Rapamycin and Pioglitazone -- an alternative for glucose/lipid control?

#1

Several folks here are reporting problems with glucose and/or lipids while on rapamycin, even at reasonable doses (say, 5mg/week). Mice with daily rapa have similar problems, and the longevity benefits with acarbose or canagliflozin are additive (-ish?). Metformin may also increase the rapa life extension in mice.

What about pioglitazone? By itself, pio looks like a promising agent for life extension – arguably superior to the other diabetes drugs at low doses. The ITP won’t have data for several years, though, and no other quality lifespan studies are available either. But more interestingly, is the action of low dose pio likely to mitigate the rapamycin caused abnormalities? Searching here I see @Bicep reports a negative result. Has anyone else tried? Do any of our resident MDs have clinically informed insights?

#2

I’ve not heard of this drug, thanks for posting about it:

#3

I said it didn’t seem to do anything. I suppose that is negative. I’m using the lowest dose of 15 mg/day. I’ve noticed nothing.

It came from Sandra Kaufmann’s talk to the church of perpetual life. It’s supposed to move fat from visceral to subcutaneous and reduce fasting blood sugar. It’s an old drug and therefore very cheap. My doc was happy to prescribe. He actually had used it for years and knew it very well. He said it would make me gain weight, and that is the biggest complaint to him.

#4

FYI…info on Glycation. Here’s the link to the Kaufmann video @Bicep mentioned. (Thanks for mentioning it, Bicep). It contains a lot of detailed information on Glycation - what it is, how to stop it, and how to fix it. I do not know Kaufmann nor can I attest to the reliability of the information but this is very interesting for anyone looking for glycation information.
Kaufmann Church of Perpetual Life video

#5

FWIW. Here are my notes from the Kaufmann presentation.

Kaufmann Glycation Solution

Why AGEs bad? Causes tissue damage that leads to downstream “aging” effects

  • Production of free radicals
  • Alter proteins & lipids: alter enzyme activity, modify immunogenicity (autoimmune)
  • Activation of inflammatory responses
  • Cross linking with long-lived proteins, i.e., collagen
  • Interaction with AGEs receptors on cell surface

Pick 1 or 2 from each category below. Note that many solutions address multiple categories.

DO NOT OVERDO ANY CATEGORY

1 Block carb digestion
— drugs: Acarbose, miglitol, voglibose
— supplements:
(1) — a-amylase inhibitors: ursolic acid, ellagic acid, catechin, kaempferol
(2) — aglucosidase inhibitors: quercitin, resveratrol, curcumin, caffeic acid, gallic acid, and others
(3) — both: luteolin, chlorogenic acid (coffee), epicatechin, hesperetin, and others

2 Inhibit glucose-6-phosphate translocate (create new glucose)
— chlorogenic acid (coffee, yerba mate), mumbaistatin, kodaistatin

3 Augment glucose GLUT4 transporter (decreased via obesity, muscle atrophy and denervation)
— up-regulate GLUT4: exercise, aloe vera, resveratrol, berberine, EGCG, gallic acid, astragalus, vanillin acid, and others

4 Inhibit Aldose reductase…block glucose to sorbitol to fructose (7-10x worse than glucose for glycation)
— Drug: epalrestat (150mg/day). Carboxylic acid derivative. Treatment of diabetic neuropathy.
— supplement: ellagic acid, quercetin, apigenin, fisetin, curcumin, cholorgenic acid, sillymarin, capsaicin, luteolin, and others.

5 AGE prevention (Reduce AGE formation)

  • Provide targets for sugars that then get disposed (arginine, lysine, cysteine (NAC))…instead of becoming AGE
  • Inhibit sugar attachment to proteins (aspirin, diclofenac (drug), pioglitazone (drug))
  • Other drug inhibitors: ACE inhibitors (blood pressure), angiotensin receptor blockers (blood pressure), metformin, aminoguanidine
  • Other non-prescription agents: cholorgenic acid, caffeic acid, gallic acid, quercetin, rutin, resveratrol, curcumn, ursolic acid, oleanolic acid, vitamins (A, C, E, B1), berberine, carnosine, spermidine, and others.

6 AGE cleanup:

  • Take sugars off proteins: carnosine, glutathione, cysteine (NAC)
  • Increase sRAGES (exercise, EGCG/green tea, pioglitazone (drug))
  • Bind to AGE for cleanup (lactoferrin)
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#6

Thanks for the notes. I have another one that I’m still looking for answers on:

It’s at a low carb down under thing, so of course reducing sugar is the answer. But she claims small dense LDL is glycated or oxidized LDL that can no longer be docked to the liver to be recycled. She says it just hangs around causing trouble. I’m wondering what it is that gets rid of this small damaged dense LDL.

Also a great graphic that shows how much more important reducing sugar is for heart disease than anything to do with regular LDL.

The first about 8 minutes is a very simple review of cholesterol.

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#7

According to Kaufmann, the clean up post AGE formation is done via;
AGE cleanup:

  • Take sugars off proteins: carnosine, glutathione, cysteine (NAC)
  • Increase sRAGES (exercise, EGCG/green tea, pioglitazone (drug))
  • Bind to AGE for cleanup (lactoferrin)

I’m doing much of this already. I’m looking into adding lactoferrin.

#8

I’m not too familiar with this: Lactoferrin - Wikipedia

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#9

Examine.com doesn’t think too highly of lactoferrin. But no detriment. My only reference is Kaufmann. I’m not leaping in but will keep my eye on lactoferrin.

I feel hopeful that the glycation issue is solvable. Many of Kaufmann’s solutions are commonly known and used supplements for general health. Low downside and good upside. Why not.

The bigger picture of CVD is confusing but it seems easy to be generally right…to move in the right direction: lower apoB (fewer small particles), better blood flow with NO (endothelial health), less glycation (cooking methods, lower blood glucose, clean up AGEs). This is my program for now.

#10

Ok, I thought maybe that might work. I wasn’t sure in the case of SLDL because it wasn’t specifically mentioned.

I do take lactoferrin already because I was worried about high Iron. It has been a problem for me.

I know it’s good for inflammation too, and anti cancer. Also great against the microbial burden.

I take Life Extension lactoferrin, but it does not have anything to keep my gut from breaking it down. The article talks about the benefits of that. I should look around when it runs out.

Thanks,

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#11

@Bicep Thanks. Good to know.

#12

I’m exploring using 7.5mg daily, (to help lose liver fat and normalize enzymes) added on top of tirzepatide (for weight loss). I think it’s a very promising longevity drug especially at the lower doses. My research on it can be found here

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#13

You’re saying Poiglitazone is a life extension drug? Isn’t Terzepatide alone enough for your fatty liver disease?

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#14

Kaufmann says Pioglitazone can help to prevent and cleanup AGEs (glycation). It was one of several pharmaceuticals and nutraceuticals she said could help with glycation. Kaufmann was very positive about this drug and mentioned other benefits that I didn’t bother to write down (as I don’t plan to seek it).
See her video and my notes in this thread.

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#15

I have a more challenging case. Tirzepatide alone hasn’t normalized my liver enzymes after 8-10 months. That’s why I’m exploring low doze Pioglitazone. ALT started trending down 1 week after adding it. We’ll see what happens next.

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#16

I said it didn’t seem to do anything. I suppose that is negative. I’m using the lowest dose of 15 mg/day. I’ve noticed nothing.

Thanks for the data point. FWIW 15mg is the lowest dose packaged in the US, I think, but 7.5mg is packaged in India.

It came from Sandra Kaufmann’s talk to the church of perpetual life. It’s supposed to move fat from visceral to subcutaneous and reduce fasting blood sugar. It’s an old drug and therefore very cheap. My doc was happy to prescribe. He actually had used it for years and knew it very well. He said it would make me gain weight, and that is the biggest complaint to him.

Yes, the fat redistribution caught my eye. Aging shifts fat to deep or ectopic locations, and it seems (IMO) reasonable to believe that this has big downstream consequences. Also vanity.

The glycation stuff in the downthread discussion is a bit speculative to me – interesting, but not something to make health decisions on. But I’d still consider it as an alternative to, say, metformin to retain insulin sensitivity with rapmycin and/or growth hormone. I think there is a small human study with GH. With rapa all I could find is this, in rats.

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#17

I’ve been taking pioglitazone 7.5mgs for a couple of years now, nice :blush: to see a fellow user.