2019-09-01 - Interview Dr. David Sinclair - Dr. Mercola interviews Dr. David Sinclair on Extending Your "Lifespan"

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    00:00:00 Welcome everyone, this is Dr. Mercola helping you take control of your health
    00:00:03 and I am just absolutely delighted to connect with Dr. David Sinclair who is a
    00:00:10 professor of genetics at Harvard Medical School and generally recognized as one
    00:00:14 of the major thought leaders in the science of how to improve our not only
    00:00:21 our lifespan but our health span. So he started in Sydney, got his PhD there and
    00:00:27 then he went over to Lundy-Garanti's lab at MIT and then went to his got his own
    00:00:32 lab at Harvard Medical School in 1999. He's been working there ever since and
    00:00:35 really come up with this astounding discoveries which we're going to talk
    00:00:38 about today but that one of the primary focuses is his new book which is called
    00:00:43 Lifespan, the revolutionary science of why we age and why we don't have to do
    00:00:49 that. And it's going to be available September 10th and if you're
    00:00:54 watching this it's not September 10th you can pre-order it on Amazon. So
    00:00:57 welcome and thank you for joining us today. Thank you, it's great to be here.
    00:01:02 Yeah, yeah so you talk about a lot of great things in there and I want to
    00:01:07 really highlight some of the concepts that you discussed because I think
    00:01:11 there's so much potential to help us and hit this really the the king of all
    00:01:17 diseases which is aging. So you talk about calorie restriction as being the
    00:01:23 only proven non-pharmacological method of consistently extending lifespan and
    00:01:29 protecting against many of the age-related diseases. And what so you and
    00:01:37 then you also discuss intermittent fasting. So I'm wondering if the one of
    00:01:41 the benefits of not eating is suppressing mTOR and activating
    00:01:45 autophagy. So I'm wondering what type of conclusions you've reached with respect
    00:01:50 to the optimal timing of the periods of the time-restricted eating and the
    00:01:57 frequency of that and how you think integrating fasting or partial fasting
    00:02:03 into that series might look like. Yeah, well we've known for probably more than
    00:02:11 now 5,000 years that being a bit hungry is good for you. So this is not
    00:02:15 revolutionary. What's been more revolutionary in the last few years is
    00:02:20 the discovery of biochemical pathways that actually seem to underlie this
    00:02:25 actual protection against disease and aging itself. And so we're not so much
    00:02:30 guessing anymore what's going on and science has gotten involved and we're
    00:02:34 doing more and more studies certainly in humans but also in animals to see what
    00:02:41 best diet works. And the bottom line, I get questions every day I wake up to
    00:02:47 probably a couple of dozen emails about this topic. Nobody actually knows what's
    00:02:52 best but we can go through them and I can talk about which is my favorite as
    00:02:58 well because there's it's not just a science aspect it's also social. We love to
    00:03:03 eat, we have traditions, we have typically three meals a day and trying to deviate
    00:03:09 from that is really quite challenging. Calorie restriction in animals and in
    00:03:13 humans is about 20 to 30 percent less than what a doctor or a veterinarian
    00:03:17 would recommend. I also struggled with that one so I certainly wouldn't
    00:03:23 recommend it. It really means you've got to be hungry for most of the time
    00:03:28 and I'm sure you get used to it but I didn't get that far. After about a
    00:03:31 week I got too hungry and I gave up. And then I didn't restrict my diet for many
    00:03:37 years actually. I had kids and that's really hard to do. But more recently what
    00:03:44 I've done which I find very easy to do is basically miss a meal once a day and
    00:03:52 I'm not hungry in the morning some people are not hungry at night. If you
    00:03:55 can go for say it's seven o'clock at night all the way through to lunchtime
    00:04:01 based on the animal studies that I've seen published and some in my lab that's
    00:04:07 very likely to do you a lot of good in the long run and in the short run. And
    00:04:13 the science behind it's really interesting I'll come back to that but
    00:04:17 there are other diets that other people have found to be effective in
    00:04:24 terms of improving biology and biochemical markers. One is the 5 plus 2
    00:04:29 diet. Michael Moseley. Exactly I'm sure many of your viewers are familiar with
    00:04:35 that one. That one is also quite doable especially if you have sodas
    00:04:43 and things like that that can actually help just bubble the water. More extreme are
    00:04:49 those diets where you go for a whole week every couple of months or every few
    00:04:55 months. I haven't tried that I'd like to. My view on that is that
    00:05:04 that's probably going to work the best if you can do it because it doesn't just
    00:05:09 trigger the short-term pathways that we've been studying in my lab. But a week
    00:05:14 of fasting will really start the body to start consuming its own protein and this
    00:05:21 is as you mentioned autophagy that's what autophagy is it's the consuming of
    00:05:25 our own biological material which is typically protein. And actually talking
    00:05:31 with people who have done these fasting regimens after about three days
    00:05:35 something different starts to kick in and people who try this tell me that
    00:05:39 they have a feeling of euphoria and they definitely get an added boost. But
    00:05:45 just let me quickly go back to why we think this works. So we've been studying
    00:05:49 in my lab for the last 20 years genes that respond to diet but fat to fasting
    00:05:55 and calorie restriction and the upshot of it is that our bodies respond to
    00:06:00 adversity or perceived adversity. They turn on these defensive pathways it
    00:06:05 changes a bunch of genes that switch on to defend our bodies. And at
    00:06:10 least from many different animals things as small as worms and flies all the way
    00:06:15 up to mice and rats these defenses of the body are extremely good at protecting
    00:06:21 us against diseases from diabetes to cancer heart disease even dementia
    00:06:27 Alzheimer's. These are things that modern medicine has struggled to combat and
    00:06:34 this seems to be the very simple way to get the body to fight against those
    00:06:37 diseases. Often I'm asked how early should you start? In the animal studies
    00:06:44 and in rat studies, mouse studies, the sooner you start the better and the
    00:06:48 longer you do this the better in your life. Clearly we don't want to be
    00:06:53 recommending or seeing teenagers or even people who are in their early 20s do
    00:06:58 this because there's still a lot going on in their bodies and their brains. But
    00:07:02 after 30 if you extrapolate from the animal studies then the longer you do
    00:07:07 this in the lifespan the better. I'm just turning 50 now and I wish I had
    00:07:11 started earlier. Yeah me too. So you mentioned stopping eating at 7 and
    00:07:16 there's a large number of people who advocate restrict not so much
    00:07:20 necessarily tying it to a specific time but at least three to four hours before
    00:07:24 you go to bed. I've been largely as a result of your exposure to your videos
    00:07:29 was been fascinated by the NAD and his family, his cousins like NADPH. When I
    00:07:35 started studying NADPH I realized that the biggest consumer of NADPH which is
    00:07:41 a molecule that essentially is a battery cell and recharges your
    00:07:44 antioxidants is fatty acid synthesis. So if you're eating shortly before you go
    00:07:52 to bed that energy can't be consumed and it must be stored as fat and that's
    00:07:56 going to really lower your NADPH levels which is not a good thing to do at night.
    00:07:59 So I'm wondering if you have any thoughts on that timing of the last meal.
    00:08:06 Yeah I do and I wish I could take some of my own advice and medicine. I think
    00:08:15 if you can have a light meal at dinner a typical European dinner. My wife's German
    00:08:20 she likes to eat small meals. That's great. I tend to snack at night so it's
    00:08:24 my downfall but yeah to be able to have that fast overnight that'll boost your
    00:08:30 energy levels up and NADPH as well. These are all good things they turn on the
    00:08:35 enzymes that we study called the sirtuins. They need NAD to function and
    00:08:39 you can use the whole night to ostensibly repair your body and protect
    00:08:45 it from what happens during the day. I also I try to take a couple of
    00:08:51 metformin pills for two reasons. One is that my family has a history of diabetes
    00:08:56 and metformin is very effective at treating diabetes and even preventing it.
    00:09:01 So I do that for disease reasons but also because the work of many labs has
    00:09:06 pointed to not just animals but tens of thousands of people in clinical trials
    00:09:11 benefiting from that drug which seems to enhance and mimic the benefits of
    00:09:17 fasting. So you talk in your book about this concept of antagonistic
    00:09:22 pleiotropy which is essentially multiple actions some of which may be
    00:09:27 counter to the intended consequence of the intervention. So with metformin you
    00:09:32 describe the benefits which is why you're taking it but you know there are
    00:09:36 some studies published that show that it's a pretty potent mitochondrial
    00:09:40 poison and that it really targets mitochondrial complex one and shuts it
    00:09:47 it radically inhibits it so that you end result is you're producing a lot less
    00:09:53 ATP. So yes it up regulates the APK but in your evaluation of the literature how do
    00:10:02 you reconcile those two? Yeah so here's how I take the literature and there's
    00:10:05 hundreds of probably even more thousands of papers that I've read on this topic.
    00:10:10 Here's my summary but you know I'm a PhD and this is one man's opinion but what I
    00:10:16 take away from it is that short-term exposure to metformin high doses yes it
    00:10:21 will inhibit complex one and lower ATP. That's also true for as veritrol by the
    00:10:26 way. What was in burperine too. Yeah right but it I regard it as hormesis a little
    00:10:33 bit of what doesn't kill you actually makes you stronger and so the body
    00:10:37 recognizing that there's low ATP levels and higher AMP levels will stimulate AMP
    00:10:43 which is known to be beneficial and will actually compensate by revving up the
    00:10:51 mitochondria and building more mitochondria in various organs
    00:10:57 particularly the muscle of your body and so you know a little bit of inhibition
    00:11:02 leads to a kickback and a compensation so that's why I think that actually
    00:11:07 metformin is beneficial even though it starts out as a as long as you don't
    00:11:12 overdose it a relatively mild mitochondrial inhibitor and you know
    00:11:17 that in the history of humanity and in animal studies there's a long literature
    00:11:21 of molecules that if you give a lot of high dose acutely it can actually kill
    00:11:27 you but little doses as long as they don't do harm can have a positive effect
    00:11:34 in the long run and you know this the same is true for fasting if you don't
    00:11:38 eat we know what happens you'll starve to death you trick the body into
    00:11:43 thinking times are tough without leaving a long lasting that any damage and the
    00:11:49 body actually does better in the long run. Okay let's get into a really
    00:11:55 important part of your book which is the balance between anabolism or the
    00:12:00 building of muscle tissue and catabolism which is the tearing down and repair and
    00:12:04 regenerate and repair of it so interestingly when you fast growth
    00:12:11 hormone levels increase and maybe you can go into that because it's it's kind
    00:12:17 of is somewhat counterintuitive because there's no nutrients available so why
    00:12:21 would you think growth hormone would increase so maybe you can discuss that a
    00:12:24 little bit in the in the influence on IGF-1. Right so so IGF-1 is something like
    00:12:32 growth hormone and and growth hormone itself also in the short run don't seem
    00:12:39 to be healthy at least in animal studies and also Nir Barzilai for Albert Einstein
    00:12:44 College of Medicine has studied long-lived families centenarian families
    00:12:48 and what he's found in particular to IGF-1 is that some families actually can
    00:12:55 have high levels of IGF-1 but still live a long time and the reason for that is
    00:12:59 that they they don't have the IGF-1 receptor that's as active. Is that
    00:13:05 Laron syndrome? That's I understand that's the growth hormone as well so
    00:13:12 it's similar no he's a he's a Ashkenazi Jewish family that has 100
    00:13:16 hundred year olds but it's a similar concept is that if you're not responding
    00:13:20 to these hormones it doesn't matter really how much the body produces you
    00:13:24 still have an effect that mimics essentially the benefits you want. It's
    00:13:34 interesting actually that the growth hormone is stimulated by fasting there
    00:13:38 must be something and I'm unaware of exactly why but we know that that
    00:13:44 fasting doesn't lead to bigger animals it's actually the opposite so it could
    00:13:49 be that and now I'm just speculating but I think it's worth discussing and
    00:13:52 thinking about that these short-term bursts of hormones may help the body
    00:13:57 recover from injury but those little spikes don't last long so that you're
    00:14:02 not having any downside. The other thing about growth hormone and I know a lot of
    00:14:06 people including viewers of this show will be wondering what about growth
    00:14:11 hormone is it dangerous in the long run should I be taking it should I not? Now
    00:14:16 now I haven't seen any evidence that growth hormone is going to make you live
    00:14:21 longer typically it's the other way around that people who have a lack of
    00:14:26 growth hormone activity live longer. The rotten dwarfs tend to have this disease
    00:14:32 but in the short run if you need to repair your body and build up new muscle
    00:14:40 which of course prevents falls and accidents in the elderly you know I'm
    00:14:44 perfectly willing to entertain the possibility that that building up body
    00:14:48 bulk and testosterone is the same will prevent these accidents that actually
    00:14:53 largely are a problem for longevity there's a saying actually that the the
    00:15:00 way to longevity the best way longevity is to hang on to the handrail and so
    00:15:05 it's real trade-off it's a trade-off you know that if I was to summarize
    00:15:11 everything that I've learned over the last 30 years it's everything in
    00:15:16 moderation and and nothing don't do anything too consistently because it's
    00:15:23 like a frog in a hot water bath or in a fry pan your body needs to be primed and
    00:15:29 then allowed to relax and challenged and then allowed to relax and so these diets
    00:15:34 and these growth hormone spikes I think they're good you just don't want them on
    00:15:39 all the time because then your body doesn't have a chance to recover and you
    00:15:42 don't get long-term benefits okay so tangenting off the elevation growth
    00:15:49 hormone during a time-restricted eating fast of 16 18 hours or even a longer
    00:15:54 fast many people believe that the optimal time to engage in resistance or
    00:16:00 strength training might be right before you have your first meal so that you're
    00:16:04 still fasting your growth hormone levels are activated and you'll get maximum
    00:16:08 benefit from the anabolic stress of the exercise which of course is increasing
    00:16:12 PGC 1 alpha mitochondrial biogenesis and a lot of other benefits that occur
    00:16:16 during exercise so anybody caught any yeah yeah this is really good you're
    00:16:22 talking about the cutting edge of thinking so people who are discussing
    00:16:26 that idea I think are similar similar to the way I'm thinking about biology you
    00:16:32 know again in the full disclaimer this is now we're discussing the cutting edge
    00:16:36 of science so we don't know fully the answers to this what makes sense to me is
    00:16:40 that we don't want too much protein in our lives we don't want to eat a steak
    00:16:46 every meal because what we've learned through the work of David Sabatini and
    00:16:51 many others in the field Matt Kaeberlein that at least in animals and it looks
    00:16:57 like in people as well that inhibiting the mTOR pathway by having a lack of
    00:17:02 amino acids certain amino acids is healthy and does actually lengthen
    00:17:07 lifespan in animals but does that mean that you shouldn't eat protein absolutely
    00:17:11 not there are times when eating protein is important same for probably
    00:17:16 testosterone same for a growth hormone and then but now we're getting into the
    00:17:21 nitty-gritty is if you are pulsing these things when do you do them together and
    00:17:26 when you do them apart and to me and what you know let me talk about what I
    00:17:30 do personally because that's that's actually a better way to approach the
    00:17:34 discussion if I'm going to have a steak I try to be vegetarian but let's say
    00:17:38 I'm gonna have a protein shake I'm gonna do that just before just after I've
    00:17:45 exercised but then I'm gonna also have a period in the week where I don't have a
    00:17:49 lot of protein and I might just have some salads and that's where I get my
    00:17:52 protein so my body is going like this but it's not out of sync at times when
    00:17:58 my body needs protein or for instance needs growth hormone so I think what
    00:18:02 you're what you're saying is is really going to be the future that we can't
    00:18:08 just say doing one thing constantly is the right thing to do and we have to
    00:18:13 time these beautifully otherwise we're causing stress and damage but then
    00:18:21 preventing the healing process by doing something else yeah well thanks I do
    00:18:26 agree with you I think this is the cutting edge and a really an important
    00:18:29 question that many of us are challenged with and especially in the fact that
    00:18:34 you so well bring out in your book is we age you get beyond 65 our protein
    00:18:38 requirements actually increase for a variety of reasons from about 1 to 1.2
    00:18:42 grams per kilogram and so the key is to cycle the suppression of autophagy by
    00:18:51 not activating mTOR and not giving these calories in protein because protein
    00:18:56 especially animal protein and branched chain amino acids will activate mTOR
    00:18:59 almost universally but I'm I can just share my example I wonder what your
    00:19:03 thoughts are on it because I have an 18 hour time restricted eating window that
    00:19:07 I don't eat and once a week I'll extend that to 42 hours so I'll take a day off
    00:19:13 so I do you think that that regular daily eating window of six hours
    00:19:18 combined with a weekly one day full fast is enough to activate autophagy and
    00:19:26 suppress mTOR and not get the downsides of continuous mTOR activation yeah it
    00:19:33 doesn't it doesn't make sense to me people haven't even done this in animal
    00:19:38 studies yet people need to do that but scientifically it makes sense to me that
    00:19:44 being hungry a little part of the day will will activate turn on NAD you'll
    00:19:50 get it in mTOR inhibition and amputinase will come on but probably the way I'm
    00:19:55 doing it which is not as diligent as you Joe I'm only doing this kind of a level
    00:20:03 of reset and I think it's good but it's not perfect what we really want to do is
    00:20:08 this and then BAM really get a big reset and start showing up the the
    00:20:15 misfolded proteins get the autophagy going get the sirtuins to go repair
    00:20:19 everything in the cell that they possibly could and so I think that's
    00:20:23 right that a little bit of stress every day and a lot of stress once in a while
    00:20:29 is a great combo but I think that that would be something to actually study I
    00:20:33 might have any I haven't seen these studies on it either I'm hoping someone
    00:20:38 this process of doing those who's really like the answers but and I guess
    00:20:43 there's the where the technology is advancing where we'll soon be able to
    00:20:47 measure metabolites more easily than in the research lab and by doing so get an
    00:20:53 indication of what might be the best strategy now in your book I was so happy
    00:20:59 when you started discussing lysine which is the shortest amino acid that we have
    00:21:04 and it's a very important one and it actually I think it may be the most
    00:21:10 common I think it's about 11 11 to 12 percent of the total amino acid content
    00:21:16 in the body and most of us I mean you didn't glycine ingest and didn't used to
    00:21:21 be an issue because we ate connective tissue and glycine is loaded in collagen
    00:21:26 so third of the proteins in collagen and connective tissue are glycine so it
    00:21:30 didn't used to be an issue but we're not eating connective tissue much anymore so
    00:21:33 unless you're consuming bone broth or collagen supplements you're not getting
    00:21:37 it so why don't you talk about the importance of glycine especially with
    00:21:40 fructose consumption that's so rampant in the United States and the advantage
    00:21:43 of doing it especially with the glycine the thionine ratio well so the reason
    00:21:50 that I take glycine actually specifically trimethyl glycine is is
    00:21:56 actually to counter what I think might be going on with an NAD booster I'm
    00:22:02 certainly not an expert in glycine other than that but I can talk about the
    00:22:07 trimethyl glycine component if you'd like sure yeah so this is a big question
    00:22:12 in my field so just to take a step back my field and a lot of what my book is
    00:22:18 about is being able to trick the body into being hungry and having exercise
    00:22:23 and one of the molecules that does that is NAD NAD stands for nicotinamide
    00:22:30 adenine dinucleotide and we have it in our body as we exercise that we get
    00:22:34 hungry it goes up as we get older it goes down and it's needed for life it's
    00:22:38 also needed for turning on these defensive enzymes that we work on
    00:22:41 concert to us now to raise in a d levels what we've done in my lab to mice for
    00:22:47 the last decade is we give them precursors to NAD so we give them
    00:22:51 molecules like nicotinamide riboside or NR or nicotinamide mononucleotide also
    00:22:58 known as NMN not to be confused with M&Ms the opposite effect and so NMN is
    00:23:06 is what I take each day I take a gram of it but the thing with nicotinamide
    00:23:11 mononucleotide NMN is that it it has this nicotinamide group on it it hangs
    00:23:16 off the the main part of the chemical and it's the first bond to break and so
    00:23:20 we see in animals and even in humans that the levels of nicotinamide go up
    00:23:25 quite rapidly after taking NMN or NR and to look to high levels of
    00:23:31 nicotinamide are not good in part because the nicotinamide gets excreted
    00:23:37 through the kidneys and it's done so that happens because it becomes
    00:23:42 methylated into methyl nicotinamide and methyl nicotinamide being used for for
    00:23:47 years as a marker of all sorts of things including at least experimentally for
    00:23:52 Parkinson's disease but the concern that's that's being talked about in
    00:23:58 social media especially is is this drain of methyl nicotinamide a problem the
    00:24:03 methyl groups are are needed for the body we need methyl for a whole range of
    00:24:08 things including antioxidants and so as a precaution I take trimethylglycine so
    00:24:14 that I continue to give my body a source of methyl groups now I don't know if
    00:24:19 that's true people ask me all the time I take as a precaution because I know
    00:24:24 that trimethylglycine is not going to hurt me glycine is good as a joke and
    00:24:29 the other thing is methylglycine is also known as betaine which on human cells is
    00:24:34 very good for them including protecting them against first so I don't see any
    00:24:40 downside it's not an expensive molecule and the upside is that I'm preventing my
    00:24:44 body from being drained of methyl groups but the reason that I can't say for sure
    00:24:48 that it's necessary actually is that our bodies can make methyl groups there's a
    00:24:53 whole pathway in fact I did a PhD on it when I was in Australia 30 years ago but
    00:24:59 so I do take it as a precaution knowing that it's probably not doing anything
    00:25:04 except goodness my boy great have you looked at methyl cobalamin or methyl
    00:25:11 folate as a I have I have actually and I think those are interesting too I
    00:25:15 couldn't say which is better in fact because nobody has studied it but those
    00:25:19 are those are options to they're actually I've seen companies selling
    00:25:24 those vitamins with methyls on them and those are vitamins that I think are
    00:25:28 worth taking as well um so those are options I think you know like all
    00:25:34 professors we like to say we need more studies before we know for sure but with
    00:25:39 in the absence of studies I think those options are the best right now so thank
    00:25:45 you for bringing up the topic of NAD one of my favorites for sure and I want
    00:25:49 to express my deepest gratitude for you for helping inspire me to understand the
    00:25:54 importance of this molecule I first recognized it when the importance of it
    00:26:00 because of course we're taught in any biochemistry class when I watched one of
    00:26:05 your videos four years ago but as I understand NAD was discovered about
    00:26:09 almost a century ago by Otto Warburg but it only recently became to be
    00:26:15 deeply appreciated as a fundamental strategy for all of health and longevity
    00:26:19 I mean it's it's a coenzyme in over 500 metabolic reactions in the body so I'm
    00:26:24 wondering from your perspective what do you believe was the catalyst for the
    00:26:29 reemergence of the prominence of NAD and longevity well I'd like to think it was
    00:26:34 work that I was doing with Lenny Guarente at MIT that's what I thought
    00:26:38 and I set me up for but I guess you know that's what I actually put in one
    00:26:43 of my new books is acknowledging you as the is really the catalyst for that well
    00:26:48 it was a team and I'm not just being coy about that we we landed at the right
    00:26:52 place at the right time we discovered genes that control aging in yeast cells
    00:26:57 ironically that's where NAD was first discovered and I would argue that if
    00:27:02 yeast weren't making alcohol we probably wouldn't have discovered NAD for a long
    00:27:05 while but yeah the Germans just didn't discover NAD and we learned in high
    00:27:10 school that NAD is essential for all these reactions so we knew that but what
    00:27:14 we didn't realize until the late 1990s was that the levels of NAD in organisms
    00:27:19 such as yeast and in our bodies as well they're really dynamic it's not just
    00:27:25 that it's a housekeeping molecule keeping us alive during the day it's
    00:27:28 going like this and in a yeast cell it's going like this and that was a shock
    00:27:32 because first of all anything that's that important you think how can it go
    00:27:37 up 50% or 100% during the day without killing us turns out it does and it's
    00:27:42 actually very helpful and the reason that we think it goes up and down is NAD
    00:27:47 isn't just making chemical reactions happen but there are proteins that sense
    00:27:51 the amount of NAD in the cell and when times are tough we're hungry or we've
    00:27:57 exercised NAD levels will actually go up and turn on these defenses and that's
    00:28:03 why when you take a molecule like NMN or give an NMN to a mouse what we
    00:28:08 think is happening is that you're tricking the body into thinking that
    00:28:13 it's exercise or that it's hungry because the NAD levels will go up so you
    00:28:17 get the benefit the protective benefits of these without actually having to
    00:28:21 necessarily exercise or diet but if you're if you're wondering is it is it
    00:28:26 fine just to take the pill and sit on the couch and eat potato the answer is
    00:28:31 probably not we I mean in full disclosure we have published that
    00:28:36 resveratrol and NMN that work through similar mechanisms do make mice
    00:28:41 healthier even if they're fatter and don't exercise but here's the important
    00:28:45 thing for those who want to maximize their body's potential maximize their
    00:28:49 life we find that the combination of low calorie diets and these NAD boosters
    00:28:56 or in the case of resveratrol we showed has a doubling effect they're actually
    00:29:01 additive and so it's not no excuse just to sit around and just pop a pill okay
    00:29:06 well I think you're right on I think that the optimizing in and most people
    00:29:13 increasing NAD levels because it goes down pretty radically as you age to the
    00:29:18 point where once you reach 80 I mean it's almost it's like now most not
    00:29:23 there a radically decreased for at a minimum so you had mentioned NMN and
    00:29:29 NRS precursors as one strategy to increase it but I'd like to discuss some
    00:29:33 other options first is the actually the NAD molecule itself NAD plus which is a
    00:29:39 charge molecule and if you swallow it it will not work at all as the success of
    00:29:43 except it's being metabolized to its precursors and reconstituted but it can
    00:29:48 be given parenterally either IV subq or transdermally and there's been a lot of
    00:29:54 dispute in literature I'd like to get your view on it but a good friend of mine
    00:29:58 who actually was just here last weekend James Clement who speaks very highly of
    00:30:01 you by the way has doing a lot of research in NAD also and uses nitty
    00:30:06 Brady's lab out in New South Wales to actually measure it and from his analysis
    00:30:10 he finds that well first of all the NAD does seem to enter the cells and
    00:30:14 there's a transporter which I didn't know about until he told me which is
    00:30:17 connection 43 that substantiates the the strategy of using NAD plus itself
    00:30:25 rather than an intermediary or precursor and we'll talk about some of the other
    00:30:28 precursors there's more than just those that we're mentioning but you know it's
    00:30:34 it's James assessment that the transdermal battery patch applied maybe
    00:30:38 once or twice a week might be an optimal strategy to to improve it and you know
    00:30:43 and he's documented by NAD mass spec measurements at Brady's lab so I'm
    00:30:48 wondering what your thoughts on that right well so there are a variety of
    00:30:53 ways to raise NAD and this list is not exhaustive but I'll talk about what
    00:31:01 ones we know of that have been really tested it's fairly extensively so you
    00:31:07 can raise NAD levels just by taking nicotinic acid or niacin and so niacin
    00:31:15 has been used for decades to lower cholesterol and the only side effect is
    00:31:20 flushing you feel a little bit warm there are slow release versions that
    00:31:26 will raise NAD and actually there are some of us myself included that are
    00:31:30 entertaining the possibility that the benefits you get are in part because it
    00:31:35 also raises NAD but in head-to-head studies that I've read niacin won't
    00:31:42 raise in 80 levels the way some of these other molecules do and I think the
    00:31:48 reason is that niacin is just a tiny part of the NAD molecule and so you know
    00:31:55 let me think of an analogy it'd be like saying I can build a house out of bricks
    00:32:00 but if you don't bring the mortar and the windows and the doors and the roof
    00:32:06 it's gonna be a lot harder and so the windows and the roof come in with
    00:32:13 molecules like NR which is nicotinic riboside and NMN which is NR but with a
    00:32:20 phosphate group added so now you've got more of the house built and you're
    00:32:25 almost at NAD and so we're getting closer and so there's there's a debate
    00:32:33 it's it's a bit of a silly debate which is better NR or NMN. In mice I can tell
    00:32:38 you that that both work well to improve the health and the lifespan of mice
    00:32:45 we've done a lifespan of NMN we haven't we're repeating it looks good NR is
    00:32:51 published that it extends the lifespan of old mice so they're both great it's
    00:32:55 really I think it's semantics to say that one is you know ten times better
    00:33:01 than the other it's just not not the case they both get into cells there are
    00:33:09 transporters for NR there's a new newly discovered transporter for NMN.
    00:33:13 Ah that must have been the last few months I have not seen that. Right yeah
    00:33:17 so it came out of Dr. Shin Imai's lab at Wash U Medical School and I wrote a
    00:33:24 News and Views article on it it looked really convincing what we don't know
    00:33:29 though is is this transporter in all cells or is it just in the gut and so
    00:33:36 you know that remains to be seen but it that it really doesn't matter it's
    00:33:42 it's irrelevant we can talk about transporters all day what really matters
    00:33:46 is do you see health benefits and do you see NAD levels going up and I guess the
    00:33:52 third important thing is are there any side effects or negative side effects I
    00:33:57 haven't seen any negative side effects and I've certainly seen niacin NR and
    00:34:01 NMN raise NAD levels and provide health benefits and as I mentioned NR and NMN
    00:34:08 seem to be better than niacin. Well niacin does have problems there's no
    00:34:13 question niacinamide even more as you well know and you've done the research
    00:34:17 actually I think your lab showed this is that the niacinamide actually inhibits
    00:34:22 sirtuins through a negative feedback loop. I'm impressed you've done your
    00:34:28 reading. Yeah I've studied this I told you you really inspired me I mean I've
    00:34:33 read hundreds of studies about this and that was one of them so the but the
    00:34:38 niacin high doses is not without side effect aside from the flushing that you
    00:34:43 mentioned which is actually a liberation of histamine from mast cells it
    00:34:47 radically consumes methyl groups so not a good idea to take high dose niacin but
    00:34:54 I've concluded and I might be wrong here I'd be interested in your thoughts and
    00:34:57 then we'll go into the details dive deeper into the NR and NMN of taking a
    00:35:04 very small dose of niacin 25 to 50 milligrams which shouldn't suck up too
    00:35:08 many methyl groups but yet still can contribute to the at least a normal
    00:35:14 human at least as I read about the 90 milligram loss of NAD plus per day
    00:35:19 because we've got nine grams in our body but we recycle 99% of it so that niacin
    00:35:24 is really only good for the salvage pathway so what are your thoughts on 25
    00:35:27 to 50 milligrams maybe twice a day because the half-life of NAD is about 12
    00:35:31 hours to use that as an augmentation strategy to the pre other precursors or
    00:35:39 itself well so there are two ways to think about one is can you stimulate the
    00:35:46 body to make more NAD because it is recycled and the other is which which
    00:35:53 would I focus my thoughts on more which is if we give the the cells so much
    00:36:02 precursor they have no no alternative but to put it into NAD and I think that
    00:36:08 those two ways of thinking are your way in my way are guiding what we do I think
    00:36:15 it's possible that low doses of nicotinic acid could stimulate the body
    00:36:21 and force the cell to make more than it otherwise would but it would have to
    00:36:27 make more than it otherwise would because the amount of NAD in your body
    00:36:31 is you know it's in the gram amounts so milligram amounts are probably not going
    00:36:36 you know by mass action push it up well that was one of the things that
    00:36:41 discouraged me from even considering it as a practical strategy because there's
    00:36:44 scrams in it so what it didn't make sense to me why taking milligrams of
    00:36:48 something would be benefit but there appears to be a benefit let's could use
    00:36:52 I'd be curious how that works so you know what my guess would be that you
    00:36:56 know I'm gonna test it because James Clement has developed this elegant
    00:37:00 blotter strategy where you can can essentially pipette a dropper to a blood
    00:37:06 on a blotter freeze it and he's getting a mass spec in his lab and he's going to
    00:37:10 be able to measure it so I'm gonna do the test this fall and and see if it
    00:37:14 makes a difference I mean I just don't know it's just theoretical at this point
    00:37:17 yeah well when it comes to NMN which we've studied for a lot and there are
    00:37:22 studies on NR in humans and I've seen insights into NMN in humans as well
    00:37:26 though that work isn't yet published I what can I reveal I can reveal that that
    00:37:34 taking doses say less than 250 milligrams don't have a big effect on
    00:37:40 NAD in the blood that would make sense you do have to take high doses but it's
    00:37:46 complicated by the observation that a single dose won't have a big long-lasting
    00:37:53 effect anyway we see that in mice as well you take one hit of NMN it'll go up
    00:38:00 maybe go about 50% and it'll quickly die die away in levels but what's
    00:38:05 interesting in the mouse and the human studies is it's more like a positive
    00:38:10 stock market where over a period of in the case of the NR study that I'm
    00:38:16 thinking of after nine days it was an accumulation up to a certain level and
    00:38:22 so if a study has only done a one time point in a human or in a mouse be
    00:38:27 careful because that's probably misleading and that you know you want to
    00:38:32 measure these things after at least nine days and hopefully after a few months
    00:38:36 where any of maybe Joe that those low doses actually start to kick in yeah
    00:38:41 what do you think the optimal dosing strategy is every 12 hours or three
    00:38:45 times a day well you know that's also not known and I probably know more than
    00:38:51 most people on the planet I don't know that's what I'm asking yeah so what do I
    00:38:56 do I take a bolus in the morning I take a gram in the morning I know a gram is
    00:39:00 likely to be raising my energy levels during day I also try to time it with my
    00:39:05 natural circadian rhythm so NAD will go up during the morning getting ready but
    00:39:12 if I take it at night what I find is that I'm actually starting to interfere
    00:39:19 with my sleep patterns interesting yeah and a lot of people have told me that
    00:39:23 that's the case as well with resveratrol as well it actually makes sense there's
    00:39:27 a few science papers on this about sort one which is the target one of the NAD
    00:39:34 requiring enzymes that we study so so one is also its activities cycling
    00:39:39 through the day with NAD turning on genes are required for morning activities
    00:39:46 at night clearing the brain at night you think if you get those out of kilter I
    00:39:51 mean it makes sense that you will not only affect your body's metabolism find
    00:39:58 it hard to sleep but you could even start to have the effects of jet lag
    00:40:02 inadvertently I'd like to think that by taking the NAD boosters when I'm
    00:40:08 traveling I'm actually resetting my body's clock and I do find you know for
    00:40:13 me in my experience I do feel better if I reset my clock with an NAD booster
    00:40:18 when I arrive at in a new time zone so how does that reconcile with the fact
    00:40:25 that NAD plus levels increased by about 30% at least that's what I've read in
    00:40:29 the literature once you're fasting so you know I'm just trying to reconcile
    00:40:34 that in fact that you're having challenges with NAD plus at night
    00:40:38 because of a sleep in effect yeah well so I'm I don't think anyone's done it
    00:40:46 24-hour time course of any in people in mice we do know that it's cycling
    00:40:53 through the day you know let's see we're right on the cutting edge here you know
    00:40:59 you have a choice you can take it at night or in the morning and I think that
    00:41:09 probably what's happening is if I take it just before I go to bed my body's not
    00:41:16 in a fasting state yet it's still got you know my dinner is still in there and
    00:41:21 so it's a it's mimicking fasting it's raising in 80 levels just when it should
    00:41:25 should be starting to to tailor off I think probably what's happening Joe's
    00:41:30 now I'm thinking out loud is towards the early morning your NAD levels are going
    00:41:35 to start coming up because that's when your stomach's empty and you've absorbed
    00:41:39 a lot of nutrients overnight as it's coming up towards you know waking up and
    00:41:43 early morning that's when I provide my boost okay catch it on the rise
    00:41:50 certainly a rational approach and then I try not to eat till lunch so I get that
    00:41:54 big spunk okay I want to dive in the weeds now on NMR and NMN and NR I had a
    00:42:02 chance to attend a lecture by Charles Brenner earlier this month and talked to
    00:42:07 him afterwards and because many people use NR not as many NMN but most of the
    00:42:16 studies done on at least NR I haven't really reviewed much of the NMN
    00:42:20 literature but the NR it's usually perennially it's intraperitoneal or IV
    00:42:27 it's not orally I mean there's some but it's not a large amount of them are done
    00:42:31 orally so and and the problem with it is as I understand is that when you swallow
    00:42:35 NR and and this has some implications for NMN too that the first bypass it
    00:42:42 goes through the liver and the liver methylates it so the liver gets plenty
    00:42:46 of NAD plus but you know the the amount that goes to other organs seems to be
    00:42:52 pretty diminished which suggests to me that a either a perennial or
    00:42:58 transmucosal approach might be a superior delivery method so which is one
    00:43:03 of the reason and I asked Brenner this after his presentation what he thought
    00:43:07 about transmucosal delivery and he said he doesn't know he thought about it and
    00:43:10 I told him that I was using rectal NR suppositories that I make myself and
    00:43:16 he thought the compliance with that would be pretty horrible but I suspect a
    00:43:20 similar story is with going with NMN and I'm wondering what your thoughts are on it.
    00:43:25 Well so we're doing the experiments that are required to actually conclude
    00:43:32 provide answers to those questions we don't know okay so what is the answer
    00:43:37 but but the experiments that are ongoing in my lab also in Anthony Sauve's lab in
    00:43:42 Cornell we we have labeled molecules labeled NMN we're giving that initially
    00:43:50 to animals and mice eventually we could do humans as well and those are the
    00:43:56 studies you need to be able to say yeah NMN's going straight into cells or is it
    00:44:01 getting modified it's early days we think that it's a lot of it goes
    00:44:06 straight in contrary to what people are gossiping about but you know we have to
    00:44:11 do the hard science I don't think it's good to just hand wave and say
    00:44:14 conclusions that aren't yet justified without the hard science.
    00:44:18 Fair enough.
    00:44:19 On the NMN side you probably noticed from the literature that we typically put NMN in
    00:44:25 drinking water.
    00:44:26 Yeah, because it's a water soluble.
    00:44:28 Yeah, so it's very soluble but it's also more stable than NR in liquid.
    00:44:32 So we have the advantage that we can do that.
    00:44:35 NR in liquid is highly unstable and that's probably the reason that it's not done typically.
    00:44:42 That way.
    00:44:43 You know but that said, we don't know what happens in the microbiome when it's ingested
    00:44:50 either are those bacteria utilizing it converting it is it different between people's microbiomes
    00:44:56 we all have different microbiomes and that's the exciting part of the research now is to
    00:45:01 figure out once you put one of these molecules into the system where does it go where are
    00:45:06 the best effects and these are important because it'll guide not just the use of the
    00:45:12 molecules in daily life as they are now solder supplements but what I'm focused on is making
    00:45:21 molecules that will be drug like and used as drugs that could treat different diseases
    00:45:26 and if one molecule is better for liver one molecule is better for muscle one gets into
    00:45:31 the brain if there are ways we can tweak the molecule and change one atom to make it
    00:45:35 last for two weeks instead of two hours that's the exciting future that I see and that's
    00:45:43 what I spend most of my time on.
    00:45:47 I'm not I mean in full disclosure everyone should know even if you see my name on a website
    00:45:51 I have no affiliation to any supplement company I'm trying to do the science and stick with
    00:45:57 clinical trials only at this point.
    00:45:59 So you have no financial interest in NMN?
    00:46:02 No well yeah I have biotech companies that I'm an advisor to and have licensed patents
    00:46:09 to the chance that I'll see money out of that's pretty low most biotechs fail so I'm not driven
    00:46:16 by that but I've never received a cent from supplements and you know one of my patents
    00:46:22 was licensed to a company once and I said I want that money to go to research in my
    00:46:27 lab instead I just think it's better for me Joe because I want to be able to maintain
    00:46:34 sure the distance and be able to just talk about the science with some credibility.
    00:46:38 Absolutely yeah I heard your podcast with Peter Ortea and you went into that great detail
    00:46:43 and there are a lot of claims being made that you're recommending a specific NAD supplement
    00:46:49 and if you see a claim like that it's it's not true it's false and you spend a good portion
    00:46:53 of your resources to send cease and desist letters for those so I'm sorry you're going
    00:47:00 to have to go through that but I want to get back to just finish up NAD and we're going
    00:47:04 to go into sirtuins and then gene editing.
    00:47:08 Do you I just did you didn't mention any thoughts on the IV or subcutaneous or transdermal NAD
    00:47:14 plus itself the entire whole NAD molecule though the you know that you're using the
    00:47:18 precursors to create and with the transporter of connexin 43 being there and lots of anecdotal
    00:47:26 evidence especially in those with substance abuse getting benefits from these these strategies
    00:47:30 I'm wondering what your thoughts are on the whole molecule being given.
    00:47:34 Yeah well you know I'm the kind of scientist I don't have an ego in this if someone can
    00:47:39 show me data that's reproducible and reproduced in other lives you know I'll take it on face
    00:47:44 value and so I've heard the anecdotes on NAD and that's it seems like there's so many
    00:47:51 stories out there that you know there's something there what I'd like to see is just like I'm
    00:47:56 doing with NMN you know doing rodent studies and like James is doing James Clement doing
    00:48:05 human studies and ultimately putting these molecules head to head yeah it's really it's
    00:48:13 can get a little annoying when you know Dr. X says this and Dr. X says that.
    00:48:18 Right right because you got to have data to back it up.
    00:48:20 Yeah I mean show me them head to head yeah that's the only way I don't care what your
    00:48:25 opinion is show me the data so that that'll be the ultimate test the problem is that these
    00:48:30 trials are really expensive and typically doing one molecule is hard enough but doing two in
    00:48:35 parallel is hard even in a mouse study we don't typically do that but that's where we need to go
    00:48:41 to be able to to be able to say which is the best it really wouldn't surprise me if NR and NMN's
    00:48:48 NADID are all beneficial in slightly subtle ways.
    00:48:56 All right well thanks for that and I hope to with James do some of this research this year
    00:49:01 and maybe this fall share some of that data with you so that we can have some hard science to back
    00:49:06 it up. Now I want to shift to sirtuins which are essentially protein environmental stress
    00:49:13 sensors that are responsible for longevity longevity proteins in simpler terms and
    00:49:19 I guess they were discovered in yeast as SIR which is silent information regulators
    00:49:26 and it suggests they work by suppressing DNA expression and this is typically done by
    00:49:34 deacetylating the DNA and other proteins. Now you did not discover resveratrol but you clearly
    00:49:43 your lab identified its effect on SIRT1 one of the seven important sirtuins in humans
    00:49:49 so resveratrol happens to to be one of the polyphenols that do it but are you familiar
    00:49:57 with any other polyphenols like quercetin or fisetin that have shown to have some impact and
    00:50:03 I want to discuss about some of the derivatives of resveratrol that you might be working on.
    00:50:09 Well yeah you've come to the right person to talk about that. So resveratrol was already
    00:50:14 known as what's called a phytoalexin it seemed to have antioxidant properties and was even
    00:50:21 thought at the time to be responsible I think some people still believe it's responsible for
    00:50:25 the French paradox where the French apparently can eat fatty foods and have great cardiovascular
    00:50:31 health on average. So that was all there in the late 80s. I came along well you know the mid 90s
    00:50:40 probably was the was the real thing when 60 Minutes did a story on it. So I came along in the late
    00:50:46 1990s or 2000s and we weren't looking at resveratrol in fact I'd never heard of resveratrol when we
    00:50:51 started working on it. The story goes like this it's a pretty funny story. We had purified the
    00:51:01 SIRT1 enzyme from humans and we were looking in collaboration with a company called Biomole
    00:51:08 and the lead scientist there was Conrad Howards he deserves a lot of
    00:51:11 credit for this. We were looking for molecules that would inhibit the enzyme and it was a
    00:51:17 collaboration and we were sharing stories and results and Conrad calls me one day and he says
    00:51:24 are you sitting down? I went I am sitting down what's up? And he goes we've got these strange
    00:51:28 molecules that may activate the enzyme and then I that that was of course music to my ears because
    00:51:35 we didn't know that NAD could be used at that point we were just on the verge of discovering
    00:51:40 that. But what we did know that was that we wanted to activate these enzymes because they're
    00:51:45 beneficial. We knew in yeast and in worms that if we put and in flies if you put extra copies of the
    00:51:52 SIRT2 and gene they would live longer so we wanted more more goodness. But finding activators
    00:51:59 of enzymes is extremely rare I think there's only a few examples in the whole history of
    00:52:04 pharmaceutical development and when you find one typically people call BS on you. But here was
    00:52:10 Conrad saying that we've got something. So we tested it in the lab and we could repeat his
    00:52:15 results yes it was an activator. But to really show that it was true we had to put it on some
    00:52:22 yeast cells and on some human cells and we did that and we found that it extended their lifespan
    00:52:29 in the case of yeast and in the case of human cells protected them. And you needed the SIRT1 gene
    00:52:35 for that to work so it wasn't just an antioxidant effect it was actually through the same
    00:52:40 mechanism that we were hoping it was. But you asked Joe about these other molecules. Well we
    00:52:46 tested with Conrad well we screened about 18,000 of them and published 21 activators in that first
    00:52:55 paper in Nature Journal 2003. Now resveratrol was the best one we had at the time and it got the
    00:53:02 most attention because the red wine story was pretty funny and interesting to the media. But
    00:53:08 there are there were others that were very close to resveratrol in structure and in potency. You
    00:53:14 mentioned quercetin, fazetin, or vicetin. These are plant molecules as well. They're all produced
    00:53:23 in response to stress when the plants are stressed dehydration or UV light and they seem to have
    00:53:29 benefits on organisms when we consume them. Interestingly what has later been discovered
    00:53:35 though rarely acknowledged is that these same molecules work on killing senescent cells. You
    00:53:40 know that your viewers will know of senescent cells the zombie cells that accumulate in our
    00:53:45 body and cause havoc. Now others have shown that quercetin, gyncroclin, and others have
    00:53:51 senolytic properties same with fazetin. But what's not recognized typically or admitted is that these
    00:53:58 molecules were discovered 15 years ago to also be SIRT1 activators. So I thought so. Yeah so it's
    00:54:04 really interesting. Now what I think is going on is evidence for a hypothesis that Conrad Howitz
    00:54:12 and I came up with which we published in Cell I think it was the year 2005. Anyway the idea is
    00:54:20 called xenohormesis. X-E-N-O-HORMESIS. And it's the idea that we've evolved to sense our environment
    00:54:27 and molecules that are produced by plants and bacteria in our environment when they're stressed.
    00:54:33 If we consume those or put them on our skin for example our bodies will recognize those. We've
    00:54:38 evolved to sense our world around us. And that's a very good way of getting a heads up if your
    00:54:43 plants are running out of nutrients or the water table is drying up. And you know before we were
    00:54:49 conscious and we had brains this was the best way for a worm or a fly to know that times were
    00:54:56 probably going to deteriorate. And what you want to do is get ready for those times of adversity
    00:55:01 before they actually happen. And so that can explain why so many molecules from the plant
    00:55:08 world have given rise to medicines and why some molecules like resveratrol and quercetin, fazedin,
    00:55:14 even aspirin have remarkable health benefits and target many different enzymes in the body.
    00:55:20 That seems to be well beyond what coincidence could explain. Interesting. So there is probably
    00:55:28 not a better person in the world to ask this question to but you so eloquently describe
    00:55:33 sirtuins as environmental stress sensors. And when I heard that description it immediately
    00:55:40 occurred to me that that's very similar to heat shock proteins, almost identical.
    00:55:45 And heat shock proteins of course for those who don't know are really important to fold your
    00:55:51 proteins back to the right conformation so they work properly. And I'm wondering if there's any
    00:55:56 similarities or am I just making this thing up? Yeah I want to quickly look at the literature
    00:56:03 because I recall that there were connections between sirtuins and heat shock proteins. I
    00:56:07 can't remember which controls which but they're connected. But in principle you're right Joe that
    00:56:14 this is all evidence of hormesis that you can stimulate the body's ability to
    00:56:19 fight against problems. So it's thought that a little bit of heat, even a little bit of cold,
    00:56:26 a little bit of hunger, some exercise, some hypoxia, lack of oxygen in your body. These are all ways of
    00:56:33 activating these defense pathways. The same pathways that we've talked about before such as
    00:56:38 sirtuins, there are seven of those which by the way NAD and resveratrol will both activate.
    00:56:46 Just to recap the mTOR which lower amino acids particularly leucine and arginine and the AMP
    00:56:52 kinase pathway so metformin and inhibition of complex one. So these are the main three
    00:56:58 defensive pathways. There are others but what's downstream of these pathways are things like heat
    00:57:03 shock proteins and transcription factors that turn on DNA repair enzymes. There's a whole litany
    00:57:09 actually that there's a thousand papers per year on what are these sensors as we call them, what do
    00:57:16 they do downstream and here's the good news actually. We used to think that we had to
    00:57:22 understand what everything those sensors do to be able to understand aging and be able to live
    00:57:28 longer but what I've been arguing actually for many years now is that we don't need to fully know what
    00:57:33 they do. Heat shock proteins are great, definitely part of it but we don't need to know everything.
    00:57:38 As long as we can find the right nodes in the cell to turn them on in the right ratios at the right
    00:57:44 time, the body has evolved to take care of the rest and we're getting to the point fortunately,
    00:57:49 it's been really remarkable to see where we know what these nodes are, we have the tools to tweak
    00:57:55 them, we can also change them naturally by fasting and exercising, we change them with molecules that
    00:58:00 we can ingest or inject but now the cutting edge is now with this toolbox when do you apply them
    00:58:08 and how much and in what combinations and that's really what people like myself and you and and
    00:58:14 your listeners are on to right now. Okay, I want to go back to NAD for a moment because there's an
    00:58:20 important component that I neglected to discuss with you and that is another strategy for increasing
    00:58:26 NAD plus levels is to not use it as much and from my review of the literature one of the primary
    00:58:33 consumed, well there's two primary ones, the inside the cell would be PARP, poly ADP ribose polymerase
    00:58:39 which is a DNA repair enzyme and it really designed to repair DNA breaks single and double
    00:58:44 stranded and every time you have a break it's my understanding that you the PARP will take
    00:58:50 suck out 100 to 100 ADP out of 100 to 150 NAD molecules and basically deplete your level by
    00:58:57 that much for every break so and then you've got TD38 for extracellular consumptions which
    00:59:03 has to do with the immune system but I'm wondering what your thoughts are on lowering PARP
    00:59:09 activation and real common not widely appreciated but what I'm passionate about is really topic of
    00:59:17 my next book is EMF exposure. I mean it's pretty well documented in the literature that I've reviewed
    00:59:22 that it does activate PARP and decreases NAD level so in my view if you could limit that exposure
    00:59:29 because you're not decreasing increasing consumption you're going to by default
    00:59:33 increase NAD levels. Yeah right well yeah this is a really interesting topic that and I could
    00:59:40 talk all day about it. So PARP enzymes you're right there's DNA repair protein the problem is when you
    00:59:47 hyperactivate this protein there's PARP1, there's PARP2, there's actually more than 14 different
    00:59:53 PARPs. They do drain NAD quite effectively in fact in my lab we've discovered another PARP that
    00:59:59 when you have inflammation it drains NAD as well so it does make sense to slow them down as you're
    01:00:07 mentioning in some cases inhibit them but you have to be really careful because you do need them.
    01:00:13 We only why would you want to inhibit them because why would you want to inhibit DNA repair?
    01:00:17 Well you wouldn't but you want to inhibit their overuse of NAD. Right by decreasing these
    01:00:24 insults that would cause them to be activated. That's the best way right because then you get
    01:00:28 the benefits of low DNA damage and the benefits of high NAD. We had a science paper in 2013 that
    01:00:34 connected all of this together that the sirtuin gene or the sirtuin enzyme this sort one we've
    01:00:40 talked about actually controls PARP activity and PARP1 is normally inhibited by a protein called
    01:00:48 DBC1 and then sirtuin one controls that process and long story short you want to activate PARP
    01:00:58 but not too much and so that's what we think is going on here this fine tuning but actually to
    01:01:03 get to what's really more interesting I think is how do you keep your levels of DNA double
    01:01:07 strand breaks to a minimum and I think that's the key one of the main keys to longevity
    01:01:15 and there's two reasons one you mentioned which is that double strand breaks drain NAD.
    01:01:21 The second which I think you're going to be familiar with because you've read my upcoming
    01:01:27 book is the idea that DNA double strand breaks also disrupt the cell's epigenome the storage of
    01:01:36 the information that we get passed down from our mothers and fathers mother and father
    01:01:44 and the packaging of the DNA. We can get to that in a minute but basically
    01:01:49 what happens is if you have a broken DNA proteins such as the sirtuins will leave their normal
    01:01:57 sites where they're regulating genes and they'll go help repair with PARP as well but then they
    01:02:03 don't all find their way back to where they came from they actually some of them get lost and get
    01:02:08 distracted and over time what we see is that these proteins are essential for maintaining
    01:02:13 cellular identity and cellular function will be lost and we see that in yeast cells. Yeast
    01:02:18 cells get old because they're moving between breaks and back again to these to genes so it's
    01:02:24 twofold so before we get to the science and I'd love to touch on that the key ways to reduce
    01:02:31 double strand breaks I think I don't know about the radiation I have to trust you on that one but
    01:02:36 CT scans. It's ionizing radiation I'm talking about non-ionizing but they both do it
    01:02:42 different mechanisms ionizing does it through hydroxyl free radicals and non-ionizing does it
    01:02:48 through carbonyl carbonate free radicals primarily through peroxynitrite. Yeah makes sense there's a
    01:02:53 lot I mean you can't avoid DNA breaks in our body every day we have about a trillion breaks
    01:02:59 you know one per cell at least and just living DNA will break especially when it's replicating
    01:03:06 itself and the cell divides you'll have a break so even if you live in a lead box at the bottom
    01:03:10 of the ocean which I don't recommend doing but you can minimize it you know I go through the
    01:03:17 the DNA scanners occasionally and I ask the people there and I've researched this as well
    01:03:23 the amount of radiation is about the same as you get on the flight but but why double your exposure
    01:03:28 you know to me it doesn't make sense so I try to if I can avoid that exposure x-rays dental x-rays
    01:03:36 you know they're important I'm not going to deny that and I think that we should know what's in our
    01:03:41 mouth but I would try not to overdo it I think any physician who does x-rays should have a good
    01:03:47 reason for doing it and usually they do but you know be aware that there are consequences to
    01:03:55 exposing your body to radiation. Okay so let's get to what you just alluded to which is the
    01:04:01 resolution of some of the epigenetic damage that accumulates through through age and what I think
    01:04:08 is one of the most fascinating aspects of your book in which you are using technology that I
    01:04:13 believe developed by another researcher in your lab Dr. George Church who developed the Chris and
    01:04:20 co-invented as I understand the CRISPR technique and you're using those gene editing techniques to
    01:04:27 insert three of the four Yamanaka transcription factors into aged mice that have either been
    01:04:35 experimentally or are blind in some way and you can actually restore their vision through this
    01:04:41 epigenetic resurrection. Yeah so we're writing up three papers now and so this is a sneak preview of
    01:04:49 what hopefully will be published later this year and what we've discovered over the last 10 years
    01:04:55 and this has been a 10-year project so I'm really grateful to the scientists in my lab who've had the
    01:05:01 endurance we've discovered what we think is is very strong evidence for what we call now
    01:05:07 epigenetic noise as a cause of aging not just in mammals but throughout life even in yeast cells.
    01:05:15 So what does that mean? So let's just quickly do a biology lesson for those who haven't been in high
    01:05:20 school for a while. So the genome we know DNA genome epigenome is the organization of that DNA
    01:05:28 and the epigenome tells the cell that they should turn on this gene to be a nerve cell and in a liver
    01:05:34 cell turn on that gene to be a liver cell and that's epigenetics and cells inherit that information
    01:05:39 just as much as they inherit their DNA. So in my book what I am proposing is that those two types
    01:05:47 of information genomic and epigenomic they're quite different. The genomic the DNA is digital
    01:05:55 which is very well preserved and can last a long time we know that DVDs last longer than cassette
    01:06:01 tapes but the problem for the epigenome is that it's analog information and anyone who's had a
    01:06:06 cassette tape or a record knows that you can you can pretty easily scratch these or lose the
    01:06:13 information in fact you can scratch your DVD and lose the information. We actually think that aging
    01:06:20 is similar to those scratches that the information to be young again is still
    01:06:24 largely in our bodies but we can access our cells can access that information just by you know
    01:06:31 metaphorically scrubbing the DVD or polishing it up so that the cell can read the right genes
    01:06:37 in the case of the DVD the right song. So with that in mind let me explain what we've discovered
    01:06:45 if so we literally have not literally but metaphorically have a way of scratching
    01:06:50 a mouse's epigenome and the way we do that is actually we cut the DNA we create these double
    01:06:55 strand breaks let the cell heal them without making mutations so there's no change to the
    01:07:00 digital information but what we see is the process of proteins moving around and trying to repair
    01:07:05 that DNA eventually introduces this epigenomic noise and the genes that were once on many of
    01:07:12 them get turned off and those that were once off come on and so liver cells start to lose
    01:07:16 their identity skin cells start to lose their identity and the consequence we think is aging
    01:07:21 and we actually will hopefully publish a paper that shows that if you create this noise in a
    01:07:26 mouse it will go through accelerated aging and not just looking old it is actually literally
    01:07:33 old if we measure the the epigenetic clock and I think many of your listeners and viewers will
    01:07:40 know that there's a clock you can measure from blood in our bodies or in a mouse and it'll tell
    01:07:45 you how old the animal is or we are biologically if we do that with our mice that we've scratched
    01:07:51 up they are literally not likely 50 older which is great okay but you might say well
    01:07:59 David that that's all fun but why do we care about making a mouse older well first of all it's good
    01:08:04 evidence that we're right about the hypothesis that every aspect of aging is recapitulated
    01:08:10 second of all we have mice now that we can change the rate of aging perhaps even accelerate aging
    01:08:15 so that they behave more like humans and we can potentially have a better mouse model for
    01:08:20 Alzheimer's for example but then the third thing is if you can give an animal something then you
    01:08:27 can actually with that knowledge take it away and that's what we've done with George in collaboration
    01:08:32 with George what we did actually was we wanted to reprogram the cells so that the genes that were
    01:08:38 once let's start with this the ones on now they they go back off and vice versa so genes that were
    01:08:46 once off come back on and what we find is that by using these three yamanaka factors you can
    01:08:53 actually find the original information in the cell that tells it to be young again and those genes
    01:08:58 actually switch and the cell behaves like it's young again and in the case of the the retina
    01:09:04 we have preliminary results that we can actually restore eyesight by rejuvenating the nerves in
    01:09:12 the retina to be young again and so that's early days of what I hope is the future where we can
    01:09:19 reprogram cells in the body doesn't have to be the retina can be any cell type in the body you think
    01:09:24 to actually not just act young but literally be molecularly young again and in my career
    01:09:31 I've seen a lot of cool stuff and I haven't seen anything this cool before I couldn't agree more
    01:09:36 it's the potential is beyond extraordinary and I'm wondering if the cells that you're
    01:09:42 injecting are they pluripotent stem cells that you're modifying with the yamanaka transcription
    01:09:48 factors we're actually we're actually just giving uh the the genes to the organism we're turning on
    01:09:56 oh with a virus adenovirus we do we use the virus that's that's used by pharmaceutical companies to
    01:10:02 correct genetic diseases so it's a an FDA approved virus that that is very easy to use in the eye
    01:10:11 actually one injection there's no immune response in the eye it's not a big one and so that's why
    01:10:16 we chose the eye actually it's not just that we we saw it as a challenge to reverse blindness
    01:10:22 but we also knew that it could be the quickest path to uh to testing this in people and helping
    01:10:29 them with this new technology so is this mostly a local effect that you're achieving
    01:10:35 uh well in the eye yes uh and and by design um you don't know the full safety profile yet so we want
    01:10:41 to be careful but we have injected mice intravenously with the virus and we've got mice that
    01:10:47 are healthy 10 months later and so far so good you know it's early days we've only been testing
    01:10:52 it on about 100 mice we have a lot more to do and it's many years of work to make sure it's safe
    01:10:57 but uh yeah i think the promise is there and it's just hopefully evidence if not proof in principle
    01:11:05 that aging is more reversible than we ever thought do you have plans on putting genes in to make
    01:11:15 additional sirtuins like all the seven her two seven sirtuin genes in humans uh to augment those
    01:11:21 i mean that's going to be better than a than a sirtuin activator if you can have them be on all
    01:11:26 the time wouldn't it be yeah it would i only use viruses when absolutely necessary i think
    01:11:32 the well-trodden path of small molecules means that there's a much greater chance of success
    01:11:37 and less chance of side effects and toxicity with viruses as great as they are and as how
    01:11:43 exciting they sound it's still a pretty it's still early days we don't know that so i i don't
    01:11:51 see a use for um viruses and sirtuins in humans at this point but i so i'll stick with small
    01:11:57 molecules but what i do see a future you know if you want to go crazy with predictions yeah yeah
    01:12:04 that that we we could see a world where where people do choose to be genetically modified um
    01:12:11 it's their choice right you wouldn't i don't think you can easily go in and modify children
    01:12:15 even though that's now being done unless it's life-threatening of course but adults you know
    01:12:21 they should be able to have a choice if there's if there's safety and it's approved then they should
    01:12:26 be able to do that and maybe there'll be a day when we are able to carry these yamanaka genes
    01:12:33 in our body and when we get sick or we have an injury uh let's say we have a detached retina or
    01:12:40 we have a broken spine uh then we get an iv that turns on those genes for a month we recover
    01:12:46 we rejuvenate and then we turn them off again until we need them again and that would be a
    01:12:52 pretty wild sci-fi future but science is pointing to at least the biology being possible i believe
    01:13:01 you mentioned that there's no rational biological requirement for death that not necessarily
    01:13:11 mortality but you could live hundreds of years theoretically so i'm wondering in your mind what
    01:13:16 you perceive as the best bridge to pass this the clearly 120 year limit that humans currently have
    01:13:24 would it be uh resetting the that epigen the methylation clock the horvath methylation
    01:13:31 clock back to zero with like hematopoietic stem cells or what do you think is the
    01:13:37 biggest step to do that right well so i put my money on on the DNA methylation reprogramming
    01:13:46 right now it's uh you know i've seen old mice regain their eyesight i haven't seen any technology
    01:13:53 able to do that previously so if you applied that technology in combination with some of the
    01:14:01 molecules we've talked about today in combination with a healthy lifestyle that we're trying to
    01:14:06 optimize in real time here i don't think anyone can say what what our limit is i mean anyone who
    01:14:14 says that there's a limit really doesn't know what they're talking about or is lying we really
    01:14:19 don't know what's possible people who have lived in to 110 115 they typically smoke they've done
    01:14:25 no exercise they had a lot of alcohol uh do you does anyone think that if they didn't have access
    01:14:33 to the kind of things that we're talking about today they couldn't have lived longer i think
    01:14:37 they definitely could have we just don't know because those people are so rare and typically
    01:14:43 they didn't expect to live so long in the first place um so yeah now now with what we know and
    01:14:49 what people in the future will know i mean why not and the longer we live the more access we
    01:14:54 have to this technology yeah you know so i think anything should be on the table
    01:15:01 it's hard to make predictions it's very easy to poke holes in these things
    01:15:04 and more often predictions are wrong rather than right but i can tell you that i firmly believe
    01:15:11 that anyone who says that there is a biological limit is wrong because there are plenty of
    01:15:16 species and not just trees and not just jellyfish there are there are warm-blooded milk-giving
    01:15:23 animals in the ocean called whales that can live hundreds of years way you know three times longer
    01:15:28 than us they're not that different from us genetically they've figured out how to stabilize
    01:15:33 their genome and repair their dna and all the stuff you need if we can learn from them i think
    01:15:39 we can live a life like that and i i think historians will look back at the past 20 years
    01:15:44 as the turning point when we realized that this was possible and finally focused our energy on the
    01:15:49 topic so you are the world expert in the sirtuins and having made the association between resveratrol
    01:15:57 and other small molecules and i'm wondering i think your lab is working on these small molecule
    01:16:03 derivatives of resveratrol and other ones that activate sirtuins far more effectively so can you
    01:16:11 comment on any ones that are in testing or close to commercial production now that might be you
    01:16:17 know orders of magnitude better right so there are a couple of things we're doing in my lab still
    01:16:25 on this topic that's not widely known but i'll share with everybody one is the the question of
    01:16:33 what is resveratrol really doing you know we came out with the bold uh hypothesis that resveratrol
    01:16:39 works through sirtuins in yeast cells and that's how it was working that was very controversial
    01:16:45 it was a shock that you could actually activate an enzyme it was a shock that you could use one
    01:16:49 molecule a quote-unquote dirty molecule to target very specifically one enzyme and i've basically
    01:16:56 spent the last decade uh testing that hypothesis time and time again and we have new research that
    01:17:03 builds upon a science paper that we had in 2013 that said that yes resveratrol is truly acting
    01:17:08 on this enzyme we now have mice that we've engineered so that they are resistant to the
    01:17:14 effects of resveratrol on the enzyme and those results look really promising the question is
    01:17:20 does resveratrol still work if you block its ability to activate the sirt1 enzyme and the
    01:17:26 answer looks like uh preliminarily yes so that that's good so the science really solid and i
    01:17:32 wanted to to let everybody know that that's that we're still working on the science on the drug
    01:17:37 side uh so certerus was a company that i co-founded in 2005 and it was my first company it was a
    01:17:44 venture ventureback company it went public and it was eventually sold to glexo smith klein um for a
    01:17:50 lot of money i i was you know a child uh got what's called diluted down to you know almost nothing
    01:18:01 or loss yeah um you know but the little money i made has been reinvested into
    01:18:07 new companies which i'm i'm excited about you know but but what did that teach me it taught me that
    01:18:14 if you let go of your work early uh it's very hard to have champion and so that work it went well but
    01:18:21 it's still not in the clinic i'll update you on that so that we made and the company made 14 000
    01:18:29 different activators of cert1 that were up to 10 000 times more potent than resveratrol
    01:18:36 those molecules some of them two of them went into mice uh and rafa to cover rafael to cover NIH
    01:18:43 he put those into mice and they they lived longer it's it's quite an a poorly recognized finding
    01:18:50 uh but it was very clear they lived longer even on a normal diet not just
    01:18:54 high fat fat mice um one of those molecules called 2104 srt 2104
    01:19:03 look great it went into a study in humans actually it was a pill given to patients with psoriasis
    01:19:09 plot type psoriasis in a small study i believe it was uh somewhere between 20 and 40 patients
    01:19:16 uh phase 2a and uh it looked really promising when the drug got into the body there was a
    01:19:23 very significant effect on the group on the disease um so glexo uh still has those molecules
    01:19:30 and i'm not sure what their plans are for those molecules but uh you can bet that i'll do
    01:19:36 everything uh in my power to make sure that they make it to patients if humanly possible
    01:19:43 we are working actually now on derivatives of the nmn molecule and any precursors and so those are
    01:19:50 exciting as well because they can boost the levels of all seven of the sirtuins not just
    01:19:55 number one and that's where my efforts are currently focused do they actually boost the
    01:20:01 sirtuin levels or they just make them work better uh mostly mostly it's it's making them more active
    01:20:08 because it's providing the co-substrate for their reaction right yep and you know gsk uh didn't they
    01:20:17 shut down that lab that they bought from your your company in 2013 and if they did do you think it was
    01:20:24 related to the fact that they didn't understand the importance of nad and if they were testing
    01:20:28 aged rats or mice it's not going to work that well unless they do something to augment the nad
    01:20:35 uh well they had a little nad program but mostly they were working on those um
    01:20:39 direct activators coming out of the resume which will work um what i think they they didn't appreciate
    01:20:48 was the um the wide scope of these molecules um that they're they were truly applicable
    01:20:58 the other thing um joe that wasn't helpful to anybody uh you know in full defense of of glaxo
    01:21:04 who are a very smart bunch of people they bought the company right as the controversy around the
    01:21:11 mechanism blew up and it was pfizer whose scientists published that this was wrong now you know all the
    01:21:18 trouble has died down now and we've i think proven without a doubt that we were right but in that in
    01:21:24 those you know years of doubt it was very hard for glaxo to keep investing the tens of dollars it
    01:21:30 was taking to go uh into larger studies um and so i think that was the biggest damage that they did
    01:21:38 uh it was actually pfizer that that caused that controversy with one publication and you know it's
    01:21:44 in in hindsight now it's it's really remarkable what one study can do to a whole field absolutely
    01:21:53 absolutely so are your nmn uh derivatives getting close to commercialization yeah they're pretty
    01:22:00 advanced um i don't talk about them a lot um mainly because we're we're not venture-packed
    01:22:05 so we don't need to promote it we're privately funded for now but i'll give i'll give everybody
    01:22:11 a bit of a sneak preview i talk a lot more about it in the book um we're in humans we are doing
    01:22:17 human clinical trials we've finished two studies at harvard medical school this is not not my study
    01:22:23 even though it's at harvard it's at the hospital nearby of course it's arm's length from me because
    01:22:29 i i at least have the perception of a conflict of interest so i'm not involved but those two
    01:22:34 studies have gone well uh no indicators that there's any trouble and so we're hoping to be
    01:22:40 able to have a phase two study at least one possibly to begin um two studies beginning later
    01:22:45 this year and early next in actually in rare diseases not in um in aging itself not yet and
    01:22:52 so actually that you reminded me to say something that's often asked of me which is why not go treat
    01:22:59 aging yeah we go ahead tell us why i know why but it's not a very good business plan can you imagine
    01:23:06 the amount of money that would take to do a trial like that not only would it be expensive but at
    01:23:11 the end of it you couldn't sell a medicine if you tried because there is no disease called aging
    01:23:16 right now i mean there is a disease called aging you can look at it in the mirror if you want
    01:23:22 but in terms of regulation it's not recognized yet yeah the the strategy it seems to me especially to
    01:23:30 obtain funding is to figure out an anti-aging strategy that does marvelous things cosmetically
    01:23:36 because the market for cosmetics is through the roof and if you have something that's effective
    01:23:40 you'll explode in revenues and you can use those revenues to support the real thing that's going to
    01:23:44 reverse aging well that's true and that's partly what lenny guarantee and his team and at least him
    01:23:51 are doing they've gone to the market first i'm taking probably just as hard if not more difficult
    01:23:58 route which is to be able to raise enough money to to get to pharmaceuticals which is
    01:24:04 um you know a lot of money it's in the hundreds of millions but i think that's the part that i i
    01:24:09 think is is a better one for me personally and for the for ultimately the product but yeah you're
    01:24:14 right it's a challenge you've got to either get on the market early with something that's not well
    01:24:19 proven or raise the money and wait five to seven years with something that is eventually proven but
    01:24:26 neither of those is an easy path no no but most good things in life aren't it's true and this is
    01:24:33 the big one now if you talk about what what's going to plague our planet and our humanity
    01:24:38 our society clearly global warming energy crisis these are obvious ones but what most people don't
    01:24:44 realize is that the future prosperity of the planet is going to depend on our ability to keep
    01:24:48 our populations healthy for longer in terms of productivity and and cost in health care and
    01:24:54 instead of doing whack-a-mole medicine where we treat one disease often too late to actually have
    01:24:59 a benefit um the approach really should be one where we're treating the cause of most diseases
    01:25:06 that will kill us which is aging itself and the idea of treating aging um was fantasy even 20 years
    01:25:14 ago but as i hope uh you and your viewers are actually appreciating now the science is top
    01:25:20 notch we we and my colleagues we publish in the world's best journals there'd be noble prizes on
    01:25:24 this the time is now to be able to translate these discoveries into medicines that can
    01:25:31 have the best chance of giving future generations even our own a chance of not being dragged down
    01:25:37 economically by the burden of dementia and um alzheimer's is a huge one but just in general
    01:25:43 frailty it sucks trillion dollars out of our economies yeah frayota is a big one well um my
    01:25:51 want to extend my deepest appreciation and gratitude for all the work you've done and
    01:25:56 are going to do because you're still a very young man the motivations for your work and your book
    01:26:01 uh lifespan the revolutionary science of why we age is genuine and pure as far as i can determine
    01:26:08 and you describe it in your book and your discussions with your grandmother and your
    01:26:12 understanding of death at a very early age four years old so um you're doing a big thing to change
    01:26:19 the world and i and uh at a level that is quite extraordinary and i deeply appreciate what you've
    01:26:25 done and would encourage people to get the book if this is a is a topic that interests them and i
    01:26:30 think it should interest most of us because it's not just about living law almost this that you
    01:26:35 know who wants to live long if you said it so so eloquently is the frailty this is without frailty
    01:26:39 obtaining the all the capacities and capabilities and certainly the mental ones that we have as a
    01:26:46 younger individual into into older age right well yeah thanks joe appreciate it i hope people who
    01:26:54 read the book come away with a new view of what's possible and some people who have read it tell me
    01:27:00 that it's changed the way they look at their own lives and that's what what i wanted to do is because
    01:27:05 i think we we forget how important this topic is that we can do things right now to to alter the
    01:27:11 course of our lives but also just the way you think about aging itself it's not something that
    01:27:18 uh we used to think about the way we used to think cancer and heart disease were diseases we
    01:27:24 couldn't treat aging is is the frontier of medicine and i talk about what we can do now
    01:27:32 and what to do in the future i also uh want to say joe i want to commend you for for doing
    01:27:37 what you do um you know i could rant on i've been the victim uh of of some really bad uh
    01:27:46 press mostly and it's not so negative but more it's it's hype and exaggeration uh things taken
    01:27:52 out of context and you know that happens a lot in print media and i think that's just the nature of
    01:27:57 the beast and you know reporters that's what they're paid to do but these these podcasts and
    01:28:03 these venues uh i mean god bless them they're a venue for a scientist to be able to be unfiltered
    01:28:11 and talk in depth about topics that people are really interested in and you know i think
    01:28:16 of one thing uh that social media and youtube and these podcasts have done it's it's allowed people
    01:28:22 to have greater understanding in depth and direct access to scientists like me which
    01:28:27 could never be done before yeah you cannot get this information on the conventional media
    01:28:32 the best you could hope for it a big spot would be maybe five maybe possibly 10 minutes although i
    01:28:38 guess some of the interviews it's very rare although like you're never going to get two or
    01:28:42 three hours like you did with joe rogan and your joe rogan podcast and others so i thank you for
    01:28:47 being so gracious i know you're a busy man and really for taking the time to really dive deep
    01:28:53 and i think you've done a magnificent job in this interview because uh you know you share stuff that
    01:28:57 i really haven't heard you talk about previously so thank you for doing that thanks joe thanks
    01:29:00 for having me on okay