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

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    * https://www.listennotes.com/de/podcasts/dr-joseph-mercola/dr-mercola-interviews-dr-w2JMfvt8-aQ/#episode


    == Transcript ==
    == Transcript ==

    Revision as of 11:21, 9 October 2023

    Transcript

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    Welcome everyone, this is Dr. Mercola helping you take control of your health
    
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    and I am just absolutely delighted to connect with Dr. David Sinclair who is a
    
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    professor of genetics at Harvard Medical School and generally recognized as one
    
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    of the major thought leaders in the science of how to improve our not only
    
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    our lifespan but our health span. So he started in Sydney, got his PhD there and
    
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    then he went over to Lundy-Garanti's lab at MIT and then went to his got his own
    
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    lab at Harvard Medical School in 1999. He's been working there ever since and
    
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    really come up with this astounding discoveries which we're going to talk
    
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    about today but that one of the primary focuses is his new book which is called
    
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    Lifespan, the revolutionary science of why we age and why we don't have to do
    
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    that. And it's going to be available September 10th and if you're
    
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    watching this it's not September 10th you can pre-order it on Amazon. So
    
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    welcome and thank you for joining us today. Thank you, it's great to be here.
    
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    Yeah, yeah so you talk about a lot of great things in there and I want to
    
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    really highlight some of the concepts that you discussed because I think
    
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    there's so much potential to help us and hit this really the the king of all
    
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    diseases which is aging. So you talk about calorie restriction as being the
    
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    only proven non-pharmacological method of consistently extending lifespan and
    
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    protecting against many of the age-related diseases. And what so you and
    
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    then you also discuss intermittent fasting. So I'm wondering if the one of
    
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    the benefits of not eating is suppressing mTOR and activating
    
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    autophagy. So I'm wondering what type of conclusions you've reached with respect
    
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    to the optimal timing of the periods of the time-restricted eating and the
    
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    frequency of that and how you think integrating fasting or partial fasting
    
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    into that series might look like. Yeah, well we've known for probably more than
    
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    now 5,000 years that being a bit hungry is good for you. So this is not
    
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    revolutionary. What's been more revolutionary in the last few years is
    
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    the discovery of biochemical pathways that actually seem to underlie this
    
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    actual protection against disease and aging itself. And so we're not so much
    
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    guessing anymore what's going on and science has gotten involved and we're
    
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    doing more and more studies certainly in humans but also in animals to see what
    
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    best diet works. And the bottom line, I get questions every day I wake up to
    
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    probably a couple of dozen emails about this topic. Nobody actually knows what's
    
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    best but we can go through them and I can talk about which is my favorite as
    
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    well because there's it's not just a science aspect it's also social. We love to
    
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    eat, we have traditions, we have typically three meals a day and trying to deviate
    
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    from that is really quite challenging. Calorie restriction in animals and in
    
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    humans is about 20 to 30 percent less than what a doctor or a veterinarian
    
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    would recommend. I also struggled with that one so I certainly wouldn't
    
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    recommend it. It really means you've got to be hungry for most of the time
    
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    and I'm sure you get used to it but I didn't get that far. After about a
    
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    week I got too hungry and I gave up. And then I didn't restrict my diet for many
    
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    years actually. I had kids and that's really hard to do. But more recently what
    
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    I've done which I find very easy to do is basically miss a meal once a day and
    
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    I'm not hungry in the morning some people are not hungry at night. If you
    
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    can go for say it's seven o'clock at night all the way through to lunchtime
    
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    based on the animal studies that I've seen published and some in my lab that's
    
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    very likely to do you a lot of good in the long run and in the short run. And
    
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    the science behind it's really interesting I'll come back to that but
    
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    there are other diets that other people have found to be effective in
    
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    terms of improving biology and biochemical markers. One is the 5 plus 2
    
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    diet. Michael Moseley. Exactly I'm sure many of your viewers are familiar with
    
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    that one. That one is also quite doable especially if you have sodas
    
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    and things like that that can actually help just bubble the water. More extreme are
    
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    those diets where you go for a whole week every couple of months or every few
    
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    months. I haven't tried that I'd like to. My view on that is that
    
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    that's probably going to work the best if you can do it because it doesn't just
    
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    trigger the short-term pathways that we've been studying in my lab. But a week
    
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    of fasting will really start the body to start consuming its own protein and this
    
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    is as you mentioned autophagy that's what autophagy is it's the consuming of
    
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    our own biological material which is typically protein. And actually talking
    
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    with people who have done these fasting regimens after about three days
    
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    something different starts to kick in and people who try this tell me that
    
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    they have a feeling of euphoria and they definitely get an added boost. But
    
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    just let me quickly go back to why we think this works. So we've been studying
    
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    in my lab for the last 20 years genes that respond to diet but fat to fasting
    
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    and calorie restriction and the upshot of it is that our bodies respond to
    
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    adversity or perceived adversity. They turn on these defensive pathways it
    
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    changes a bunch of genes that switch on to defend our bodies. And at
    
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    least from many different animals things as small as worms and flies all the way
    
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    up to mice and rats these defenses of the body are extremely good at protecting
    
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    us against diseases from diabetes to cancer heart disease even dementia
    
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    Alzheimer's. These are things that modern medicine has struggled to combat and
    
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    this seems to be the very simple way to get the body to fight against those
    
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    diseases. Often I'm asked how early should you start? In the animal studies
    
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    and in rat studies, mouse studies, the sooner you start the better and the
    
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    longer you do this the better in your life. Clearly we don't want to be
    
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    recommending or seeing teenagers or even people who are in their early 20s do
    
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    this because there's still a lot going on in their bodies and their brains. But
    
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    after 30 if you extrapolate from the animal studies then the longer you do
    
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    this in the lifespan the better. I'm just turning 50 now and I wish I had
    
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    started earlier. Yeah me too. So you mentioned stopping eating at 7 and
    
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    there's a large number of people who advocate restrict not so much
    
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    necessarily tying it to a specific time but at least three to four hours before
    
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    you go to bed. I've been largely as a result of your exposure to your videos
    
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    was been fascinated by the NAD and his family, his cousins like NADPH. When I
    
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    started studying NADPH I realized that the biggest consumer of NADPH which is
    
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    a molecule that essentially is a battery cell and recharges your
    
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    antioxidants is fatty acid synthesis. So if you're eating shortly before you go
    
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    to bed that energy can't be consumed and it must be stored as fat and that's
    
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    going to really lower your NADPH levels which is not a good thing to do at night.
    
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    So I'm wondering if you have any thoughts on that timing of the last meal.
    
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    Yeah I do and I wish I could take some of my own advice and medicine. I think
    
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    if you can have a light meal at dinner a typical European dinner. My wife's German
    
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    she likes to eat small meals. That's great. I tend to snack at night so it's
    
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    my downfall but yeah to be able to have that fast overnight that'll boost your
    
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    energy levels up and NADPH as well. These are all good things they turn on the
    
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    enzymes that we study called the sirtuins. They need NAD to function and
    
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    you can use the whole night to ostensibly repair your body and protect
    
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    it from what happens during the day. I also I try to take a couple of
    
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    metformin pills for two reasons. One is that my family has a history of diabetes
    
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    and metformin is very effective at treating diabetes and even preventing it.
    
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    So I do that for disease reasons but also because the work of many labs has
    
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    pointed to not just animals but tens of thousands of people in clinical trials
    
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    benefiting from that drug which seems to enhance and mimic the benefits of
    
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    fasting. So you talk in your book about this concept of antagonistic
    
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    pleiotropy which is essentially multiple actions some of which may be
    
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    counter to the intended consequence of the intervention. So with metformin you
    
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    describe the benefits which is why you're taking it but you know there are
    
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    some studies published that show that it's a pretty potent mitochondrial
    
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    poison and that it really targets mitochondrial complex one and shuts it
    
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    it radically inhibits it so that you end result is you're producing a lot less
    
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    ATP. So yes it up regulates the APK but in your evaluation of the literature how do
    
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    you reconcile those two? Yeah so here's how I take the literature and there's
    
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    hundreds of probably even more thousands of papers that I've read on this topic.
    
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    Here's my summary but you know I'm a PhD and this is one man's opinion but what I
    
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    take away from it is that short-term exposure to metformin high doses yes it
    
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    will inhibit complex one and lower ATP. That's also true for as veritrol by the
    
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    way. What was in burperine too. Yeah right but it I regard it as hormesis a little
    
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    bit of what doesn't kill you actually makes you stronger and so the body
    
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    recognizing that there's low ATP levels and higher AMP levels will stimulate AMP
    
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    which is known to be beneficial and will actually compensate by revving up the
    
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    mitochondria and building more mitochondria in various organs
    
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    particularly the muscle of your body and so you know a little bit of inhibition
    
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    leads to a kickback and a compensation so that's why I think that actually
    
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    metformin is beneficial even though it starts out as a as long as you don't
    
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    overdose it a relatively mild mitochondrial inhibitor and you know
    
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    that in the history of humanity and in animal studies there's a long literature
    
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    of molecules that if you give a lot of high dose acutely it can actually kill
    
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    you but little doses as long as they don't do harm can have a positive effect
    
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    in the long run and you know this the same is true for fasting if you don't
    
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    eat we know what happens you'll starve to death you trick the body into
    
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    thinking times are tough without leaving a long lasting that any damage and the
    
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    body actually does better in the long run. Okay let's get into a really
    
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    important part of your book which is the balance between anabolism or the
    
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    building of muscle tissue and catabolism which is the tearing down and repair and
    
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    regenerate and repair of it so interestingly when you fast growth
    
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    hormone levels increase and maybe you can go into that because it's it's kind
    
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    of is somewhat counterintuitive because there's no nutrients available so why
    
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    would you think growth hormone would increase so maybe you can discuss that a
    
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    little bit in the in the influence on IGF-1. Right so so IGF-1 is something like
    
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    growth hormone and and growth hormone itself also in the short run don't seem
    
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    to be healthy at least in animal studies and also Nir Barzilai for Albert Einstein
    
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    College of Medicine has studied long-lived families centenarian families
    
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    and what he's found in particular to IGF-1 is that some families actually can
    
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    have high levels of IGF-1 but still live a long time and the reason for that is
    
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    that they they don't have the IGF-1 receptor that's as active. Is that
    
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    Laron syndrome? That's I understand that's the growth hormone as well so
    
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    it's similar no he's a he's a Ashkenazi Jewish family that has 100
    
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    hundred year olds but it's a similar concept is that if you're not responding
    
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    to these hormones it doesn't matter really how much the body produces you
    
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    still have an effect that mimics essentially the benefits you want. It's
    
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    interesting actually that the growth hormone is stimulated by fasting there
    
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    must be something and I'm unaware of exactly why but we know that that
    
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    fasting doesn't lead to bigger animals it's actually the opposite so it could
    
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    be that and now I'm just speculating but I think it's worth discussing and
    
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    thinking about that these short-term bursts of hormones may help the body
    
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    recover from injury but those little spikes don't last long so that you're
    
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    not having any downside. The other thing about growth hormone and I know a lot of
    
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    people including viewers of this show will be wondering what about growth
    
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    hormone is it dangerous in the long run should I be taking it should I not? Now
    
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    now I haven't seen any evidence that growth hormone is going to make you live
    
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    longer typically it's the other way around that people who have a lack of
    
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    growth hormone activity live longer. The rotten dwarfs tend to have this disease
    
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    but in the short run if you need to repair your body and build up new muscle
    
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    which of course prevents falls and accidents in the elderly you know I'm
    
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    perfectly willing to entertain the possibility that that building up body
    
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    bulk and testosterone is the same will prevent these accidents that actually
    
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    largely are a problem for longevity there's a saying actually that the the
    
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    way to longevity the best way longevity is to hang on to the handrail and so
    
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    it's real trade-off it's a trade-off you know that if I was to summarize
    
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    everything that I've learned over the last 30 years it's everything in
    
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    moderation and and nothing don't do anything too consistently because it's
    
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    like a frog in a hot water bath or in a fry pan your body needs to be primed and
    
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    then allowed to relax and challenged and then allowed to relax and so these diets
    
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    and these growth hormone spikes I think they're good you just don't want them on
    
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    all the time because then your body doesn't have a chance to recover and you
    
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    don't get long-term benefits okay so tangenting off the elevation growth
    
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    hormone during a time-restricted eating fast of 16 18 hours or even a longer
    
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    fast many people believe that the optimal time to engage in resistance or
    
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    strength training might be right before you have your first meal so that you're
    
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    still fasting your growth hormone levels are activated and you'll get maximum
    
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    benefit from the anabolic stress of the exercise which of course is increasing
    
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    PGC 1 alpha mitochondrial biogenesis and a lot of other benefits that occur
    
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    during exercise so anybody caught any yeah yeah this is really good you're
    
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    talking about the cutting edge of thinking so people who are discussing
    
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    that idea I think are similar similar to the way I'm thinking about biology you
    
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    know again in the full disclaimer this is now we're discussing the cutting edge
    
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    of science so we don't know fully the answers to this what makes sense to me is
    
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    that we don't want too much protein in our lives we don't want to eat a steak
    
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    every meal because what we've learned through the work of David Sabatini and
    
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    many others in the field Matt Kaeberlein that at least in animals and it looks
    
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    like in people as well that inhibiting the mTOR pathway by having a lack of
    
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    amino acids certain amino acids is healthy and does actually lengthen
    
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    lifespan in animals but does that mean that you shouldn't eat protein absolutely
    
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    not there are times when eating protein is important same for probably
    
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    testosterone same for a growth hormone and then but now we're getting into the
    
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    nitty-gritty is if you are pulsing these things when do you do them together and
    
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    when you do them apart and to me and what you know let me talk about what I
    
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    do personally because that's that's actually a better way to approach the
    
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    discussion if I'm going to have a steak I try to be vegetarian but let's say
    
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    I'm gonna have a protein shake I'm gonna do that just before just after I've
    
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    exercised but then I'm gonna also have a period in the week where I don't have a
    
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    lot of protein and I might just have some salads and that's where I get my
    
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    protein so my body is going like this but it's not out of sync at times when
    
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    my body needs protein or for instance needs growth hormone so I think what
    
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    you're what you're saying is is really going to be the future that we can't
    
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    just say doing one thing constantly is the right thing to do and we have to
    
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    time these beautifully otherwise we're causing stress and damage but then
    
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    preventing the healing process by doing something else yeah well thanks I do
    
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    agree with you I think this is the cutting edge and a really an important
    
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    question that many of us are challenged with and especially in the fact that
    
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    you so well bring out in your book is we age you get beyond 65 our protein
    
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    requirements actually increase for a variety of reasons from about 1 to 1.2
    
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    grams per kilogram and so the key is to cycle the suppression of autophagy by
    
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    not activating mTOR and not giving these calories in protein because protein
    
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    especially animal protein and branched chain amino acids will activate mTOR
    
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    almost universally but I'm I can just share my example I wonder what your
    
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    thoughts are on it because I have an 18 hour time restricted eating window that
    
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    I don't eat and once a week I'll extend that to 42 hours so I'll take a day off
    
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    so I do you think that that regular daily eating window of six hours
    
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    combined with a weekly one day full fast is enough to activate autophagy and
    
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    suppress mTOR and not get the downsides of continuous mTOR activation yeah it
    
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    doesn't it doesn't make sense to me people haven't even done this in animal
    
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    studies yet people need to do that but scientifically it makes sense to me that
    
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    being hungry a little part of the day will will activate turn on NAD you'll
    
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    get it in mTOR inhibition and amputinase will come on but probably the way I'm
    
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    doing it which is not as diligent as you Joe I'm only doing this kind of a level
    
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    of reset and I think it's good but it's not perfect what we really want to do is
    
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    this and then BAM really get a big reset and start showing up the the
    
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    misfolded proteins get the autophagy going get the sirtuins to go repair
    
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    everything in the cell that they possibly could and so I think that's
    
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    right that a little bit of stress every day and a lot of stress once in a while
    
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    is a great combo but I think that that would be something to actually study I
    
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    might have any I haven't seen these studies on it either I'm hoping someone
    
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    this process of doing those who's really like the answers but and I guess
    
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    there's the where the technology is advancing where we'll soon be able to
    
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    measure metabolites more easily than in the research lab and by doing so get an
    
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    indication of what might be the best strategy now in your book I was so happy
    
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    when you started discussing lysine which is the shortest amino acid that we have
    
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    and it's a very important one and it actually I think it may be the most
    
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    common I think it's about 11 11 to 12 percent of the total amino acid content
    
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    in the body and most of us I mean you didn't glycine ingest and didn't used to
    
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    be an issue because we ate connective tissue and glycine is loaded in collagen
    
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    so third of the proteins in collagen and connective tissue are glycine so it
    
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    didn't used to be an issue but we're not eating connective tissue much anymore so
    
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    unless you're consuming bone broth or collagen supplements you're not getting
    
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    it so why don't you talk about the importance of glycine especially with
    
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    fructose consumption that's so rampant in the United States and the advantage
    
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    of doing it especially with the glycine the thionine ratio well so the reason
    
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    that I take glycine actually specifically trimethyl glycine is is
    
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    actually to counter what I think might be going on with an NAD booster I'm
    
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    certainly not an expert in glycine other than that but I can talk about the
    
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    trimethyl glycine component if you'd like sure yeah so this is a big question
    
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    in my field so just to take a step back my field and a lot of what my book is
    
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    about is being able to trick the body into being hungry and having exercise
    
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    and one of the molecules that does that is NAD NAD stands for nicotinamide
    
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    adenine dinucleotide and we have it in our body as we exercise that we get
    
    259
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    hungry it goes up as we get older it goes down and it's needed for life it's
    
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    also needed for turning on these defensive enzymes that we work on
    
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    concert to us now to raise in a d levels what we've done in my lab to mice for
    
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    the last decade is we give them precursors to NAD so we give them
    
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    molecules like nicotinamide riboside or NR or nicotinamide mononucleotide also
    
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    known as NMN not to be confused with M&Ms the opposite effect and so NMN is
    
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    is what I take each day I take a gram of it but the thing with nicotinamide
    
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    mononucleotide NMN is that it it has this nicotinamide group on it it hangs
    
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    off the the main part of the chemical and it's the first bond to break and so
    
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    we see in animals and even in humans that the levels of nicotinamide go up
    
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    quite rapidly after taking NMN or NR and to look to high levels of
    
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    nicotinamide are not good in part because the nicotinamide gets excreted
    
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    through the kidneys and it's done so that happens because it becomes
    
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    methylated into methyl nicotinamide and methyl nicotinamide being used for for
    
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    years as a marker of all sorts of things including at least experimentally for
    
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    Parkinson's disease but the concern that's that's being talked about in
    
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    social media especially is is this drain of methyl nicotinamide a problem the
    
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    methyl groups are are needed for the body we need methyl for a whole range of
    
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    things including antioxidants and so as a precaution I take trimethylglycine so
    
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    that I continue to give my body a source of methyl groups now I don't know if
    
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    that's true people ask me all the time I take as a precaution because I know
    
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    that trimethylglycine is not going to hurt me glycine is good as a joke and
    
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    the other thing is methylglycine is also known as betaine which on human cells is
    
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    very good for them including protecting them against first so I don't see any
    
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    downside it's not an expensive molecule and the upside is that I'm preventing my
    
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    body from being drained of methyl groups but the reason that I can't say for sure
    
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    that it's necessary actually is that our bodies can make methyl groups there's a
    
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    whole pathway in fact I did a PhD on it when I was in Australia 30 years ago but
    
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    so I do take it as a precaution knowing that it's probably not doing anything
    
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    except goodness my boy great have you looked at methyl cobalamin or methyl
    
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    folate as a I have I have actually and I think those are interesting too I
    
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    couldn't say which is better in fact because nobody has studied it but those
    
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    are those are options to they're actually I've seen companies selling
    
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    those vitamins with methyls on them and those are vitamins that I think are
    
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    worth taking as well um so those are options I think you know like all
    
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    professors we like to say we need more studies before we know for sure but with
    
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    in the absence of studies I think those options are the best right now so thank
    
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    you for bringing up the topic of NAD one of my favorites for sure and I want
    
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    to express my deepest gratitude for you for helping inspire me to understand the
    
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    importance of this molecule I first recognized it when the importance of it
    
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    because of course we're taught in any biochemistry class when I watched one of
    
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    your videos four years ago but as I understand NAD was discovered about
    
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    almost a century ago by Otto Warburg but it only recently became to be
    
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    deeply appreciated as a fundamental strategy for all of health and longevity
    
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    I mean it's it's a coenzyme in over 500 metabolic reactions in the body so I'm
    
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    wondering from your perspective what do you believe was the catalyst for the
    
    305
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    reemergence of the prominence of NAD and longevity well I'd like to think it was
    
    306
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    work that I was doing with Lenny Guarente at MIT that's what I thought
    
    307
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    and I set me up for but I guess you know that's what I actually put in one
    
    308
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    of my new books is acknowledging you as the is really the catalyst for that well
    
    309
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    it was a team and I'm not just being coy about that we we landed at the right
    
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    place at the right time we discovered genes that control aging in yeast cells
    
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    ironically that's where NAD was first discovered and I would argue that if
    
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    yeast weren't making alcohol we probably wouldn't have discovered NAD for a long
    
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    while but yeah the Germans just didn't discover NAD and we learned in high
    
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    school that NAD is essential for all these reactions so we knew that but what
    
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    we didn't realize until the late 1990s was that the levels of NAD in organisms
    
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    such as yeast and in our bodies as well they're really dynamic it's not just
    
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    that it's a housekeeping molecule keeping us alive during the day it's
    
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    going like this and in a yeast cell it's going like this and that was a shock
    
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    because first of all anything that's that important you think how can it go
    
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    up 50% or 100% during the day without killing us turns out it does and it's
    
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    actually very helpful and the reason that we think it goes up and down is NAD
    
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    isn't just making chemical reactions happen but there are proteins that sense
    
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    the amount of NAD in the cell and when times are tough we're hungry or we've
    
    324
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    exercised NAD levels will actually go up and turn on these defenses and that's
    
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    why when you take a molecule like NMN or give an NMN to a mouse what we
    
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    think is happening is that you're tricking the body into thinking that
    
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    it's exercise or that it's hungry because the NAD levels will go up so you
    
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    get the benefit the protective benefits of these without actually having to
    
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    necessarily exercise or diet but if you're if you're wondering is it is it
    
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    fine just to take the pill and sit on the couch and eat potato the answer is
    
    331
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    probably not we I mean in full disclosure we have published that
    
    332
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    resveratrol and NMN that work through similar mechanisms do make mice
    
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    healthier even if they're fatter and don't exercise but here's the important
    
    334
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    thing for those who want to maximize their body's potential maximize their
    
    335
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    life we find that the combination of low calorie diets and these NAD boosters
    
    336
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    or in the case of resveratrol we showed has a doubling effect they're actually
    
    337
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    additive and so it's not no excuse just to sit around and just pop a pill okay
    
    338
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    well I think you're right on I think that the optimizing in and most people
    
    339
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    increasing NAD levels because it goes down pretty radically as you age to the
    
    340
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    point where once you reach 80 I mean it's almost it's like now most not
    
    341
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    there a radically decreased for at a minimum so you had mentioned NMN and
    
    342
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    NRS precursors as one strategy to increase it but I'd like to discuss some
    
    343
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    other options first is the actually the NAD molecule itself NAD plus which is a
    
    344
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    charge molecule and if you swallow it it will not work at all as the success of
    
    345
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    except it's being metabolized to its precursors and reconstituted but it can
    
    346
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    be given parenterally either IV subq or transdermally and there's been a lot of
    
    347
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    dispute in literature I'd like to get your view on it but a good friend of mine
    
    348
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    who actually was just here last weekend James Clement who speaks very highly of
    
    349
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    you by the way has doing a lot of research in NAD also and uses nitty
    
    350
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    Brady's lab out in New South Wales to actually measure it and from his analysis
    
    351
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    he finds that well first of all the NAD does seem to enter the cells and
    
    352
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    there's a transporter which I didn't know about until he told me which is
    
    353
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    connection 43 that substantiates the the strategy of using NAD plus itself
    
    354
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    rather than an intermediary or precursor and we'll talk about some of the other
    
    355
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    precursors there's more than just those that we're mentioning but you know it's
    
    356
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    it's James assessment that the transdermal battery patch applied maybe
    
    357
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    once or twice a week might be an optimal strategy to to improve it and you know
    
    358
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    and he's documented by NAD mass spec measurements at Brady's lab so I'm
    
    359
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    wondering what your thoughts on that right well so there are a variety of
    
    360
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    ways to raise NAD and this list is not exhaustive but I'll talk about what
    
    361
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    ones we know of that have been really tested it's fairly extensively so you
    
    362
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    can raise NAD levels just by taking nicotinic acid or niacin and so niacin
    
    363
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    has been used for decades to lower cholesterol and the only side effect is
    
    364
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    flushing you feel a little bit warm there are slow release versions that
    
    365
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    will raise NAD and actually there are some of us myself included that are
    
    366
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    entertaining the possibility that the benefits you get are in part because it
    
    367
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    also raises NAD but in head-to-head studies that I've read niacin won't
    
    368
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    raise in 80 levels the way some of these other molecules do and I think the
    
    369
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    reason is that niacin is just a tiny part of the NAD molecule and so you know
    
    370
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    let me think of an analogy it'd be like saying I can build a house out of bricks
    
    371
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    but if you don't bring the mortar and the windows and the doors and the roof
    
    372
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    it's gonna be a lot harder and so the windows and the roof come in with
    
    373
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    molecules like NR which is nicotinic riboside and NMN which is NR but with a
    
    374
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    phosphate group added so now you've got more of the house built and you're
    
    375
    00:32:25,660 --> 00:32:33,380
    almost at NAD and so we're getting closer and so there's there's a debate
    
    376
    00:32:33,420 --> 00:32:38,700
    it's it's a bit of a silly debate which is better NR or NMN. In mice I can tell
    
    377
    00:32:38,700 --> 00:32:45,500
    you that that both work well to improve the health and the lifespan of mice
    
    378
    00:32:45,500 --> 00:32:51,340
    we've done a lifespan of NMN we haven't we're repeating it looks good NR is
    
    379
    00:32:51,340 --> 00:32:55,380
    published that it extends the lifespan of old mice so they're both great it's
    
    380
    00:32:55,380 --> 00:33:01,180
    really I think it's semantics to say that one is you know ten times better
    
    381
    00:33:01,180 --> 00:33:09,540
    than the other it's just not not the case they both get into cells there are
    
    382
    00:33:09,540 --> 00:33:13,540
    transporters for NR there's a new newly discovered transporter for NMN.
    
    383
    00:33:13,540 --> 00:33:17,500
    Ah that must have been the last few months I have not seen that. Right yeah
    
    384
    00:33:17,500 --> 00:33:24,820
    so it came out of Dr. Shin Imai's lab at Wash U Medical School and I wrote a
    
    385
    00:33:24,820 --> 00:33:29,900
    News and Views article on it it looked really convincing what we don't know
    
    386
    00:33:29,900 --> 00:33:36,820
    though is is this transporter in all cells or is it just in the gut and so
    
    387
    00:33:36,820 --> 00:33:42,060
    you know that remains to be seen but it that it really doesn't matter it's
    
    388
    00:33:42,060 --> 00:33:46,500
    it's irrelevant we can talk about transporters all day what really matters
    
    389
    00:33:46,500 --> 00:33:52,660
    is do you see health benefits and do you see NAD levels going up and I guess the
    
    390
    00:33:52,660 --> 00:33:56,980
    third important thing is are there any side effects or negative side effects I
    
    391
    00:33:57,260 --> 00:34:01,940
    haven't seen any negative side effects and I've certainly seen niacin NR and
    
    392
    00:34:01,940 --> 00:34:08,580
    NMN raise NAD levels and provide health benefits and as I mentioned NR and NMN
    
    393
    00:34:08,580 --> 00:34:13,980
    seem to be better than niacin. Well niacin does have problems there's no
    
    394
    00:34:13,980 --> 00:34:17,340
    question niacinamide even more as you well know and you've done the research
    
    395
    00:34:17,340 --> 00:34:22,700
    actually I think your lab showed this is that the niacinamide actually inhibits
    
    396
    00:34:22,700 --> 00:34:28,740
    sirtuins through a negative feedback loop. I'm impressed you've done your
    
    397
    00:34:28,740 --> 00:34:33,500
    reading. Yeah I've studied this I told you you really inspired me I mean I've
    
    398
    00:34:33,500 --> 00:34:38,860
    read hundreds of studies about this and that was one of them so the but the
    
    399
    00:34:38,860 --> 00:34:43,420
    niacin high doses is not without side effect aside from the flushing that you
    
    400
    00:34:43,420 --> 00:34:47,300
    mentioned which is actually a liberation of histamine from mast cells it
    
    401
    00:34:47,380 --> 00:34:54,260
    radically consumes methyl groups so not a good idea to take high dose niacin but
    
    402
    00:34:54,260 --> 00:34:57,540
    I've concluded and I might be wrong here I'd be interested in your thoughts and
    
    403
    00:34:57,540 --> 00:35:04,060
    then we'll go into the details dive deeper into the NR and NMN of taking a
    
    404
    00:35:04,060 --> 00:35:08,900
    very small dose of niacin 25 to 50 milligrams which shouldn't suck up too
    
    405
    00:35:08,900 --> 00:35:14,980
    many methyl groups but yet still can contribute to the at least a normal
    
    406
    00:35:14,980 --> 00:35:19,300
    human at least as I read about the 90 milligram loss of NAD plus per day
    
    407
    00:35:19,300 --> 00:35:24,380
    because we've got nine grams in our body but we recycle 99% of it so that niacin
    
    408
    00:35:24,380 --> 00:35:27,860
    is really only good for the salvage pathway so what are your thoughts on 25
    
    409
    00:35:27,860 --> 00:35:31,740
    to 50 milligrams maybe twice a day because the half-life of NAD is about 12
    
    410
    00:35:31,740 --> 00:35:38,860
    hours to use that as an augmentation strategy to the pre other precursors or
    
    411
    00:35:39,220 --> 00:35:46,100
    itself well so there are two ways to think about one is can you stimulate the
    
    412
    00:35:46,100 --> 00:35:53,220
    body to make more NAD because it is recycled and the other is which which
    
    413
    00:35:53,220 --> 00:36:02,020
    would I focus my thoughts on more which is if we give the the cells so much
    
    414
    00:36:02,020 --> 00:36:08,820
    precursor they have no no alternative but to put it into NAD and I think that
    
    415
    00:36:08,820 --> 00:36:15,020
    those two ways of thinking are your way in my way are guiding what we do I think
    
    416
    00:36:15,020 --> 00:36:21,180
    it's possible that low doses of nicotinic acid could stimulate the body
    
    417
    00:36:21,180 --> 00:36:27,460
    and force the cell to make more than it otherwise would but it would have to
    
    418
    00:36:27,460 --> 00:36:31,300
    make more than it otherwise would because the amount of NAD in your body
    
    419
    00:36:31,300 --> 00:36:36,420
    is you know it's in the gram amounts so milligram amounts are probably not going
    
    420
    00:36:36,420 --> 00:36:41,300
    you know by mass action push it up well that was one of the things that
    
    421
    00:36:41,300 --> 00:36:44,780
    discouraged me from even considering it as a practical strategy because there's
    
    422
    00:36:44,780 --> 00:36:48,500
    scrams in it so what it didn't make sense to me why taking milligrams of
    
    423
    00:36:48,500 --> 00:36:52,140
    something would be benefit but there appears to be a benefit let's could use
    
    424
    00:36:52,140 --> 00:36:56,100
    I'd be curious how that works so you know what my guess would be that you
    
    425
    00:36:56,100 --> 00:37:00,380
    know I'm gonna test it because James Clement has developed this elegant
    
    426
    00:37:00,380 --> 00:37:06,540
    blotter strategy where you can can essentially pipette a dropper to a blood
    
    427
    00:37:06,540 --> 00:37:10,140
    on a blotter freeze it and he's getting a mass spec in his lab and he's going to
    
    428
    00:37:10,140 --> 00:37:14,420
    be able to measure it so I'm gonna do the test this fall and and see if it
    
    429
    00:37:14,420 --> 00:37:17,140
    makes a difference I mean I just don't know it's just theoretical at this point
    
    430
    00:37:17,140 --> 00:37:22,500
    yeah well when it comes to NMN which we've studied for a lot and there are
    
    431
    00:37:22,500 --> 00:37:26,620
    studies on NR in humans and I've seen insights into NMN in humans as well
    
    432
    00:37:26,620 --> 00:37:34,140
    though that work isn't yet published I what can I reveal I can reveal that that
    
    433
    00:37:34,140 --> 00:37:40,460
    taking doses say less than 250 milligrams don't have a big effect on
    
    434
    00:37:40,460 --> 00:37:46,020
    NAD in the blood that would make sense you do have to take high doses but it's
    
    435
    00:37:46,020 --> 00:37:53,660
    complicated by the observation that a single dose won't have a big long-lasting
    
    436
    00:37:53,660 --> 00:38:00,260
    effect anyway we see that in mice as well you take one hit of NMN it'll go up
    
    437
    00:38:00,260 --> 00:38:05,260
    maybe go about 50% and it'll quickly die die away in levels but what's
    
    438
    00:38:05,260 --> 00:38:10,260
    interesting in the mouse and the human studies is it's more like a positive
    
    439
    00:38:10,260 --> 00:38:16,060
    stock market where over a period of in the case of the NR study that I'm
    
    440
    00:38:16,060 --> 00:38:22,060
    thinking of after nine days it was an accumulation up to a certain level and
    
    441
    00:38:22,060 --> 00:38:27,460
    so if a study has only done a one time point in a human or in a mouse be
    
    442
    00:38:27,460 --> 00:38:32,540
    careful because that's probably misleading and that you know you want to
    
    443
    00:38:32,540 --> 00:38:36,580
    measure these things after at least nine days and hopefully after a few months
    
    444
    00:38:36,580 --> 00:38:41,460
    where any of maybe Joe that those low doses actually start to kick in yeah
    
    445
    00:38:41,460 --> 00:38:45,580
    what do you think the optimal dosing strategy is every 12 hours or three
    
    446
    00:38:45,580 --> 00:38:51,860
    times a day well you know that's also not known and I probably know more than
    
    447
    00:38:51,860 --> 00:38:56,500
    most people on the planet I don't know that's what I'm asking yeah so what do I
    
    448
    00:38:56,500 --> 00:39:00,900
    do I take a bolus in the morning I take a gram in the morning I know a gram is
    
    449
    00:39:00,900 --> 00:39:05,420
    likely to be raising my energy levels during day I also try to time it with my
    
    450
    00:39:05,420 --> 00:39:12,940
    natural circadian rhythm so NAD will go up during the morning getting ready but
    
    451
    00:39:12,940 --> 00:39:19,220
    if I take it at night what I find is that I'm actually starting to interfere
    
    452
    00:39:19,220 --> 00:39:23,620
    with my sleep patterns interesting yeah and a lot of people have told me that
    
    453
    00:39:23,620 --> 00:39:27,420
    that's the case as well with resveratrol as well it actually makes sense there's
    
    454
    00:39:27,420 --> 00:39:34,460
    a few science papers on this about sort one which is the target one of the NAD
    
    455
    00:39:34,460 --> 00:39:39,140
    requiring enzymes that we study so so one is also its activities cycling
    
    456
    00:39:39,140 --> 00:39:45,740
    through the day with NAD turning on genes are required for morning activities
    
    457
    00:39:46,460 --> 00:39:51,660
    at night clearing the brain at night you think if you get those out of kilter I
    
    458
    00:39:51,660 --> 00:39:58,060
    mean it makes sense that you will not only affect your body's metabolism find
    
    459
    00:39:58,060 --> 00:40:02,060
    it hard to sleep but you could even start to have the effects of jet lag
    
    460
    00:40:02,060 --> 00:40:08,940
    inadvertently I'd like to think that by taking the NAD boosters when I'm
    
    461
    00:40:08,940 --> 00:40:13,460
    traveling I'm actually resetting my body's clock and I do find you know for
    
    462
    00:40:13,460 --> 00:40:18,860
    me in my experience I do feel better if I reset my clock with an NAD booster
    
    463
    00:40:18,860 --> 00:40:25,540
    when I arrive at in a new time zone so how does that reconcile with the fact
    
    464
    00:40:25,540 --> 00:40:29,860
    that NAD plus levels increased by about 30% at least that's what I've read in
    
    465
    00:40:29,860 --> 00:40:34,860
    the literature once you're fasting so you know I'm just trying to reconcile
    
    466
    00:40:34,860 --> 00:40:38,060
    that in fact that you're having challenges with NAD plus at night
    
    467
    00:40:38,060 --> 00:40:46,300
    because of a sleep in effect yeah well so I'm I don't think anyone's done it
    
    468
    00:40:46,300 --> 00:40:53,420
    24-hour time course of any in people in mice we do know that it's cycling
    
    469
    00:40:53,420 --> 00:40:59,860
    through the day you know let's see we're right on the cutting edge here you know
    
    470
    00:40:59,860 --> 00:41:09,460
    you have a choice you can take it at night or in the morning and I think that
    
    471
    00:41:09,460 --> 00:41:16,100
    probably what's happening is if I take it just before I go to bed my body's not
    
    472
    00:41:16,100 --> 00:41:21,260
    in a fasting state yet it's still got you know my dinner is still in there and
    
    473
    00:41:21,260 --> 00:41:25,860
    so it's a it's mimicking fasting it's raising in 80 levels just when it should
    
    474
    00:41:25,860 --> 00:41:30,700
    should be starting to to tailor off I think probably what's happening Joe's
    
    475
    00:41:30,700 --> 00:41:35,580
    now I'm thinking out loud is towards the early morning your NAD levels are going
    
    476
    00:41:35,580 --> 00:41:39,020
    to start coming up because that's when your stomach's empty and you've absorbed
    
    477
    00:41:39,020 --> 00:41:43,980
    a lot of nutrients overnight as it's coming up towards you know waking up and
    
    478
    00:41:43,980 --> 00:41:50,260
    early morning that's when I provide my boost okay catch it on the rise
    
    479
    00:41:50,260 --> 00:41:54,460
    certainly a rational approach and then I try not to eat till lunch so I get that
    
    480
    00:41:54,500 --> 00:42:02,260
    big spunk okay I want to dive in the weeds now on NMR and NMN and NR I had a
    
    481
    00:42:02,260 --> 00:42:07,260
    chance to attend a lecture by Charles Brenner earlier this month and talked to
    
    482
    00:42:07,260 --> 00:42:16,720
    him afterwards and because many people use NR not as many NMN but most of the
    
    483
    00:42:16,720 --> 00:42:20,860
    studies done on at least NR I haven't really reviewed much of the NMN
    
    484
    00:42:20,860 --> 00:42:27,700
    literature but the NR it's usually perennially it's intraperitoneal or IV
    
    485
    00:42:27,700 --> 00:42:31,940
    it's not orally I mean there's some but it's not a large amount of them are done
    
    486
    00:42:31,940 --> 00:42:35,980
    orally so and and the problem with it is as I understand is that when you swallow
    
    487
    00:42:35,980 --> 00:42:42,020
    NR and and this has some implications for NMN too that the first bypass it
    
    488
    00:42:42,020 --> 00:42:46,540
    goes through the liver and the liver methylates it so the liver gets plenty
    
    489
    00:42:46,660 --> 00:42:52,420
    of NAD plus but you know the the amount that goes to other organs seems to be
    
    490
    00:42:52,420 --> 00:42:58,980
    pretty diminished which suggests to me that a either a perennial or
    
    491
    00:42:58,980 --> 00:43:03,140
    transmucosal approach might be a superior delivery method so which is one
    
    492
    00:43:03,140 --> 00:43:07,100
    of the reason and I asked Brenner this after his presentation what he thought
    
    493
    00:43:07,100 --> 00:43:10,180
    about transmucosal delivery and he said he doesn't know he thought about it and
    
    494
    00:43:10,180 --> 00:43:16,140
    I told him that I was using rectal NR suppositories that I make myself and
    
    495
    00:43:16,380 --> 00:43:20,860
    he thought the compliance with that would be pretty horrible but I suspect a
    
    496
    00:43:20,860 --> 00:43:25,300
    similar story is with going with NMN and I'm wondering what your thoughts are on it.
    
    497
    00:43:25,300 --> 00:43:32,660
    Well so we're doing the experiments that are required to actually conclude
    
    498
    00:43:32,660 --> 00:43:37,660
    provide answers to those questions we don't know okay so what is the answer
    
    499
    00:43:37,660 --> 00:43:42,460
    but but the experiments that are ongoing in my lab also in Anthony Sauve's lab in
    
    500
    00:43:42,780 --> 00:43:50,940
    Cornell we we have labeled molecules labeled NMN we're giving that initially
    
    501
    00:43:50,940 --> 00:43:56,260
    to animals and mice eventually we could do humans as well and those are the
    
    502
    00:43:56,260 --> 00:44:01,380
    studies you need to be able to say yeah NMN's going straight into cells or is it
    
    503
    00:44:01,380 --> 00:44:06,940
    getting modified it's early days we think that it's a lot of it goes
    
    504
    00:44:06,940 --> 00:44:11,620
    straight in contrary to what people are gossiping about but you know we have to
    
    505
    00:44:11,620 --> 00:44:14,900
    do the hard science I don't think it's good to just hand wave and say
    
    506
    00:44:14,900 --> 00:44:18,500
    conclusions that aren't yet justified without the hard science.
    
    507
    00:44:18,500 --> 00:44:19,500
    Fair enough.
    
    508
    00:44:19,500 --> 00:44:25,380
    On the NMN side you probably noticed from the literature that we typically put NMN in
    
    509
    00:44:25,380 --> 00:44:26,380
    drinking water.
    
    510
    00:44:26,380 --> 00:44:28,380
    Yeah, because it's a water soluble.
    
    511
    00:44:28,380 --> 00:44:32,900
    Yeah, so it's very soluble but it's also more stable than NR in liquid.
    
    512
    00:44:32,900 --> 00:44:35,580
    So we have the advantage that we can do that.
    
    513
    00:44:35,580 --> 00:44:41,380
    NR in liquid is highly unstable and that's probably the reason that it's not done typically.
    
    514
    00:44:42,140 --> 00:44:43,140
    That way.
    
    515
    00:44:43,140 --> 00:44:50,820
    You know but that said, we don't know what happens in the microbiome when it's ingested
    
    516
    00:44:50,820 --> 00:44:56,460
    either are those bacteria utilizing it converting it is it different between people's microbiomes
    
    517
    00:44:56,460 --> 00:45:01,220
    we all have different microbiomes and that's the exciting part of the research now is to
    
    518
    00:45:01,220 --> 00:45:06,740
    figure out once you put one of these molecules into the system where does it go where are
    
    519
    00:45:06,740 --> 00:45:12,820
    the best effects and these are important because it'll guide not just the use of the
    
    520
    00:45:12,820 --> 00:45:21,660
    molecules in daily life as they are now solder supplements but what I'm focused on is making
    
    521
    00:45:21,660 --> 00:45:26,620
    molecules that will be drug like and used as drugs that could treat different diseases
    
    522
    00:45:26,620 --> 00:45:31,860
    and if one molecule is better for liver one molecule is better for muscle one gets into
    
    523
    00:45:31,860 --> 00:45:35,940
    the brain if there are ways we can tweak the molecule and change one atom to make it
    
    524
    00:45:35,940 --> 00:45:43,140
    last for two weeks instead of two hours that's the exciting future that I see and that's
    
    525
    00:45:43,140 --> 00:45:47,140
    what I spend most of my time on.
    
    526
    00:45:47,140 --> 00:45:51,740
    I'm not I mean in full disclosure everyone should know even if you see my name on a website
    
    527
    00:45:51,740 --> 00:45:57,420
    I have no affiliation to any supplement company I'm trying to do the science and stick with
    
    528
    00:45:57,420 --> 00:45:59,900
    clinical trials only at this point.
    
    529
    00:45:59,940 --> 00:46:02,460
    So you have no financial interest in NMN?
    
    530
    00:46:02,460 --> 00:46:09,860
    No well yeah I have biotech companies that I'm an advisor to and have licensed patents
    
    531
    00:46:09,860 --> 00:46:16,260
    to the chance that I'll see money out of that's pretty low most biotechs fail so I'm not driven
    
    532
    00:46:16,260 --> 00:46:22,100
    by that but I've never received a cent from supplements and you know one of my patents
    
    533
    00:46:22,100 --> 00:46:27,780
    was licensed to a company once and I said I want that money to go to research in my
    
    534
    00:46:27,780 --> 00:46:34,060
    lab instead I just think it's better for me Joe because I want to be able to maintain
    
    535
    00:46:34,060 --> 00:46:38,980
    sure the distance and be able to just talk about the science with some credibility.
    
    536
    00:46:38,980 --> 00:46:43,700
    Absolutely yeah I heard your podcast with Peter Ortea and you went into that great detail
    
    537
    00:46:43,700 --> 00:46:49,500
    and there are a lot of claims being made that you're recommending a specific NAD supplement
    
    538
    00:46:49,500 --> 00:46:53,980
    and if you see a claim like that it's it's not true it's false and you spend a good portion
    
    539
    00:46:53,980 --> 00:47:00,660
    of your resources to send cease and desist letters for those so I'm sorry you're going
    
    540
    00:47:00,660 --> 00:47:04,020
    to have to go through that but I want to get back to just finish up NAD and we're going
    
    541
    00:47:04,020 --> 00:47:08,260
    to go into sirtuins and then gene editing.
    
    542
    00:47:08,260 --> 00:47:14,100
    Do you I just did you didn't mention any thoughts on the IV or subcutaneous or transdermal NAD
    
    543
    00:47:14,100 --> 00:47:18,140
    plus itself the entire whole NAD molecule though the you know that you're using the
    
    544
    00:47:18,140 --> 00:47:26,380
    precursors to create and with the transporter of connexin 43 being there and lots of anecdotal
    
    545
    00:47:26,380 --> 00:47:30,860
    evidence especially in those with substance abuse getting benefits from these these strategies
    
    546
    00:47:30,860 --> 00:47:34,620
    I'm wondering what your thoughts are on the whole molecule being given.
    
    547
    00:47:34,620 --> 00:47:39,260
    Yeah well you know I'm the kind of scientist I don't have an ego in this if someone can
    
    548
    00:47:39,260 --> 00:47:44,780
    show me data that's reproducible and reproduced in other lives you know I'll take it on face
    
    549
    00:47:44,780 --> 00:47:51,340
    value and so I've heard the anecdotes on NAD and that's it seems like there's so many
    
    550
    00:47:51,340 --> 00:47:56,900
    stories out there that you know there's something there what I'd like to see is just like I'm
    
    551
    00:47:56,900 --> 00:48:05,020
    doing with NMN you know doing rodent studies and like James is doing James Clement doing
    
    552
    00:48:05,020 --> 00:48:13,900
    human studies and ultimately putting these molecules head to head yeah it's really it's
    
    553
    00:48:13,980 --> 00:48:18,220
    can get a little annoying when you know Dr. X says this and Dr. X says that.
    
    554
    00:48:18,220 --> 00:48:20,220
    Right right because you got to have data to back it up.
    
    555
    00:48:20,220 --> 00:48:25,420
    Yeah I mean show me them head to head yeah that's the only way I don't care what your
    
    556
    00:48:25,420 --> 00:48:30,860
    opinion is show me the data so that that'll be the ultimate test the problem is that these
    
    557
    00:48:30,860 --> 00:48:35,900
    trials are really expensive and typically doing one molecule is hard enough but doing two in
    
    558
    00:48:35,900 --> 00:48:41,260
    parallel is hard even in a mouse study we don't typically do that but that's where we need to go
    
    559
    00:48:41,260 --> 00:48:47,500
    to be able to to be able to say which is the best it really wouldn't surprise me if NR and NMN's
    
    560
    00:48:48,140 --> 00:48:54,540
    NADID are all beneficial in slightly subtle ways.
    
    561
    00:48:56,220 --> 00:49:01,820
    All right well thanks for that and I hope to with James do some of this research this year
    
    562
    00:49:01,820 --> 00:49:06,060
    and maybe this fall share some of that data with you so that we can have some hard science to back
    
    563
    00:49:06,060 --> 00:49:13,420
    it up. Now I want to shift to sirtuins which are essentially protein environmental stress
    
    564
    00:49:13,420 --> 00:49:18,540
    sensors that are responsible for longevity longevity proteins in simpler terms and
    
    565
    00:49:19,740 --> 00:49:25,500
    I guess they were discovered in yeast as SIR which is silent information regulators
    
    566
    00:49:26,780 --> 00:49:34,220
    and it suggests they work by suppressing DNA expression and this is typically done by
    
    567
    00:49:34,220 --> 00:49:43,100
    deacetylating the DNA and other proteins. Now you did not discover resveratrol but you clearly
    
    568
    00:49:43,100 --> 00:49:48,620
    your lab identified its effect on SIRT1 one of the seven important sirtuins in humans
    
    569
    00:49:49,340 --> 00:49:56,940
    so resveratrol happens to to be one of the polyphenols that do it but are you familiar
    
    570
    00:49:57,820 --> 00:50:03,740
    with any other polyphenols like quercetin or fisetin that have shown to have some impact and
    
    571
    00:50:03,820 --> 00:50:08,300
    I want to discuss about some of the derivatives of resveratrol that you might be working on.
    
    572
    00:50:09,420 --> 00:50:14,700
    Well yeah you've come to the right person to talk about that. So resveratrol was already
    
    573
    00:50:14,700 --> 00:50:21,340
    known as what's called a phytoalexin it seemed to have antioxidant properties and was even
    
    574
    00:50:21,340 --> 00:50:25,500
    thought at the time to be responsible I think some people still believe it's responsible for
    
    575
    00:50:25,500 --> 00:50:31,500
    the French paradox where the French apparently can eat fatty foods and have great cardiovascular
    
    576
    00:50:31,500 --> 00:50:40,300
    health on average. So that was all there in the late 80s. I came along well you know the mid 90s
    
    577
    00:50:40,300 --> 00:50:46,460
    probably was the was the real thing when 60 Minutes did a story on it. So I came along in the late
    
    578
    00:50:46,460 --> 00:50:51,980
    1990s or 2000s and we weren't looking at resveratrol in fact I'd never heard of resveratrol when we
    
    579
    00:50:51,980 --> 00:51:01,260
    started working on it. The story goes like this it's a pretty funny story. We had purified the
    
    580
    00:51:01,260 --> 00:51:07,020
    SIRT1 enzyme from humans and we were looking in collaboration with a company called Biomole
    
    581
    00:51:08,220 --> 00:51:10,940
    and the lead scientist there was Conrad Howards he deserves a lot of
    
    582
    00:51:11,500 --> 00:51:17,500
    credit for this. We were looking for molecules that would inhibit the enzyme and it was a
    
    583
    00:51:17,500 --> 00:51:23,580
    collaboration and we were sharing stories and results and Conrad calls me one day and he says
    
    584
    00:51:24,220 --> 00:51:28,780
    are you sitting down? I went I am sitting down what's up? And he goes we've got these strange
    
    585
    00:51:28,780 --> 00:51:35,820
    molecules that may activate the enzyme and then I that that was of course music to my ears because
    
    586
    00:51:35,820 --> 00:51:40,220
    we didn't know that NAD could be used at that point we were just on the verge of discovering
    
    587
    00:51:40,220 --> 00:51:45,820
    that. But what we did know that was that we wanted to activate these enzymes because they're
    
    588
    00:51:45,820 --> 00:51:52,140
    beneficial. We knew in yeast and in worms that if we put and in flies if you put extra copies of the
    
    589
    00:51:52,940 --> 00:51:59,980
    SIRT2 and gene they would live longer so we wanted more more goodness. But finding activators
    
    590
    00:51:59,980 --> 00:52:04,700
    of enzymes is extremely rare I think there's only a few examples in the whole history of
    
    591
    00:52:04,700 --> 00:52:10,700
    pharmaceutical development and when you find one typically people call BS on you. But here was
    
    592
    00:52:10,700 --> 00:52:15,340
    Conrad saying that we've got something. So we tested it in the lab and we could repeat his
    
    593
    00:52:15,340 --> 00:52:22,460
    results yes it was an activator. But to really show that it was true we had to put it on some
    
    594
    00:52:22,460 --> 00:52:28,460
    yeast cells and on some human cells and we did that and we found that it extended their lifespan
    
    595
    00:52:29,260 --> 00:52:34,700
    in the case of yeast and in the case of human cells protected them. And you needed the SIRT1 gene
    
    596
    00:52:35,740 --> 00:52:39,580
    for that to work so it wasn't just an antioxidant effect it was actually through the same
    
    597
    00:52:40,300 --> 00:52:46,460
    mechanism that we were hoping it was. But you asked Joe about these other molecules. Well we
    
    598
    00:52:46,460 --> 00:52:55,980
    tested with Conrad well we screened about 18,000 of them and published 21 activators in that first
    
    599
    00:52:55,980 --> 00:53:02,620
    paper in Nature Journal 2003. Now resveratrol was the best one we had at the time and it got the
    
    600
    00:53:02,620 --> 00:53:08,380
    most attention because the red wine story was pretty funny and interesting to the media. But
    
    601
    00:53:08,380 --> 00:53:14,220
    there are there were others that were very close to resveratrol in structure and in potency. You
    
    602
    00:53:14,220 --> 00:53:23,180
    mentioned quercetin, fazetin, or vicetin. These are plant molecules as well. They're all produced
    
    603
    00:53:23,180 --> 00:53:29,260
    in response to stress when the plants are stressed dehydration or UV light and they seem to have
    
    604
    00:53:29,260 --> 00:53:35,020
    benefits on organisms when we consume them. Interestingly what has later been discovered
    
    605
    00:53:35,020 --> 00:53:40,140
    though rarely acknowledged is that these same molecules work on killing senescent cells. You
    
    606
    00:53:40,140 --> 00:53:45,020
    know that your viewers will know of senescent cells the zombie cells that accumulate in our
    
    607
    00:53:45,020 --> 00:53:51,740
    body and cause havoc. Now others have shown that quercetin, gyncroclin, and others have
    
    608
    00:53:51,740 --> 00:53:58,060
    senolytic properties same with fazetin. But what's not recognized typically or admitted is that these
    
    609
    00:53:58,060 --> 00:54:04,620
    molecules were discovered 15 years ago to also be SIRT1 activators. So I thought so. Yeah so it's
    
    610
    00:54:04,700 --> 00:54:12,540
    really interesting. Now what I think is going on is evidence for a hypothesis that Conrad Howitz
    
    611
    00:54:12,540 --> 00:54:20,540
    and I came up with which we published in Cell I think it was the year 2005. Anyway the idea is
    
    612
    00:54:20,540 --> 00:54:27,580
    called xenohormesis. X-E-N-O-HORMESIS. And it's the idea that we've evolved to sense our environment
    
    613
    00:54:27,580 --> 00:54:32,780
    and molecules that are produced by plants and bacteria in our environment when they're stressed.
    
    614
    00:54:33,340 --> 00:54:38,460
    If we consume those or put them on our skin for example our bodies will recognize those. We've
    
    615
    00:54:38,460 --> 00:54:43,100
    evolved to sense our world around us. And that's a very good way of getting a heads up if your
    
    616
    00:54:43,100 --> 00:54:49,420
    plants are running out of nutrients or the water table is drying up. And you know before we were
    
    617
    00:54:49,420 --> 00:54:56,220
    conscious and we had brains this was the best way for a worm or a fly to know that times were
    
    618
    00:54:56,220 --> 00:55:01,900
    probably going to deteriorate. And what you want to do is get ready for those times of adversity
    
    619
    00:55:01,900 --> 00:55:08,220
    before they actually happen. And so that can explain why so many molecules from the plant
    
    620
    00:55:08,220 --> 00:55:13,820
    world have given rise to medicines and why some molecules like resveratrol and quercetin, fazedin,
    
    621
    00:55:14,380 --> 00:55:20,540
    even aspirin have remarkable health benefits and target many different enzymes in the body.
    
    622
    00:55:20,540 --> 00:55:28,460
    That seems to be well beyond what coincidence could explain. Interesting. So there is probably
    
    623
    00:55:28,460 --> 00:55:33,820
    not a better person in the world to ask this question to but you so eloquently describe
    
    624
    00:55:33,820 --> 00:55:40,540
    sirtuins as environmental stress sensors. And when I heard that description it immediately
    
    625
    00:55:40,540 --> 00:55:45,100
    occurred to me that that's very similar to heat shock proteins, almost identical.
    
    626
    00:55:45,740 --> 00:55:51,100
    And heat shock proteins of course for those who don't know are really important to fold your
    
    627
    00:55:51,100 --> 00:55:56,860
    proteins back to the right conformation so they work properly. And I'm wondering if there's any
    
    628
    00:55:56,860 --> 00:56:03,100
    similarities or am I just making this thing up? Yeah I want to quickly look at the literature
    
    629
    00:56:03,100 --> 00:56:07,100
    because I recall that there were connections between sirtuins and heat shock proteins. I
    
    630
    00:56:07,100 --> 00:56:13,180
    can't remember which controls which but they're connected. But in principle you're right Joe that
    
    631
    00:56:14,460 --> 00:56:18,140
    this is all evidence of hormesis that you can stimulate the body's ability to
    
    632
    00:56:19,180 --> 00:56:26,220
    fight against problems. So it's thought that a little bit of heat, even a little bit of cold,
    
    633
    00:56:26,220 --> 00:56:33,820
    a little bit of hunger, some exercise, some hypoxia, lack of oxygen in your body. These are all ways of
    
    634
    00:56:33,820 --> 00:56:38,780
    activating these defense pathways. The same pathways that we've talked about before such as
    
    635
    00:56:38,780 --> 00:56:45,340
    sirtuins, there are seven of those which by the way NAD and resveratrol will both activate.
    
    636
    00:56:46,300 --> 00:56:52,700
    Just to recap the mTOR which lower amino acids particularly leucine and arginine and the AMP
    
    637
    00:56:52,700 --> 00:56:58,780
    kinase pathway so metformin and inhibition of complex one. So these are the main three
    
    638
    00:56:58,780 --> 00:57:03,260
    defensive pathways. There are others but what's downstream of these pathways are things like heat
    
    639
    00:57:03,260 --> 00:57:09,980
    shock proteins and transcription factors that turn on DNA repair enzymes. There's a whole litany
    
    640
    00:57:09,980 --> 00:57:16,700
    actually that there's a thousand papers per year on what are these sensors as we call them, what do
    
    641
    00:57:16,700 --> 00:57:22,380
    they do downstream and here's the good news actually. We used to think that we had to
    
    642
    00:57:22,380 --> 00:57:28,060
    understand what everything those sensors do to be able to understand aging and be able to live
    
    643
    00:57:28,060 --> 00:57:33,420
    longer but what I've been arguing actually for many years now is that we don't need to fully know what
    
    644
    00:57:33,420 --> 00:57:38,780
    they do. Heat shock proteins are great, definitely part of it but we don't need to know everything.
    
    645
    00:57:38,780 --> 00:57:44,540
    As long as we can find the right nodes in the cell to turn them on in the right ratios at the right
    
    646
    00:57:44,540 --> 00:57:49,180
    time, the body has evolved to take care of the rest and we're getting to the point fortunately,
    
    647
    00:57:49,180 --> 00:57:55,100
    it's been really remarkable to see where we know what these nodes are, we have the tools to tweak
    
    648
    00:57:55,100 --> 00:58:00,940
    them, we can also change them naturally by fasting and exercising, we change them with molecules that
    
    649
    00:58:00,940 --> 00:58:08,460
    we can ingest or inject but now the cutting edge is now with this toolbox when do you apply them
    
    650
    00:58:08,460 --> 00:58:14,220
    and how much and in what combinations and that's really what people like myself and you and and
    
    651
    00:58:14,220 --> 00:58:20,140
    your listeners are on to right now. Okay, I want to go back to NAD for a moment because there's an
    
    652
    00:58:20,140 --> 00:58:26,380
    important component that I neglected to discuss with you and that is another strategy for increasing
    
    653
    00:58:26,380 --> 00:58:33,740
    NAD plus levels is to not use it as much and from my review of the literature one of the primary
    
    654
    00:58:33,740 --> 00:58:39,020
    consumed, well there's two primary ones, the inside the cell would be PARP, poly ADP ribose polymerase
    
    655
    00:58:39,660 --> 00:58:44,220
    which is a DNA repair enzyme and it really designed to repair DNA breaks single and double
    
    656
    00:58:44,220 --> 00:58:49,900
    stranded and every time you have a break it's my understanding that you the PARP will take
    
    657
    00:58:50,620 --> 00:58:57,580
    suck out 100 to 100 ADP out of 100 to 150 NAD molecules and basically deplete your level by
    
    658
    00:58:57,580 --> 00:59:03,580
    that much for every break so and then you've got TD38 for extracellular consumptions which
    
    659
    00:59:03,580 --> 00:59:09,900
    has to do with the immune system but I'm wondering what your thoughts are on lowering PARP
    
    660
    00:59:09,900 --> 00:59:17,100
    activation and real common not widely appreciated but what I'm passionate about is really topic of
    
    661
    00:59:17,100 --> 00:59:22,220
    my next book is EMF exposure. I mean it's pretty well documented in the literature that I've reviewed
    
    662
    00:59:22,220 --> 00:59:28,940
    that it does activate PARP and decreases NAD level so in my view if you could limit that exposure
    
    663
    00:59:29,820 --> 00:59:33,660
    because you're not decreasing increasing consumption you're going to by default
    
    664
    00:59:33,660 --> 00:59:40,860
    increase NAD levels. Yeah right well yeah this is a really interesting topic that and I could
    
    665
    00:59:40,860 --> 00:59:47,260
    talk all day about it. So PARP enzymes you're right there's DNA repair protein the problem is when you
    
    666
    00:59:47,260 --> 00:59:53,740
    hyperactivate this protein there's PARP1, there's PARP2, there's actually more than 14 different
    
    667
    00:59:53,740 --> 00:59:59,980
    PARPs. They do drain NAD quite effectively in fact in my lab we've discovered another PARP that
    
    668
    00:59:59,980 --> 01:00:07,260
    when you have inflammation it drains NAD as well so it does make sense to slow them down as you're
    
    669
    01:00:07,260 --> 01:00:13,660
    mentioning in some cases inhibit them but you have to be really careful because you do need them.
    
    670
    01:00:13,660 --> 01:00:17,500
    We only why would you want to inhibit them because why would you want to inhibit DNA repair?
    
    671
    01:00:17,500 --> 01:00:24,460
    Well you wouldn't but you want to inhibit their overuse of NAD. Right by decreasing these
    
    672
    01:00:24,460 --> 01:00:28,380
    insults that would cause them to be activated. That's the best way right because then you get
    
    673
    01:00:28,380 --> 01:00:34,780
    the benefits of low DNA damage and the benefits of high NAD. We had a science paper in 2013 that
    
    674
    01:00:34,780 --> 01:00:40,540
    connected all of this together that the sirtuin gene or the sirtuin enzyme this sort one we've
    
    675
    01:00:40,540 --> 01:00:48,940
    talked about actually controls PARP activity and PARP1 is normally inhibited by a protein called
    
    676
    01:00:48,940 --> 01:00:58,220
    DBC1 and then sirtuin one controls that process and long story short you want to activate PARP
    
    677
    01:00:58,220 --> 01:01:03,100
    but not too much and so that's what we think is going on here this fine tuning but actually to
    
    678
    01:01:03,100 --> 01:01:07,660
    get to what's really more interesting I think is how do you keep your levels of DNA double
    
    679
    01:01:07,660 --> 01:01:15,260
    strand breaks to a minimum and I think that's the key one of the main keys to longevity
    
    680
    01:01:15,980 --> 01:01:20,540
    and there's two reasons one you mentioned which is that double strand breaks drain NAD.
    
    681
    01:01:21,260 --> 01:01:27,900
    The second which I think you're going to be familiar with because you've read my upcoming
    
    682
    01:01:27,900 --> 01:01:35,660
    book is the idea that DNA double strand breaks also disrupt the cell's epigenome the storage of
    
    683
    01:01:36,380 --> 01:01:43,180
    the information that we get passed down from our mothers and fathers mother and father
    
    684
    01:01:44,780 --> 01:01:48,700
    and the packaging of the DNA. We can get to that in a minute but basically
    
    685
    01:01:49,420 --> 01:01:57,500
    what happens is if you have a broken DNA proteins such as the sirtuins will leave their normal
    
    686
    01:01:57,500 --> 01:02:03,660
    sites where they're regulating genes and they'll go help repair with PARP as well but then they
    
    687
    01:02:03,660 --> 01:02:08,620
    don't all find their way back to where they came from they actually some of them get lost and get
    
    688
    01:02:08,620 --> 01:02:13,340
    distracted and over time what we see is that these proteins are essential for maintaining
    
    689
    01:02:13,340 --> 01:02:18,700
    cellular identity and cellular function will be lost and we see that in yeast cells. Yeast
    
    690
    01:02:18,700 --> 01:02:24,700
    cells get old because they're moving between breaks and back again to these to genes so it's
    
    691
    01:02:24,700 --> 01:02:31,180
    twofold so before we get to the science and I'd love to touch on that the key ways to reduce
    
    692
    01:02:31,180 --> 01:02:36,060
    double strand breaks I think I don't know about the radiation I have to trust you on that one but
    
    693
    01:02:36,860 --> 01:02:42,540
    CT scans. It's ionizing radiation I'm talking about non-ionizing but they both do it
    
    694
    01:02:42,540 --> 01:02:48,060
    different mechanisms ionizing does it through hydroxyl free radicals and non-ionizing does it
    
    695
    01:02:48,060 --> 01:02:53,660
    through carbonyl carbonate free radicals primarily through peroxynitrite. Yeah makes sense there's a
    
    696
    01:02:53,660 --> 01:02:59,180
    lot I mean you can't avoid DNA breaks in our body every day we have about a trillion breaks
    
    697
    01:02:59,900 --> 01:03:06,060
    you know one per cell at least and just living DNA will break especially when it's replicating
    
    698
    01:03:06,060 --> 01:03:10,380
    itself and the cell divides you'll have a break so even if you live in a lead box at the bottom
    
    699
    01:03:10,380 --> 01:03:17,660
    of the ocean which I don't recommend doing but you can minimize it you know I go through the
    
    700
    01:03:17,660 --> 01:03:23,180
    the DNA scanners occasionally and I ask the people there and I've researched this as well
    
    701
    01:03:23,180 --> 01:03:28,140
    the amount of radiation is about the same as you get on the flight but but why double your exposure
    
    702
    01:03:28,940 --> 01:03:36,940
    you know to me it doesn't make sense so I try to if I can avoid that exposure x-rays dental x-rays
    
    703
    01:03:36,940 --> 01:03:41,260
    you know they're important I'm not going to deny that and I think that we should know what's in our
    
    704
    01:03:41,260 --> 01:03:47,900
    mouth but I would try not to overdo it I think any physician who does x-rays should have a good
    
    705
    01:03:47,900 --> 01:03:55,660
    reason for doing it and usually they do but you know be aware that there are consequences to
    
    706
    01:03:55,740 --> 01:04:01,100
    exposing your body to radiation. Okay so let's get to what you just alluded to which is the
    
    707
    01:04:01,740 --> 01:04:08,060
    resolution of some of the epigenetic damage that accumulates through through age and what I think
    
    708
    01:04:08,060 --> 01:04:13,260
    is one of the most fascinating aspects of your book in which you are using technology that I
    
    709
    01:04:13,260 --> 01:04:20,700
    believe developed by another researcher in your lab Dr. George Church who developed the Chris and
    
    710
    01:04:20,700 --> 01:04:27,260
    co-invented as I understand the CRISPR technique and you're using those gene editing techniques to
    
    711
    01:04:27,260 --> 01:04:35,340
    insert three of the four Yamanaka transcription factors into aged mice that have either been
    
    712
    01:04:35,340 --> 01:04:41,580
    experimentally or are blind in some way and you can actually restore their vision through this
    
    713
    01:04:41,580 --> 01:04:49,740
    epigenetic resurrection. Yeah so we're writing up three papers now and so this is a sneak preview of
    
    714
    01:04:49,740 --> 01:04:55,260
    what hopefully will be published later this year and what we've discovered over the last 10 years
    
    715
    01:04:55,260 --> 01:05:01,020
    and this has been a 10-year project so I'm really grateful to the scientists in my lab who've had the
    
    716
    01:05:01,020 --> 01:05:07,740
    endurance we've discovered what we think is is very strong evidence for what we call now
    
    717
    01:05:07,740 --> 01:05:15,100
    epigenetic noise as a cause of aging not just in mammals but throughout life even in yeast cells.
    
    718
    01:05:15,740 --> 01:05:20,380
    So what does that mean? So let's just quickly do a biology lesson for those who haven't been in high
    
    719
    01:05:20,380 --> 01:05:28,060
    school for a while. So the genome we know DNA genome epigenome is the organization of that DNA
    
    720
    01:05:28,060 --> 01:05:34,220
    and the epigenome tells the cell that they should turn on this gene to be a nerve cell and in a liver
    
    721
    01:05:34,220 --> 01:05:39,100
    cell turn on that gene to be a liver cell and that's epigenetics and cells inherit that information
    
    722
    01:05:39,100 --> 01:05:47,020
    just as much as they inherit their DNA. So in my book what I am proposing is that those two types
    
    723
    01:05:47,020 --> 01:05:55,020
    of information genomic and epigenomic they're quite different. The genomic the DNA is digital
    
    724
    01:05:55,020 --> 01:06:01,420
    which is very well preserved and can last a long time we know that DVDs last longer than cassette
    
    725
    01:06:01,420 --> 01:06:06,620
    tapes but the problem for the epigenome is that it's analog information and anyone who's had a
    
    726
    01:06:06,620 --> 01:06:13,260
    cassette tape or a record knows that you can you can pretty easily scratch these or lose the
    
    727
    01:06:13,260 --> 01:06:19,580
    information in fact you can scratch your DVD and lose the information. We actually think that aging
    
    728
    01:06:20,220 --> 01:06:24,140
    is similar to those scratches that the information to be young again is still
    
    729
    01:06:24,140 --> 01:06:30,540
    largely in our bodies but we can access our cells can access that information just by you know
    
    730
    01:06:31,100 --> 01:06:37,740
    metaphorically scrubbing the DVD or polishing it up so that the cell can read the right genes
    
    731
    01:06:37,740 --> 01:06:44,540
    in the case of the DVD the right song. So with that in mind let me explain what we've discovered
    
    732
    01:06:45,180 --> 01:06:49,660
    if so we literally have not literally but metaphorically have a way of scratching
    
    733
    01:06:50,300 --> 01:06:55,500
    a mouse's epigenome and the way we do that is actually we cut the DNA we create these double
    
    734
    01:06:55,500 --> 01:07:00,460
    strand breaks let the cell heal them without making mutations so there's no change to the
    
    735
    01:07:00,460 --> 01:07:05,100
    digital information but what we see is the process of proteins moving around and trying to repair
    
    736
    01:07:05,100 --> 01:07:12,220
    that DNA eventually introduces this epigenomic noise and the genes that were once on many of
    
    737
    01:07:12,220 --> 01:07:16,700
    them get turned off and those that were once off come on and so liver cells start to lose
    
    738
    01:07:16,700 --> 01:07:21,980
    their identity skin cells start to lose their identity and the consequence we think is aging
    
    739
    01:07:21,980 --> 01:07:26,700
    and we actually will hopefully publish a paper that shows that if you create this noise in a
    
    740
    01:07:26,700 --> 01:07:33,500
    mouse it will go through accelerated aging and not just looking old it is actually literally
    
    741
    01:07:33,500 --> 01:07:40,780
    old if we measure the the epigenetic clock and I think many of your listeners and viewers will
    
    742
    01:07:40,780 --> 01:07:45,100
    know that there's a clock you can measure from blood in our bodies or in a mouse and it'll tell
    
    743
    01:07:45,100 --> 01:07:51,020
    you how old the animal is or we are biologically if we do that with our mice that we've scratched
    
    744
    01:07:51,020 --> 01:07:58,540
    up they are literally not likely 50 older which is great okay but you might say well
    
    745
    01:07:59,260 --> 01:08:04,780
    David that that's all fun but why do we care about making a mouse older well first of all it's good
    
    746
    01:08:04,780 --> 01:08:10,140
    evidence that we're right about the hypothesis that every aspect of aging is recapitulated
    
    747
    01:08:10,140 --> 01:08:15,420
    second of all we have mice now that we can change the rate of aging perhaps even accelerate aging
    
    748
    01:08:15,420 --> 01:08:20,700
    so that they behave more like humans and we can potentially have a better mouse model for
    
    749
    01:08:20,700 --> 01:08:27,660
    Alzheimer's for example but then the third thing is if you can give an animal something then you
    
    750
    01:08:27,660 --> 01:08:32,380
    can actually with that knowledge take it away and that's what we've done with George in collaboration
    
    751
    01:08:32,380 --> 01:08:38,380
    with George what we did actually was we wanted to reprogram the cells so that the genes that were
    
    752
    01:08:38,380 --> 01:08:46,620
    once let's start with this the ones on now they they go back off and vice versa so genes that were
    
    753
    01:08:46,620 --> 01:08:53,180
    once off come back on and what we find is that by using these three yamanaka factors you can
    
    754
    01:08:53,180 --> 01:08:58,380
    actually find the original information in the cell that tells it to be young again and those genes
    
    755
    01:08:58,380 --> 01:09:03,660
    actually switch and the cell behaves like it's young again and in the case of the the retina
    
    756
    01:09:04,620 --> 01:09:12,460
    we have preliminary results that we can actually restore eyesight by rejuvenating the nerves in
    
    757
    01:09:12,460 --> 01:09:19,260
    the retina to be young again and so that's early days of what I hope is the future where we can
    
    758
    01:09:19,260 --> 01:09:24,140
    reprogram cells in the body doesn't have to be the retina can be any cell type in the body you think
    
    759
    01:09:24,780 --> 01:09:31,580
    to actually not just act young but literally be molecularly young again and in my career
    
    760
    01:09:31,580 --> 01:09:36,780
    I've seen a lot of cool stuff and I haven't seen anything this cool before I couldn't agree more
    
    761
    01:09:36,780 --> 01:09:42,380
    it's the potential is beyond extraordinary and I'm wondering if the cells that you're
    
    762
    01:09:42,380 --> 01:09:48,140
    injecting are they pluripotent stem cells that you're modifying with the yamanaka transcription
    
    763
    01:09:48,140 --> 01:09:56,220
    factors we're actually we're actually just giving uh the the genes to the organism we're turning on
    
    764
    01:09:56,220 --> 01:10:02,620
    oh with a virus adenovirus we do we use the virus that's that's used by pharmaceutical companies to
    
    765
    01:10:02,620 --> 01:10:11,100
    correct genetic diseases so it's a an FDA approved virus that that is very easy to use in the eye
    
    766
    01:10:11,100 --> 01:10:16,380
    actually one injection there's no immune response in the eye it's not a big one and so that's why
    
    767
    01:10:16,380 --> 01:10:22,460
    we chose the eye actually it's not just that we we saw it as a challenge to reverse blindness
    
    768
    01:10:22,460 --> 01:10:29,580
    but we also knew that it could be the quickest path to uh to testing this in people and helping
    
    769
    01:10:29,580 --> 01:10:33,820
    them with this new technology so is this mostly a local effect that you're achieving
    
    770
    01:10:35,180 --> 01:10:41,020
    uh well in the eye yes uh and and by design um you don't know the full safety profile yet so we want
    
    771
    01:10:41,020 --> 01:10:47,820
    to be careful but we have injected mice intravenously with the virus and we've got mice that
    
    772
    01:10:47,820 --> 01:10:52,540
    are healthy 10 months later and so far so good you know it's early days we've only been testing
    
    773
    01:10:52,540 --> 01:10:57,260
    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
    
    774
    01:10:57,980 --> 01:11:05,020
    but uh yeah i think the promise is there and it's just hopefully evidence if not proof in principle
    
    775
    01:11:05,740 --> 01:11:14,620
    that aging is more reversible than we ever thought do you have plans on putting genes in to make
    
    776
    01:11:15,500 --> 01:11:21,820
    additional sirtuins like all the seven her two seven sirtuin genes in humans uh to augment those
    
    777
    01:11:21,820 --> 01:11:26,700
    i mean that's going to be better than a than a sirtuin activator if you can have them be on all
    
    778
    01:11:26,700 --> 01:11:31,980
    the time wouldn't it be yeah it would i only use viruses when absolutely necessary i think
    
    779
    01:11:32,540 --> 01:11:37,580
    the well-trodden path of small molecules means that there's a much greater chance of success
    
    780
    01:11:37,580 --> 01:11:43,180
    and less chance of side effects and toxicity with viruses as great as they are and as how
    
    781
    01:11:43,180 --> 01:11:51,660
    exciting they sound it's still a pretty it's still early days we don't know that so i i don't
    
    782
    01:11:51,660 --> 01:11:57,580
    see a use for um viruses and sirtuins in humans at this point but i so i'll stick with small
    
    783
    01:11:57,580 --> 01:12:03,020
    molecules but what i do see a future you know if you want to go crazy with predictions yeah yeah
    
    784
    01:12:04,060 --> 01:12:11,020
    that that we we could see a world where where people do choose to be genetically modified um
    
    785
    01:12:11,020 --> 01:12:15,500
    it's their choice right you wouldn't i don't think you can easily go in and modify children
    
    786
    01:12:15,500 --> 01:12:21,500
    even though that's now being done unless it's life-threatening of course but adults you know
    
    787
    01:12:21,500 --> 01:12:26,780
    they should be able to have a choice if there's if there's safety and it's approved then they should
    
    788
    01:12:26,780 --> 01:12:33,420
    be able to do that and maybe there'll be a day when we are able to carry these yamanaka genes
    
    789
    01:12:33,420 --> 01:12:40,220
    in our body and when we get sick or we have an injury uh let's say we have a detached retina or
    
    790
    01:12:40,220 --> 01:12:46,460
    we have a broken spine uh then we get an iv that turns on those genes for a month we recover
    
    791
    01:12:46,460 --> 01:12:52,060
    we rejuvenate and then we turn them off again until we need them again and that would be a
    
    792
    01:12:52,060 --> 01:13:00,060
    pretty wild sci-fi future but science is pointing to at least the biology being possible i believe
    
    793
    01:13:01,020 --> 01:13:11,420
    you mentioned that there's no rational biological requirement for death that not necessarily
    
    794
    01:13:11,420 --> 01:13:16,300
    mortality but you could live hundreds of years theoretically so i'm wondering in your mind what
    
    795
    01:13:16,300 --> 01:13:24,060
    you perceive as the best bridge to pass this the clearly 120 year limit that humans currently have
    
    796
    01:13:24,620 --> 01:13:31,980
    would it be uh resetting the that epigen the methylation clock the horvath methylation
    
    797
    01:13:31,980 --> 01:13:36,540
    clock back to zero with like hematopoietic stem cells or what do you think is the
    
    798
    01:13:37,420 --> 01:13:46,780
    biggest step to do that right well so i put my money on on the DNA methylation reprogramming
    
    799
    01:13:46,780 --> 01:13:53,980
    right now it's uh you know i've seen old mice regain their eyesight i haven't seen any technology
    
    800
    01:13:53,980 --> 01:14:01,660
    able to do that previously so if you applied that technology in combination with some of the
    
    801
    01:14:01,660 --> 01:14:06,620
    molecules we've talked about today in combination with a healthy lifestyle that we're trying to
    
    802
    01:14:06,620 --> 01:14:14,540
    optimize in real time here i don't think anyone can say what what our limit is i mean anyone who
    
    803
    01:14:14,540 --> 01:14:19,420
    says that there's a limit really doesn't know what they're talking about or is lying we really
    
    804
    01:14:19,420 --> 01:14:25,820
    don't know what's possible people who have lived in to 110 115 they typically smoke they've done
    
    805
    01:14:25,820 --> 01:14:33,580
    no exercise they had a lot of alcohol uh do you does anyone think that if they didn't have access
    
    806
    01:14:33,580 --> 01:14:37,820
    to the kind of things that we're talking about today they couldn't have lived longer i think
    
    807
    01:14:37,820 --> 01:14:43,180
    they definitely could have we just don't know because those people are so rare and typically
    
    808
    01:14:43,820 --> 01:14:49,340
    they didn't expect to live so long in the first place um so yeah now now with what we know and
    
    809
    01:14:49,340 --> 01:14:54,780
    what people in the future will know i mean why not and the longer we live the more access we
    
    810
    01:14:54,780 --> 01:15:00,060
    have to this technology yeah you know so i think anything should be on the table
    
    811
    01:15:01,100 --> 01:15:04,060
    it's hard to make predictions it's very easy to poke holes in these things
    
    812
    01:15:04,860 --> 01:15:11,740
    and more often predictions are wrong rather than right but i can tell you that i firmly believe
    
    813
    01:15:11,740 --> 01:15:16,540
    that anyone who says that there is a biological limit is wrong because there are plenty of
    
    814
    01:15:16,540 --> 01:15:23,340
    species and not just trees and not just jellyfish there are there are warm-blooded milk-giving
    
    815
    01:15:23,340 --> 01:15:28,860
    animals in the ocean called whales that can live hundreds of years way you know three times longer
    
    816
    01:15:28,860 --> 01:15:33,580
    than us they're not that different from us genetically they've figured out how to stabilize
    
    817
    01:15:33,580 --> 01:15:39,020
    their genome and repair their dna and all the stuff you need if we can learn from them i think
    
    818
    01:15:39,020 --> 01:15:44,860
    we can live a life like that and i i think historians will look back at the past 20 years
    
    819
    01:15:44,860 --> 01:15:49,740
    as the turning point when we realized that this was possible and finally focused our energy on the
    
    820
    01:15:49,740 --> 01:15:57,900
    topic so you are the world expert in the sirtuins and having made the association between resveratrol
    
    821
    01:15:57,900 --> 01:16:03,180
    and other small molecules and i'm wondering i think your lab is working on these small molecule
    
    822
    01:16:03,180 --> 01:16:11,100
    derivatives of resveratrol and other ones that activate sirtuins far more effectively so can you
    
    823
    01:16:11,100 --> 01:16:17,900
    comment on any ones that are in testing or close to commercial production now that might be you
    
    824
    01:16:17,900 --> 01:16:25,100
    know orders of magnitude better right so there are a couple of things we're doing in my lab still
    
    825
    01:16:25,100 --> 01:16:33,020
    on this topic that's not widely known but i'll share with everybody one is the the question of
    
    826
    01:16:33,020 --> 01:16:39,580
    what is resveratrol really doing you know we came out with the bold uh hypothesis that resveratrol
    
    827
    01:16:39,580 --> 01:16:45,340
    works through sirtuins in yeast cells and that's how it was working that was very controversial
    
    828
    01:16:45,340 --> 01:16:49,980
    it was a shock that you could actually activate an enzyme it was a shock that you could use one
    
    829
    01:16:49,980 --> 01:16:56,460
    molecule a quote-unquote dirty molecule to target very specifically one enzyme and i've basically
    
    830
    01:16:56,460 --> 01:17:02,220
    spent the last decade uh testing that hypothesis time and time again and we have new research that
    
    831
    01:17:03,260 --> 01:17:08,620
    builds upon a science paper that we had in 2013 that said that yes resveratrol is truly acting
    
    832
    01:17:08,620 --> 01:17:14,940
    on this enzyme we now have mice that we've engineered so that they are resistant to the
    
    833
    01:17:14,940 --> 01:17:20,460
    effects of resveratrol on the enzyme and those results look really promising the question is
    
    834
    01:17:20,460 --> 01:17:26,380
    does resveratrol still work if you block its ability to activate the sirt1 enzyme and the
    
    835
    01:17:26,380 --> 01:17:32,700
    answer looks like uh preliminarily yes so that that's good so the science really solid and i
    
    836
    01:17:32,700 --> 01:17:37,740
    wanted to to let everybody know that that's that we're still working on the science on the drug
    
    837
    01:17:37,740 --> 01:17:44,780
    side uh so certerus was a company that i co-founded in 2005 and it was my first company it was a
    
    838
    01:17:44,780 --> 01:17:50,700
    venture ventureback company it went public and it was eventually sold to glexo smith klein um for a
    
    839
    01:17:50,700 --> 01:17:59,260
    lot of money i i was you know a child uh got what's called diluted down to you know almost nothing
    
    840
    01:18:01,020 --> 01:18:07,420
    or loss yeah um you know but the little money i made has been reinvested into
    
    841
    01:18:07,980 --> 01:18:13,660
    new companies which i'm i'm excited about you know but but what did that teach me it taught me that
    
    842
    01:18:14,620 --> 01:18:21,740
    if you let go of your work early uh it's very hard to have champion and so that work it went well but
    
    843
    01:18:21,740 --> 01:18:28,620
    it's still not in the clinic i'll update you on that so that we made and the company made 14 000
    
    844
    01:18:29,420 --> 01:18:35,420
    different activators of cert1 that were up to 10 000 times more potent than resveratrol
    
    845
    01:18:36,140 --> 01:18:42,860
    those molecules some of them two of them went into mice uh and rafa to cover rafael to cover NIH
    
    846
    01:18:43,420 --> 01:18:49,740
    he put those into mice and they they lived longer it's it's quite an a poorly recognized finding
    
    847
    01:18:50,380 --> 01:18:53,820
    uh but it was very clear they lived longer even on a normal diet not just
    
    848
    01:18:54,380 --> 01:19:01,820
    high fat fat mice um one of those molecules called 2104 srt 2104
    
    849
    01:19:03,100 --> 01:19:09,420
    look great it went into a study in humans actually it was a pill given to patients with psoriasis
    
    850
    01:19:09,420 --> 01:19:16,220
    plot type psoriasis in a small study i believe it was uh somewhere between 20 and 40 patients
    
    851
    01:19:16,860 --> 01:19:23,980
    uh phase 2a and uh it looked really promising when the drug got into the body there was a
    
    852
    01:19:23,980 --> 01:19:30,620
    very significant effect on the group on the disease um so glexo uh still has those molecules
    
    853
    01:19:30,620 --> 01:19:36,540
    and i'm not sure what their plans are for those molecules but uh you can bet that i'll do
    
    854
    01:19:36,540 --> 01:19:41,980
    everything uh in my power to make sure that they make it to patients if humanly possible
    
    855
    01:19:43,020 --> 01:19:50,220
    we are working actually now on derivatives of the nmn molecule and any precursors and so those are
    
    856
    01:19:50,860 --> 01:19:55,660
    exciting as well because they can boost the levels of all seven of the sirtuins not just
    
    857
    01:19:55,660 --> 01:20:01,180
    number one and that's where my efforts are currently focused do they actually boost the
    
    858
    01:20:01,260 --> 01:20:08,460
    sirtuin levels or they just make them work better uh mostly mostly it's it's making them more active
    
    859
    01:20:08,460 --> 01:20:17,100
    because it's providing the co-substrate for their reaction right yep and you know gsk uh didn't they
    
    860
    01:20:17,100 --> 01:20:24,300
    shut down that lab that they bought from your your company in 2013 and if they did do you think it was
    
    861
    01:20:24,300 --> 01:20:28,860
    related to the fact that they didn't understand the importance of nad and if they were testing
    
    862
    01:20:28,860 --> 01:20:34,140
    aged rats or mice it's not going to work that well unless they do something to augment the nad
    
    863
    01:20:35,100 --> 01:20:38,940
    uh well they had a little nad program but mostly they were working on those um
    
    864
    01:20:39,500 --> 01:20:48,220
    direct activators coming out of the resume which will work um what i think they they didn't appreciate
    
    865
    01:20:48,220 --> 01:20:58,140
    was the um the wide scope of these molecules um that they're they were truly applicable
    
    866
    01:20:58,140 --> 01:21:04,060
    the other thing um joe that wasn't helpful to anybody uh you know in full defense of of glaxo
    
    867
    01:21:04,060 --> 01:21:11,020
    who are a very smart bunch of people they bought the company right as the controversy around the
    
    868
    01:21:11,020 --> 01:21:18,140
    mechanism blew up and it was pfizer whose scientists published that this was wrong now you know all the
    
    869
    01:21:18,140 --> 01:21:24,300
    trouble has died down now and we've i think proven without a doubt that we were right but in that in
    
    870
    01:21:24,300 --> 01:21:30,700
    those you know years of doubt it was very hard for glaxo to keep investing the tens of dollars it
    
    871
    01:21:30,700 --> 01:21:38,860
    was taking to go uh into larger studies um and so i think that was the biggest damage that they did
    
    872
    01:21:38,860 --> 01:21:44,700
    uh it was actually pfizer that that caused that controversy with one publication and you know it's
    
    873
    01:21:44,700 --> 01:21:52,460
    in in hindsight now it's it's really remarkable what one study can do to a whole field absolutely
    
    874
    01:21:53,420 --> 01:22:00,780
    absolutely so are your nmn uh derivatives getting close to commercialization yeah they're pretty
    
    875
    01:22:00,780 --> 01:22:05,420
    advanced um i don't talk about them a lot um mainly because we're we're not venture-packed
    
    876
    01:22:05,420 --> 01:22:11,260
    so we don't need to promote it we're privately funded for now but i'll give i'll give everybody
    
    877
    01:22:11,260 --> 01:22:17,100
    a bit of a sneak preview i talk a lot more about it in the book um we're in humans we are doing
    
    878
    01:22:17,100 --> 01:22:23,820
    human clinical trials we've finished two studies at harvard medical school this is not not my study
    
    879
    01:22:23,820 --> 01:22:29,020
    even though it's at harvard it's at the hospital nearby of course it's arm's length from me because
    
    880
    01:22:29,020 --> 01:22:34,140
    i i at least have the perception of a conflict of interest so i'm not involved but those two
    
    881
    01:22:34,140 --> 01:22:40,060
    studies have gone well uh no indicators that there's any trouble and so we're hoping to be
    
    882
    01:22:40,060 --> 01:22:45,420
    able to have a phase two study at least one possibly to begin um two studies beginning later
    
    883
    01:22:45,420 --> 01:22:52,700
    this year and early next in actually in rare diseases not in um in aging itself not yet and
    
    884
    01:22:52,700 --> 01:22:59,420
    so actually that you reminded me to say something that's often asked of me which is why not go treat
    
    885
    01:22:59,420 --> 01:23:06,860
    aging yeah we go ahead tell us why i know why but it's not a very good business plan can you imagine
    
    886
    01:23:06,860 --> 01:23:11,260
    the amount of money that would take to do a trial like that not only would it be expensive but at
    
    887
    01:23:11,260 --> 01:23:16,380
    the end of it you couldn't sell a medicine if you tried because there is no disease called aging
    
    888
    01:23:16,380 --> 01:23:21,500
    right now i mean there is a disease called aging you can look at it in the mirror if you want
    
    889
    01:23:22,300 --> 01:23:30,380
    but in terms of regulation it's not recognized yet yeah the the strategy it seems to me especially to
    
    890
    01:23:30,380 --> 01:23:36,220
    obtain funding is to figure out an anti-aging strategy that does marvelous things cosmetically
    
    891
    01:23:36,220 --> 01:23:40,300
    because the market for cosmetics is through the roof and if you have something that's effective
    
    892
    01:23:40,300 --> 01:23:44,460
    you'll explode in revenues and you can use those revenues to support the real thing that's going to
    
    893
    01:23:44,460 --> 01:23:51,180
    reverse aging well that's true and that's partly what lenny guarantee and his team and at least him
    
    894
    01:23:51,820 --> 01:23:58,300
    are doing they've gone to the market first i'm taking probably just as hard if not more difficult
    
    895
    01:23:58,300 --> 01:24:03,740
    route which is to be able to raise enough money to to get to pharmaceuticals which is
    
    896
    01:24:04,540 --> 01:24:09,260
    um you know a lot of money it's in the hundreds of millions but i think that's the part that i i
    
    897
    01:24:09,260 --> 01:24:14,700
    think is is a better one for me personally and for the for ultimately the product but yeah you're
    
    898
    01:24:14,700 --> 01:24:19,900
    right it's a challenge you've got to either get on the market early with something that's not well
    
    899
    01:24:19,900 --> 01:24:26,460
    proven or raise the money and wait five to seven years with something that is eventually proven but
    
    900
    01:24:26,460 --> 01:24:33,020
    neither of those is an easy path no no but most good things in life aren't it's true and this is
    
    901
    01:24:33,020 --> 01:24:38,220
    the big one now if you talk about what what's going to plague our planet and our humanity
    
    902
    01:24:38,220 --> 01:24:44,380
    our society clearly global warming energy crisis these are obvious ones but what most people don't
    
    903
    01:24:44,380 --> 01:24:48,860
    realize is that the future prosperity of the planet is going to depend on our ability to keep
    
    904
    01:24:48,860 --> 01:24:54,620
    our populations healthy for longer in terms of productivity and and cost in health care and
    
    905
    01:24:54,620 --> 01:24:59,820
    instead of doing whack-a-mole medicine where we treat one disease often too late to actually have
    
    906
    01:24:59,820 --> 01:25:06,700
    a benefit um the approach really should be one where we're treating the cause of most diseases
    
    907
    01:25:06,700 --> 01:25:14,300
    that will kill us which is aging itself and the idea of treating aging um was fantasy even 20 years
    
    908
    01:25:14,300 --> 01:25:20,380
    ago but as i hope uh you and your viewers are actually appreciating now the science is top
    
    909
    01:25:20,380 --> 01:25:24,460
    notch we we and my colleagues we publish in the world's best journals there'd be noble prizes on
    
    910
    01:25:24,460 --> 01:25:30,140
    this the time is now to be able to translate these discoveries into medicines that can
    
    911
    01:25:31,100 --> 01:25:37,180
    have the best chance of giving future generations even our own a chance of not being dragged down
    
    912
    01:25:37,180 --> 01:25:43,980
    economically by the burden of dementia and um alzheimer's is a huge one but just in general
    
    913
    01:25:43,980 --> 01:25:51,740
    frailty it sucks trillion dollars out of our economies yeah frayota is a big one well um my
    
    914
    01:25:51,740 --> 01:25:56,380
    want to extend my deepest appreciation and gratitude for all the work you've done and
    
    915
    01:25:56,380 --> 01:26:01,340
    are going to do because you're still a very young man the motivations for your work and your book
    
    916
    01:26:01,900 --> 01:26:08,700
    uh lifespan the revolutionary science of why we age is genuine and pure as far as i can determine
    
    917
    01:26:08,700 --> 01:26:12,940
    and you describe it in your book and your discussions with your grandmother and your
    
    918
    01:26:12,940 --> 01:26:19,500
    understanding of death at a very early age four years old so um you're doing a big thing to change
    
    919
    01:26:19,500 --> 01:26:25,500
    the world and i and uh at a level that is quite extraordinary and i deeply appreciate what you've
    
    920
    01:26:25,500 --> 01:26:30,460
    done and would encourage people to get the book if this is a is a topic that interests them and i
    
    921
    01:26:30,460 --> 01:26:35,260
    think it should interest most of us because it's not just about living law almost this that you
    
    922
    01:26:35,260 --> 01:26:39,820
    know who wants to live long if you said it so so eloquently is the frailty this is without frailty
    
    923
    01:26:39,820 --> 01:26:46,300
    obtaining the all the capacities and capabilities and certainly the mental ones that we have as a
    
    924
    01:26:46,300 --> 01:26:54,300
    younger individual into into older age right well yeah thanks joe appreciate it i hope people who
    
    925
    01:26:54,300 --> 01:27:00,700
    read the book come away with a new view of what's possible and some people who have read it tell me
    
    926
    01:27:00,700 --> 01:27:05,100
    that it's changed the way they look at their own lives and that's what what i wanted to do is because
    
    927
    01:27:05,100 --> 01:27:11,900
    i think we we forget how important this topic is that we can do things right now to to alter the
    
    928
    01:27:11,900 --> 01:27:18,220
    course of our lives but also just the way you think about aging itself it's not something that
    
    929
    01:27:18,940 --> 01:27:24,460
    uh we used to think about the way we used to think cancer and heart disease were diseases we
    
    930
    01:27:24,460 --> 01:27:32,060
    couldn't treat aging is is the frontier of medicine and i talk about what we can do now
    
    931
    01:27:32,060 --> 01:27:37,900
    and what to do in the future i also uh want to say joe i want to commend you for for doing
    
    932
    01:27:37,900 --> 01:27:46,380
    what you do um you know i could rant on i've been the victim uh of of some really bad uh
    
    933
    01:27:46,380 --> 01:27:52,700
    press mostly and it's not so negative but more it's it's hype and exaggeration uh things taken
    
    934
    01:27:52,700 --> 01:27:57,900
    out of context and you know that happens a lot in print media and i think that's just the nature of
    
    935
    01:27:57,900 --> 01:28:03,820
    the beast and you know reporters that's what they're paid to do but these these podcasts and
    
    936
    01:28:03,820 --> 01:28:11,260
    these venues uh i mean god bless them they're a venue for a scientist to be able to be unfiltered
    
    937
    01:28:11,260 --> 01:28:16,460
    and talk in depth about topics that people are really interested in and you know i think
    
    938
    01:28:16,460 --> 01:28:22,940
    of one thing uh that social media and youtube and these podcasts have done it's it's allowed people
    
    939
    01:28:22,940 --> 01:28:27,500
    to have greater understanding in depth and direct access to scientists like me which
    
    940
    01:28:27,500 --> 01:28:32,780
    could never be done before yeah you cannot get this information on the conventional media
    
    941
    01:28:32,780 --> 01:28:38,300
    the best you could hope for it a big spot would be maybe five maybe possibly 10 minutes although i
    
    942
    01:28:38,300 --> 01:28:42,460
    guess some of the interviews it's very rare although like you're never going to get two or
    
    943
    01:28:42,460 --> 01:28:47,260
    three hours like you did with joe rogan and your joe rogan podcast and others so i thank you for
    
    944
    01:28:47,260 --> 01:28:53,340
    being so gracious i know you're a busy man and really for taking the time to really dive deep
    
    945
    01:28:53,340 --> 01:28:57,020
    and i think you've done a magnificent job in this interview because uh you know you share stuff that
    
    946
    01:28:57,020 --> 01:29:00,940
    i really haven't heard you talk about previously so thank you for doing that thanks joe thanks
    
    947
    01:29:00,940 --> 01:29:03,100
    for having me on okay