you mentioned about, you know, the different types of metabolic stress,
whether that be exercise or intermittent fasting, and how there's an increase
in BDNF in the brain in animal studies.
And I kind of want to go back to seeing what your thoughts are in translating
these animal studies to humans.
Obviously, animals have very different metabolic rates than humans.
For example, if you were to fast a rodent for 48 hours, they lose 20% of their body
weight, whereas a human would only lose 2% of their body weight from a 48-hour fast.
But I also want to ask you, have you seen additive effects
in your studies on animals?
Or have you looked at additive effects of animals that are constantly
exercising or routinely, you know, so a physically active animal
with their little exercise wheel.
But you also expose them to these periods of food scarcity, intermittent fasting.
Are the two combined better than just one type of metabolic stress?
There is evidence that we've obtained that combination of exercise and
intermittent fasting can be better.
I'll give you two examples that we published.
One was, we published a long time ago, a former graduate student Alexis Stranahan.
And it's actually relatively simple, the studies of design.
But we had normal mice and we had mice that have type 2 diabetes.
And they have type 2 diabetes because they're genetically engineered to
have a defective leptin receptor.
Leptin is a hormone that when you eat a meal and your stomach gets
full, it's released into the blood.
And it travels up to your brain, a region called the hypothalamus.
And, essentially, it tells you you're full, stop eating.
So, these diabetic mice, leptin-receptor mutant mice, they
don't get the stop-eating signal.
So, they're presumably always hungry.
Okay.
So, then what Alexis did is she divided these normal mice and
diabetic mice into four groups.
The normal laboratory conditions, which is they're sedentary in relatively
small cages, no running wheels.
And then, they are fed ad libitum.
And they can eat as much as they want every day.
And she had a third group that were fed ad libitum.
And they had running wheels in the cages.
And then, the fourth group...
What a minute, what did I say?
Yeah, sorry.
I figured what to say.
So, she had ad libitum/sedentary, ad libitum/running wheels.
And then, she had every-other-day fasting/ sedentary, every-other-day
fasting/ running wheels.
And she let them go for three months.
And then, she took out their brains.
And there's a brain region called the hippocampus, which is in many
respects the most intensively studied brain region for several reasons.
One, it's critical for learning and memory.
It's kind of all the information from our eyes, our ears, our other
senses, funnels into the hippocampus.
And that's where the initial, if you will, associations between a sight and sound.
You know, a bear jumping out on the trail and growling, you hear its growl.
The next time you go walking on the trail, you hear a bear growl, you don't have to
see it to have a mental image of a bear.
So, the hippocampus is critical for these initial associations.
And then, a second reason the hippocampus is heavily studied is it's
a focus of dysfunction and pathology in Alzheimer's disease, epileptic
seizures, even stroke in some instances.
And the third reason is, it's easy to study because the circuitry is actually
relatively simple compared to the cortex.
So, we can put electrodes in the glutamatergic neurons here.
And we stimulate glutamatergic neurons down here, and we can record that,
we can activate a GABAergic neuron and record reduction in activity.
So, anyway, what Alexis found was that...
First, what she did is she measured the number of synapses along the dendrites,
the part of the neuron that receives information coming from another neuron.
So, she simply counted.
Not simply, it actually takes a lot of work, but counted
synapses and found two things.
One, the diabetic mice, regardless of whether they were intermittent
fasting or had running wheels in their cages, had smaller number of
synapses than did the normal mice.
And then, she found that the running-wheel exercise and the intermittent fasting
increase the number of synapses.
And the combination of intermittent fasting plus running wheel got a further
increase in the number of synapses.
Okay.
So, that suggests that intermittent fasting can enhance the effects
of running on increasing number of synapses between neurons.
And then, she took the other hippocampus from the brain and measured BDNF levels.
I mentioned BDNF is important for learning and memory.
It's actually also important for formation of new synapses.
And she found that the intermittent fasting and the exercise, each alone,
increased BDNF levels and the combination got a further boost to BDNF levels.
But she did not find that in the diabetic mice, synapse levels came
up to the level of normal mice.
You know, so there was some beneficial effect, but you couldn't get it back
like they had never been diabetic.
Okay.
So, that's one example.
Then the second example has to do with endurance exercise.
And this work was done by former postdoc Krisztina Marosi,
and a postdoc fellow Keelin.
I'm actually looking at it.
Can you see this?
Yes.
Can you see the whole picture?
I can, yeah.
So, this is about a running group from the lab about 2016 or something.
Anyway, so the work I'm going to talk about now is done by Keelin
Moehl and Krisztina Marosi.
Krisztina is not on here.
She wasn't fast enough to make our 18.
So, what they did is they took mice and they had four groups, these are
all normal mice, ad libitum/sedentary, ad libitum/daily treadmill training
for 45 minutes every day for 2 months.
Then she had a group every-other-day fasting/ no treadmill training.
And then, the final group was daily treadmill training while they're on
every-other-day fasting for two months.
And then, at the end of the two months, they did a maximum endurance test.
Sorry.
So, 45 minutes a day on the treadmill, and then every week, they increased either
the speed of the treadmill or the incline.
So, they're actually, you know, increasing the work over the two months.
So, they did maximum endurance and test, how long can the mouse stay on
the test treadmill without giving up.
And they found that, as you'd expect, the animals that have not done treadmill
training had much poorer endurance than the animals that did treadmill
training, regardless of whether they were on intermittent fasting or not.
But there was a statistically significantly better endurance in the mice
that were on intermittent fasting during the two months of the treadmill training.
And they measured ketones, which were elevated with intermittent fasting,
and the exercise increased the ketone levels much more, almost twice as
much, when you take their blood after the end of the treadmill training.
And then, they got a lot of analysis of the blood.
They did something called metabolomics.
And then, they took out muscle cells from the soleus muscle, which is an
endurance muscle in the leg of the mice.
And they did some measurements that suggested that intermittent fasting
and the exercise increased the number of mitochondria in the muscle cells.
And that the increase was the most on the other combination of
intermittent fasting and the exercise.