- [Dr. Patrick]: Let me ask you this.
This is kind of something that comes to my mind.
I don't think it's often thought about this way, at least, in the field.
But, you know, because NAD is required for cells that have a really high energetic demand
like activated immune cells, for example, activated immune cells require a lot of ATP
for energy and a lot of NAD.
And if you think about like chronic inflammation, how, you know, especially as you get older,
and you're unhealthy, and with age, you know, basically it is increasing.
If you're having more activated immune cells, is there any way to test if, like, the NAD,
like there's a triage where NAD is kind of being sucked away to these activated immune
cells and, like, then your mitochondria are now suffering and you get, like, mitochondrial
decay because you're sort of shunting all this NAD to, like, take care of, you know,
what your body thinks is potentially an infection that could kill you, right?
So there's probably some sort of evolutionary mechanisms at play that say, "Oh, yeah, immune
cells need this NAD more than mitochondria," or something, I don't know.
So it'd be kind of interesting.
Do you follow what I'm saying where...?
- [Dr. Sinclair]: Oh, I absolutely do.
I think you're probably right in thinking along the same lines that as you get older,
you're losing the ability to make NAD, but you're also chewing it up.
And as it gets worse and worse as you get older, the immune system is a big drain on
NAD, and actually, so is DNA repair with the activation of PARPs.
And once you drain NAD a little bit, then your PARPs and your immune system won't work,
but then they'll need more NAD because you'll get more damage.
And this is a positive feedback in a bad way so that once you start going down the NAD
decline, the cells just start to need more, and more, and more with accumulating DNA damage.
And that's actually what happens in yeast cells, going back to those little critters
that we found that they became overwhelmed with damaged DNA and the sirtuins were overwhelmed,
they had to go over and repair that genomic instability, the DNA instability.
And one of the reasons old cells became sterile, which is a hallmark of yeast aging, is because
the sirtuins are keeping the cells fertile back here, but they're so distracted by all
this other DNA damage that's going on over here that they lose their identity.
And that's a theme that we've discovered is likely true in mammals as well, that accumulations
of DNA damage distract the sirtuins from their normal job of keeping a cell with the proper
gene expression, and cellular identity and we see the loss of cellular identity over
time in mice, at least.
And what we're trying to do is to raise NAD levels back up so that they can fix the DNA
damage, but also get back to where they came from and make sure the cell doesn't lose its
identity too much.
- [Dr. Patrick]: I didn't know sirtuins played a direct role, and I guess they're regulating
so many genes that they're playing a role in DNA repair and DNA damage.
- [Dr. Sinclair]: Well, they're one of the first proteins to get to a broken chromosome.
- [Dr. Patrick]: Really?
- [Dr. Sinclair]: Yeah, we discovered that.
It's a while ago, it was a cell paper in 1999, if anyone would like to look it up.
Mills, myself, and Guarente published that.
SIR2 goes to a broken DNA end and then helps recruit other proteins.
- [Dr. Patrick]: A single-strand break or...?
- [Dr. Sinclair]: Double.
- [Dr. Patrick]: Double?
Really?
So, like gamma-H2AX?
- [Dr. Sinclair]: Yeah.
So the first thing that happens is gamma-H2AX gets lit up on the break and then within seconds,
SIRT1 brings in HDAC1, helps remodel the DNA in the chromatin so that it's ready for the
repair proteins to come in and without SIRT1 getting there, these other repair proteins
are very inefficient...
- [Dr. Patrick]: Interesting, I didn't know that.
- [Dr. Sinclair]: ...but they're distracted.
Sirtuins should actually be regulating genes elsewhere.
- [Dr. Patrick]: Right.
Wow.
That's really important to know..
- [Dr. Sinclair]: Right.
This is all part of my idea, my hypothesis called the information theory of aging, is
that we're really losing the information regulation over time and all of these other things that
occur such as telomere loss, and mitochondria loss, and loss of proteostasis, as Andy would
call it, loss of protein folding mechanisms, this could be upstream of all of that, that
our cells lose their identity and don't turn on the right genes the way they did when we
were young.
But the trick is how do you get everybody to go back and reset?
And that's what we've been working on.