- [Dr. Patrick]: I became familiar with your work back in those days when I was actually
doing research on these little nematode worms.
And I remember some of your work was on resveratrol and how resveratrol, like, helped to regulate
one of these, I guess, longevity pathways.
Sirtuin, the sirtuins and how that was involved, and basically if you could activate them and
certain ones seem to delay aging.
So maybe you could talk a little bit about both sirtuins and also what resveratrol is.
- [Dr. Sinclair]: Oh, sure.
Let's start with sirtuins.
So when I arrived at MIT, it had just been discovered that there was a gene called SIR4
that when it was mutated, it would make the yeast cells live longer.
In a fair amount of work, we figured out that the SIR proteins, which are enzymes that control
gene expression, genes on and off, they would become dysregulated over time and we found
out that's because they were being distracted by a whole bunch of DNA instability that was
accumulating in those cells.
But the lesson was that the sirtuin enzymes that were controlling genes were also controlling
lifespan, which was a real breakthrough.
No one had really expected to find gene regulators controlling aging.
We thought we'd find antioxidant producers and DNA repair proteins.
That's not what we found, not initially.
And so the sirtuins became very interesting in yeast and Matt Kaeberlein who's now out
in Seattle, he's a leader in the field as well.
He came in and his first project in the lab was to put an extra copy of one of the SIR
genes, number two, SIR2 into yeast and those yeast lived 30% longer, and later, Lenny's
lab and my lab at Harvard showed that this was through a process of mimicking calorie
restriction.
If you have a lot of sirtuins, you get the benefits of calorie restriction or dieting
and other types of little stresses on the cell like heat and a bit of a lack of amino
acids.
And if you get rid of the sirtuin or SIR2 gene, the real breakthrough was that now calorie
restriction doesn't work anymore.
And that whole setup was the basis of most of the research that the field has been doing
since in the sirtuin field.
Trying to understand that concept of what we learned in the 1990s in our bodies and
in mice.
And I'm lucky and happy to say that a lot of it is very similar in our bodies as well.
- [Dr. Patrick]: And when you say calorie restriction, usually, you're talking about
for, like in mammals and humans like eating 30% less than you normally would or something?
- [Dr. Sinclair]: Yeah.
Well, in the old days, we typically would take out 30%, sometimes even 40% of the food
with the mice and they'd be hungry all the time and it wasn't very pleasant.
With yeast, if you're wondering how do you calorie restrict yeast, we just dropped the
level of sugar in the Petri dish.
I think it was fivefold and that was enough to make them live longer, but they still grew
quite happily.
These days, as you're aware, intermittent fasting seems to kick these longevity genes
into action.
The sirtuins still come on, but you don't always need to be hungry.
You can eat, you know, four days out of a week or even six days out of week and still
have a period of fasting that gets the sirtuin activity up to levels that we think would
be beneficial.
- [Dr. Patrick]: Right.
Yeah.
And there's certainly a lot of overlap, at least in the scientific literature between
calorie restriction and intermittent fasting having beneficial effects, a variety of beneficial
health effects.
But, you know, some of the differences would obviously be, you know, when you are intermittent
fasting, you're shifting your metabolism from carbohydrate, glucose, to fatty acid metabolism
and you start to, you know, ketogenesis can kick in after, at least if you're doing a
more prolonged type of intermittent fast.
So, there's certainly a little bit of differences as well between those.
- [Dr. Sinclair]: Right.
Well, one thing that's interesting that connects everything is, so we showed in 2005 in a Science
paper that when you take a calorie-restricted rat and look at its organs...we looked at
the liver and muscle, the levels of one of the sirtuin genes, number one, we have seven
of these genes.
So we looked at number one because we only had an antibody in those days to number one.
It went up dramatically.
I think it was about five to tenfold in levels in the calorie-restricted livers.
And then we recapitulated calorie restriction in the Petri dish.
We grew cells in serum from animals that had been calorie-restricted and we found that
that was also enough to stimulate this boost of sirtuin production.
But getting back to what you did in Andy Dillin's lab, we found out the reason it went up in
the dish was because of having low insulin and IGF-1 levels.
Because when we put back in normal insulin levels in IGF-1, the sirtuins went back down.
And that was a nice link between...for the first time in mammals, the sirtuins, calorie
restriction, and the insulin pathway.