Qualy #19 - A unifying theory of aging

**Peter Attia** (0:05)
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Earlier, you spoke about sort of eight or nine central tenets of aging.
We've covered some of them, but I'm guessing that your book is gonna go into this in greater detail, but can you rehash what you, or at least as many of those as you're gonna recall on the spot, not to put you on the spot, that's a long list.

**David Sinclair** (1:25)
Yeah, sure, there's epigenetic change, there's cells-to-cell communication and inflammation, there's, let me count, there's analytics, so senescent cells build up, there's protein misfolding, there's telomere loss and genomic instability, there's metabolic changes, so NP kinase and metformin would address that, and then there's responses to, what do you call it, 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.

**Peter Attia** (1:58)
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 perturb more than one of those. But like senescence seems somewhat uncoupled from nutrient sensing, doesn't it?

**David Sinclair** (2:14)
It may, but I...

**Peter Attia** (2:15)
And I'm not asking that rhetorically, like I just don't know.

**David Sinclair** (2:18)
Well, no, the answer is we think that we've found an explanation for all of these things to happen.

**Peter Attia** (2:24)
A unifying theory?

**David Sinclair** (2:25)
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 Sirtuin story in yeast.
And hopefully the listeners who have stuck with this podcast are still with us, because this is the punchline.

**Peter Attia** (2:38)
Yeah, I promise you they are with us.

**David Sinclair** (2:40)
So the punchline is that, so this is all off the top of my head here. We haven't published this yet, but I'm gonna tell you my thoughts and your listeners. So the genome is digital information. It's very easy to preserve. It's the reason we went from analog to digital in the 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. Okay, 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. Okay, 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 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.