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

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

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

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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

281
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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

287
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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

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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

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of my new books is acknowledging you as the is really the catalyst for that well

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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

315
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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

317
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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

319
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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

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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

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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

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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

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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
00:30:34,020 --> 00:30:38,900
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
00:31:01,580 --> 00:31:07,700
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
00:31:15,300 --> 00:31:20,540
has been used for decades to lower cholesterol and the only side effect is

364
00:31:20,540 --> 00:31:26,060
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
00:32:00,740 --> 00:32:05,220
but if you don't bring the mortar and the windows and the doors and the roof

372
00:32:06,180 --> 00:32:13,220
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
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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
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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