2019-09-01 - Interview Dr. David Sinclair - Dr. Mercola interviews Dr. David Sinclair on Extending Your "Lifespan": Difference between revisions
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{| style="padding-top: 1em;" | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:00 | |||
| Welcome everyone, this is Dr. Mercola helping you take control of your health | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:03 | |||
| and I am just absolutely delighted to connect with Dr. David Sinclair who is a | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:10 | |||
| professor of genetics at Harvard Medical School and generally recognized as one | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:14 | |||
| of the major thought leaders in the science of how to improve our not only | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:21 | |||
| our lifespan but our health span. So he started in Sydney, got his PhD there and | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:27 | |||
| then he went over to Lundy-Garanti's lab at MIT and then went to his got his own | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:32 | |||
| lab at Harvard Medical School in 1999. He's been working there ever since and | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:35 | |||
| really come up with this astounding discoveries which we're going to talk | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:38 | |||
| about today but that one of the primary focuses is his new book which is called | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:43 | |||
| Lifespan, the revolutionary science of why we age and why we don't have to do | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:49 | |||
| that. And it's going to be available September 10th and if you're | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:54 | |||
| watching this it's not September 10th you can pre-order it on Amazon. So | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:00:57 | |||
| welcome and thank you for joining us today. Thank you, it's great to be here. | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:02 | |||
| Yeah, yeah so you talk about a lot of great things in there and I want to | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:07 | |||
| really highlight some of the concepts that you discussed because I think | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:11 | |||
| there's so much potential to help us and hit this really the the king of all | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:17 | |||
| diseases which is aging. So you talk about calorie restriction as being the | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:23 | |||
| only proven non-pharmacological method of consistently extending lifespan and | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:29 | |||
| protecting against many of the age-related diseases. And what so you and | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:37 | |||
| then you also discuss intermittent fasting. So I'm wondering if the one of | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:41 | |||
| the benefits of not eating is suppressing mTOR and activating | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:45 | |||
| autophagy. So I'm wondering what type of conclusions you've reached with respect | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:50 | |||
| to the optimal timing of the periods of the time-restricted eating and the | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:01:57 | |||
| frequency of that and how you think integrating fasting or partial fasting | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:03 | |||
| into that series might look like. Yeah, well we've known for probably more than | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:11 | |||
| now 5,000 years that being a bit hungry is good for you. So this is not | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:15 | |||
| revolutionary. What's been more revolutionary in the last few years is | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:20 | |||
| the discovery of biochemical pathways that actually seem to underlie this | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:25 | |||
| actual protection against disease and aging itself. And so we're not so much | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:30 | |||
| guessing anymore what's going on and science has gotten involved and we're | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:34 | |||
| doing more and more studies certainly in humans but also in animals to see what | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:41 | |||
| best diet works. And the bottom line, I get questions every day I wake up to | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:47 | |||
| probably a couple of dozen emails about this topic. Nobody actually knows what's | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:52 | |||
| best but we can go through them and I can talk about which is my favorite as | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:02:58 | |||
| well because there's it's not just a science aspect it's also social. We love to | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:03 | |||
| eat, we have traditions, we have typically three meals a day and trying to deviate | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:09 | |||
| from that is really quite challenging. Calorie restriction in animals and in | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:13 | |||
| humans is about 20 to 30 percent less than what a doctor or a veterinarian | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:17 | |||
| would recommend. I also struggled with that one so I certainly wouldn't | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:23 | |||
| recommend it. It really means you've got to be hungry for most of the time | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:28 | |||
| and I'm sure you get used to it but I didn't get that far. After about a | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:31 | |||
| week I got too hungry and I gave up. And then I didn't restrict my diet for many | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:37 | |||
| years actually. I had kids and that's really hard to do. But more recently what | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:44 | |||
| I've done which I find very easy to do is basically miss a meal once a day and | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:52 | |||
| I'm not hungry in the morning some people are not hungry at night. If you | |||
|- | |||
| style="min-width:4em; color: grey; text-align: right; padding-right: 1em; vertical-align: top;" | 00:03:55 | |||
| can go for say it's seven o'clock at night all the way through to lunchtime | |||
|- | |||
Revision as of 02:19, 12 October 2023
Transcript
Transcript
00:00:00 | Welcome everyone, this is Dr. Mercola helping you take control of your health |
00:00:03 | and I am just absolutely delighted to connect with Dr. David Sinclair who is a |
00:00:10 | professor of genetics at Harvard Medical School and generally recognized as one |
00:00:14 | of the major thought leaders in the science of how to improve our not only |
00:00:21 | our lifespan but our health span. So he started in Sydney, got his PhD there and |
00:00:27 | then he went over to Lundy-Garanti's lab at MIT and then went to his got his own |
00:00:32 | lab at Harvard Medical School in 1999. He's been working there ever since and |
00:00:35 | really come up with this astounding discoveries which we're going to talk |
00:00:38 | about today but that one of the primary focuses is his new book which is called |
00:00:43 | Lifespan, the revolutionary science of why we age and why we don't have to do |
00:00:49 | that. And it's going to be available September 10th and if you're |
00:00:54 | watching this it's not September 10th you can pre-order it on Amazon. So |
00:00:57 | welcome and thank you for joining us today. Thank you, it's great to be here. |
00:01:02 | Yeah, yeah so you talk about a lot of great things in there and I want to |
00:01:07 | really highlight some of the concepts that you discussed because I think |
00:01:11 | there's so much potential to help us and hit this really the the king of all |
00:01:17 | diseases which is aging. So you talk about calorie restriction as being the |
00:01:23 | only proven non-pharmacological method of consistently extending lifespan and |
00:01:29 | protecting against many of the age-related diseases. And what so you and |
00:01:37 | then you also discuss intermittent fasting. So I'm wondering if the one of |
00:01:41 | the benefits of not eating is suppressing mTOR and activating |
00:01:45 | autophagy. So I'm wondering what type of conclusions you've reached with respect |
00:01:50 | to the optimal timing of the periods of the time-restricted eating and the |
00:01:57 | frequency of that and how you think integrating fasting or partial fasting |
00:02:03 | into that series might look like. Yeah, well we've known for probably more than |
00:02:11 | now 5,000 years that being a bit hungry is good for you. So this is not |
00:02:15 | revolutionary. What's been more revolutionary in the last few years is |
00:02:20 | the discovery of biochemical pathways that actually seem to underlie this |
00:02:25 | actual protection against disease and aging itself. And so we're not so much |
00:02:30 | guessing anymore what's going on and science has gotten involved and we're |
00:02:34 | doing more and more studies certainly in humans but also in animals to see what |
00:02:41 | best diet works. And the bottom line, I get questions every day I wake up to |
00:02:47 | probably a couple of dozen emails about this topic. Nobody actually knows what's |
00:02:52 | best but we can go through them and I can talk about which is my favorite as |
00:02:58 | well because there's it's not just a science aspect it's also social. We love to |
00:03:03 | eat, we have traditions, we have typically three meals a day and trying to deviate |
00:03:09 | from that is really quite challenging. Calorie restriction in animals and in |
00:03:13 | humans is about 20 to 30 percent less than what a doctor or a veterinarian |
00:03:17 | would recommend. I also struggled with that one so I certainly wouldn't |
00:03:23 | recommend it. It really means you've got to be hungry for most of the time |
00:03:28 | and I'm sure you get used to it but I didn't get that far. After about a |
00:03:31 | week I got too hungry and I gave up. And then I didn't restrict my diet for many |
00:03:37 | years actually. I had kids and that's really hard to do. But more recently what |
00:03:44 | I've done which I find very easy to do is basically miss a meal once a day and |
00:03:52 | I'm not hungry in the morning some people are not hungry at night. If you |
00:03:55 | can go for say it's seven o'clock at night all the way through to lunchtime |
00:04:01 | based on the animal studies that I've seen published and some in my lab that's |
00:04:07 | very likely to do you a lot of good in the long run and in the short run. And |
00:04:13 | the science behind it's really interesting I'll come back to that but |
00:04:17 | there are other diets that other people have found to be effective in |
00:04:24 | terms of improving biology and biochemical markers. One is the 5 plus 2 |
00:04:29 | diet. Michael Moseley. Exactly I'm sure many of your viewers are familiar with |
00:04:35 | that one. That one is also quite doable especially if you have sodas |
00:04:43 | and things like that that can actually help just bubble the water. More extreme are |
00:04:49 | those diets where you go for a whole week every couple of months or every few |
00:04:55 | months. I haven't tried that I'd like to. My view on that is that |
00:05:04 | that's probably going to work the best if you can do it because it doesn't just |
00:05:09 | trigger the short-term pathways that we've been studying in my lab. But a week |
00:05:14 | of fasting will really start the body to start consuming its own protein and this |
00:05:21 | is as you mentioned autophagy that's what autophagy is it's the consuming of |
00:05:25 | our own biological material which is typically protein. And actually talking |
00:05:31 | with people who have done these fasting regimens after about three days |
00:05:35 | something different starts to kick in and people who try this tell me that |
00:05:39 | they have a feeling of euphoria and they definitely get an added boost. But |
00:05:45 | just let me quickly go back to why we think this works. So we've been studying |
00:05:49 | in my lab for the last 20 years genes that respond to diet but fat to fasting |
00:05:55 | and calorie restriction and the upshot of it is that our bodies respond to |
00:06:00 | adversity or perceived adversity. They turn on these defensive pathways it |
00:06:05 | changes a bunch of genes that switch on to defend our bodies. And at |
00:06:10 | least from many different animals things as small as worms and flies all the way |
00:06:15 | up to mice and rats these defenses of the body are extremely good at protecting |
00:06:21 | us against diseases from diabetes to cancer heart disease even dementia |
00:06:27 | Alzheimer's. These are things that modern medicine has struggled to combat and |
00:06:34 | this seems to be the very simple way to get the body to fight against those |
00:06:37 | diseases. Often I'm asked how early should you start? In the animal studies |
00:06:44 | and in rat studies, mouse studies, the sooner you start the better and the |
00:06:48 | longer you do this the better in your life. Clearly we don't want to be |
00:06:53 | recommending or seeing teenagers or even people who are in their early 20s do |
00:06:58 | this because there's still a lot going on in their bodies and their brains. But |
00:07:02 | after 30 if you extrapolate from the animal studies then the longer you do |
00:07:07 | this in the lifespan the better. I'm just turning 50 now and I wish I had |
00:07:11 | started earlier. Yeah me too. So you mentioned stopping eating at 7 and |
00:07:16 | there's a large number of people who advocate restrict not so much |
00:07:20 | necessarily tying it to a specific time but at least three to four hours before |
00:07:24 | you go to bed. I've been largely as a result of your exposure to your videos |
00:07:29 | was been fascinated by the NAD and his family, his cousins like NADPH. When I |
00:07:35 | started studying NADPH I realized that the biggest consumer of NADPH which is |
00:07:41 | a molecule that essentially is a battery cell and recharges your |
00:07:44 | antioxidants is fatty acid synthesis. So if you're eating shortly before you go |
00:07:52 | to bed that energy can't be consumed and it must be stored as fat and that's |
00:07:56 | going to really lower your NADPH levels which is not a good thing to do at night. |
00:07:59 | So I'm wondering if you have any thoughts on that timing of the last meal. |
00:08:06 | Yeah I do and I wish I could take some of my own advice and medicine. I think |
00:08:15 | if you can have a light meal at dinner a typical European dinner. My wife's German |
00:08:20 | she likes to eat small meals. That's great. I tend to snack at night so it's |
00:08:24 | my downfall but yeah to be able to have that fast overnight that'll boost your |
00:08:30 | energy levels up and NADPH as well. These are all good things they turn on the |
00:08:35 | enzymes that we study called the sirtuins. They need NAD to function and |
00:08:39 | you can use the whole night to ostensibly repair your body and protect |
00:08:45 | it from what happens during the day. I also I try to take a couple of |
00:08:51 | metformin pills for two reasons. One is that my family has a history of diabetes |
00:08:56 | and metformin is very effective at treating diabetes and even preventing it. |
00:09:01 | So I do that for disease reasons but also because the work of many labs has |
00:09:06 | pointed to not just animals but tens of thousands of people in clinical trials |
00:09:11 | benefiting from that drug which seems to enhance and mimic the benefits of |
00:09:17 | fasting. So you talk in your book about this concept of antagonistic |
00:09:22 | pleiotropy which is essentially multiple actions some of which may be |
00:09:27 | counter to the intended consequence of the intervention. So with metformin you |
00:09:32 | describe the benefits which is why you're taking it but you know there are |
00:09:36 | some studies published that show that it's a pretty potent mitochondrial |
00:09:40 | poison and that it really targets mitochondrial complex one and shuts it |
00:09:47 | it radically inhibits it so that you end result is you're producing a lot less |
00:09:53 | ATP. So yes it up regulates the APK but in your evaluation of the literature how do |
00:10:02 | you reconcile those two? Yeah so here's how I take the literature and there's |
00:10:05 | hundreds of probably even more thousands of papers that I've read on this topic. |
00:10:10 | Here's my summary but you know I'm a PhD and this is one man's opinion but what I |
00:10:16 | take away from it is that short-term exposure to metformin high doses yes it |
00:10:21 | will inhibit complex one and lower ATP. That's also true for as veritrol by the |
00:10:26 | way. What was in burperine too. Yeah right but it I regard it as hormesis a little |
00:10:33 | bit of what doesn't kill you actually makes you stronger and so the body |
00:10:37 | recognizing that there's low ATP levels and higher AMP levels will stimulate AMP |
00:10:43 | which is known to be beneficial and will actually compensate by revving up the |
00:10:51 | mitochondria and building more mitochondria in various organs |
00:10:57 | particularly the muscle of your body and so you know a little bit of inhibition |
00:11:02 | leads to a kickback and a compensation so that's why I think that actually |
00:11:07 | metformin is beneficial even though it starts out as a as long as you don't |
00:11:12 | overdose it a relatively mild mitochondrial inhibitor and you know |
00:11:17 | that in the history of humanity and in animal studies there's a long literature |
00:11:21 | of molecules that if you give a lot of high dose acutely it can actually kill |
00:11:27 | you but little doses as long as they don't do harm can have a positive effect |
00:11:34 | in the long run and you know this the same is true for fasting if you don't |
00:11:38 | eat we know what happens you'll starve to death you trick the body into |
00:11:43 | thinking times are tough without leaving a long lasting that any damage and the |
00:11:49 | body actually does better in the long run. Okay let's get into a really |
00:11:55 | important part of your book which is the balance between anabolism or the |
00:12:00 | building of muscle tissue and catabolism which is the tearing down and repair and |
00:12:04 | regenerate and repair of it so interestingly when you fast growth |
00:12:11 | hormone levels increase and maybe you can go into that because it's it's kind |
00:12:17 | of is somewhat counterintuitive because there's no nutrients available so why |
00:12:21 | would you think growth hormone would increase so maybe you can discuss that a |
00:12:24 | little bit in the in the influence on IGF-1. Right so so IGF-1 is something like |
00:12:32 | growth hormone and and growth hormone itself also in the short run don't seem |
00:12:39 | to be healthy at least in animal studies and also Nir Barzilai for Albert Einstein |
00:12:44 | College of Medicine has studied long-lived families centenarian families |
00:12:48 | and what he's found in particular to IGF-1 is that some families actually can |
00:12:55 | have high levels of IGF-1 but still live a long time and the reason for that is |
00:12:59 | that they they don't have the IGF-1 receptor that's as active. Is that |
00:13:05 | Laron syndrome? That's I understand that's the growth hormone as well so |
00:13:12 | it's similar no he's a he's a Ashkenazi Jewish family that has 100 |
00:13:16 | hundred year olds but it's a similar concept is that if you're not responding |
00:13:20 | to these hormones it doesn't matter really how much the body produces you |
00:13:24 | still have an effect that mimics essentially the benefits you want. It's |
00:13:34 | interesting actually that the growth hormone is stimulated by fasting there |
00:13:38 | must be something and I'm unaware of exactly why but we know that that |
00:13:44 | fasting doesn't lead to bigger animals it's actually the opposite so it could |
00:13:49 | be that and now I'm just speculating but I think it's worth discussing and |
00:13:52 | thinking about that these short-term bursts of hormones may help the body |
00:13:57 | recover from injury but those little spikes don't last long so that you're |
00:14:02 | not having any downside. The other thing about growth hormone and I know a lot of |
00:14:06 | people including viewers of this show will be wondering what about growth |
00:14:11 | hormone is it dangerous in the long run should I be taking it should I not? Now |
00:14:16 | now I haven't seen any evidence that growth hormone is going to make you live |
00:14:21 | longer typically it's the other way around that people who have a lack of |
00:14:26 | growth hormone activity live longer. The rotten dwarfs tend to have this disease |
00:14:32 | but in the short run if you need to repair your body and build up new muscle |
00:14:40 | which of course prevents falls and accidents in the elderly you know I'm |
00:14:44 | perfectly willing to entertain the possibility that that building up body |
00:14:48 | bulk and testosterone is the same will prevent these accidents that actually |
00:14:53 | largely are a problem for longevity there's a saying actually that the the |
00:15:00 | way to longevity the best way longevity is to hang on to the handrail and so |
00:15:05 | it's real trade-off it's a trade-off you know that if I was to summarize |
00:15:11 | everything that I've learned over the last 30 years it's everything in |
00:15:16 | moderation and and nothing don't do anything too consistently because it's |
00:15:23 | like a frog in a hot water bath or in a fry pan your body needs to be primed and |
00:15:29 | then allowed to relax and challenged and then allowed to relax and so these diets |
00:15:34 | and these growth hormone spikes I think they're good you just don't want them on |
00:15:39 | all the time because then your body doesn't have a chance to recover and you |
00:15:42 | don't get long-term benefits okay so tangenting off the elevation growth |
00:15:49 | hormone during a time-restricted eating fast of 16 18 hours or even a longer |
00:15:54 | fast many people believe that the optimal time to engage in resistance or |
00:16:00 | strength training might be right before you have your first meal so that you're |
00:16:04 | still fasting your growth hormone levels are activated and you'll get maximum |
00:16:08 | benefit from the anabolic stress of the exercise which of course is increasing |
00:16:12 | PGC 1 alpha mitochondrial biogenesis and a lot of other benefits that occur |
00:16:16 | during exercise so anybody caught any yeah yeah this is really good you're |
00:16:22 | talking about the cutting edge of thinking so people who are discussing |
00:16:26 | that idea I think are similar similar to the way I'm thinking about biology you |
00:16:32 | know again in the full disclaimer this is now we're discussing the cutting edge |
00:16:36 | of science so we don't know fully the answers to this what makes sense to me is |
00:16:40 | that we don't want too much protein in our lives we don't want to eat a steak |
00:16:46 | every meal because what we've learned through the work of David Sabatini and |
00:16:51 | many others in the field Matt Kaeberlein that at least in animals and it looks |
00:16:57 | like in people as well that inhibiting the mTOR pathway by having a lack of |
00:17:02 | amino acids certain amino acids is healthy and does actually lengthen |
00:17:07 | lifespan in animals but does that mean that you shouldn't eat protein absolutely |
00:17:11 | not there are times when eating protein is important same for probably |
00:17:16 | testosterone same for a growth hormone and then but now we're getting into the |
00:17:21 | nitty-gritty is if you are pulsing these things when do you do them together and |
00:17:26 | when you do them apart and to me and what you know let me talk about what I |
00:17:30 | do personally because that's that's actually a better way to approach the |
00:17:34 | discussion if I'm going to have a steak I try to be vegetarian but let's say |
00:17:38 | I'm gonna have a protein shake I'm gonna do that just before just after I've |
00:17:45 | exercised but then I'm gonna also have a period in the week where I don't have a |
00:17:49 | lot of protein and I might just have some salads and that's where I get my |
00:17:52 | protein so my body is going like this but it's not out of sync at times when |
00:17:58 | my body needs protein or for instance needs growth hormone so I think what |
00:18:02 | you're what you're saying is is really going to be the future that we can't |
00:18:08 | just say doing one thing constantly is the right thing to do and we have to |
00:18:13 | time these beautifully otherwise we're causing stress and damage but then |
00:18:21 | preventing the healing process by doing something else yeah well thanks I do |
00:18:26 | agree with you I think this is the cutting edge and a really an important |
00:18:29 | question that many of us are challenged with and especially in the fact that |
00:18:34 | you so well bring out in your book is we age you get beyond 65 our protein |
00:18:38 | requirements actually increase for a variety of reasons from about 1 to 1.2 |
00:18:42 | grams per kilogram and so the key is to cycle the suppression of autophagy by |
00:18:51 | not activating mTOR and not giving these calories in protein because protein |
00:18:56 | especially animal protein and branched chain amino acids will activate mTOR |
00:18:59 | almost universally but I'm I can just share my example I wonder what your |
00:19:03 | thoughts are on it because I have an 18 hour time restricted eating window that |
00:19:07 | I don't eat and once a week I'll extend that to 42 hours so I'll take a day off |
00:19:13 | so I do you think that that regular daily eating window of six hours |
00:19:18 | combined with a weekly one day full fast is enough to activate autophagy and |
00:19:26 | suppress mTOR and not get the downsides of continuous mTOR activation yeah it |
00:19:33 | doesn't it doesn't make sense to me people haven't even done this in animal |
00:19:38 | studies yet people need to do that but scientifically it makes sense to me that |
00:19:44 | being hungry a little part of the day will will activate turn on NAD you'll |
00:19:50 | get it in mTOR inhibition and amputinase will come on but probably the way I'm |
00:19:55 | doing it which is not as diligent as you Joe I'm only doing this kind of a level |
00:20:03 | of reset and I think it's good but it's not perfect what we really want to do is |
00:20:08 | this and then BAM really get a big reset and start showing up the the |
00:20:15 | misfolded proteins get the autophagy going get the sirtuins to go repair |
00:20:19 | everything in the cell that they possibly could and so I think that's |
00:20:23 | right that a little bit of stress every day and a lot of stress once in a while |
00:20:29 | is a great combo but I think that that would be something to actually study I |
00:20:33 | might have any I haven't seen these studies on it either I'm hoping someone |
00:20:38 | this process of doing those who's really like the answers but and I guess |
00:20:43 | there's the where the technology is advancing where we'll soon be able to |
00:20:47 | measure metabolites more easily than in the research lab and by doing so get an |
00:20:53 | indication of what might be the best strategy now in your book I was so happy |
00:20:59 | when you started discussing lysine which is the shortest amino acid that we have |
00:21:04 | and it's a very important one and it actually I think it may be the most |
00:21:10 | common I think it's about 11 11 to 12 percent of the total amino acid content |
00:21:16 | in the body and most of us I mean you didn't glycine ingest and didn't used to |
00:21:21 | be an issue because we ate connective tissue and glycine is loaded in collagen |
00:21:26 | so third of the proteins in collagen and connective tissue are glycine so it |
00:21:30 | didn't used to be an issue but we're not eating connective tissue much anymore so |
00:21:33 | unless you're consuming bone broth or collagen supplements you're not getting |
00:21:37 | it so why don't you talk about the importance of glycine especially with |
00:21:40 | fructose consumption that's so rampant in the United States and the advantage |
00:21:43 | of doing it especially with the glycine the thionine ratio well so the reason |
00:21:50 | that I take glycine actually specifically trimethyl glycine is is |
00:21:56 | actually to counter what I think might be going on with an NAD booster I'm |
00:22:02 | certainly not an expert in glycine other than that but I can talk about the |
00:22:07 | trimethyl glycine component if you'd like sure yeah so this is a big question |
00:22:12 | in my field so just to take a step back my field and a lot of what my book is |
00:22:18 | about is being able to trick the body into being hungry and having exercise |
00:22:23 | and one of the molecules that does that is NAD NAD stands for nicotinamide |
00:22:30 | adenine dinucleotide and we have it in our body as we exercise that we get |
00:22:34 | hungry it goes up as we get older it goes down and it's needed for life it's |
00:22:38 | also needed for turning on these defensive enzymes that we work on |
00:22:41 | concert to us now to raise in a d levels what we've done in my lab to mice for |
00:22:47 | the last decade is we give them precursors to NAD so we give them |
00:22:51 | molecules like nicotinamide riboside or NR or nicotinamide mononucleotide also |
00:22:58 | known as NMN not to be confused with M&Ms the opposite effect and so NMN is |
00:23:06 | is what I take each day I take a gram of it but the thing with nicotinamide |
00:23:11 | mononucleotide NMN is that it it has this nicotinamide group on it it hangs |
00:23:16 | off the the main part of the chemical and it's the first bond to break and so |
00:23:20 | we see in animals and even in humans that the levels of nicotinamide go up |
00:23:25 | quite rapidly after taking NMN or NR and to look to high levels of |
00:23:31 | nicotinamide are not good in part because the nicotinamide gets excreted |
00:23:37 | through the kidneys and it's done so that happens because it becomes |
00:23:42 | methylated into methyl nicotinamide and methyl nicotinamide being used for for |
00:23:47 | years as a marker of all sorts of things including at least experimentally for |
00:23:52 | Parkinson's disease but the concern that's that's being talked about in |
00:23:58 | social media especially is is this drain of methyl nicotinamide a problem the |
00:24:03 | methyl groups are are needed for the body we need methyl for a whole range of |
00:24:08 | things including antioxidants and so as a precaution I take trimethylglycine so |
00:24:14 | that I continue to give my body a source of methyl groups now I don't know if |
00:24:19 | that's true people ask me all the time I take as a precaution because I know |
00:24:24 | that trimethylglycine is not going to hurt me glycine is good as a joke and |
00:24:29 | the other thing is methylglycine is also known as betaine which on human cells is |
00:24:34 | very good for them including protecting them against first so I don't see any |
00:24:40 | downside it's not an expensive molecule and the upside is that I'm preventing my |
00:24:44 | body from being drained of methyl groups but the reason that I can't say for sure |
00:24:48 | that it's necessary actually is that our bodies can make methyl groups there's a |
00:24:53 | whole pathway in fact I did a PhD on it when I was in Australia 30 years ago but |
00:24:59 | so I do take it as a precaution knowing that it's probably not doing anything |
00:25:04 | except goodness my boy great have you looked at methyl cobalamin or methyl |
00:25:11 | folate as a I have I have actually and I think those are interesting too I |
00:25:15 | couldn't say which is better in fact because nobody has studied it but those |
00:25:19 | are those are options to they're actually I've seen companies selling |
00:25:24 | those vitamins with methyls on them and those are vitamins that I think are |
00:25:28 | worth taking as well um so those are options I think you know like all |
00:25:34 | professors we like to say we need more studies before we know for sure but with |
00:25:39 | in the absence of studies I think those options are the best right now so thank |
00:25:45 | you for bringing up the topic of NAD one of my favorites for sure and I want |
00:25:49 | to express my deepest gratitude for you for helping inspire me to understand the |
00:25:54 | importance of this molecule I first recognized it when the importance of it |
00:26:00 | because of course we're taught in any biochemistry class when I watched one of |
00:26:05 | your videos four years ago but as I understand NAD was discovered about |
00:26:09 | almost a century ago by Otto Warburg but it only recently became to be |
00:26:15 | deeply appreciated as a fundamental strategy for all of health and longevity |
00:26:19 | I mean it's it's a coenzyme in over 500 metabolic reactions in the body so I'm |
00:26:24 | wondering from your perspective what do you believe was the catalyst for the |
00:26:29 | reemergence of the prominence of NAD and longevity well I'd like to think it was |
00:26:34 | work that I was doing with Lenny Guarente at MIT that's what I thought |
00:26:38 | and I set me up for but I guess you know that's what I actually put in one |
00:26:43 | of my new books is acknowledging you as the is really the catalyst for that well |
00:26:48 | it was a team and I'm not just being coy about that we we landed at the right |
00:26:52 | place at the right time we discovered genes that control aging in yeast cells |
00:26:57 | ironically that's where NAD was first discovered and I would argue that if |
00:27:02 | yeast weren't making alcohol we probably wouldn't have discovered NAD for a long |
00:27:05 | while but yeah the Germans just didn't discover NAD and we learned in high |
00:27:10 | school that NAD is essential for all these reactions so we knew that but what |
00:27:14 | we didn't realize until the late 1990s was that the levels of NAD in organisms |
00:27:19 | such as yeast and in our bodies as well they're really dynamic it's not just |
00:27:25 | that it's a housekeeping molecule keeping us alive during the day it's |
00:27:28 | going like this and in a yeast cell it's going like this and that was a shock |
00:27:32 | because first of all anything that's that important you think how can it go |
00:27:37 | up 50% or 100% during the day without killing us turns out it does and it's |
00:27:42 | actually very helpful and the reason that we think it goes up and down is NAD |
00:27:47 | isn't just making chemical reactions happen but there are proteins that sense |
00:27:51 | the amount of NAD in the cell and when times are tough we're hungry or we've |
00:27:57 | exercised NAD levels will actually go up and turn on these defenses and that's |
00:28:03 | why when you take a molecule like NMN or give an NMN to a mouse what we |
00:28:08 | think is happening is that you're tricking the body into thinking that |
00:28:13 | it's exercise or that it's hungry because the NAD levels will go up so you |
00:28:17 | get the benefit the protective benefits of these without actually having to |
00:28:21 | necessarily exercise or diet but if you're if you're wondering is it is it |
00:28:26 | fine just to take the pill and sit on the couch and eat potato the answer is |
00:28:31 | probably not we I mean in full disclosure we have published that |
00:28:36 | resveratrol and NMN that work through similar mechanisms do make mice |
00:28:41 | healthier even if they're fatter and don't exercise but here's the important |
00:28:45 | thing for those who want to maximize their body's potential maximize their |
00:28:49 | life we find that the combination of low calorie diets and these NAD boosters |
00:28:56 | or in the case of resveratrol we showed has a doubling effect they're actually |
00:29:01 | additive and so it's not no excuse just to sit around and just pop a pill okay |
00:29:06 | well I think you're right on I think that the optimizing in and most people |
00:29:13 | increasing NAD levels because it goes down pretty radically as you age to the |
00:29:18 | point where once you reach 80 I mean it's almost it's like now most not |
00:29:23 | there a radically decreased for at a minimum so you had mentioned NMN and |
00:29:29 | NRS precursors as one strategy to increase it but I'd like to discuss some |
00:29:33 | other options first is the actually the NAD molecule itself NAD plus which is a |
00:29:39 | charge molecule and if you swallow it it will not work at all as the success of |
00:29:43 | except it's being metabolized to its precursors and reconstituted but it can |
00:29:48 | be given parenterally either IV subq or transdermally and there's been a lot of |
00:29:54 | dispute in literature I'd like to get your view on it but a good friend of mine |
00:29:58 | who actually was just here last weekend James Clement who speaks very highly of |
00:30:01 | you by the way has doing a lot of research in NAD also and uses nitty |
00:30:06 | Brady's lab out in New South Wales to actually measure it and from his analysis |
00:30:10 | he finds that well first of all the NAD does seem to enter the cells and |
00:30:14 | there's a transporter which I didn't know about until he told me which is |
00:30:17 | connection 43 that substantiates the the strategy of using NAD plus itself |
00:30:25 | rather than an intermediary or precursor and we'll talk about some of the other |
00:30:28 | precursors there's more than just those that we're mentioning but you know it's |
00:30:34 | it's James assessment that the transdermal battery patch applied maybe |
00:30:38 | once or twice a week might be an optimal strategy to to improve it and you know |
00:30:43 | and he's documented by NAD mass spec measurements at Brady's lab so I'm |
00:30:48 | wondering what your thoughts on that right well so there are a variety of |
00:30:53 | ways to raise NAD and this list is not exhaustive but I'll talk about what |
00:31:01 | ones we know of that have been really tested it's fairly extensively so you |
00:31:07 | can raise NAD levels just by taking nicotinic acid or niacin and so niacin |
00:31:15 | has been used for decades to lower cholesterol and the only side effect is |
00:31:20 | flushing you feel a little bit warm there are slow release versions that |
00:31:26 | will raise NAD and actually there are some of us myself included that are |
00:31:30 | entertaining the possibility that the benefits you get are in part because it |
00:31:35 | also raises NAD but in head-to-head studies that I've read niacin won't |
00:31:42 | raise in 80 levels the way some of these other molecules do and I think the |
00:31:48 | reason is that niacin is just a tiny part of the NAD molecule and so you know |
00:31:55 | let me think of an analogy it'd be like saying I can build a house out of bricks |
00:32:00 | but if you don't bring the mortar and the windows and the doors and the roof |
00:32:06 | it's gonna be a lot harder and so the windows and the roof come in with |
00:32:13 | molecules like NR which is nicotinic riboside and NMN which is NR but with a |
00:32:20 | phosphate group added so now you've got more of the house built and you're |
00:32:25 | almost at NAD and so we're getting closer and so there's there's a debate |
00:32:33 | it's it's a bit of a silly debate which is better NR or NMN. In mice I can tell |
00:32:38 | you that that both work well to improve the health and the lifespan of mice |
00:32:45 | we've done a lifespan of NMN we haven't we're repeating it looks good NR is |
00:32:51 | published that it extends the lifespan of old mice so they're both great it's |
00:32:55 | really I think it's semantics to say that one is you know ten times better |
00:33:01 | than the other it's just not not the case they both get into cells there are |
00:33:09 | transporters for NR there's a new newly discovered transporter for NMN. |
00:33:13 | Ah that must have been the last few months I have not seen that. Right yeah |
00:33:17 | so it came out of Dr. Shin Imai's lab at Wash U Medical School and I wrote a |
00:33:24 | News and Views article on it it looked really convincing what we don't know |
00:33:29 | though is is this transporter in all cells or is it just in the gut and so |
00:33:36 | you know that remains to be seen but it that it really doesn't matter it's |
00:33:42 | it's irrelevant we can talk about transporters all day what really matters |
00:33:46 | is do you see health benefits and do you see NAD levels going up and I guess the |
00:33:52 | third important thing is are there any side effects or negative side effects I |
00:33:57 | haven't seen any negative side effects and I've certainly seen niacin NR and |
00:34:01 | NMN raise NAD levels and provide health benefits and as I mentioned NR and NMN |
00:34:08 | seem to be better than niacin. Well niacin does have problems there's no |
00:34:13 | question niacinamide even more as you well know and you've done the research |
00:34:17 | actually I think your lab showed this is that the niacinamide actually inhibits |
00:34:22 | sirtuins through a negative feedback loop. I'm impressed you've done your |
00:34:28 | reading. Yeah I've studied this I told you you really inspired me I mean I've |
00:34:33 | read hundreds of studies about this and that was one of them so the but the |
00:34:38 | niacin high doses is not without side effect aside from the flushing that you |
00:34:43 | mentioned which is actually a liberation of histamine from mast cells it |
00:34:47 | radically consumes methyl groups so not a good idea to take high dose niacin but |
00:34:54 | I've concluded and I might be wrong here I'd be interested in your thoughts and |
00:34:57 | then we'll go into the details dive deeper into the NR and NMN of taking a |
00:35:04 | very small dose of niacin 25 to 50 milligrams which shouldn't suck up too |
00:35:08 | many methyl groups but yet still can contribute to the at least a normal |
00:35:14 | human at least as I read about the 90 milligram loss of NAD plus per day |
00:35:19 | because we've got nine grams in our body but we recycle 99% of it so that niacin |
00:35:24 | is really only good for the salvage pathway so what are your thoughts on 25 |
00:35:27 | to 50 milligrams maybe twice a day because the half-life of NAD is about 12 |
00:35:31 | hours to use that as an augmentation strategy to the pre other precursors or |
00:35:39 | itself well so there are two ways to think about one is can you stimulate the |
00:35:46 | body to make more NAD because it is recycled and the other is which which |
00:35:53 | would I focus my thoughts on more which is if we give the the cells so much |
00:36:02 | precursor they have no no alternative but to put it into NAD and I think that |
00:36:08 | those two ways of thinking are your way in my way are guiding what we do I think |
00:36:15 | it's possible that low doses of nicotinic acid could stimulate the body |
00:36:21 | and force the cell to make more than it otherwise would but it would have to |
00:36:27 | make more than it otherwise would because the amount of NAD in your body |
00:36:31 | is you know it's in the gram amounts so milligram amounts are probably not going |
00:36:36 | you know by mass action push it up well that was one of the things that |
00:36:41 | discouraged me from even considering it as a practical strategy because there's |
00:36:44 | scrams in it so what it didn't make sense to me why taking milligrams of |
00:36:48 | something would be benefit but there appears to be a benefit let's could use |
00:36:52 | I'd be curious how that works so you know what my guess would be that you |
00:36:56 | know I'm gonna test it because James Clement has developed this elegant |
00:37:00 | blotter strategy where you can can essentially pipette a dropper to a blood |
00:37:06 | on a blotter freeze it and he's getting a mass spec in his lab and he's going to |
00:37:10 | be able to measure it so I'm gonna do the test this fall and and see if it |
00:37:14 | makes a difference I mean I just don't know it's just theoretical at this point |
00:37:17 | yeah well when it comes to NMN which we've studied for a lot and there are |
00:37:22 | studies on NR in humans and I've seen insights into NMN in humans as well |
00:37:26 | though that work isn't yet published I what can I reveal I can reveal that that |
00:37:34 | taking doses say less than 250 milligrams don't have a big effect on |
00:37:40 | NAD in the blood that would make sense you do have to take high doses but it's |
00:37:46 | complicated by the observation that a single dose won't have a big long-lasting |
00:37:53 | effect anyway we see that in mice as well you take one hit of NMN it'll go up |
00:38:00 | maybe go about 50% and it'll quickly die die away in levels but what's |
00:38:05 | interesting in the mouse and the human studies is it's more like a positive |
00:38:10 | stock market where over a period of in the case of the NR study that I'm |
00:38:16 | thinking of after nine days it was an accumulation up to a certain level and |
00:38:22 | so if a study has only done a one time point in a human or in a mouse be |
00:38:27 | careful because that's probably misleading and that you know you want to |
00:38:32 | measure these things after at least nine days and hopefully after a few months |
00:38:36 | where any of maybe Joe that those low doses actually start to kick in yeah |
00:38:41 | what do you think the optimal dosing strategy is every 12 hours or three |
00:38:45 | times a day well you know that's also not known and I probably know more than |
00:38:51 | most people on the planet I don't know that's what I'm asking yeah so what do I |
00:38:56 | do I take a bolus in the morning I take a gram in the morning I know a gram is |
00:39:00 | likely to be raising my energy levels during day I also try to time it with my |
00:39:05 | natural circadian rhythm so NAD will go up during the morning getting ready but |
00:39:12 | if I take it at night what I find is that I'm actually starting to interfere |
00:39:19 | with my sleep patterns interesting yeah and a lot of people have told me that |
00:39:23 | that's the case as well with resveratrol as well it actually makes sense there's |
00:39:27 | a few science papers on this about sort one which is the target one of the NAD |
00:39:34 | requiring enzymes that we study so so one is also its activities cycling |
00:39:39 | through the day with NAD turning on genes are required for morning activities |
00:39:46 | at night clearing the brain at night you think if you get those out of kilter I |
00:39:51 | mean it makes sense that you will not only affect your body's metabolism find |
00:39:58 | it hard to sleep but you could even start to have the effects of jet lag |
00:40:02 | inadvertently I'd like to think that by taking the NAD boosters when I'm |
00:40:08 | traveling I'm actually resetting my body's clock and I do find you know for |
00:40:13 | me in my experience I do feel better if I reset my clock with an NAD booster |
00:40:18 | when I arrive at in a new time zone so how does that reconcile with the fact |
00:40:25 | that NAD plus levels increased by about 30% at least that's what I've read in |
00:40:29 | the literature once you're fasting so you know I'm just trying to reconcile |
00:40:34 | that in fact that you're having challenges with NAD plus at night |
00:40:38 | because of a sleep in effect yeah well so I'm I don't think anyone's done it |
00:40:46 | 24-hour time course of any in people in mice we do know that it's cycling |
00:40:53 | through the day you know let's see we're right on the cutting edge here you know |
00:40:59 | you have a choice you can take it at night or in the morning and I think that |
00:41:09 | probably what's happening is if I take it just before I go to bed my body's not |
00:41:16 | in a fasting state yet it's still got you know my dinner is still in there and |
00:41:21 | so it's a it's mimicking fasting it's raising in 80 levels just when it should |
00:41:25 | should be starting to to tailor off I think probably what's happening Joe's |
00:41:30 | now I'm thinking out loud is towards the early morning your NAD levels are going |
00:41:35 | to start coming up because that's when your stomach's empty and you've absorbed |
00:41:39 | a lot of nutrients overnight as it's coming up towards you know waking up and |
00:41:43 | early morning that's when I provide my boost okay catch it on the rise |
00:41:50 | certainly a rational approach and then I try not to eat till lunch so I get that |
00:41:54 | big spunk okay I want to dive in the weeds now on NMR and NMN and NR I had a |
00:42:02 | chance to attend a lecture by Charles Brenner earlier this month and talked to |
00:42:07 | him afterwards and because many people use NR not as many NMN but most of the |
00:42:16 | studies done on at least NR I haven't really reviewed much of the NMN |
00:42:20 | literature but the NR it's usually perennially it's intraperitoneal or IV |
00:42:27 | it's not orally I mean there's some but it's not a large amount of them are done |
00:42:31 | orally so and and the problem with it is as I understand is that when you swallow |
00:42:35 | NR and and this has some implications for NMN too that the first bypass it |
00:42:42 | goes through the liver and the liver methylates it so the liver gets plenty |
00:42:46 | of NAD plus but you know the the amount that goes to other organs seems to be |
00:42:52 | pretty diminished which suggests to me that a either a perennial or |
00:42:58 | transmucosal approach might be a superior delivery method so which is one |
00:43:03 | of the reason and I asked Brenner this after his presentation what he thought |
00:43:07 | about transmucosal delivery and he said he doesn't know he thought about it and |
00:43:10 | I told him that I was using rectal NR suppositories that I make myself and |
00:43:16 | he thought the compliance with that would be pretty horrible but I suspect a |
00:43:20 | similar story is with going with NMN and I'm wondering what your thoughts are on it. |
00:43:25 | Well so we're doing the experiments that are required to actually conclude |
00:43:32 | provide answers to those questions we don't know okay so what is the answer |
00:43:37 | but but the experiments that are ongoing in my lab also in Anthony Sauve's lab in |
00:43:42 | Cornell we we have labeled molecules labeled NMN we're giving that initially |
00:43:50 | to animals and mice eventually we could do humans as well and those are the |
00:43:56 | studies you need to be able to say yeah NMN's going straight into cells or is it |
00:44:01 | getting modified it's early days we think that it's a lot of it goes |
00:44:06 | straight in contrary to what people are gossiping about but you know we have to |
00:44:11 | do the hard science I don't think it's good to just hand wave and say |
00:44:14 | conclusions that aren't yet justified without the hard science. |
00:44:18 | Fair enough. |
00:44:19 | On the NMN side you probably noticed from the literature that we typically put NMN in |
00:44:25 | drinking water. |
00:44:26 | Yeah, because it's a water soluble. |
00:44:28 | Yeah, so it's very soluble but it's also more stable than NR in liquid. |
00:44:32 | So we have the advantage that we can do that. |
00:44:35 | NR in liquid is highly unstable and that's probably the reason that it's not done typically. |
00:44:42 | That way. |
00:44:43 | You know but that said, we don't know what happens in the microbiome when it's ingested |
00:44:50 | either are those bacteria utilizing it converting it is it different between people's microbiomes |
00:44:56 | we all have different microbiomes and that's the exciting part of the research now is to |
00:45:01 | figure out once you put one of these molecules into the system where does it go where are |
00:45:06 | the best effects and these are important because it'll guide not just the use of the |
00:45:12 | molecules in daily life as they are now solder supplements but what I'm focused on is making |
00:45:21 | molecules that will be drug like and used as drugs that could treat different diseases |
00:45:26 | and if one molecule is better for liver one molecule is better for muscle one gets into |
00:45:31 | the brain if there are ways we can tweak the molecule and change one atom to make it |
00:45:35 | last for two weeks instead of two hours that's the exciting future that I see and that's |
00:45:43 | what I spend most of my time on. |
00:45:47 | I'm not I mean in full disclosure everyone should know even if you see my name on a website |
00:45:51 | I have no affiliation to any supplement company I'm trying to do the science and stick with |
00:45:57 | clinical trials only at this point. |
00:45:59 | So you have no financial interest in NMN? |
00:46:02 | No well yeah I have biotech companies that I'm an advisor to and have licensed patents |
00:46:09 | to the chance that I'll see money out of that's pretty low most biotechs fail so I'm not driven |
00:46:16 | by that but I've never received a cent from supplements and you know one of my patents |
00:46:22 | was licensed to a company once and I said I want that money to go to research in my |
00:46:27 | lab instead I just think it's better for me Joe because I want to be able to maintain |
00:46:34 | sure the distance and be able to just talk about the science with some credibility. |
00:46:38 | Absolutely yeah I heard your podcast with Peter Ortea and you went into that great detail |
00:46:43 | and there are a lot of claims being made that you're recommending a specific NAD supplement |
00:46:49 | and if you see a claim like that it's it's not true it's false and you spend a good portion |
00:46:53 | of your resources to send cease and desist letters for those so I'm sorry you're going |
00:47:00 | to have to go through that but I want to get back to just finish up NAD and we're going |
00:47:04 | to go into sirtuins and then gene editing. |
00:47:08 | Do you I just did you didn't mention any thoughts on the IV or subcutaneous or transdermal NAD |
00:47:14 | plus itself the entire whole NAD molecule though the you know that you're using the |
00:47:18 | precursors to create and with the transporter of connexin 43 being there and lots of anecdotal |
00:47:26 | evidence especially in those with substance abuse getting benefits from these these strategies |
00:47:30 | I'm wondering what your thoughts are on the whole molecule being given. |
00:47:34 | Yeah well you know I'm the kind of scientist I don't have an ego in this if someone can |
00:47:39 | show me data that's reproducible and reproduced in other lives you know I'll take it on face |
00:47:44 | value and so I've heard the anecdotes on NAD and that's it seems like there's so many |
00:47:51 | stories out there that you know there's something there what I'd like to see is just like I'm |
00:47:56 | doing with NMN you know doing rodent studies and like James is doing James Clement doing |
00:48:05 | human studies and ultimately putting these molecules head to head yeah it's really it's |
00:48:13 | can get a little annoying when you know Dr. X says this and Dr. X says that. |
00:48:18 | Right right because you got to have data to back it up. |
00:48:20 | Yeah I mean show me them head to head yeah that's the only way I don't care what your |
00:48:25 | opinion is show me the data so that that'll be the ultimate test the problem is that these |
00:48:30 | trials are really expensive and typically doing one molecule is hard enough but doing two in |
00:48:35 | parallel is hard even in a mouse study we don't typically do that but that's where we need to go |
00:48:41 | to be able to to be able to say which is the best it really wouldn't surprise me if NR and NMN's |
00:48:48 | NADID are all beneficial in slightly subtle ways. |
00:48:56 | All right well thanks for that and I hope to with James do some of this research this year |
00:49:01 | and maybe this fall share some of that data with you so that we can have some hard science to back |
00:49:06 | it up. Now I want to shift to sirtuins which are essentially protein environmental stress |
00:49:13 | sensors that are responsible for longevity longevity proteins in simpler terms and |
00:49:19 | I guess they were discovered in yeast as SIR which is silent information regulators |
00:49:26 | and it suggests they work by suppressing DNA expression and this is typically done by |
00:49:34 | deacetylating the DNA and other proteins. Now you did not discover resveratrol but you clearly |
00:49:43 | your lab identified its effect on SIRT1 one of the seven important sirtuins in humans |
00:49:49 | so resveratrol happens to to be one of the polyphenols that do it but are you familiar |
00:49:57 | with any other polyphenols like quercetin or fisetin that have shown to have some impact and |
00:50:03 | I want to discuss about some of the derivatives of resveratrol that you might be working on. |
00:50:09 | Well yeah you've come to the right person to talk about that. So resveratrol was already |
00:50:14 | known as what's called a phytoalexin it seemed to have antioxidant properties and was even |
00:50:21 | thought at the time to be responsible I think some people still believe it's responsible for |
00:50:25 | the French paradox where the French apparently can eat fatty foods and have great cardiovascular |
00:50:31 | health on average. So that was all there in the late 80s. I came along well you know the mid 90s |
00:50:40 | probably was the was the real thing when 60 Minutes did a story on it. So I came along in the late |
00:50:46 | 1990s or 2000s and we weren't looking at resveratrol in fact I'd never heard of resveratrol when we |
00:50:51 | started working on it. The story goes like this it's a pretty funny story. We had purified the |
00:51:01 | SIRT1 enzyme from humans and we were looking in collaboration with a company called Biomole |
00:51:08 | and the lead scientist there was Conrad Howards he deserves a lot of |
00:51:11 | credit for this. We were looking for molecules that would inhibit the enzyme and it was a |
00:51:17 | collaboration and we were sharing stories and results and Conrad calls me one day and he says |
00:51:24 | are you sitting down? I went I am sitting down what's up? And he goes we've got these strange |
00:51:28 | molecules that may activate the enzyme and then I that that was of course music to my ears because |
00:51:35 | we didn't know that NAD could be used at that point we were just on the verge of discovering |
00:51:40 | that. But what we did know that was that we wanted to activate these enzymes because they're |
00:51:45 | beneficial. We knew in yeast and in worms that if we put and in flies if you put extra copies of the |
00:51:52 | SIRT2 and gene they would live longer so we wanted more more goodness. But finding activators |
00:51:59 | of enzymes is extremely rare I think there's only a few examples in the whole history of |
00:52:04 | pharmaceutical development and when you find one typically people call BS on you. But here was |
00:52:10 | Conrad saying that we've got something. So we tested it in the lab and we could repeat his |
00:52:15 | results yes it was an activator. But to really show that it was true we had to put it on some |
00:52:22 | yeast cells and on some human cells and we did that and we found that it extended their lifespan |
00:52:29 | in the case of yeast and in the case of human cells protected them. And you needed the SIRT1 gene |
00:52:35 | for that to work so it wasn't just an antioxidant effect it was actually through the same |
00:52:40 | mechanism that we were hoping it was. But you asked Joe about these other molecules. Well we |
00:52:46 | tested with Conrad well we screened about 18,000 of them and published 21 activators in that first |
00:52:55 | paper in Nature Journal 2003. Now resveratrol was the best one we had at the time and it got the |
00:53:02 | most attention because the red wine story was pretty funny and interesting to the media. But |
00:53:08 | there are there were others that were very close to resveratrol in structure and in potency. You |
00:53:14 | mentioned quercetin, fazetin, or vicetin. These are plant molecules as well. They're all produced |
00:53:23 | in response to stress when the plants are stressed dehydration or UV light and they seem to have |
00:53:29 | benefits on organisms when we consume them. Interestingly what has later been discovered |
00:53:35 | though rarely acknowledged is that these same molecules work on killing senescent cells. You |
00:53:40 | know that your viewers will know of senescent cells the zombie cells that accumulate in our |
00:53:45 | body and cause havoc. Now others have shown that quercetin, gyncroclin, and others have |
00:53:51 | senolytic properties same with fazetin. But what's not recognized typically or admitted is that these |
00:53:58 | molecules were discovered 15 years ago to also be SIRT1 activators. So I thought so. Yeah so it's |
00:54:04 | really interesting. Now what I think is going on is evidence for a hypothesis that Conrad Howitz |
00:54:12 | and I came up with which we published in Cell I think it was the year 2005. Anyway the idea is |
00:54:20 | called xenohormesis. X-E-N-O-HORMESIS. And it's the idea that we've evolved to sense our environment |
00:54:27 | and molecules that are produced by plants and bacteria in our environment when they're stressed. |
00:54:33 | If we consume those or put them on our skin for example our bodies will recognize those. We've |
00:54:38 | evolved to sense our world around us. And that's a very good way of getting a heads up if your |
00:54:43 | plants are running out of nutrients or the water table is drying up. And you know before we were |
00:54:49 | conscious and we had brains this was the best way for a worm or a fly to know that times were |
00:54:56 | probably going to deteriorate. And what you want to do is get ready for those times of adversity |
00:55:01 | before they actually happen. And so that can explain why so many molecules from the plant |
00:55:08 | world have given rise to medicines and why some molecules like resveratrol and quercetin, fazedin, |
00:55:14 | even aspirin have remarkable health benefits and target many different enzymes in the body. |
00:55:20 | That seems to be well beyond what coincidence could explain. Interesting. So there is probably |
00:55:28 | not a better person in the world to ask this question to but you so eloquently describe |
00:55:33 | sirtuins as environmental stress sensors. And when I heard that description it immediately |
00:55:40 | occurred to me that that's very similar to heat shock proteins, almost identical. |
00:55:45 | And heat shock proteins of course for those who don't know are really important to fold your |
00:55:51 | proteins back to the right conformation so they work properly. And I'm wondering if there's any |
00:55:56 | similarities or am I just making this thing up? Yeah I want to quickly look at the literature |
00:56:03 | because I recall that there were connections between sirtuins and heat shock proteins. I |
00:56:07 | can't remember which controls which but they're connected. But in principle you're right Joe that |
00:56:14 | this is all evidence of hormesis that you can stimulate the body's ability to |
00:56:19 | fight against problems. So it's thought that a little bit of heat, even a little bit of cold, |
00:56:26 | a little bit of hunger, some exercise, some hypoxia, lack of oxygen in your body. These are all ways of |
00:56:33 | activating these defense pathways. The same pathways that we've talked about before such as |
00:56:38 | sirtuins, there are seven of those which by the way NAD and resveratrol will both activate. |
00:56:46 | Just to recap the mTOR which lower amino acids particularly leucine and arginine and the AMP |
00:56:52 | kinase pathway so metformin and inhibition of complex one. So these are the main three |
00:56:58 | defensive pathways. There are others but what's downstream of these pathways are things like heat |
00:57:03 | shock proteins and transcription factors that turn on DNA repair enzymes. There's a whole litany |
00:57:09 | actually that there's a thousand papers per year on what are these sensors as we call them, what do |
00:57:16 | they do downstream and here's the good news actually. We used to think that we had to |
00:57:22 | understand what everything those sensors do to be able to understand aging and be able to live |
00:57:28 | longer but what I've been arguing actually for many years now is that we don't need to fully know what |
00:57:33 | they do. Heat shock proteins are great, definitely part of it but we don't need to know everything. |
00:57:38 | As long as we can find the right nodes in the cell to turn them on in the right ratios at the right |
00:57:44 | time, the body has evolved to take care of the rest and we're getting to the point fortunately, |
00:57:49 | it's been really remarkable to see where we know what these nodes are, we have the tools to tweak |
00:57:55 | them, we can also change them naturally by fasting and exercising, we change them with molecules that |
00:58:00 | we can ingest or inject but now the cutting edge is now with this toolbox when do you apply them |
00:58:08 | and how much and in what combinations and that's really what people like myself and you and and |
00:58:14 | your listeners are on to right now. Okay, I want to go back to NAD for a moment because there's an |
00:58:20 | important component that I neglected to discuss with you and that is another strategy for increasing |
00:58:26 | NAD plus levels is to not use it as much and from my review of the literature one of the primary |
00:58:33 | consumed, well there's two primary ones, the inside the cell would be PARP, poly ADP ribose polymerase |
00:58:39 | which is a DNA repair enzyme and it really designed to repair DNA breaks single and double |
00:58:44 | stranded and every time you have a break it's my understanding that you the PARP will take |
00:58:50 | suck out 100 to 100 ADP out of 100 to 150 NAD molecules and basically deplete your level by |
00:58:57 | that much for every break so and then you've got TD38 for extracellular consumptions which |
00:59:03 | has to do with the immune system but I'm wondering what your thoughts are on lowering PARP |
00:59:09 | activation and real common not widely appreciated but what I'm passionate about is really topic of |
00:59:17 | my next book is EMF exposure. I mean it's pretty well documented in the literature that I've reviewed |
00:59:22 | that it does activate PARP and decreases NAD level so in my view if you could limit that exposure |
00:59:29 | because you're not decreasing increasing consumption you're going to by default |
00:59:33 | increase NAD levels. Yeah right well yeah this is a really interesting topic that and I could |
00:59:40 | talk all day about it. So PARP enzymes you're right there's DNA repair protein the problem is when you |
00:59:47 | hyperactivate this protein there's PARP1, there's PARP2, there's actually more than 14 different |
00:59:53 | PARPs. They do drain NAD quite effectively in fact in my lab we've discovered another PARP that |
00:59:59 | when you have inflammation it drains NAD as well so it does make sense to slow them down as you're |
01:00:07 | mentioning in some cases inhibit them but you have to be really careful because you do need them. |
01:00:13 | We only why would you want to inhibit them because why would you want to inhibit DNA repair? |
01:00:17 | Well you wouldn't but you want to inhibit their overuse of NAD. Right by decreasing these |
01:00:24 | insults that would cause them to be activated. That's the best way right because then you get |
01:00:28 | the benefits of low DNA damage and the benefits of high NAD. We had a science paper in 2013 that |
01:00:34 | connected all of this together that the sirtuin gene or the sirtuin enzyme this sort one we've |
01:00:40 | talked about actually controls PARP activity and PARP1 is normally inhibited by a protein called |
01:00:48 | DBC1 and then sirtuin one controls that process and long story short you want to activate PARP |
01:00:58 | but not too much and so that's what we think is going on here this fine tuning but actually to |
01:01:03 | get to what's really more interesting I think is how do you keep your levels of DNA double |
01:01:07 | strand breaks to a minimum and I think that's the key one of the main keys to longevity |
01:01:15 | and there's two reasons one you mentioned which is that double strand breaks drain NAD. |
01:01:21 | The second which I think you're going to be familiar with because you've read my upcoming |
01:01:27 | book is the idea that DNA double strand breaks also disrupt the cell's epigenome the storage of |
01:01:36 | the information that we get passed down from our mothers and fathers mother and father |
01:01:44 | and the packaging of the DNA. We can get to that in a minute but basically |
01:01:49 | what happens is if you have a broken DNA proteins such as the sirtuins will leave their normal |
01:01:57 | sites where they're regulating genes and they'll go help repair with PARP as well but then they |
01:02:03 | don't all find their way back to where they came from they actually some of them get lost and get |
01:02:08 | distracted and over time what we see is that these proteins are essential for maintaining |
01:02:13 | cellular identity and cellular function will be lost and we see that in yeast cells. Yeast |
01:02:18 | cells get old because they're moving between breaks and back again to these to genes so it's |
01:02:24 | twofold so before we get to the science and I'd love to touch on that the key ways to reduce |
01:02:31 | double strand breaks I think I don't know about the radiation I have to trust you on that one but |
01:02:36 | CT scans. It's ionizing radiation I'm talking about non-ionizing but they both do it |
01:02:42 | different mechanisms ionizing does it through hydroxyl free radicals and non-ionizing does it |
01:02:48 | through carbonyl carbonate free radicals primarily through peroxynitrite. Yeah makes sense there's a |
01:02:53 | lot I mean you can't avoid DNA breaks in our body every day we have about a trillion breaks |
01:02:59 | you know one per cell at least and just living DNA will break especially when it's replicating |
01:03:06 | itself and the cell divides you'll have a break so even if you live in a lead box at the bottom |
01:03:10 | of the ocean which I don't recommend doing but you can minimize it you know I go through the |
01:03:17 | the DNA scanners occasionally and I ask the people there and I've researched this as well |
01:03:23 | the amount of radiation is about the same as you get on the flight but but why double your exposure |
01:03:28 | you know to me it doesn't make sense so I try to if I can avoid that exposure x-rays dental x-rays |
01:03:36 | you know they're important I'm not going to deny that and I think that we should know what's in our |
01:03:41 | mouth but I would try not to overdo it I think any physician who does x-rays should have a good |
01:03:47 | reason for doing it and usually they do but you know be aware that there are consequences to |
01:03:55 | exposing your body to radiation. Okay so let's get to what you just alluded to which is the |
01:04:01 | resolution of some of the epigenetic damage that accumulates through through age and what I think |
01:04:08 | is one of the most fascinating aspects of your book in which you are using technology that I |
01:04:13 | believe developed by another researcher in your lab Dr. George Church who developed the Chris and |
01:04:20 | co-invented as I understand the CRISPR technique and you're using those gene editing techniques to |
01:04:27 | insert three of the four Yamanaka transcription factors into aged mice that have either been |
01:04:35 | experimentally or are blind in some way and you can actually restore their vision through this |
01:04:41 | epigenetic resurrection. Yeah so we're writing up three papers now and so this is a sneak preview of |
01:04:49 | what hopefully will be published later this year and what we've discovered over the last 10 years |
01:04:55 | and this has been a 10-year project so I'm really grateful to the scientists in my lab who've had the |
01:05:01 | endurance we've discovered what we think is is very strong evidence for what we call now |
01:05:07 | epigenetic noise as a cause of aging not just in mammals but throughout life even in yeast cells. |
01:05:15 | So what does that mean? So let's just quickly do a biology lesson for those who haven't been in high |
01:05:20 | school for a while. So the genome we know DNA genome epigenome is the organization of that DNA |
01:05:28 | and the epigenome tells the cell that they should turn on this gene to be a nerve cell and in a liver |
01:05:34 | cell turn on that gene to be a liver cell and that's epigenetics and cells inherit that information |
01:05:39 | just as much as they inherit their DNA. So in my book what I am proposing is that those two types |
01:05:47 | of information genomic and epigenomic they're quite different. The genomic the DNA is digital |
01:05:55 | which is very well preserved and can last a long time we know that DVDs last longer than cassette |
01:06:01 | tapes but the problem for the epigenome is that it's analog information and anyone who's had a |
01:06:06 | cassette tape or a record knows that you can you can pretty easily scratch these or lose the |
01:06:13 | information in fact you can scratch your DVD and lose the information. We actually think that aging |
01:06:20 | is similar to those scratches that the information to be young again is still |
01:06:24 | largely in our bodies but we can access our cells can access that information just by you know |
01:06:31 | metaphorically scrubbing the DVD or polishing it up so that the cell can read the right genes |
01:06:37 | in the case of the DVD the right song. So with that in mind let me explain what we've discovered |
01:06:45 | if so we literally have not literally but metaphorically have a way of scratching |
01:06:50 | a mouse's epigenome and the way we do that is actually we cut the DNA we create these double |
01:06:55 | strand breaks let the cell heal them without making mutations so there's no change to the |
01:07:00 | digital information but what we see is the process of proteins moving around and trying to repair |
01:07:05 | that DNA eventually introduces this epigenomic noise and the genes that were once on many of |
01:07:12 | them get turned off and those that were once off come on and so liver cells start to lose |
01:07:16 | their identity skin cells start to lose their identity and the consequence we think is aging |
01:07:21 | and we actually will hopefully publish a paper that shows that if you create this noise in a |
01:07:26 | mouse it will go through accelerated aging and not just looking old it is actually literally |
01:07:33 | old if we measure the the epigenetic clock and I think many of your listeners and viewers will |
01:07:40 | know that there's a clock you can measure from blood in our bodies or in a mouse and it'll tell |
01:07:45 | you how old the animal is or we are biologically if we do that with our mice that we've scratched |
01:07:51 | up they are literally not likely 50 older which is great okay but you might say well |
01:07:59 | David that that's all fun but why do we care about making a mouse older well first of all it's good |
01:08:04 | evidence that we're right about the hypothesis that every aspect of aging is recapitulated |
01:08:10 | second of all we have mice now that we can change the rate of aging perhaps even accelerate aging |
01:08:15 | so that they behave more like humans and we can potentially have a better mouse model for |
01:08:20 | Alzheimer's for example but then the third thing is if you can give an animal something then you |
01:08:27 | can actually with that knowledge take it away and that's what we've done with George in collaboration |
01:08:32 | with George what we did actually was we wanted to reprogram the cells so that the genes that were |
01:08:38 | once let's start with this the ones on now they they go back off and vice versa so genes that were |
01:08:46 | once off come back on and what we find is that by using these three yamanaka factors you can |
01:08:53 | actually find the original information in the cell that tells it to be young again and those genes |
01:08:58 | actually switch and the cell behaves like it's young again and in the case of the the retina |
01:09:04 | we have preliminary results that we can actually restore eyesight by rejuvenating the nerves in |
01:09:12 | the retina to be young again and so that's early days of what I hope is the future where we can |
01:09:19 | reprogram cells in the body doesn't have to be the retina can be any cell type in the body you think |
01:09:24 | to actually not just act young but literally be molecularly young again and in my career |
01:09:31 | I've seen a lot of cool stuff and I haven't seen anything this cool before I couldn't agree more |
01:09:36 | it's the potential is beyond extraordinary and I'm wondering if the cells that you're |
01:09:42 | injecting are they pluripotent stem cells that you're modifying with the yamanaka transcription |
01:09:48 | factors we're actually we're actually just giving uh the the genes to the organism we're turning on |
01:09:56 | oh with a virus adenovirus we do we use the virus that's that's used by pharmaceutical companies to |
01:10:02 | correct genetic diseases so it's a an FDA approved virus that that is very easy to use in the eye |
01:10:11 | actually one injection there's no immune response in the eye it's not a big one and so that's why |
01:10:16 | we chose the eye actually it's not just that we we saw it as a challenge to reverse blindness |
01:10:22 | but we also knew that it could be the quickest path to uh to testing this in people and helping |
01:10:29 | them with this new technology so is this mostly a local effect that you're achieving |
01:10:35 | uh well in the eye yes uh and and by design um you don't know the full safety profile yet so we want |
01:10:41 | to be careful but we have injected mice intravenously with the virus and we've got mice that |
01:10:47 | are healthy 10 months later and so far so good you know it's early days we've only been testing |
01:10:52 | it on about 100 mice we have a lot more to do and it's many years of work to make sure it's safe |
01:10:57 | but uh yeah i think the promise is there and it's just hopefully evidence if not proof in principle |
01:11:05 | that aging is more reversible than we ever thought do you have plans on putting genes in to make |
01:11:15 | additional sirtuins like all the seven her two seven sirtuin genes in humans uh to augment those |
01:11:21 | i mean that's going to be better than a than a sirtuin activator if you can have them be on all |
01:11:26 | the time wouldn't it be yeah it would i only use viruses when absolutely necessary i think |
01:11:32 | the well-trodden path of small molecules means that there's a much greater chance of success |
01:11:37 | and less chance of side effects and toxicity with viruses as great as they are and as how |
01:11:43 | exciting they sound it's still a pretty it's still early days we don't know that so i i don't |
01:11:51 | see a use for um viruses and sirtuins in humans at this point but i so i'll stick with small |
01:11:57 | molecules but what i do see a future you know if you want to go crazy with predictions yeah yeah |
01:12:04 | that that we we could see a world where where people do choose to be genetically modified um |
01:12:11 | it's their choice right you wouldn't i don't think you can easily go in and modify children |
01:12:15 | even though that's now being done unless it's life-threatening of course but adults you know |
01:12:21 | they should be able to have a choice if there's if there's safety and it's approved then they should |
01:12:26 | be able to do that and maybe there'll be a day when we are able to carry these yamanaka genes |
01:12:33 | in our body and when we get sick or we have an injury uh let's say we have a detached retina or |
01:12:40 | we have a broken spine uh then we get an iv that turns on those genes for a month we recover |
01:12:46 | we rejuvenate and then we turn them off again until we need them again and that would be a |
01:12:52 | pretty wild sci-fi future but science is pointing to at least the biology being possible i believe |
01:13:01 | you mentioned that there's no rational biological requirement for death that not necessarily |
01:13:11 | mortality but you could live hundreds of years theoretically so i'm wondering in your mind what |
01:13:16 | you perceive as the best bridge to pass this the clearly 120 year limit that humans currently have |
01:13:24 | would it be uh resetting the that epigen the methylation clock the horvath methylation |
01:13:31 | clock back to zero with like hematopoietic stem cells or what do you think is the |
01:13:37 | biggest step to do that right well so i put my money on on the DNA methylation reprogramming |
01:13:46 | right now it's uh you know i've seen old mice regain their eyesight i haven't seen any technology |
01:13:53 | able to do that previously so if you applied that technology in combination with some of the |
01:14:01 | molecules we've talked about today in combination with a healthy lifestyle that we're trying to |
01:14:06 | optimize in real time here i don't think anyone can say what what our limit is i mean anyone who |
01:14:14 | says that there's a limit really doesn't know what they're talking about or is lying we really |
01:14:19 | don't know what's possible people who have lived in to 110 115 they typically smoke they've done |
01:14:25 | no exercise they had a lot of alcohol uh do you does anyone think that if they didn't have access |
01:14:33 | to the kind of things that we're talking about today they couldn't have lived longer i think |
01:14:37 | they definitely could have we just don't know because those people are so rare and typically |
01:14:43 | they didn't expect to live so long in the first place um so yeah now now with what we know and |
01:14:49 | what people in the future will know i mean why not and the longer we live the more access we |
01:14:54 | have to this technology yeah you know so i think anything should be on the table |
01:15:01 | it's hard to make predictions it's very easy to poke holes in these things |
01:15:04 | and more often predictions are wrong rather than right but i can tell you that i firmly believe |
01:15:11 | that anyone who says that there is a biological limit is wrong because there are plenty of |
01:15:16 | species and not just trees and not just jellyfish there are there are warm-blooded milk-giving |
01:15:23 | animals in the ocean called whales that can live hundreds of years way you know three times longer |
01:15:28 | than us they're not that different from us genetically they've figured out how to stabilize |
01:15:33 | their genome and repair their dna and all the stuff you need if we can learn from them i think |
01:15:39 | we can live a life like that and i i think historians will look back at the past 20 years |
01:15:44 | as the turning point when we realized that this was possible and finally focused our energy on the |
01:15:49 | topic so you are the world expert in the sirtuins and having made the association between resveratrol |
01:15:57 | and other small molecules and i'm wondering i think your lab is working on these small molecule |
01:16:03 | derivatives of resveratrol and other ones that activate sirtuins far more effectively so can you |
01:16:11 | comment on any ones that are in testing or close to commercial production now that might be you |
01:16:17 | know orders of magnitude better right so there are a couple of things we're doing in my lab still |
01:16:25 | on this topic that's not widely known but i'll share with everybody one is the the question of |
01:16:33 | what is resveratrol really doing you know we came out with the bold uh hypothesis that resveratrol |
01:16:39 | works through sirtuins in yeast cells and that's how it was working that was very controversial |
01:16:45 | it was a shock that you could actually activate an enzyme it was a shock that you could use one |
01:16:49 | molecule a quote-unquote dirty molecule to target very specifically one enzyme and i've basically |
01:16:56 | spent the last decade uh testing that hypothesis time and time again and we have new research that |
01:17:03 | builds upon a science paper that we had in 2013 that said that yes resveratrol is truly acting |
01:17:08 | on this enzyme we now have mice that we've engineered so that they are resistant to the |
01:17:14 | effects of resveratrol on the enzyme and those results look really promising the question is |
01:17:20 | does resveratrol still work if you block its ability to activate the sirt1 enzyme and the |
01:17:26 | answer looks like uh preliminarily yes so that that's good so the science really solid and i |
01:17:32 | wanted to to let everybody know that that's that we're still working on the science on the drug |
01:17:37 | side uh so certerus was a company that i co-founded in 2005 and it was my first company it was a |
01:17:44 | venture ventureback company it went public and it was eventually sold to glexo smith klein um for a |
01:17:50 | lot of money i i was you know a child uh got what's called diluted down to you know almost nothing |
01:18:01 | or loss yeah um you know but the little money i made has been reinvested into |
01:18:07 | new companies which i'm i'm excited about you know but but what did that teach me it taught me that |
01:18:14 | if you let go of your work early uh it's very hard to have champion and so that work it went well but |
01:18:21 | it's still not in the clinic i'll update you on that so that we made and the company made 14 000 |
01:18:29 | different activators of cert1 that were up to 10 000 times more potent than resveratrol |
01:18:36 | those molecules some of them two of them went into mice uh and rafa to cover rafael to cover NIH |
01:18:43 | he put those into mice and they they lived longer it's it's quite an a poorly recognized finding |
01:18:50 | uh but it was very clear they lived longer even on a normal diet not just |
01:18:54 | high fat fat mice um one of those molecules called 2104 srt 2104 |
01:19:03 | look great it went into a study in humans actually it was a pill given to patients with psoriasis |
01:19:09 | plot type psoriasis in a small study i believe it was uh somewhere between 20 and 40 patients |
01:19:16 | uh phase 2a and uh it looked really promising when the drug got into the body there was a |
01:19:23 | very significant effect on the group on the disease um so glexo uh still has those molecules |
01:19:30 | and i'm not sure what their plans are for those molecules but uh you can bet that i'll do |
01:19:36 | everything uh in my power to make sure that they make it to patients if humanly possible |
01:19:43 | we are working actually now on derivatives of the nmn molecule and any precursors and so those are |
01:19:50 | exciting as well because they can boost the levels of all seven of the sirtuins not just |
01:19:55 | number one and that's where my efforts are currently focused do they actually boost the |
01:20:01 | sirtuin levels or they just make them work better uh mostly mostly it's it's making them more active |
01:20:08 | because it's providing the co-substrate for their reaction right yep and you know gsk uh didn't they |
01:20:17 | shut down that lab that they bought from your your company in 2013 and if they did do you think it was |
01:20:24 | related to the fact that they didn't understand the importance of nad and if they were testing |
01:20:28 | aged rats or mice it's not going to work that well unless they do something to augment the nad |
01:20:35 | uh well they had a little nad program but mostly they were working on those um |
01:20:39 | direct activators coming out of the resume which will work um what i think they they didn't appreciate |
01:20:48 | was the um the wide scope of these molecules um that they're they were truly applicable |
01:20:58 | the other thing um joe that wasn't helpful to anybody uh you know in full defense of of glaxo |
01:21:04 | who are a very smart bunch of people they bought the company right as the controversy around the |
01:21:11 | mechanism blew up and it was pfizer whose scientists published that this was wrong now you know all the |
01:21:18 | trouble has died down now and we've i think proven without a doubt that we were right but in that in |
01:21:24 | those you know years of doubt it was very hard for glaxo to keep investing the tens of dollars it |
01:21:30 | was taking to go uh into larger studies um and so i think that was the biggest damage that they did |
01:21:38 | uh it was actually pfizer that that caused that controversy with one publication and you know it's |
01:21:44 | in in hindsight now it's it's really remarkable what one study can do to a whole field absolutely |
01:21:53 | absolutely so are your nmn uh derivatives getting close to commercialization yeah they're pretty |
01:22:00 | advanced um i don't talk about them a lot um mainly because we're we're not venture-packed |
01:22:05 | so we don't need to promote it we're privately funded for now but i'll give i'll give everybody |
01:22:11 | a bit of a sneak preview i talk a lot more about it in the book um we're in humans we are doing |
01:22:17 | human clinical trials we've finished two studies at harvard medical school this is not not my study |
01:22:23 | even though it's at harvard it's at the hospital nearby of course it's arm's length from me because |
01:22:29 | i i at least have the perception of a conflict of interest so i'm not involved but those two |
01:22:34 | studies have gone well uh no indicators that there's any trouble and so we're hoping to be |
01:22:40 | able to have a phase two study at least one possibly to begin um two studies beginning later |
01:22:45 | this year and early next in actually in rare diseases not in um in aging itself not yet and |
01:22:52 | so actually that you reminded me to say something that's often asked of me which is why not go treat |
01:22:59 | aging yeah we go ahead tell us why i know why but it's not a very good business plan can you imagine |
01:23:06 | the amount of money that would take to do a trial like that not only would it be expensive but at |
01:23:11 | the end of it you couldn't sell a medicine if you tried because there is no disease called aging |
01:23:16 | right now i mean there is a disease called aging you can look at it in the mirror if you want |
01:23:22 | but in terms of regulation it's not recognized yet yeah the the strategy it seems to me especially to |
01:23:30 | obtain funding is to figure out an anti-aging strategy that does marvelous things cosmetically |
01:23:36 | because the market for cosmetics is through the roof and if you have something that's effective |
01:23:40 | you'll explode in revenues and you can use those revenues to support the real thing that's going to |
01:23:44 | reverse aging well that's true and that's partly what lenny guarantee and his team and at least him |
01:23:51 | are doing they've gone to the market first i'm taking probably just as hard if not more difficult |
01:23:58 | route which is to be able to raise enough money to to get to pharmaceuticals which is |
01:24:04 | um you know a lot of money it's in the hundreds of millions but i think that's the part that i i |
01:24:09 | think is is a better one for me personally and for the for ultimately the product but yeah you're |
01:24:14 | right it's a challenge you've got to either get on the market early with something that's not well |
01:24:19 | proven or raise the money and wait five to seven years with something that is eventually proven but |
01:24:26 | neither of those is an easy path no no but most good things in life aren't it's true and this is |
01:24:33 | the big one now if you talk about what what's going to plague our planet and our humanity |
01:24:38 | our society clearly global warming energy crisis these are obvious ones but what most people don't |
01:24:44 | realize is that the future prosperity of the planet is going to depend on our ability to keep |
01:24:48 | our populations healthy for longer in terms of productivity and and cost in health care and |
01:24:54 | instead of doing whack-a-mole medicine where we treat one disease often too late to actually have |
01:24:59 | a benefit um the approach really should be one where we're treating the cause of most diseases |
01:25:06 | that will kill us which is aging itself and the idea of treating aging um was fantasy even 20 years |
01:25:14 | ago but as i hope uh you and your viewers are actually appreciating now the science is top |
01:25:20 | notch we we and my colleagues we publish in the world's best journals there'd be noble prizes on |
01:25:24 | this the time is now to be able to translate these discoveries into medicines that can |
01:25:31 | have the best chance of giving future generations even our own a chance of not being dragged down |
01:25:37 | economically by the burden of dementia and um alzheimer's is a huge one but just in general |
01:25:43 | frailty it sucks trillion dollars out of our economies yeah frayota is a big one well um my |
01:25:51 | want to extend my deepest appreciation and gratitude for all the work you've done and |
01:25:56 | are going to do because you're still a very young man the motivations for your work and your book |
01:26:01 | uh lifespan the revolutionary science of why we age is genuine and pure as far as i can determine |
01:26:08 | and you describe it in your book and your discussions with your grandmother and your |
01:26:12 | understanding of death at a very early age four years old so um you're doing a big thing to change |
01:26:19 | the world and i and uh at a level that is quite extraordinary and i deeply appreciate what you've |
01:26:25 | done and would encourage people to get the book if this is a is a topic that interests them and i |
01:26:30 | think it should interest most of us because it's not just about living law almost this that you |
01:26:35 | know who wants to live long if you said it so so eloquently is the frailty this is without frailty |
01:26:39 | obtaining the all the capacities and capabilities and certainly the mental ones that we have as a |
01:26:46 | younger individual into into older age right well yeah thanks joe appreciate it i hope people who |
01:26:54 | read the book come away with a new view of what's possible and some people who have read it tell me |
01:27:00 | that it's changed the way they look at their own lives and that's what what i wanted to do is because |
01:27:05 | i think we we forget how important this topic is that we can do things right now to to alter the |
01:27:11 | course of our lives but also just the way you think about aging itself it's not something that |
01:27:18 | uh we used to think about the way we used to think cancer and heart disease were diseases we |
01:27:24 | couldn't treat aging is is the frontier of medicine and i talk about what we can do now |
01:27:32 | and what to do in the future i also uh want to say joe i want to commend you for for doing |
01:27:37 | what you do um you know i could rant on i've been the victim uh of of some really bad uh |
01:27:46 | press mostly and it's not so negative but more it's it's hype and exaggeration uh things taken |
01:27:52 | out of context and you know that happens a lot in print media and i think that's just the nature of |
01:27:57 | the beast and you know reporters that's what they're paid to do but these these podcasts and |
01:28:03 | these venues uh i mean god bless them they're a venue for a scientist to be able to be unfiltered |
01:28:11 | and talk in depth about topics that people are really interested in and you know i think |
01:28:16 | of one thing uh that social media and youtube and these podcasts have done it's it's allowed people |
01:28:22 | to have greater understanding in depth and direct access to scientists like me which |
01:28:27 | could never be done before yeah you cannot get this information on the conventional media |
01:28:32 | the best you could hope for it a big spot would be maybe five maybe possibly 10 minutes although i |
01:28:38 | guess some of the interviews it's very rare although like you're never going to get two or |
01:28:42 | three hours like you did with joe rogan and your joe rogan podcast and others so i thank you for |
01:28:47 | being so gracious i know you're a busy man and really for taking the time to really dive deep |
01:28:53 | and i think you've done a magnificent job in this interview because uh you know you share stuff that |
01:28:57 | i really haven't heard you talk about previously so thank you for doing that thanks joe thanks |
01:29:00 | for having me on okay |