- [Dr. Patrick]: Something that comes to mind when you...
So you're talking about, really, this important role that calorie restriction or intermittent
fasting plays in activating this sirtuin pathway and also deactivating things like the insulin
signaling pathway and IGF-1 pathway, it is the fact that the sirtuins are regulated by
something called NAD, nicotinamide adenine dinucleotide plus.
But that is something that actually, those levels rise during a fasted state.
- [Dr. Sinclair]: They sure do...
Right.
And in response to exercise as well.
And so the reason NAD is so exciting compared to the 1980s when we thought it was just a
housekeeping molecule for reactions, is that the levels of NAD go up and down depending
on not just what you eat, but whether you're exercising and even what time of day it is.
So, during the day, your NAD levels will rise and then you eat a big meal and they'll go
down again.
And it's...
We think it's one of the reasons you also get jet lag, is your NAD cycles are out of
whack.
- [Dr. Patrick]: Is it on a circadian rhythm?
Is it completely regulated by meal intake?
- [Dr. Sinclair]: It's a combination.
It will be going up and down with circadian rhythms, mostly, but you can adjust it within
the...
- [Dr. Patrick]: What about macronutrient composition?
Like if you eat more high fat versus carbohydrate?
- [Dr. Sinclair]: Yeah, no one knows.
That would be a good experiment.
The circadian field hasn't looked at nutrition as far as I'm aware.
But what I can tell you anecdotally is that if I raise my NAD levels when I'm traveling,
I feel a lot better if I have a shot of an NAD booster in the morning when I get to Australia,
which I travel to pretty often.
And so I don't know if it's truly working, we need more than one person in a clinical
trial.
But it fits with the mouse studies, which is that you can use NAD to reset your clock.
What's interesting about this is that NAD isn't being driven by the clock, the clock
is being driven by NAD.
- [Dr. Patrick]: Okay.
Yeah.
So for people that are viewing or listening, the clock, meaning what's regulating circadian
rhythm?
- [Dr. Sinclair]: Yeah.
How your organs coordinate what time of day it is.
And when you're jetlagged, your brain might realize that it's morning because your eyesight,
you know, sees sunlight, but your liver still thinks it's the middle of the night, so you
feel queasy.
And that's the feeling.
- [Dr. Patrick]: And the reason why NAD is...
I mean, NAD is really important for a variety of metabolic...
I mean, it's required for metabolism, for metabolizing glucose, metabolizing fatty acids,
your mitochondria need it.
But it's also important for a variety of other tissues as well, activating sirtuins and then
DNA repair enzyme, PARP.
- [Dr. Sinclair]: Yeah.
Right.
You could argue that NAD is the most important molecule in the body, maybe with the exception
of ATP, but without either of them, you're dead in about 30 seconds.
So NAD and ATP were probably the first two molecules that life on this planet used to
survive.
And it's, to me...
And amino acids as well.
And so isn't it interesting that the amino acid levels, ATP, and NAD are the three main
molecules in our bodies that are sensed as to what our environment is like and whether
we need to hunker down and survive or go forth and multiply?
And those are the three main pathways.
There's the sirtuins, there's AMP kinase, which is the metformin pathway.
And then there's mTOR, which is rapamycin, which I'm sure you and many of your listeners
are aware.
But we're tapping into very early aspects of life that's found all over the planet and
that's why I think we're having such big effects in the animals.
Often, people say it's too good to be true.
You know, you tweak one pathway and all this good stuff happens.
Well, these are pathways that have existed for going back probably more than 3 billion
years.
And we're only just learning how easy and seemingly safe it is to tweak them.