#12

Will be interesting to see what happened in the upcoming full text of the ITP study with astaxanthin. Unlike rapa, it apparently only extended life span in males.

#13

One thing that slipped my mind was that astaxanthin is a potent activator of the longevity gene FOXO3.

I apologize for this slip up and I will now reconsider taking it on certain non rapamycin days. This could certainly account for the longevity effect.

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#14

Thanks for the update. I was thinking of taking astaxanthin the 4 days prior to taking my once weekly rapamycin. Doing this on a regular basis may be useful, but it’s just a thought at this time. I’m reluctant to add another supplement without very good reason.

#15

I’m now thinking that the mTOR effects are minor but the FOXO3 activation is a big deal. This may be a nice addition and I’ll do something similar.

1 Like
#16

I started to take astaxanthin because I had read it increases albumin.
If you use the Levine calculator, albumin increases reduce biological age.
Not sure if that could also be important mechanism

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#17

I was intrigued by Rich Miller’s statement in the interview (not yet published) that Meclizine improves lifespan in males (the female data is still pending given their longer average lifespan than males). Meclizine appears to be a safe and inexpensive over-the-counter mTORC1 inhibitor.

#18

That is pretty intriguing, Brandy. Unfortunately meclizine is an antihistamine and anticholinergic, so short term exposure can cause drowsiness, urinary retention, increased risk of falls in the elderly, and long-term exposure likely increase risk of dementia. Maybe a human could get the mTOR inhibition benefits while minimizing the risks by taking it for 1 or 2 days/week(?) Half life is 5 to 6 hours, much shorter than rapamycin.

3 Likes
#19

That’s interesting. In some studies high albumin levels were the most consistent common denominator of centenarians. It has also been speculated that some of the Conboy’s successes are due to replacing old blood with an albumin solution.
I’ll have to check that out re astaxanthin.

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#20

Thanks, David. From my reading, I was under the impression that meclizine was a pretty safe OTC drug.

According to the meclizine package insert Clinical Pharmacology section (link below), meclizine “has a marked effect in blocking the vasodepressor response to histamine, but only a slight blocking action against acetylcholine.”

In this article (pg 1347), it states there is a “…relatively safe profile from a wide range of meclizine doses used clinically and lack of clear relationship of Cmax with adverse effects (up to 225 mg/d for 9.5 years with no adverse effects reported)…”

Meclizine Metabolism and Pharmacokinetics.pdf (616.8 KB)

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#21

I didn’t mean to sound alarmist (I mean it’s OTC for a reason), and if used one or two days a week, maybe it’s not a big problem for most people. It knocks me out, though, and antihistamines aren’t good for sleep quality. Still, hopefully the pros of chronic use outweigh the cons(?)

1 Like
#22

@ rivasp12

First of all, I didn’t realize Astaxanthin was such a powerful antioxidant…100X more than Vitamin E.

FOXO3 has some notoriety as a longevity gene (originating in Japan), but the research is highly conflicting. It is NOT settled at all that this gene is bonafide longevity gene.

So I did some sleuthing on Astaxanthin/longevity.

“By activating the FOXO3 gene common in all humans, we can make it act like the “longevity” version”

No paper was referenced nor could I find published. I reached out to the principal author" Dr. Bradley Willcox, MD, Professor and Director of Research at the Department of Geriatric Medicine, JABSOM, and Principal Investigator of the National Institutes of Health-funded Kuakini Hawaii Lifespan and Healthspan Studies"

I didn’t get a response, but I did get a call from the CEO of Cardamax (Wilcox redirect), the company promoting this high bioavailability Astaxanthin.

https://cardaxpharma.com/about-us/

The company has been around since 2014, but seems to be gasping lately, major cost reductions, I think the CEO is a one man show. They abandoned all pharma pursuits, focusing only on a retail product.

ZanthoSyn® – Cardax, Inc. | CDXI (2-3X blood absorption vs conventional)

The CEO didn’t provide me any reference to the paper, some general comments about associations to longevity gene expression. He never did say why it wasn’t published.

So then I brought up the the fact that the Miller lab is doing an ITP on Astaxanthin, and asked him if it was his product they were using…he confirmed they sponsored the trial.

I will wait to see the end results and pathway insight (Q4 2022 he said), but it seems to be a “hail mary” play by another company trying to promote a natural molecule without any significant clinical trial merit.

As a marketer, you can “imagine” the hype this product would gain if it showed any longevity merit in mice.

2 Likes
#23

Nice job Mac doing a deeper dive into it.
I’m fairly certain that Richard Miller states in the interview that astaxanthin is giving life extension results but he’s not yet able to discuss it.

#24

Will be curious to see the dosing as well.

Cardamax ran a cardio trial with their product:

https://cardaxpharma.com/chase-clinical-trial/

Even at 96 mg PER DAY, underwhelming to say the least. These results could probably be achieved (exceeded?) by eating one less cheeseburger per day.

#25

Another good new interview with Richard Miller

3 Likes
#26

A silly question, but do you know if other supplements that inhibit mTOR are just like rapamycin, not necessarily selective about inhibiting mTORC1? If so, is there some kind of ranking about which mTOR inhibitors inhibit mTORC2 the most?

#27

Great thread, very interesting!

#28

Actually - this is a very good question. I don’t know if the research is summarized anywhere… I think we probably need to pull it together or try to get the data from one of the noted researchers who focus on this, like Dudley Lamming. I can reach out to him as I’ve spoken with him before.

Part of the issue is that no two compounds will necessarily inhibit mTORC1 and mTORC2 the same way, and especially not the same as rapamycin - in fact its very unlikely because the molecule is a different shape. Also - there is a consideration with repect to how longer term use impacts mTORC1 and mTORC2; as you probably know rapamycin blocks mTORC1 in the short term, but not mTORC2, but over the longer term (weeks of higher dose) eventually there are feedback mechanisms that cause mTORC2 to be increasingly blocked.

The other issue is what other things the molecule might interact with or block - other pathways… which may or may not be known.

For example - you can see in the new research on other mTORC1 inhibitors that I covered in the BAAM meeting that discusses Meclizine as a good mTORC1 inhibitor. See in some of the photos I took of the presentation - a list of other compounds that are good at blocking mTORC1.

With regard to Meclizine - they did a single assay for mTORC1 and mTORC2, but did not do an assay after several weeks of meclizine use on the mice - so while its unlikely that meclizine has the same feedback loop that causes eventual inhibition of mTORC2 with ongoing high doses as rapamycin does, it is a possibility that it does eventually block mTORC 2. See the Slide 4 in the second part of the posting below - you can click on the slide image to make it larger, and see the compounds reported on and their relevant mTORC1 inhibition and mTORC2 inhibition (from a single assay after one or two days use of the compound).

#29

I read somewhere that the supplement Rutin inhibits mtor. You might want to check that out.

#30

Yes, please do let us know what Dudley Lamming has to say.

Some additional questions:

i) Are there any amino acids that selectively activate mTORC2?

ii) What is the influence of extended fasting on mTORC2?

iii) Everolimus has a much shorter half-life than rapamycin. What does this mean for mTORC2 inhibition? Would it mean everolimus is indeed a superior rapalog from this perspective?

iv) Some people supplement rapamycin along with grapefruit juice for improved bioavailability. But perhaps this also increases the half-life/elimination time? What is the implication of this for mTORC2?

1 Like
#31

Q[quote=“shc, post:30, topic:1155, full:true”]
Yes, please do let us know what Dudley Lamming has to say.

Some additional questions:

i) Are there any amino acids that selectively activate mTORC2?

ii) What is the influence of extended fasting on mTORC2?

iii) Everolimus has a much shorter half-life than rapamycin. What does this mean for mTORC2 inhibition? Would it mean everolimus is indeed a superior rapalog from this perspective?

iv) Some people supplement rapamycin along with grapefruit juice for improved bioavailability. But perhaps this also increases the half-life/elimination time? What is the implication of this for mTORC2?
[/quote]

I’m also interested to get answers on Qii and iii