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

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00:00:59.240 subscribe so without further delay i hope you enjoy today's quali earlier you spoke about sort of eight

00:01:08.020 or nine central tenets of aging we've covered some of them but i know and i'm guessing that your book

00:01:15.440 is going to go into this in greater detail but can you rehash what you or at least as many of those as

00:01:21.080 you're going to recall on the spot not to put you on the spot that's a long list uh yeah sure

00:01:25.820 there's epigenetic change the cells of cell communication and inflammation there's let me

00:01:30.820 count this analytics so senescent cells build up there's protein misfolding there's telomere loss

00:01:36.880 and genomic instability there's metabolic changes so mp kinase and metformin would address that

00:01:43.240 and then there's uh responses to what you call amino acids and other nutrient inputs and those

00:01:51.320 collectively go awry during aging but what causes all of those to happen that's something that we've

00:01:57.340 been working on for quite a while and you think those are more coupled than they are uncoupled those

00:02:01.780 pathways or do you think that i mean there are clearly situations in which external stressors can

00:02:07.540 perturb more than one of those but like senescence seems somewhat uncoupled from nutrient sensing

00:02:13.300 doesn't it uh it may but and i'm not asking that rhetorically like i just i just don't know

00:02:18.080 no the answer is we think that we've found an explanation for all of these things to happen

00:02:23.980 a unifying theory right so i've kept it close to my vest for a number of years but it actually goes

00:02:29.920 all the way back to the sirtuin story in yeast and hopefully the listeners who've stuck with this

00:02:35.860 podcast are still with us because they will punchline yeah they i promise you they are with us so the

00:02:41.100 punchline is that so this is all off top my head here we haven't published this yet but i'm i'm gonna

00:02:47.740 tell you my my thoughts and your listeners so the genome is digital information it's very easy to

00:02:55.880 preserve it's the reason we went from analog to digital in the 2000s dna is four letters it's digital

00:03:01.620 it's easy to replicate it's easy to store you can boil it it's very robust and so what we've actually

00:03:06.540 come to discover is that the genome is fairly intact in old people and old animals we've

00:03:12.060 sequenced the genomes of lots of old mice and all the genes are still largely intact so what's going

00:03:17.640 wrong well the other part of information that you inherit from your parents is the epigenetic

00:03:24.200 information okay and i use that term loosely but basically it means what's the pattern of gene

00:03:28.840 expression which genes to turn on and off at which time and that is analog information okay that has

00:03:35.820 to be analog because instead of just being a single code it has to operate in three dimensions actually

00:03:40.880 four if you count time and so that's an analog system and it's constantly adapting to what we eat

00:03:46.720 what we what we drink if we run when we sleep and you have to turn genes on and off all the time

00:03:52.460 but that pattern of gene expression that's set down when we're young because it's analog analog

00:03:58.420 information doesn't last very long anyone who's had a record player or magnetic tape knows that

00:04:05.100 these things don't last and that's the problem i think with aging is that we don't lose the digital

00:04:09.660 information so the compact disc of our lives is still intact when we're old but it's as if we've got

00:04:15.460 a scratched cd and the cells don't read the right genes at the right time anymore and they lose their

00:04:20.380 identity in fact if we there's a analogy which is called waddington's landscape where in the 1950s

00:04:26.480 waddington drew a picture it's a beautiful picture of some hills it's a mountainscape and cells actually

00:04:32.520 roll down the mountainscape and land in different valleys down below and that's to you know before we

00:04:38.120 had he had access to the genome that was his way of saying this is how cells know what they are they

00:04:43.320 land in these valleys and they stay there but what i think is happening during aging is due to the

00:04:48.160 vibration of noise over time we lose that pattern of gene expression we lose that information

00:04:53.600 epigenetic information and those cells or those marbles in waddington's landscape they jump over

00:05:00.020 into different valleys and lose their identity so your neurons are not functional like neurons anymore

00:05:04.660 your liver cells are more like neurons and we see that in our lab we're just writing up a couple of

00:05:10.620 papers right now for this and we're able to actually manipulate the epigenome in cells and in mice and

00:05:19.360 have a look what happens to those animals and the prediction is that you get all the hallmarks of

00:05:23.840 aging you know the challenge with this entire space is you think back to the time in the 1950s when he

00:05:28.780 made when he created that analogy and it's in some ways it's amazing that it could still be relevant 75

00:05:35.300 80 years later whatever it is on the other hand it it humbles you to realize how much more has been

00:05:42.400 learned about that process in that time and sometimes i think about it because you and i are interested in the

00:05:48.220 same problem that i'm worried i just don't know anything you know i'm worried that in 10 years

00:05:54.240 i'll look back at my hypotheses and my not even my hypothesis just my understanding of the current

00:05:59.580 state of the art today and think you know what that was directionally right but it was so oversimplified

00:06:06.060 and oh my goodness like you know so it's sort of like we're back in this problem of time like we're

00:06:11.980 going to run out of time and i mean how confident are you that because you and i are almost the same age

00:06:17.300 like how confident are you that in our lifetime we will see step function changes in human longevity

00:06:23.680 and to put this in context there really hasn't been a step function change in human longevity

00:06:30.100 probably since the introduction of sanitation i mean everything has been quite incremental maybe

00:06:35.420 antibiotics vaccinations antibiotics have probably been the last step function change will we see one in

00:06:41.300 our lifetime how confident are you i'm getting more and more confident honestly when i started in this

00:06:46.160 field i thought we'd probably not see the type of technologies that i'm seeing now it's making my

00:06:51.340 head spin not just in the technologies but also the uh the investment and the number of people working

00:06:56.740 on this now this was the back order of biology when we started and there's been some new results which

00:07:02.060 i'll just hint upon because um we haven't published and it's very early but i've seen it sounds like a

00:07:08.220 scene out of blade runner but i've seen things you wouldn't believe no it's it's maybe not that

00:07:13.500 dramatic but let me go back to the compact disc analogy you've got the scratched cd how do you

00:07:19.240 find the polish what is that let's go back to the yeast analogy what causes those scratches why do you

00:07:24.400 get loss of gene regulation anyone who was paying attention earlier on in this conversation will

00:07:30.020 remember that these dna breaks in the chromosome broken chromosomes distract the sur complex and they

00:07:36.400 move away and you get the expression of genes that have no right being on

00:07:40.920 because the sirtuins have lost they're they're distracted from the deactivation function and

00:07:46.900 they're dealing with the repair function exactly so using that what we've got a lot of evidence for

00:07:52.240 now is that something very similar if not essentially identical in principle happens in mammals as we age

00:07:58.580 what that means is that insults to the genome and one of the major insults is a double strand break but

00:08:04.920 there are probably others cause these proteins sirtuins and other factors i'm not saying only

00:08:10.080 sirtuins but factors that control gene expression silencing and other things have a dual role we

00:08:16.240 know in dna repair and other things such as responding to stresses heat whatever but this is

00:08:23.320 the cell's way of coordinating gene expression changes hunkering down during times of adversity

00:08:28.320 and going off to repair the system which in this case we study dna breaks and that's a beautiful system

00:08:34.520 when you're young it works great you get exposed to cosmic rays or you go out in the sun you got lots of

00:08:39.400 dna breaks eventually these proteins will go repair those breaks and then go back to where they came

00:08:45.180 from to settle down the response to turn off the inflammation to turn off the dna repair when it's

00:08:50.380 not needed but the problem we think is it's antagonistic pleiotropy okay so peter medewar and

00:08:57.100 the other brilliant scientists in the 50s speculated i think correctly is that things that are really good

00:09:02.640 for you when you're young come back to bite you in the ass when you're older and i think that's what's

00:09:06.400 happening here is that this response to these stresses like a break end up not just distracting

00:09:10.780 these proteins but end up disrupting the actual structure of our chromatin and these proteins don't

00:09:16.420 always go back to where they came from 100 do that for 70 or 80 years and it's not surprising that the

00:09:23.340 genes that were once perfectly programmed and turned on at the right time lose their ability to do that and

00:09:29.280 we've got remnants of that program when we're 70 and 80 but what's exciting is that information is

00:09:35.860 still there to be accessed the question is how do you get the cells to remember to access at the right

00:09:40.340 time what's that polish and i think we're pretty close to finding that i hope you enjoyed today's

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The Peter Attia Drive - September 05, 2019

Qualy #19 - A unifying theory of aging

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