[Dom]: I think it's influencing the absorption of B12 in some way that I don't really know.
[Rhonda]: Does metformin...is it doing anything in addition to mimicking a lot of the same
signaling pathways that caloric restriction does?
Like, is there something additional that...you know?
[Dom]: Yeah, yeah, AMP kinase, for sure.
So without a doubt, I mean, it's mimicking many of the pathways of associated with calorie
restriction and with fasting.
To what degree it's mimicking that relative to a length or duration of fasting?
I don't know.
We're doing some work right now looking at AMP kinase and mTOR, and downstream and upstream
signaling insulin and these things, and trying to get a picture of this, at least in a rodent
model.
And then, I'd like to ultimately replicate some of this stuff in humans, but what I think,
I think metformin would be best used maybe in pulsing it a few times a year.
A lot of these things, metabolic interventions tend to work best when you cycle them, I think.
And I really have not been doing that, but I think it's a theory that I have been working
on.
I need my scrapbook.
[Rhonda]: Why do you think that is?
[Dom]: Because your body is similar with ketoadaptation that your body can, kind of, reset to that
level, initially fasting on the ketogenic diet is sort of a stress and it can induce
a hormetic effect in gene transcription and then we, sort of, get used to that.
You know, our gluconeogenesis is upregulated to that level, but I think it's good to maybe
pick probably not a high-carb diet, but maybe a Paleo diet a low-carb ketogenic diet and
maybe something in between and do some intermittent fasting on occasional days.
So I think this promotes metabolic flexibility.
It allows our body to adapt to different situations without being, kind of, overwhelmed by the
stressor of it.
So I think, to some extent, it is hormesis.
And interestingly, metformin causes mitochondrial stress, and actually, mitochondrial damage.
Some researchers coined the term that it's stimulating reactive oxygen species production
and causing mitochondria dysfunction, metformin is, and this is kind of well known in the
field.
So the general feeling is that, "Well, if I take metformin and I go exercise, why is
it not killing my exercise capacity or my VO2 max or making me lethargic or tired?"
It's not doing that, actually I think it's enhancing.
There was a [crosstalk 01:25:34] study.
[Rhonda]: Does it affect biogenesis?
[Dom]: It does.
So yeah, so the thought that it's kind of stimulating, there's a hormetic effect.
It's damaging the mitochondria, some people believe this, and you get a secondary, yeah,
effect through that way, like it's, kind of like an exercise drug.
But I approached it from the perspective that metformin could lower blood glucose at least
if it was high and it activated AMP kinase, and it may decrease circulating insulin.
So I approached it as a cancer drug from that perspective, but the more conferences we go
to, there's a plethora of data coming out of metformin and a lot of people are studying
it from the perspective of impaired complex I or complex II activity in the mitochondria.
So they're looking at it from that perspective.
[Rhonda]: Interesting.
[Dom]: I know.