[Rhonda]: Something else that really seems to change with fasting is the NAD levels,
and that’s something that, you know, your lab has studied extensively with the sirtuins.
So, maybe could you talk a little bit about…
Because NAD is also extremely exciting to me, and it’s pretty popular these days as
well.
[Dr. Verdin]: Yes.
So, NAD has emerged as one of these critical intermediary metabolites.
Think of ketone bodies, NAD, all, I call them currencies.
I mean, so think about the organism as a country.
You need to circulate energy, and NAD is one way that our body is utilizing within the
cell to convert and transfer energy.
It’s almost like the Brinkman truck.
It carries the money.
And NAD is a hydride acceptor.
While we oxidize foods, it can actually serve as an acceptor for electron, and then it can
transfer them, for example, to the respiratory chain.
So, it’s one way for the energy to be circulated within the cell, and there’s growing evidence
that its level decrease during aging.
Why that happens is still one of the big mysteries, and so this has yielded a whole approach.
They’re trying to understand, first, what are the consequences of decreased NAD levels,
and one of the consequences is that enzymes like sirtuins which rely on NAD to exert all
of their beneficial activities actually function less well.
That’s what happens during aging.
But, also many other enzymes that are involved in our metabolism are relying on NAD, and
so they function less well, so your intermediary metabolism functions less well.
The sirtuins, which are global regulators, function less well.
Your…
Anyways, I lost my…
[Rhonda]: You’re basically falling apart.
[Dr. Verdin]: Yeah.
Essentially, you know, everything becomes a little less efficient.
So, out of these discoveries came the idea that maybe we should replenish the decreasing
levels of NAD, and so this has yielded some discoveries, such as nicotinamide riboside,
nicotinamide mononucleotide, which are now being taken by a lot of people with the hope
that they will, you know, correct some of these problems.
One word of caution I think there is, we do not know why these levels decrease.
They could decrease because we have decreased production of NAD, but it could also decrease
because we have accelerated destruction of NAD, which means, if it’s accelerated destruction,
bringing more into it is sort of like pouring more NAD in a leaky sink.
So, I think a lot of our work right now is trying to understand what is the cause of
the decrease in NAD during aging, because I think it will yield very different solutions.
If you find that there’s a leaky sink, we’ll work at plugging the sink versus keeping pouring
water.
[Rhonda]: I have a theory.
[Dr. Verdin]: Yes.
[Rhonda]: So, I know, you know, I did a lot of work with DNA damage, and knowing that
one of the main enzymes…
[Dr. Verdin]: PARP.
[Rhonda]: Exactly.
I mean, if you think about…
So one of the main enzymes that repairs damage as we age, DNA damage, PARP, requires NAD,
and it’s like if you’re accumulating more and more damage as you age, you have to repair
more of that damage, and the more and more damage you’re having, maybe it’s sucking
the NAD sort of like almost a triage where you got to keep repairing that damage, so
then other things like the mitochondria suffer.
So…
[Dr. Verdin]: I completely agree, and so there are two major theories right now that have
been proposed in terms of why does NAD go down.
One is activated PARP, and, indeed, as we age, we accumulate DNA damage.
That’s been shown, especially in the brain recently, and so the idea is, by activating
PARP, you constantly deplete your NAD levels.
The second one is we all have in our body a so-called salvage pathway for NAD, because
NAD turns over.
There’s this so-called salvaged pathway that allows it to be recycled back to…so
we can get NAD from the food, but also we salvage the one that we utilize, and the salvage
pathway has been shown to becoming paralyzed while you age.
There’s an enzyme called NAMPT that has received a lot of attention.
That enzyme tends to be inhibited by chronic inflammation and a high-fat diet.
So, it could be a combination of both of these things, but it could be actually working on
another mechanism, which is that there might be accelerated destruction by other enzymes
beyond par.
And getting some exciting results in this direction.
[Rhonda]: Cool.