2022-01-26 - Podcast Dr. David Sinclair - NMN, NR, Resveratrol, Metformin & Other Longevity Molecules: Difference between revisions

=== Kicking Off Episode Four: Longevity Molecules ===

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| - Welcome to the Lifespan podcast, where we discuss the science of aging and how to be healthier at any stage of life.

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| I'm David Sinclair. I'm a professor at Harvard Medical School and Co-director of the Paul F. Glenn Center for Aging Research.

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| And I'm joined today by my lovely co-author and cohost, Matthew LaPlante.<br>- Hey, how are we doing?<br>- [David] Hey, welcome.

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| - Feeling good today.<br>- [Matthew] Back at it again.<br>- We are. We're here today to talk about how to live longer and better.

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| - As part of this podcast series, this deep dive into things that you can do to slow, stop, and reverse aging.

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| - That is true and today is going to be a really interesting one.<br>- This is going to be the one that everybody,

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| I mean, this is the one that everybody's been begging for.<br>- That is true. We've been monitoring the responses to tweets

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| and Instagram posts, and most of them are, David, just tell us what to take.

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| - [Matthew] The nice ones.<br>- Yeah.<br>- Some of those aren't very nice either, but yeah, please, please, please.

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| Should I take NR? Should I take NMN? What should I do with Metformin? We're going to be talking about all of that today.

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| - We are, and our research team has been spending weeks on this, and if you can't see, I'm actually sitting in front of many pages of notes here.

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| We're going to go deep dive into what is fact and what is not fact. What is known, what is not known, because there's so much misinformation out there,

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| especially with supplements.<br>- Yeah. We do need to say we usually take a moment

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| to thank our sponsors, we're going to do that of course, but we also have to take a moment to say we are not medical doctors. We are not medical doctors.

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| We are not medical doctors.<br>- What he said. I'm a PhD, I'm a researcher.

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| I can read the literature. I've been doing it for the last 30 years. I distill that for everybody.

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| But of course, if you want to try supplement or even change your diet radically, please talk to your physician before you change anything.

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| Because some of the things we'll talk about today can affect your body in, hopefully, many good ways, but sometimes can be dangerous depending on the person.

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| And everybody's different.<br>- And what we want to do is give people the ability to have a more intelligent

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| and informed conversation with their physician.<br>- Exactly.<br>- Okay, with that out of the way, now we should thank our sponsors.

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| - Let's do that, because this podcast is free to anybody who wants to watch or listen.

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=== Thanking the Sponsors ===

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| Our first sponsor is Levels. Levels is an app that syncs with a continuous glucose monitor, which they provide,

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| I've learned that grapes spike my glucose, white rice, but actually potatoes aren't that bad.

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| It's not just interesting, it's also a lot of fun to see what's going on inside your body.

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| So if you'd like to try Levels, you can skip the 150,000 person wait list. And you can join today by going to levels.link/sinclair.

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| That's levels.link/sinclair. Today's podcast is also brought to us by Inside Tracker.

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| Inside Tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body

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| and reach your health goals. I've been using Inside Tracker for over a decade and also serve as chair of their advisory board.

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| I really like Inside Tracker because they make it easy to get your blood test. Either someone can come to your home like they do for me, or we can go to a clinic.

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| They then present the blood analysis in an easy to understand dashboard that provides recommendations for improving your health.

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| If you'd like to try Inside Tracker, you should go visit them at insidetracker.com/sinclair

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| and you'll get 25% off every Inside Tracker plan. Use sinclair as the code at the checkout.

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| Today's episode is also brought to us by Athletic Greens, the all-in-one daily drink to support

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| better health and peak performance. Athletic Greens is a greens powder developed from a complex blend of 75 vitamins,

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| minerals, and whole foods sourced ingredients. It's filled with adaptogens for calvary, probiotics and digestive enzymes for gut health,

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| as well as vitamin C and zinc citrate for immune support. I've been drinking Athletic Greens

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| in the morning for many years and I do that because I don't often eat perfectly and I travel a lot

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| and I can rest assured that I'm getting all the nutrients I need for optimal health.

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=== An Additional Boost Beyond Adversity Mimetics ===

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| Okay, Matt, let's dive in. There's a lot to get through today and I know everyone's waiting to hear

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| what we have to say today.<br>- In the last episode, David, we talked about adversity mimetics. These are the things that we can do in our modern lives

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| to mirror the sorts of stresses we faced across our evolutionary history. But even if you're engaged in doing these things

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| like we've talked about already, fasting and getting lots of exercise, getting out of your comfort zone,

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| our modern lives are still designed around comfort and sedentariness, is that a word?

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| - Sedentary lifestyles?<br>- [Matthew] Sedentary lifestyles. And that's not to mention the fact that even before modern times we aged, right?

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| So if we're going to combat aging we may need an additional boost.

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| Do you believe we may need an additional boost?<br>- Well I do and I've been doing this since my early thirties.

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| We'll talk about my program at the end of this episode, but really what we want to do today

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| is to talk about some of the major supplements and medicines that are thought and have the greatest

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| scientific evidence to be able to give you wellness now as well as long-term health in the future.<br>- Supplements and medicines,

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=== Drugs vs. Supplements and Highlight Points ===

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| drugs and supplements, molecules and drugs. There are a lot of different terms that we're probably going to throw around

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| and we're going to use them fairly synonymously. But in fairness, let's define drug versus supplement, at least.

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| - Right, first of all, most drugs are chemicals, okay?

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| But some are naturally occurring and some are freely available over the counter, OTC. And that's because they've been in our food supply before

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| and the FDA doesn't regulate them. They fall under what's called generally recognized as safe, or GRAS.

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| And that's why you can pick up whole variety of molecules from the plant world, 'cause they're already in our food supply.

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| Therefore the government thinks, well, they're probably okay, even if they're a thousand times more

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| concentrated than what you're eating.<br>- Which may or may not be the case, right?<br>- Right, and so that's why you always have to be careful.

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| You have to monitor yourself, like I have been with my blood work for many years to make sure that you're not hurting parts of your body.

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| Your liver particularly could be sensitive to some of these molecules, even if they are available freely at the pharmacy or the vitamin shop.

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| A different story about drugs. Drugs are regulated molecules because they have the chance to actually cause damage.

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| And many drugs actually do have serious side effects that need to be carefully monitored and discussed with the doctor.

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| Even those that are very safe. Like we'll talk about Metformin. These are regulated by the government

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| because they are not in the food supply. There are artificial molecules that could theoretically do damage.

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| - And there are literally thousands of drugs and supplements that someone somewhere

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| will tell you we'll help you with health spans and lifespans. We're not going to talk about

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| thousands of drugs and supplements today.<br>- No, maybe in future episodes we'll come back, but we want to hit the high points today.

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| - And so that's why today we're going to move through some of the most popular and some of the most promising. These are things that most people can have access to,

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| or find a physician who, if the need exists, will prescribe.

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| - Right, and I get emails and I get all sorts of texts every day, DMs, what should I take?

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| What about this? What about that? What's the dose. When should I take it? What should I take it with? Is it okay to take this drug with exercise or not?

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| That's what we're going to cover today. Your most pressing questions answered here today.

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| - And so we're going to talk about NAD boosters. We're going to talk about Metformin, berberine, rapamycin, spermidine, resveratrol,

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| fisetin and quercetin, and probably a few others. But those were sort of the highlight points.

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| If you're only interested in one of these, or if you watch this whole episode need a reminder,

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| the show notes are going to be timestamped so that you can immediately go to berberine and find it and click on it.

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| - That's right, included in the show notes are the scientific references that we now have in front of us that we're going to talk about

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| so that people can do a deep dive, even deeper than what we're going to do here today.<br>- There's one more thing that we'll link

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| to in the show notes that's on your website that I think is valuable for people to know about. You're involved in a lot of different companies.

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| You're an entrepreneur, you're a researcher. You have I don't know how many patents.

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| There are plenty of people who would say, oh, this guy's just trying to sell stuff. If they suspect that you might have a conflict of interest,

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| they can go and look at your disclosures.<br>- I do disclose everything that I do. My lab has a website. You can Google Sinclair Lab.

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| And if you click through my bio, there's a link to all the work that I do outside of Harvard,

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| as well as what we do at Harvard, of course, but importantly, I've never sold any supplement in my life.

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| - And that's not because you're a bad salesman. It's because you haven't actually tried to sell. I mean, there's a difference between

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| having not sold a supplement and having tried to sell a supplement and not sold a supplement.<br>- Right, I've actively kept myself away from the supplement industry because I want to be able

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| to talk about things without any bias.<br>- Not for a lack of opportunity though,

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| there's plenty of people who would love to put your face on a package.<br>- Well, and they do, without my permission. You can see my face on the internet.

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| But if you see that, know that it's not with my permission and I do actively try to stop that.<br>- To get into this let's use some of the same framing

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=== Longevity Molecules Target the Survival Circuit ===

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| that we've used for the other conversation. And that's these three longevity pathways, three longevity genes that we've been talking about.

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| sirtuins, AMPK, and mTOR. Different drugs and supplements are thought

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| to work on these different pathways in different ways. And we'll sort of like categorize them in those three buckets today.

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| - Exactly, and the thing to also remember is that these three survival pathways we've talked about, and in episode one we talked a lot about,

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| are responding to our environment. Whether you're exercising or fasting they'll turn on, but also appreciate that they talk to each other

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| and some drugs or supplements will activate one of these and talk to the other two. So it's a network and we're still

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| trying to figure out exactly what the optimal combination for each individual might be. Whether to tweak it with this molecule

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| and then exercise here and then fast that day. We don't know all the answers, but we are going to present the cutting

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| edge science here today.<br>- And I think it's been really interesting. I've been working with you for, what,

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| like about four years now. And in that time a lot of the molecules that we knew to be working on one of these pathways,

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| there's been further research that has said, oh, that's not just an AMPK effect. There's also an mTOR connection there.

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| - Well they definitely talk to each other. Because if you're low on immuno acids and it'll turn on the mTOR protection pathway,

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| that will then tell the other survival pathways to do their thing too.

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| It's like the Pentagon where there's centrally coordinated defenses and basically what we're trying to do

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| is to make prank phone call to the Pentagon to say there's an emergency and they'll send out the troops in various ways and protect the body,

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| even though there's no immediate threat.<br>- I like that analogy. That's fun. Let's talk about the class of molecules

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=== NAD Boosters ===

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| that you've worked most extensively on in your lab. These are known as NAD boosters.

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| Talk a little bit about why NAD is important in our bodies.

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| It's really important, if it disappears, we're screwed, right?<br>- Well, we'd be dead in 30 seconds. We need it for energy but it was discovered

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| about 100 years ago by Germans who were looking at extracts in yeast. And there was this component called NAD

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| that was necessary for chemical reactions.<br>- We didn't say what that stands for, that's?

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| - So NAD stands for nicotinamide, which is vitamin B3, and adenine dinucleotide. This is a sugar and a phosphate.

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| The important part about it is that our cells use NAD to transfer hydrogen atoms

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| between proteins and even DNA. That is really important for life and without it

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| we can't make chemical energy, which is in the form of ATP, which we'll talk about later

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| because that's important for Metformin. NAD is found in abundance. There's many grams of it in the body.

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| It's probably, with the exception of ATP, the most abundant molecule we have in the body. It helps us make energy but it

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| also has this other function that's just as important that we worked on and just co-discovered in the 2000s.

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| It activates the sirtuins and the sirtuins are these defensive enzymes that, like the Pentagon, send out the troops.

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| The problem is as we get older we make less NAD and we also destroy it more for reasons

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| that we don't fully understand, but it leads to a decline in our ability to fight off aging and the diseases that it causes.

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| - And this is because NAD is a sensor for adversity.

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| - It is, if you exercise, it's known, and fast, it's known to raise NAD levels.

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| But even if you exercise and have the healthiest diet, you're still going to have lower NAD levels by the time,

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| you know, you're in the latter half of your life. So that's why these supplements are thought to help because they'll boost up those older levels of NAD

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| to where they were when you were young.<br>- Okay. So let's talk about the first NAD booster.

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=== Nicotinamide Riboside ===

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| Probably the most well-known, it's definitely the most well studied of the NAD boosters, and probably the most taken used. That's NR.

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| - Which stands for nicotinamide riboside. So that's the vitamin B3 plus the sugar.

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| Without the N part, which is a phosphate, we'll get to the phosphate, that's important later.

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| It may make a difference, but NR has been taken over the counter or through websites for, what, since 2014,

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| either solely just as a capsule or there's some companies that sell it in combination with other molecules.

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| - And because it's been pretty well studied in humans, there've been plenty of human studies,

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| at least in the short term that show little to no side effects. This is a pretty safe molecule.

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| - That's for sure. We know that if you take it as a supplement to swallow the pill, either 250 milligrams

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| per day or a gram, there's no apparent negative side effects, and in fact, you will raise

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| NAD levels in blood tests.<br>- So I think this is an important distinction to make, though, like there's a difference between

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| safe and effective, right? Just because we say something as safe, doesn't mean it's going to work enough. And in fact sometimes things that are the most safe

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| aren't going to work at all. That's why they're so safe is they don't have any effect. But we do know that NR is largely safe, you know,

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| millions of people around the world take it. NRs have been well studied in animals as well.

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| And let's start with that because we actually know more about what NR does in the bodies of animals than we do in the bodies of humans.

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| - Well let's start with yeast. Go even further back.<br>- Okay, yeah.<br>- So that's where it was first discovered.

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| NR was a newly discovered molecule back in the early 2000s. It's found a little bit in milk and other food selves.

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| And if it was fed to yeast, they lived longer by turning on the yeast sirtuin pathway.<br>- Okay. How much longer were the yeast living?

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| - Generally yeast live about 30% longer when you give them these molecules, similar to choleric restriction.

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| And that's what this was doing, mimicking choleric restriction, 'cause both activate the sirtuins and give increased genome stability

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| and epigenome stability that lengthens their life.<br>- And those kinds of findings make you really interested

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| because you're really interested the sirtuin activation. And so you've been part of a group of scientists

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| that have been looking at this.<br>- Yeah, one of the first things that we discovered, this is now, we're talking 2002, 2003 in my lab,

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| is that there's an NAD synthesis gene called PNC1. In our body it's called NAMPT.

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| And it gets activated by these mild stressors. In a yeast cell it's low salt, it's low sugar, heat.

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| And that turns on the synthesis of NAD and we found that extended lifespan. And then a few years later it was shown

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| you can mimic this effect with this NR.<br>- How does the NR turn into NAD?

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| - So NR has to go through an intermediate molecule. Let's start with the mouth. You swallow your NR, it'll go into the gut.

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| Some of it will be metabolized by the gut bacteria, but most of it will go into the bloodstream

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| and then flow around and then get taken up into your muscle, into your brain and other cells, by transport that's called ENTs.

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| And there it's converted into NMN by what are called NRKs. And then you add the phosphate

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| and you've got this thing, NMN. What's NMN? Nicotinamide mononucleotide.

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| And then the cell puts two of those together to make NAD.<br>- And when we do this in laboratory animals,

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| you mentioned in yeast it extends life by 30%. What have we seen in mice,

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| which are a little closer to you and I than yeast is?<br>- Yeah, it's going back a number of years ago.

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| It was found that NR, when given to mice, extends their lifespan by about 9%.

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| But it was given to them late in life at about 700 days, which is a pretty old mouse, that'd be like a 70 year old human, but it still worked.

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| But they're also in improvements in health, they had more mitochondria, which is the energy. They had more athleticism, less inflammation.

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| And so that was the first real study that said, okay, maybe supplementing with these molecules

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| like NR or NMN might have some long-term health benefits as well in humans.<br>- Among the other health benefits

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| that have been seen by researchers who have given NR to animals and lab enhanced oxidative metabolism.

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| Let's talk about that.<br>- So they burn more fat, they get thinner. And that also means that they're burning more oxygen and that's thought to be really good

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| at staving off diabetes, type two diabetes, as well as improving lifespan.<br>- Let's carry this now into the human studies because what we don't have for reasons

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| that maybe are obvious, but I'm going to state it any way, which is that humans live a very long life. And it's really hard to put humans

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| into a control group and a test group across a very long time, then control for every variable that's possible,

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| is longitudinal studies that show increases in lifespan as a result of taking NR.

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| But we do have studies that have sought to show similar health benefits

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| to what we've seen in rodents.<br>- Somewhat. I would say, NR,

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| there've been a few positive results. Not a lot. Before we'd get to that I think

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| it's worth talking about why can't we just take vitamin B3, which is a precursor to NR.

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| You can but it doesn't raise NAD levels anywhere near the level that NR does. NR doesn't seem to be as effective as NMN.

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| So the closer you get to NAD with your molecule, the better it seems. And that's probably because you need

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| to bring in other components. So if you just take vitamin B3, you need a sugar and a phosphate. If you just take NR, you need the phosphate.

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| Phosphate is pretty rare in the body. It's in your bones, it's in your DNA. And maybe when you take NR one of the issues

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| is that you need to find a phosphate head on there before it becomes active.<br>- Okay, back to the human studies on NR.

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| We have sought to see, by we I mean the research community,

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| I don't mean necessarily you and me, we've sought to see the same sorts of effects

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| that have been seen in models, organism studies.

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| Sometimes that's happened. Sometimes it's not. Is that fair to say?

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| - That's very fair to say. With NR there've been a handful of studies in humans showing that low dose, 250 milligrams per day,

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| up to a pretty large dose, a gram a day, does raise NAD levels, but it takes about 9 to 10 days to get to those peak levels.

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| What we've also seen is, or others have seen, is lower inflammation as well as some other markers

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| such as minor changes in body composition. But these other things which are lower blood sugar,

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| improvements in insulin sensitivity, increased mitochondria, those haven't been born out just yet

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| in these short term studies with NR.<br>- Sorry, so these are the things that were present

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| in the mice who also lived longer.<br>- Right, yeah. Now it could be that you need a longer

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| term exposure of these people. These have been fairly short-term studies. Or that humans are not the same as mice.

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| - So would you say, I mean, if somebody tells you, oh, David, I've been taking NR for so many times,

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| you're not rolling your eyes, but you're not convinced at this point. The jury's still out.

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| - Well, it depends what you're asking. If it's to lower inflammation, yeah, it probably works. There's also a study that was put out by a group

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| that combined NR with [indistinct], which is a resveratrol-like molecule, We'll talk about resveratrol next,

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| that found that in ALS patients, Lou Gehrig's disease, there was an improvement in their daily function.

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| So that is somewhat promising. I think that of course we need more studies. That's what we really need here to be able

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| to make any sort of conclusion about what the long-term effects of taking this supplement are.<br>- It's fair to say that in the sirtuin

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=== Nicotinamide Mononucleotide ===

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| activated compound research community, there's kind of team NR and then there's team NMN.

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| Your lab really focuses on NMN and I think if people were sort of like following

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| what you said earlier about how NR turns into NAD,

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| they might go, oh, well, NR turns into NMN, NMN turns into NAD, so why don't we just

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| take NMN to begin with anyway. And you had mentioned earlier phosphate, and that's an important component of this question.

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| - Well, it is. NR is more popular because it's cheaper to make. It doesn't have that phosphate which can be expensive

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| to put on the molecule through chemistry. And that's why most people started using NR first in humans and in mouse experiments.

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| I didn't have a horse in the race. I didn't care which one. In fact, I'd prefer if both worked according to,

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| you know, my theories, but what we found through empirical studies, basically,

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| we're looking at which ones work better, my lab and others, including Matt [indistinct], who's at Wash U,

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| who treated a mitochondrial disorder and we were treating regular mice on treadmills. We found that NMN just worked better at the same dose.

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| We don't actually understand why it could be that this phosphate addition is one of the reasons, but, you know, just based on observations

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| in our hands and in others, NMN works better than NR.<br>- When we supplement with NMN,

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| when NMN is given to organisms in the lab, what's happening?

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| - Well, it's a little different, there's been an argument in the literature that NMN doesn't get into cells. And similarly, NAD is really a big molecule

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| because it's got multiple components. And that also has a real struggle to get it into cells.

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| Neurons take it up but other cells typically need to break it down into its various components and then re-uptake it.

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| And that's important because some people actually are giving themselves NAD through the IV route. When it comes to NMN what happens

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| is it was recently discovered by Shin Imai at Wash U, his team discovered that there's a specific transporter

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| that takes NMN out of the liquid outside the cells inside the cell and its name is SLC128A.

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| Still debated, a lot of things to figure out. But I think it's just best to say, okay,

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| we know what's happening when you give it to animals, we are starting to learn what happens to people.

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| We of course want to understand how it's working, but the fact that it does work is the most important point.

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| - So when it comes to NMN, there's been a number of animals studies showing, for instance, similar to NR, restores NAD levels,

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| it enhances insulin sensitivity. One of the things that was surprising to me is that we don't have a study that shows

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| NMNs effect across analysis entire lifespan yet.<br>- Well, we have half a life span.

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| Shin Imai showed that it actually was pretty good at slowing down the effects of aging,

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| but he stopped the experiment because he ran out of NMN. It used to be rare stuff. Now you can buy it.

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| But we took up the challenge and we've been doing these studies for the last few years in my lab. Now, preliminarily, these mice have less frailty.

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| We've reported that out in the scientific community. They seem to be younger, having better activity,

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| better mitochondrial function. They run further. The lifespan looks promising. We've done it once and they do live longer on NMN.

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| The doses are out 400mgs per kg.<br>- How much longer?<br>- At this point by recollections,

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| about 10 to 15%, but particularly strong in females.<br>- Okay, so not particularly, like, wholly different than what we saw

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| in the NR cases with the mice.<br>- Right, a little bit better than that, but certainly those mice are healthier

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| and more active and are more youthful.<br>- And you said it was more pronounced in the females,

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| or at least according to the first phase of this it's more pronounced in the females.<br>- Right, well we had fewer females

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| so we have to repeat that. So we've now got a larger cohort of mice. We're repeating the whole thing. We'll see how it goes.

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| But right now with the small number of females, yeah. They did do better than the male.<br>- And even though mice live pretty short lives,

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| what we have to understand here is that there's still live two, three years on average. Right, and so in order to see lifespan extension,

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| especially if they live much longer, it takes some time to do these studies.<br>- Yeah, it's quite painful actually,

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| because you think about this, an average experiment takes three years and then you have to repeat it. So that's now six years.

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| Then to analyze the data and publish it is another three or four. That's a decades worth of work for one experiment.

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| And, you know, your career only goes for about five of those times. So, five experiments?

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| - Well, that's how careers used to go. But we're going to change that, right?<br>- We're going to live a lot longer.

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| We run things in parallel as well. That's important. But we can also mimic things, not just in animals,

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| but growing tissues in the dish will be the subject of a later episode.<br>- So, so far what I'm hearing is in animals,

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| NR and NMN both have some similar effects, right? Lengthening lifespan, restoring mitochondrial activity,

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| restoring NAD levels, enhancing insulin sensitivity. But in NR the human studies haven't always

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| confirmed that that's the exact same thing that's happening in humans. What are we seeing in the human studies for NMN?

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| - I know a fair bit about the effect of NAD boosters in humans because I'm helping a group that is actually

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| doing clinical trials at Harvard Medical School and they've been giving a molecule that's similar to NMN to subjects for many years now.

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| First of all, importantly, there's been no evidence of any negative side effects. That's important.

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| We're about to learn whether it actually does anything that's similar to the mice. We don't have results in yet, but hopefully by 2022,

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| we'll actually know if people have more energy, more mitochondrial function, better blood flow, more endurance, which is what we saw in those mice.

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| - There's been a little bit less human research on NMN then in NR,

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| but we're starting to see just in the last couple of years, especially sort of a flood of studies

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| being published, early results, for instance, from Yoshino et al. in 2021 showed increase

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| insulin stimulated glucose disposal. We talked about this a little bit when this study came out,

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| you were pretty excited about it. Tell me why.<br>- It's one of the real first proofs that NMN does something in humans

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| the way it works in mice. So this was a 10 week study. It's well done, it's randomized, placebo controlled.

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| It was 250 milligrams, which is a relatively low dose. Remember, I'm taking in my clinical trials,

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| a gram and two grams, this is 250 milligrams. Nevertheless, it improved what you said,

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| insulin stimulated glucose disposal. That's basically insulin sensitivity. And that's a hallmark of longevity.

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| Keeping the glucose out of the bloodstream, keeping it low levels is a hallmark of wellness and ultimately longer life.

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| So that's the beginning but we have a lot more to figure out. We need to figure out if that increased endurance that we see in my lab with NMN

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| treated mice is true for humans. We also want to note, are organs protected? Other labs, not mine, but other labs have shown that NMN

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| protects the organs when they're damaged. Kidney and heart, the two main ones. Even increased wound healing.

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| I'd love to know if NMN does that in humans. That'd be a big deal. Kidney injury is huge.

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| And particularly, I don't know if you know this, but most surgeries on the heart end up

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| damaging the kidneys and there's not much you can do about it. So ultimately we've seen a glimpse with Yoshino et al.

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| My studies that I'm involved with at Harvard Medical School are looking promising, we'll know more next year,

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| but yeah, there's a lot more in the works. And there are other NAD boosting molecules that have been made that are even better than NMN.

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| So-called NCEs called, new chemical entities. And those I'm aware of probably in the next year

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| will go into the first human study.<br>- I mean, that can be a whole episode of this podcast in and of itself, yeah.

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| - We should do it.<br>- Yeah, okay. Why don't we just give NAD directly?

|}

=== NAD Intravenous Drips ===

{| style="padding-top: 1em;"

| We're talking about like NAD boosters. NR creates NMN, NMN creates NAD, that boosts NAD.

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| Or NMN boosts NAD, but it all gets us to NAD. So why don't we just, you know, set up the drip line and get it going?

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| - Well, we don't, but others do. There's a lot of activity going on in Florida and LA,

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| particularly, of having large drips, long drips of over an hour of NAD.

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| - These are not in a study settings. This is not in a research setting. This are like people trying this out.

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| - Well, they're done under medical supervision, but I haven't yet seen a placebo-controlled trial

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| that would tell us for sure if it's just wishful thinking or not. I don't think so given how many people

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| have been now treated and there's a serious amount of anecdotal data on this, better mood,

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| better energy, but you know, you cannot conclude anything unless you actually have one of these placebo-controlled trials.

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| I'd love to be involved if anybody's going to do one, I'd love to help. But I'm asked this probably every day.

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| NAD IVs, do they work? My answer has to be we don't know yet.<br>- What do we think they might be doing?

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| I mean, what are people trying them for?<br>- Well they're used for various things. It's been used for many years are to treat addiction,

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| whether it's drug or alcohol, it's also used for depression, and also increasingly for hangovers.

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| - Is it as good as the Australian hangover cure that you've given me a few times?<br>- Oh, the raw egg and the Vegemite?

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| I hope it's better than that.<br>- Because the truth is that doesn't work. I just pretend it works because it makes you happy.

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| - That's true and you're one of the few people that eat my Vegemite. But the reason that it probably works

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| is there's an enzyme that detoxifies alcohol called alcohol dehydrogenase, and a lot of Asians are susceptible

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| to high levels of alcohol because they lack a lot of this enzyme. Alcohol dehydrogenase needs NAD.

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| And so what's probably happening is when you wake up with a hangover, you lack NAD, your liver is depleted,

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| and if you take NMN or NR, you can raise those levels back up, get your liver working again,

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| and get rid of the excess alcohol.<br>- So you think chances are that is actually,

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| it's not just like a placebo effect. That there's a chance that, like, it makes sense that that would work.

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| - I think makes sense is the right words to use, you know, I'm a Harvard professor. I'm not going to say something works

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| unless I've seen hardcore proof. And I hope that'll come in the next year or so.<br>- Just so I'm clear on this though,

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| 'cause it's still a little fuzzy to me. I can understand why we might want to use NAD.

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| I'm not understanding why we're not starting, for instance, all the research with NAD and then

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| moving backwards to NMN and then moving backwards to NR.<br>- It all started in yeast when I was at Harvard early 2000s.

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| Even in yeast if you give them NAD it doesn't work because it's too big, it doesn't get taken up into the cells.

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| So what we want to do is back off in size. So the next smaller molecule behind NAD is NMN

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| and there we know there's a transporter protein that sucks it into cells and NR is even smaller and it gets taken up even better into cells.

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| And so that's the reason why it may be that NMN is at the sweet spot of the right size,

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| but also has the right components to make just the right amount of NAD.<br>- It feels like a good time to talk about bioavailability and making things

|}

=== Bioavailability of NAD Boosters ===

{| style="padding-top: 1em;"

| available to our body's machinery. How do we make NR and NMN most bioavailable?

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| - Just swallowing it is enough in our studies to raise NAD by two to three fold.<br>- So if you buy the, for instance,

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| the capsules, they're often sold in capsules, just swallowing. That's going to be?<br>- Or the powder, just drink it.

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| We make tablets and give it to the patients that way, the subjects, but there were others, there was a sublingual version.

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| I have heard there's evidence that works. I haven't yet seen it. It makes sense that it would be

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| absorbed under the tongue, or you can inject it.<br>- In terms of the research right now,

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| it doesn't seem like there's a huge advantage one way or another?<br>- No, I haven't seen any reason for saying that you need to put it onto your tongue versus swallow it.

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| What I can say for sure is that I've seen so much data on swallowing it that it definitely works to raise NAD levels.

|}

=== NAD and Cancer ===

{| style="padding-top: 1em;"

| - There has been some concern around the use of NAD boosters

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| when it comes to the potential that it might stimulate cancer growth.

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| And obviously that's something that we don't want to be dismissive of. It does you no good to be boosting your NADs

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| and extending your lifespan if you're just giving yourself cancer. What's the latest research on that

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| and how concerned should people be?<br>- Well, so most of these studies, actually, there's only two main studies have been done in mice.

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| So here's what they are. There was one, again, out of Washington University by a different group that found

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| that knocking down the levels of NAD in brain tumors slowed the growth of the tumor.

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| And unfortunately the news story ended up being, oh, NAD causes cancer, which is not the same, right? That's the complete opposite.

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| So that study, I wouldn't put a lot of stock into, but there is one other study that came out in 2019

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| by [indistinct] and they found that NAMPT, this NAD boosting gene,

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| it increases the number of senescent cells and makes them more inflammatory, giving out these SAS proteins as they're called,

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| the senescence associated secretory phenotype is the word, but also there were mice that were predisposed

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| to pancreatic cancer and when given NMN they developed more precancerous and cancerous growths

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| when they consumed this NMN. Exactly how it works we're not sure, but it might be because it was down-regulating

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| a tumor suppressor gene called P53.<br>- And this was a subgroup of mice that were already predisposed.

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| They had a gene that made them more likely to get cancer.<br>- Right, but remember we fed NMN to mice,

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| but normal mice, not predisposed, and if anything they lived longer and healthier. So it's a question whether it's this

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| predisposition that's the difference.<br>- Something to watch for and to think about and to work into anyone's calculations

|-