, has a range of normal. And what was interesting in this article is that what they discovered is that when you are in the high normal range, over 142 millimoles of sodium per liter is really how it's reported out, that you had a significant increase in your chances of having an older biological age based on a particular algorithm where they look at either eight or 15 relatively simple biomarkers. I can read those off to you here in a minute. But the point is that you had a greater chance of being biologically older, and you also had a significant increase in mortality, like a 20% increase in mortality.

So, is it the eight glasses of water, or is it the higher serum sodium? And I think, in this case, what's important to pay attention to is the serum sodium. And the way that you drive serum sodium down is by drinking free water, which means water without electrolytes in it like sodium. And so, that's kind of the take-home message here, I think. It's also interesting to note that you can have too much water, and the mortality went back up when the serum sodium got below 138. So, there was kind of this sweet spot, and it really looked like the ultimate sweet spot was 138.5 to 139.5. That seemed to be the ultimate sweet spot. Anything off of that was associated with some increased risk. And the way they were measuring biological age was basically to take blood sugar, cholesterol, and hemoglobin A1C, which is three months running average of blood sugar.

GFR, which is basically the glomerular filtration rate, is a measure of kidney function. How much air you could move in one second on a breathing test, what your systolic blood pressure was, what your blood urea nitrogen was, that BUN we measured, and another measure of kidney function cystatin C, which is muscle mass independent measure of function. And then, what's your body mass index? And then that was the nine biomarker panel. And then they added a couple of things to it. They added creatinine, uric acid, albumin, glycated albumin, C reactor protein, and fructosamine, a two-week look back at blood sugar. So, really, what they're looking at here is blood sugar, kidney function, lung function, cholesterol, body mass, and inflammation. And those were really kind of the primary drivers here.

Steve Reiter: What do you think about using those as a biological age marker?

Dr. Gladden: I think it's a validated technique, and it's been looked at, and it has been validated as a technique to get an idea of biological age. However, one thing we've discovered is that we're really all a mosaic of ages. And so, you could have one biological age here, but you could have a cardiac age that's actually different, an arterial age is actually different, a different brain age, a DNA methylation age that's different, an immune system age that's different, et cetera. And so, to really actually understand where you are vulnerable and where do you actually need to apply attention, it's more than just getting to a number of biological age. It's more about tearing apart the pieces of it to understand, well, “where do I need to focus?” “How do I really optimize my health here?” And I think that becomes more valuable.

So, we've taken it much further than nine or 15 biomarkers. I mean, we're measuring well over 60 at this point in time to really get an idea of where people are at, and that's actually expanding now. But we think that that's a critical piece is to bring all that into balance. Now, serum sodium is certainly something we have been measuring. Potassium, creatinine, cystatin C, all of these things we measure on a regular basis for our clients. So, none of that is lost on us. But I do think that this idea of staying well hydrated is important. But I'll tell you this too, and we talked about this a little bit, that people have different genetics around serum sodium. They have different set points.

Steve Reiter: Yeah, we talked about this before we hit record. You had mentioned that the slaves who successfully made it over in the 17th century, 18th century, and early 19th century, that the ones who made it over had good serum sodium retention.

Dr. Gladden: Yeah. This was true for slaves coming from Africa to South America, the US, or wherever. Horrific, horrific part of history.

Steve Reiter: Yeah. Yes.

Dr. Gladden: Just horrific, right, without question, and the conditions they were subjected to were completely horrific. And there's been slave trade. There's slave trade today. I mean, there's been slaves all around the world, and people have been mistreated for eons. I mean, talk about being a galley slave in Rome or something. But the point is that people that were able to survive that extreme deprivation of food and water and everything like that to make it across that journey, they had better genetics to be able to retain serum sodium. And so, they were able to survive. But while it was a survival to come across, it became a liability later on because they would hang on to sodium. And once they had access to sodium in their diets and things like that, it would raise their blood pressure, and they'd have more strokes, heart attacks, cardiovascular disease, if you will, more kidney disease, more kidney failure. And so, it just goes to show you a lot of genetics are kind of binary like that. So, it's an asset in one set of conditions and a liability in another.

Steve Reiter: Sickle cell is beneficial if you're in Africa and dealing with malaria.

Dr. Gladden: Exactly. Right. But the rest of the time, it's a curse.

Steve Reiter: Yeah.

Dr. Gladden: Exactly. So, anyway, the point is that if you're hearing this and listening to this and you're saying: “Well, geez, I need to drink eight glasses a day.” Okay, well, you may want to start there, but where you really may want to start is: “What is my serum sodium?” It's an easy test. Any doctor that's ever done any blood test on you has that information. What is my serum sodium? And then, if you want to look further, there are different genes that you can look into that actually have to do with your body's ability to retain serum sodium. And so, we won't rattle all those off right here, but those can be looked at in panels related to cardiovascular and blood pressure health. And when you look at those, all of a sudden, you can factor that into your thought process too. What is my set point for sodium, and do I need to drink ten glasses of water a day to try to compensate or lower the sodium in my diet, or what other measures do I need to take?

Steve Reiter: If you're in a sauna regularly, you obviously need to bump up that number from eight glasses to something that helps keep your serum sodium at that optimal level.

Dr. Gladden: Yeah, well, that's an interesting thing. So, you're in the sauna, and you're sweating well, you're losing sodium in the sauna too, and you're also losing fluid, and so you want to rehydrate. So, using the sauna and rehydrating with water would be a good way to lower your serum sodium if you tend to have a higher serum sodium. On the other hand, if you're in low serum sodium doing a sauna, you want to replete, and you want to be eating some salt. So, I did some recent testing that showed that I actually needed more salt because of the sauna use and the exercise that I do and things like that. So, I've actually had, I'm not doing it so much right this minute, but I was using a little bit more salt to try to compensate for some of that.

Steve Reiter: And when you say a little more salt, are you just putting a pinch of salt in your water? Are you throwing a little extra salt on your food?

Dr. Gladden: Yeah, a little extra salt on the food. The foods I eat are pretty much- I don't buy pre-processed foods. I pretty much buy regular things and cook it, and then I'll take a one-shake of salt on it kind of thing. Just it's not like heavy salt; it's just adding a little salt.

Steve Reiter: Okay. So, in these studies, one of the questions that I had for you beforehand is when our listeners and myself are seeing these headlines on network news and the major news reports-

Dr. Gladden: So, when these things show up, and you see these, it's really important to also be able to read the study and understand whether or not it's a meta-analysis. Are they going back and looking at a lot of other studies and then trying to draw conclusions from 10 other studies that they looked at? Or did they look at ten other studies to help them formulate a question that they wanted to answer, and then they basically constructed their own study? Then you want to know how many people were in it, how were people excluded? How long did it run for? Or how long was the follow-up after the study enrollment was done? Things of that nature because all of it has to do with its validity. And if you are not one of the study participants, then the study may not apply to you. What we're talking about here is people over the age of 40. So, if you're 32, everything we're talking about here you have to take with a grain of salt now, no pun intended.

So, the thing is a drink, a slug of water, or a shot of water. So, it doesn't mean that you probably wouldn't want to stay well hydrated. I think you would. But I'm just saying that studies are, they'll always have limitations to them, and they're never perfect. And so, you have to look at them for what they are. But then you also have to understand that there are other factors at play, like what are the genetics at play and things like that, which are rarely looked at, and just take a bunch of people all the same age and throw them into a study, and it's heterogeneous. And then sometimes what comes out of it isn't really particularly useful for you. So, you just have to look at all these things with a little bit of a jaundiced eye.

Steve Reiter: I'm reminded of the quote that Mark Twain made famous. “There are three types of lies in the world: lies, damned lies, and statistics.”

Dr. Gladden: That's a great quote of Mark Twain. But that's true because in studies, you can actually ferret out relationships and associations and all kinds of things and report them, and they may or may not have anything to do with reality. You have to understand that people that are publishing stuff, in order to get it published, they have to show something, and in order to show something, they use statistics to do it. And so, they're slicing and dicing their data to be able to show something. It's how they get funded. It's how they keep their tenure. It's how they do what they do as an academic. So, anyway, just I've really become skeptical of the literature. In fact, there are things where all the studies that get published, I forget what the percentage is now that I've read it somewhere, 50 to 70% of it is subsequently disproven.

Steve Reiter: Wow. Wow.

Dr. Gladden: Right. Yeah. It's phenomenal. It's phenomenal. And it has to do with how these things are structured. So, this double-blind placebo-controlled trial, that's going to be the holy grail of what we're supposed to do. Well, not exactly. You have to really look at it through your own lens to figure out what works. That being said, I think you want to stay well-hydrated. I think you don't want to be eating big meals. I think you do want to fast, but you don't want to overcompensate for that by jamming a lot of calories into your system, and I think you want to stay well-hydrated but not over-hydrated.

Steve Reiter: The last thing that we wanted to talk about is late in '22, the FDA made a decision about NMN, very popular longevity supplement that Dr. David Sinclair is a big proponent of. I've heard Dr. Huberman and Dr. Attia talk about it. We've talked about it here on the podcast. Talk about the FDA's decision and its implications for NMN as a supplement, as something that our listeners have been using or have considered using.

Dr. Gladden: Right. Well, David Sinclair is a famous researcher in longevity, and really, he's a Ph.D. He's not an MD, he's a Ph.D. And he has basically shown that having good NAD levels as you go through life activates sirtuin genes, and sirtuin genes are a genetic cascade of activities in the body that promote longevity. And so, to have higher NAD levels, some people will get IVs of NAD. But we don't think that's a smart idea because it doesn't last very long. It's been shown that it doesn't even get into your cells.

Steve Reiter: And it's expensive as hell.

Dr. Gladden: It's expensive, and it's uncomfortable. It only gets into the plasma. It doesn't cross over into the cell. And so, you may get some benefit from it, but we think that you're really much better off optimizing your own NAD production. So, yes, NAD is an important molecule. So, then the question is: “Well then, how do I optimize my NAD?” Well, it turns out you optimize your NAD by-

Steve Reiter: And for listeners that are brand new to the podcast, what is NAD? Just give a 30,000-foot view of what NAD is and its importance.

Dr. Gladden: Yeah, NAD is a molecule that's involved in energy production in the mitochondria. It's also a co-factor for a number of enzymes, and those enzymes don't work unless NAD is around as their co-factor. So, the sirtuins are an example of NAD-dependent enzymes. NADs are also used up by an enzyme called PPAR gamma, which is important for mitochondrial function. And then it's also used, NAD is also used up inside the mitochondria itself to make ATP. So, it shows up in a lot of different cycles. And then NAD itself, there's a way to recycle it. So, just like ATP goes to ADP and then it can go back to ATP again, NAD can go to NADH and then back to NAD, and it's the ratio of NAD to NADH that's really the critical factor.

But anyway, there are recycling pathways there. And you can also impact the amount of NAD by providing precursors up to a point. And the precursors are niacin, nicotinamide, nicotinamide riboside and NMN. And it was only recently that NMN was shown to actually be able to get into cells and actually be part of the NAD production. In other words, exogenous NMN would actually show up in endogenous NAD production. Prior to that, it was skeptical. People were skeptical about whether or not it would actually work, but it does work. And Sinclair really popularized NMN as the best molecule to allow you to make NAD. Well, it turns out that you develop senescent cells as you go through life through aging. And when you have senescent cells, you produce something called CD38 and CD38 gobbles up NAD.

It chews it up. So, now you have a problem as you go through life, both with production and overconsumption. And so, how do you block that? Well, you block CD38 with parsley. Something in parsley called apigenin will block CD38. So, eating herbs, which we've talked about before, are incredibly helpful. But eating parsley, in particular, will help to block CD38. So, you can take NMN, and you can take a form of NMN called beta NMN, which is what Sinclair was using in his research, and he started a company to be able to patent it and to bring it forward as a drug.

And so, once it got patented and they got an IND from the FDA, an Investigational New Drug designation from the FDA, then all of a sudden the issue became, well, beta NMN is going to come off the market because now it's an investigational new drug and it's protected as an investigational new drug. Well, this happened with NAC, and it also went through a similar kind of scenario, and it was taken off the market initially but then was put back on the market. And the thing is that I don't think that NMN is going to go away. Sinclair's come out and talked about that, and I think you're still going to be able to get NMN as a precursor for NAD. There are other companies out there, though. There's one called Nuchido TIME that's out of England.

Steve Reiter: I was just going to talk about them. I was just going to talk about that.

Dr. Gladden: We've had them on the podcast also. And Nuchido TIME is really interesting because they have an approach of, rather than just supplying, say, NMN or niacin or nicotinamide riboside as a precursor, their approach is basically to provide a number of things that work together in concert, if you will, to help with the recycling, to help with the production. So, they have things like sophora, [inaudible 00:41:38] different flavonoids with quercetin, rutin, and troxerutin. These basically activate the salvage pathway. They have alpha lipoic acid, which also helps to boost NAD in a couple of different ways. It activates AMPK, which leads the body to produce fresh NAD, and it also promotes a pathway for the conversion of NADH back to NAD. So, they add alpha-lipoic acid to their product. They use parsley for the reasons we just talked about, to block CD38 consumption of NAD.

They use EGCG from green tea, which is also beneficial in the process. It inhibits an enzyme that breaks down NAD, and then they use a little bit of vitamin C as an antioxidant, and they added in a little bit of zinc, and they also put in some black pepper that improves the absorption of some of their ingredients. And that's their proprietary formula, having those things all in one pill. And so, they also have niacin as a precursor, just plain old niacin, and they've shown in their research that you can get a 240% increase in NAD if you do that. So, it's an interesting conversation. I personally don't think NMN is going to go away. I think once they got the IND designation, I think there was a lot of worry about that. But at the end of the day, I don't think it's going to be a problem.

If you like NMN and you're going to take NMN, I think you're going to be able to take NMN. If you can't, and you want to go another direction, you can take Nuchido TIME. There was an article that I think is what I've heard is poorly done, looking at nicotinamide riboside being associated with metastatic breast cancer. I will say that in cancer patients, we are very careful about NAD. We don't give NAD precursors. And if you're listening to this and you have cancer, NAD is energy; it's fuel. And so, cancer cells can utilize that fuel too. So, for people that have had malignancies or cancers, we don't use NAD or NAD precursors, like NMN or Nuchido TIME, because we're just trying to be very cautious in that regard. So, it's like everything. There's good to everything and bad to everything.