Transcript of a conversation about autophagy, fasting, and pharmacologic activators (metformin, pioglitazone, lithium). Speakers discuss mechanisms (AMPK activation, mTOR inhibition), pioglitazone’s effects on glucose, mitochondrial PGC-1α, visceral fat redistribution, and upregulation of Klotho; they also touch on gene therapy for Klotho and caution about irreversible genetic interventions.
When we're talking about, let's say, autophagy, right? One common thing that people do to enhance autophagy is fast. You know, it modulates the MK and the MTOR pathways. And it's one of the ways that we see potential increases in longevity in, you know, yeast, fruit fly, other organisms. Some would argue that a big part of it is the calorie restriction, not the compressed feeding window. But nonetheless, there's, there's some autophagy that takes place via that and some of these other things that people do that are, you know, hormetic stressors. What would you use as some type of agonist for something like that?
So that's actually really funny. I thought we were going to do it the other way around. From top to bottom. You're starting at the bottom. So in order to activate autophagy, you need to tell your body that you have fewer calories available. So you need to activate AMP kinase, right, or deactivate mtor. There are several medications that do this. The most infamous of course is metformin. A lot of longevity folks are on metformin, so that's an easy one to start with. But several other ones do it too. Pigletasone does it. Lithium does it. So autophagy is actually a pretty easy category to hit.
What was that? Pioglitazone. Describe that one to me.
So, so pioglitazone is a really interesting drug. It is sold as a diabetic drug. What it is is a P A R R gamma activator. What is that, we ask. So it basically controls glucose metabolism, but it also has some, some alpha activity. And what it does is several things. So number one, it lowers your glucose levels. Number two, in your mitochondria, it activates your PCG1 alpha, which is really quite useful. One of the most important things I think that it does is it actually mobilizes your visceral fat. So if you are getting older and your visceral fat is building up, that's actually extremely bad for you. It's a bad sign of, you know, near death. So what P glitazone does is it mobilizes your visceral fat and moves it into subcutaneous compartments where number one, you look more youthful, but in fact you reducing cause of death. So P glitazone is just an amazing, amazing drug.
Would you say that P glitazone would trump metformin when it comes to a lot of these autophagy and MTOR modulating mechanisms?
I would actually, yeah.
Is it a, a new drug? Do a lot of people know about this?
No, it's not a new drug at all. Some people don't like it because it will put an extra pound on you. So if you're fat, you get a whiff fatter. But if you are thin, it doesn't really do that. And it's a few other cool things up its, up its. Up its sleeve. For example, it activates Clotho. Very few things do that. And that, that's sort of like a cool thing that it does. And because one of the other things is because it reduces glucose, it actually also inhibits age formation, so advanced glycation and production. So it hits many, many reasons or categories of aging.
What's the mechanism of action via which you would gain fat?
Because it's sort of mucking around you with your parr alpha activity.
So basically, your body has a choice. Am I going to use fats or am I going to use glucose?
Oh, I see. So you're burning more glucose and thus you're dipping into less of your fat stores.
That is correct. But what it does do to the fat is it redistributes it.
Okay. You also mentioned that with Pioglitazone, it can upregulate the Clotho pathways. I've talked about Cloth a little bit on the show, but can you explain why that would be beneficial?
So, to be perfectly honest, we don't exactly know what Clotho does, but it's demonstrated that at least in kidney cells, if you have a plethora of it around your cells, you do significantly better. A lot of people are trying to figure out exactly why that is. Everyone's trying to upregulate your Clotho, but in terms of actual specific cellular mechanisms, we don't really know yet.
It has an effect on cognition, too, doesn't it?
It does. It has positive effects everywhere. The highest levels are in your kidney, but it does. It gets everywhere. And there's an absolute correlation between higher levels and just cellular health. But again, in terms of absolute specific mechanisms in the action, we don't know.
Yeah. When I interviewed Dr. Adil Khan a few months ago, he was even looking into gene therapy, I think by the company Mini Circle for Clotho, that I don't know if it's been approved or even released yet, but apparently that's one of the gene therapy targets that should be rolling out, I would imagine, in the next year for Clotho. What do you think about that? That whole realm of gene therapy?
I have to say I'm a little skeptical. I like the idea that we can titrate medications or titrate the input of things because we don't actually know if sometimes too much of a good thing is not necessarily good. And once you put something in your genetic makeup, there's no taking it back.
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