The Peter Attia Drive - Qualy #19 - A unifying theory of aging

Episode Date: September 5, 2019

Today's episode of The Qualys is from podcast #27 – David Sinclair, Ph.D.: Slowing aging – sirtuins, NAD, and the epigenetics of aging.   The Qualys is a subscriber-exclusive podcast, released Tuesday through Friday, and published exclusively on our private, subscriber-only podcast feed. Qualys is short-hand for “qualifying round,” which are typically the fastest laps driven in a race car—done before the race to determine starting position on the grid for race day. The Qualys are short (i.e., “fast”), typically less than ten minutes, and highlight the best questions, topics, and tactics discussed on The Drive. Occasionally, we will also release an episode on the main podcast feed for non-subscribers, which is what you are listening to now. Learn more: https://peterattiamd.com/podcast/qualys/   Subscribe to receive access to all episodes of The Qualys (and other exclusive subscriber-only content): https://peterattiamd.com/subscribe/  Connect with Peter on Facebook.com/PeterAttiaMD | Twitter.com/PeterAttiaMD | Instagram.com/PeterAttiaMD

Welcome to the Qualies, a subscriber exclusive podcast. Qualies is just a shorthand slang for a qualification round, which is something you do prior to the race, just a little bit quicker. Qualies podcast features episodes that are short, and we're hoping for less than 10 minutes each, which highlight the best questions, topics, tactics, etc. discussed on previous episodes of the drive. We recognize many of you as new listeners to the podcast may not have the time to go back and listen to every episode, and those of you who have already listened may have forgotten. So the new episodes of the quality is going to be released Tuesday through Friday,

and they're going to be published exclusively on our private subscriber-only podcast feed. Now occasionally we're going to release quality episodes in the main feed, which is what you're about to hear now. If you enjoy these episodes, and if you're interested in hearing more, as well as receiving all of the other subscriber exclusive content, which is growing by the month, you can visit us at pteratia-md.com-forward-slash- subscribe. So without further delay, I hope you enjoy today's quality. So without further delay, I hope you enjoy today's quality. Earlier you spoke about sort of eight or nine central tenants of aging. We've covered some of them, but I know, and I'm guessing that your book is going to go into this in greater detail.

But can you rehash what you, or at least as many of those as you're going to recall on the spot, not to put you on the spot. That's a long list. Yeah, sure. There's epigenetic change. It sells a cell communication and inflammation. There's a lot of account this analytics. So senescent cells build up. There's protein misfolding. There's telomere loss and genomic instability.

There's metabolic changes. So impi kinase and then metformin would address that. And then there's responses to what are called amino acids and other nutrient inputs. And those collectively go awry during aging. But what causes all of those to happen? That's something that we've been working on for quite a while. And you think those are more coupled than they are uncoupled, those pathways, or do you

think that, I mean, there are clearly situations in which external stressors can perturbed more than one of those, but like, senescence seems somewhat uncoupled from nutrient sensing, doesn't it? It may, but I. And I'm not asking that rhetorically, like I just don't know. All that, no, the answer is we think

that we've found an explanation for all of these things to happen. A unifying theory? Right. So I've kept it close to my vest for a number of years, but it actually goes all the way back to the sort of two-in-store in East. And hopefully the listeners who've stuck with this podcast are still with us because they will punch you.

Yeah, I promise you they are with us. So the punchline is that, so this is all off top of my head here. We haven't published this yet, but I'm going to tell you my thoughts and your listeners. So the genome is digital information. It's very easy to preserve. The reason we went from analog to digital in 2000s, DNA is four letters. It's digital. It's easy to replicate. It's easy to store. You can boil it, it's very robust. And so what we've actually come to discover is that the genome is fairly intact in old people and old animals.

We've sequenced the genomes of lots of old mice, and all the genes are still largely intact. So what's going wrong? Well, the other part of information that you inherit from your parents is the epigenetic information. And I use that term loosely, but basically it means what's the pattern of gene expression, which genes are turned on and off at which time.

And that is analog information. That has to be analog because instead of just being a single code, it has to operate in three dimensions, actually four if you count time. And so that's an analog system and it's constantly adapting to what we eat, what we drink, if we run, when we sleep. And you have to turn genes on and off all the time. But that pattern of gene expression that's set down when we're

young, because it's analog, analog information doesn't last very long. Anyone who's had a record player or magnetic tape knows that these things don't last and that's the problem I think with aging is that we don't lose the digital information So the compact disk of our lives is still intact when we're old But it's as if we've got a scratched CD and the cells don't read the right genes at the right time anymore and they lose their identity In fact, if we there's a analogy which is called Warrington's landscape lose their identity. In fact, if there's an analogy, which is called Warrington's landscape, where in the 1950s Warrington drew a picture, it's a beautiful picture of some hills, it's a mountain scape, and cells actually rolled down the mountain scape and landed different

valleys down below. And that's two, before we had, he had access to the genome. That was his way of saying, this is how cells know what they are. They land in these valleys and they stay there. But what I think is happening during aging is due to the vibration of noise over time, we lose that pattern of gene expression. We lose that information, kept genetic information, and those cells, or those marbles in Wartington's landscape, they jump over into different valleys and lose their identity. So your neurons are not functional, like neurons anymore, you'll live your cells and more like neurons. And we see that in our lab. We're just writing up a couple of papers right now for this. And we're able to actually manipulate the epigenome in cells and in mice and have a look what happens to those animals. And

the prediction is that you get all the homoxid aging. You know, the challenge with this entire space is you think back to the time in the 1950s when he made, when he created that analogy. And it's in some ways it's amazing that it could still be relevant, 75, 80 years later, whatever it is. On the other hand, it, it humbles you to realize how much more has been learned about that process in that time. And sometimes I think about it because you and I are interested in the same problem that I'm worried I just don't know anything. You know, I'm worried that in 10 years I'll look back at my hypotheses and not even my

hypothesis, just my understanding of the current state of the art today and think, you know, that was directionally right, but it was so oversimplified. And oh my goodness, like, you know, so it's sort of like we're back in this problem of time, like we're going to run out of time. And I mean, how confident are you that, because you and I are almost the same age, like how confident are you that in our lifetime, we will see step function changes in human longevity. And to put this in context, there really hasn't been a step function changes in human longevity. And to put this in context, there really hasn't been a step function change

in human longevity probably since the introduction of sanitation. I mean, everything has been quite incremental, maybe antibiotics, vaccinations, antibiotics have probably been the last step function change. Will we see one in our lifetime? How confident are you? I'm getting more and more confident.

Honestly, when I started in this field, I thought we'd probably not see the type of technologies that I'm seeing now. It's making my head spin, not just in the technologies, but also the investment and the number of people working on this now. This was the back order of biology when we started. And there's been some new results,

which I'll just hint upon because we haven't published, and it's very early, but I've seen, it sounds like a scene out of Blade Runner, but I've seen things you wouldn't believe, and it's maybe not that dramatic. But let me go back to the compact disk analogy. You've got the scratched CD. How do you find the polish? What is that? Let's go back to the yeast analogy.

What causes those scratches? Why do you get loss of gene regulation? Anyone who is paying attention early running this conversation will remember that these DNA breaks in the chromosome, broken chromosomes distract the cirro complex and they move away and you get the expression of genes that have no right being on. Because the circoins have lost their distracted from the deactivation function and they're dealing with the repair function. Exactly. So using that, what we've got a lot of evidence for now

is that something very similar, if not essentially identical in principle, happens in mammals as we age. What that means is that insults to the genome and one of the major insults is a double strand break, but they're probably others. Cause these proteins, sirtoins and other factors, I'm not saying only Sirtoins, but factors that control gene expression, silencing and other things.

Have a dual role, we know, in DNA repair and other things, such as responding to stresses, heat, whatever. But this is the cell's way of coordinating gene expression changes, hunkering down during times of adversity and going off to repair the system, which in this case we study DNA breaks. And that's a beautiful system when you're young. It works great. You get exposed to cosmic rays or you go out on the sun, you got lots of DNA breaks, eventually these proteins will go, repair those breaks, and then go back to where they came from to settle down the response, to turn off the inflammation, to turn off the DNA eventually these proteins will go, repair those breaks, and then go back to where they came

from to settle down the response, to turn off the inflammation, to turn off the DNA repair when it's not needed. But the problem we think is it's antagonistic pleotropy. Okay, so Peter Metawar and the other brilliant scientists in the 50s speculated, I think, correctly, is that things are really good for you when you're young, come back to bite you and the ass when you're older. And I think that's what's happening here, is that this response to these stresses, like a break, end up not just distracting these proteins, but end up disrupting the actual structure of our chromatin, and these proteins don't always go back to where they came from 100%. Do that for 70 or 80 years. And it's not surprising that the genes that were once perfectly programmed

and turned on at the right time lose their ability to do that. And we've got remnants of that program when we're a 70 and 80. But what's exciting is that information is still there to be accessed. The question is how do you get the cells to remember to access at the right time? What's that polish? And I think we're pretty close to finding that. I hope you enjoyed today's quality. Now sit tight for that legal disclaimer.

This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical

advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously for all of my disclosures. The companies I invest in and or advise, please visit peteratiamd.com forward slash about.