New Richard Miller / ITP Paper: Astaxanthin and meclizine extend lifespan 12%, 8% respectively

[RapAdmin]

Finally, the official Astaxanthin and Meclizine results and paper out of Richard Miller’s ITP program:

In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n ) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang–Allison test.

The disappointing news:

Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex.

see our past discussion thread on Meclizine (and the problems with Meclizine): Meclizine / Dramamine II, Approx 15% Lifespan Increase, Another mTORC1 Inhibitor
Discussions on Astaxanthin here: Astaxanthin: A Potential Treatment in Disease and Aging, Lifespan Increase
and here: Astaxanthin, Natural vs. Synthetic - Your Thoughts?

Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin,...

Full Paper below:

s11357-023-01011-0.pdf (1.9 MB)

[RapamycinCurious]

I haven’t read this yet in full:

In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm [!!] and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang–Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan …
https://rd.springer.com/article/10.1007/s11357-023-01011-0

The lifespan data table:

Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin,...

The controls used for the fisetin studies were unusually short-lived, and it couldn’t even pass this low bar. They tried both a cyclic and a continuous dosing protocol, as advised by James Kirkland: no dice.

[AnUser]

Astaxanthin is a very good one, improves visual processing and cognition if I remember correctly as well and should be pretty safe.

Meclizine is available OTC in Europe. Perfect.
Mayo Clinic says it is not OTC in the US but I can find it on Amazon there OTC? Who is right?

[Virilius]

A median 12% lifespan extension and a trend towards maximum lifespan extension is great news for astaxanthin. I can see why they are testing a dose 5x lower now.
Maybe this will lead to higher dosed astaxanthin entering the market soon?

[cl-user]

The Asta supplied by Cardax consisted of synthetic Asta finely dispersed in a water dispersible beadlet formulation. The superior bioavailability of synthetic Asta beadlets compared to microalgal Asta was demonstrated in a human pharmacokinetic study (approximately threefold higher exposure in plasma over 24 h; [66]
[…]
Importantly, synthetic Asta is a pure form of Asta, whereas microalgal and other natural extracts of Asta are complex mixtures of Asta esters, Asta, and other byproducts [68,69,70].
[…]
Synthetic Asta has demonstrated efficacy across a range of human, animal, and cell culture studies, for example [72,73,74], and its excellent safety profile has been well established in rigorous toxicity studies [20, 75].
[…]
Synthetic Asta beadlets are also utilized in the following commercially available dietary supplements: ZanthoSyn® (Cardax, Honolulu, HI) and AX3™ (AX3 Life, Honolulu, HI).

[cl-user]

zanthosyn.com
10% with Z-ALOHA

[Neo]

@RapAdmin

The disappointing news:

Important to note that

Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects.

[desertshores]

Yes, I have bought it from Amazon.
The question is: Do we need still another mTORC1 inhibitor?
Maybe, if it inhibits mTORC1 but leaves mTORC2 alone.
If it doesn’t affect mTORC2 then it might be worthwhile.
I have used it in the past and found it to be a worthwhile sleep aid. (discussion in another thread)
This is the brand I bought:

Amazon.com: Rugby Meclizine Anti-Nausea Tablets - 25 Mg, 100 per Bottle, 3...

[Agetron]

Was on fisetin 3 years ago… then heard had no life benefits, ran out of it and went off… new info. on its benefits… back on past 6 months.

Just read this trial. Hmmmmm… yeah, I am done with it.

[Radiata]

How is ppm dosing converted to human dosages?

What does this Asta dose equate to? Was this the ~4g+ per day amount you were aiming to take in the other thread @RapAdmin?

[RapAdmin]

Yes… from other threads: Post from Meclizine discussion here:

Here is the math:

The ITP used 800ppm in food (see attached photo). And 800ppm is 0.08%. A typical mouse weighs about 0.025kg and eats about 4g of food per day, so 0.08% is 3.2mg of Dramamine for the mouse per day. That is a dose of 3.2mg/0.025kg=128mg/kg. Divide by 12.3 to allometrically scale to humans, to get a human equivalent dose of (128mg/kg)/12.3=10.4mg/kg. So for a 70kg human, that would be 728mg of Dramamine per day.

From @gpaiao in this post

Using the meclizine calculation.

4000ppm / 800ppm
X / 728mg (70kg person)

5 * 728mg = 3.64g/day for a 70kg person ?

[Lost]

@Neo

Important to note that

Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects.

That’s a disappointment. As I’ve said previously, I think DMF is modestly promising. Can anyone with more knowledge on the mouse literature comment on the dosing? In particular, what is the rough human equivalent to the doses they used?

[Boldi]

3.64 grams? I’ve been taking astaxanthin for years, but at 4mg. How do you even find a dose in grams?

[AnUser]

I don’t think that’s meant to be taken literally as perfect translation. Something can be much more potent in humans. Different animals after all.
Does anyone know what the rapamycin dose is in mice studies equivalent to humans?

[LukeMV]

I see chatter but haven’t seen anyone answer yet.

What is the human equivalent dose of Astaxanthin they used in the ITP?

[RapamycinCurious]

@AnUser

I don’t think that’s meant to be taken literally as perfect translation. Something can be much more potent in humans. Different animals after all.

Different animals, yes — but the HED dose and allometric scaling already take account of a lot of that, and but we have at present no rational reason to suppose that humans would need less rather than more or the expected amount of asta they suggest. I note that the European Food Safety Administration found a NOAEL of 10 mg astaxanthin/kg bw per day (in rats, so do the full conversion) based on prothrombin time (bleeding) and some evidence of liver toxicity.
https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2014.3757

@AnUser

Does anyone know what the rapamycin dose is in mice studies equivalent to humans?

See this handy if depressing table from our intrepid administrator:

What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity?

Yes - In one study ( of the 45+ studies of rapamycin in mice) they did finally find an upper dose of rapamycin that no longer increased lifespan in those female mice. It was an extremely high dose though. I should note that in mice there is a significant dose / response difference between male mice and female mice. This difference is not seen in humans. Most of people currently using rapamycin seem to be (in mouse equivalent dosing) in the low levels tested (note: mice were dosed rapamycin in their food, daily, so that is another difference - vs. us using rapamycin dosed once weekly or so). Here are the National Institutes on Aging Results from their rapamycin studies (these are the best rapamycin studies): Sirolimus Dose mg/kg/day Dose Blood/Sirolimus Level Male Median LS Increase Female Median LS Increase 4.7ppm ∼2.24 3 to 4 ng/mL 3% 16% 14ppm ~6.67 9-16 ng/mL 13% 21% 42ppm ~20 23-80 ng/mL 23% 26% Here are results from all the higher dose studies I could find: …

[AnUser]

Can we use what is deemed safe in humans afaik (0.5 mg a day or 5 mg weekly) rapamycin, and base the dose of astaxathin on it? From information of mice-safe human conversion?

[Vlasko]

@LukeMV

What is the human equivalent dose of Astaxanthin they used in the ITP?

With regard to the synthetic astaxanthin they used at 1840 ppm feed:

To convert from ppm feed in mice to mg/kg bodyweight in humans:

Step 1: Convert PPM in mouse chow to mg/kg bodyweight in mice by multiplying by a factor of 0.150: (or divide by 7)

1840 ÷ 7 ≈ 263 mg/kg (*)

Step 2: Apply allometric scaling to convert from mouse to human (divide by 12.3):

263 mg/kg ÷ 12.3 = 21.4 mg/kg. (**)

Step 3: Multiply by human weight in kg to determine personal dosage estimate. For example, a 70 kg person:

21.4 mg/kg × 70 kg = 1498 mg. Approximately 1.5 grams.

Tables:

Sources:

(*) Nair A, Morsy MA, Jacob S. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development. Drug Dev Res . 2018;79(8):373-382. doi:10.1002/ddr.21461.

(**) Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm . 2016;7(2):27-31. doi:10.4103/0976-0105.177703

[LukeMV]

Thank you!

Wow. 4-12 milligrams is the recommended human dose usually.

I hope we haven’t been wasting our time with baby doses all this time

[DeStrider]

I’m sure baby doses of Astaxanthin have some effect. Whether that is the full effect or not is debatable. It does seem to help prevent sunburn at a 10 mg daily dose.