very interesting, Mark.
So, to kind of shift back to the women part of this story.
There's been a lot of questions about whether or not fasting affects women
differently, different than men.
And if women should fast or if it affects their cycle, menstrual cycle or
hormones like thyroid, things like that.
Whether we're talking about like intermittent fast that's like longer
than time-restricted eating, something more like a maybe 24 to 48 hour, or
perhaps even more prolonged fast.
Do you have any thoughts about that?
Yeah.
Major calorie restriction, so, I'll start with animals then go to humans.
So, in animals, for example, I had one postdoc Bronwen Martin in 2005
or something, she took rats and she put them ad libitum feeding,
20% daily calorie restriction, 40% daily calorie restriction, which is
a lot, or every-other-day fasting.
And she had both males and females.
So, and then she followed them over time.
And then, the females, she essentially did vaginal swabs to do staging of the cycle.
And so, as far as that goes, the rats with 20% daily calorie restriction, there
was no change in their estrous cycle.
The rats with 40% calorie restriction, and this was over a
period of like 4 or 6 months, they shut down, they stopped cycling.
And they lost a lot of body fat over those months.
Then, the rats on every-other-day fasting, they kept cycling but there
was some increase in irregularity of, you know, the timing between the cycles,
but they were still presumably fertile.
Then, she did all sorts of stuff.
She tested their learning and memory.
Oh, then, interestingly in males, even at the 40% daily calorie restriction.
So, the males, their sperm count didn't change.
And they didn't lose as much body weight as the females over these months.
And she looked at like this though, the activity of the
rats moving around the cage.
And the females, when they're on major calorie restriction, became very active.
Like, they're moving around the cage a lot.
Looking for food, maybe?
So, my interpretation of this.
And we had like a few sentences in the discussion on the article.
Okay.
In the wild, if animals are getting to the point of starvation, so that
would be the 40% calorie restriction.
The females, they don't want to get pregnant.
Or if they get pregnant, there's no food to support, you
know, development, their baby.
So they shut down their cycling, they become more active looking for food.
The males, before the male starve to death, it will be advantageous to them to
be able to inseminate as many females as possible before they die of starvation.
So, they stay fertile.
So that's my interpretation.
You know, the female has the egg that's the potential passing the genes on.
You know, so I don't know.
But with the intermittent fasting, they kept cycling.
And their activity in the cage increased a little bit, but they
maintain pretty good body fat compared to the 40% calorie restriction.
One issue is, and this applies mainly to adolescent girls, if an
adolescent girl goes to intermittent fasting eating pattern, would she
be more prone to developing anorexia nervosa, which is a kind of obsessive
compulsive like psychiatric disorder?
The answer is we don't know.
We just don't know.
So, from an evolutionary perspective, you would think
that would be selected against.
But, you know, and it's not clear.
I guess, I don't know enough about anorexia nervosa.
But, you know, back in human recorded history, is anorexia nervosa even common?
Or is this something that has arisen more as girls are more conscious
of their body image and so on?
And, you know, therefore, there's this psychological factor that I
don't know if that's something that...
I guess what I'm saying, it doesn't make sense to me that anorexia nervosa would
be something that will not be strongly selected against during evolution.
And these girls often, they usually quit cycling, too.
You know, so, yeah, I guess we just don't know.
On the one hand, intuitively, I'd say, it won't be a good idea to
recommend this to adolescent girls.
But if they're with obesity or overweight, I don't know.
We just don't know.
I think that seems like maybe okay, but we just don't know.
You're talking about with adolescent girls?
Yeah.
Well, so what about women that are not adolescent and, you know, do not have
an eating disorder and are perhaps even normal weight, not obese or overweight?
Is there a concern with other hormonal imbalances?
I don't even know, necessarily, is it a bad thing?
I mean, if you're amenorrheic for a short period of time, and you go back to eating
normal calories, what does that mean?
Do you delay your reproductive lifespan longer?
Or is there even implications that...?
Well, in animals, that's what happens.
So, for example, we're going to take these rats and do 40% calorie
restriction for 3 months or 4 months so that they stop cycling.
And then, you put them back ad libitum feeding again, they
gain their body weight back.
They start cycling.
These aren't our studies.
These are other studies.
Then, those rats will be able to have, keep cycling to an older age than they
would have previously stopped cycling.
So, in other words, in theory, maybe you could extend age of menopause by
shutting down cycling for 10 years.
I don't know.
This is like just...
Speculation.
This is just thinking and not anything that's approaching it coming close to
even encouraging someone to do something like that, which would be crazy.
But it's an interesting thing to think about.
I don't know.
There haven't been studies.
This is a big thing that's lacking in this field is studying hormones, except for
simple things like leptin and ghrelin.
So, for example, FSH, LH, oxytocin, yeah, anything to produce.
Oh, we do know, in animals anyway, there seems to be increased activation
of the hypothalamic, pituitary, adrenal stress response system.
And that's the system that results in increased levels of cortisol.
And this was something that was noted early on in the animal studies.
The animals live longer when they're on calorie restriction
or intermittent fasting.
But they have elevated cortisol levels, which is usually, you know, in the
clinical arena, that's not a good thing because it can suppress the immune system.
However, so the animals are living longer.
And we did a study, Jaewon Lee was a graduate student, went out
in Kentucky and then he came to Baltimore with me when I moved.
So, this gets a little bit into endocrinology.
Cortisol, there's two receptors for cortisol, two proteins inside
the cell that bind the cortisol.
And those cortisol-binding proteins are transcription factors.
So, cortisol comes from the blood in your cells.
It could be a muscle cell, a nerve cell doesn't matter.
And they bind to the receptor.
And then, which is a transcription factor, it then goes into the nucleus and
affects the expression of certain genes.
In fact, the Nobel Prize was given to the person who...
Oh, Jesus, I'm blanking on the name.
I should know who discovered this.
Okay.
So, I mentioned there's two receptors for cortisol.
One is called the glucocorticoid receptor or GR.
The other is called the mineralocorticoid receptor or MR.
And, okay, so there's been a lot of studies on cortisol
in relation to chronic, uncontrollable psychosocial stress.
So,people who are, you know, whether it's, you know, their work or life
situation, they're chronically stressed out, they have elevated cortisol levels.
And it's been shown that, in that case, in the brain, nerve cells in the brain have
a decreased level of one of the cortisol receptors, the MR, and an increase in GR.
So, the way that the cells are responding to the cortisol is
changing, not just the cortisol.
So, we did a study where we measured levels of GR and MR, the two different
receptors for cortisol, in the hippocampus of mice that had been on every-other-day
fasting, or ad libitum control feeding.
And what we found is that, in contrast to chronic uncontrollable stress, the
intermittent fasting caused a decrease in levels of GR and a sustained level of MR.
So, the take home message is there's increased activation of stress response
pathways with intermittent fasting.
But the ways your cells respond to the stress is different than the bad ways
your cells will respond to bad types of stress, chronic uncontrollable stress.
That's really important.
That's a very important point to make.