Ast Alleviated Cognitive Impairment via mTOR Activation
In AD animal models, mTOR regulates a series of physiological processes involved in learning and memory (Bhattacharya et al.* 2012*). To elucidate the effect of Ast on learning and memory in APP/PS1 mouse, the MWM test and PAT were performed. In theMWMtest, APP/PS1 mice showed a longer escape latency in the spatial navigation test as compared to the WT group. Ast treatment significantly reduced the escape latency in APP/PS1 mice (* p< 0.05, Fig.1A*). Representative tracks of each mice group on day 7 of the navigation test and day 8 of the spatial probe test are shown in Fig.* 1B*. In the exploratory experiment, compared with the WT group, APP/PS1 mice stayed in the target quadrant for a significantly shorter duration and crossed the target quadrant fewer times (* p< 0.05, Fig.1C and D*).
Spatial learning was improved in the Ast-treated APP/PS1 mice (* p< 0.05). After 24 h of training, we performed the PAT to assess the conditional fear and memory in mice, and observed that memory retention was significantly improved after Ast treatment (p< 0.05, Fig.1E and F). These findings suggest that Ast treatment significantly alleviates the cognitive impairments in APP/PS1 transgenic mice. Moreover, the observed effects of Ast treatment were significantly attenuated by intraperitoneal injection of the mTOR inhibitor rapamycin (* p< 0.05, Fig.1A and F*) suggesting that Ast improves learning and memory via mTOR activation in APP/PS1 transgenic mice.
Ast Treatment Activated the mTOR Pathway
Ast treatment significantly enhanced both working memory and memory recall in APP/PS1 mice as determined by Morris water maze; these effects of Ast were attenuated by coadministration of rapamycin. Next, we investigated whether the neuroprotective properties of Ast are mediated via the activation of themTOR pathway in APP/PS1 transgenic mice.
Ast treatment markedly increased the levels of phosphorylated (activated) mTOR and phosphorylated S6 in the cerebral cortex of APP/PS1 transgenic mice (* p< 0.05; Fig.2A and D*). This increase in the levels of p-mTOR and p-S6 in the cerebral cortex was attenuated by intraperitoneal injection of the mTOR inhibitor rapamycin (* p< 0.05, Fig.2A and D*). These findings suggest that Ast could effectively activate the mTOR pathway in APP/PS1 transgenic mice.
Its hard to tell how this applies exactly. I assume that the mTOR pathway is the same in this AD model mouse is going to function the same as any other mTOR pathway. The Alzheimers Disease aspects of the model may or may not be relevant to our experiences.
It does seem likely that the issue of mTOR activation is something we need to factor in. It would seem like you donât want to simultaneously inhibit mTOR via Rapamycin at the same time adding Astaxanthin which activates mTOR. From the sounds of this paper - Rapamycin is the stronger inhibitor of mTOR than Astaxanthin as a promoter (because the rapamycin cancelled out the Astaxanthin effects). So - I would guess, from my limited knowledge, that youâd want to dose Astaxanthin a few days after the rapamycin (e.g. days 3,4,5,6,7). Anyone else have thoughts on how you might best combine the two?
we report that Ast can activate the mammalian target of rapamycin (mTOR) pathway in the 8-month-old APP/PS1 transgenic mouse model of AD
Thats kinda what I was thinking, however, biology being so unpredictable, who really knows? But being a novice biohacker Iâm thinking; why not try? I have also chosen to work out on rapamycin days, mostly because it feels good, even though that is speculated that this may counteract the mTOR suppression.
Iâm a bit skeptical of the quoted amounts of astaxanthin in the capsules from the âCost per 4mg astaxanthinâ graphic.
Astaxanthin is a keto-carotenoid within a group of chemical compounds known as terpenes. Algae (Haematococcus pluvialis) are the primary natural source of astaxanthin in the aquatic food chain. The microalgae accumulate the highest levels of astaxanthin in nature other than potentially, engineered cyanobacteria.
Itâs very difficult to extract and purify the algae to high % of astaxanthin. There are usually other safe and efficacious carotenoids in the compound ie beta carotene. Do we know the purity of astaxanthin in these products?
The paper below outlines composition amounts for a couple of the products and seems to indicate astaxanthin at much lower levels, perhaps 10% or less? Do we know the source and purity of the astaxanthin in the ITP Lab?
My view on astaxanthin is simply eat some salmon. Good bang for your buck and you donât have be particularly concerned about whether the astaxanthin is actually there or not - heard of red food coloring found instead of astaxanthin in supplements.
If you prefer synthetic astaxanthin - farmed salmon has it at low cost. If you prefer algae derived ânaturalâ astaxanthin - wild caught sockeye salmon (not particularly cost effective).
Alrhough these are good suggestions the problem arises when you wish to constrain overall food intake and dont have tha spare dietary capacity for enough salmon.
Depends how much you are constraining. I think itâs quite practical in most cases. A typical person can do âmildâ 10% or even moderate CR with 100 g of salmon. ~200 calories isnât really all that much to get ~4mg astaxanthin. (Iâm not saying that anyone should be on CR - but CR diets are a way to illustrate low total calorie without malnutrition).
Hereâs an example of a ~1200-calorie CR diet with 99% complete nutrition. One can choose to switch some of the cheese and eggs for whole grains, beans, and berries. (This is not my diet, I just grabbed the first one I could find)
Really hard to do significantly less than 1,200 cal without a lot of supplements for any extended period of time. But considering roughly ~2,000 calories a day for women and ~2,500 for men is typically right around the âofficial recommendationâ - I think itâs pretty reasonable to say most people can pull it off through diet rather than unnecessarily go to a lot of extra supplements.
But then again, I have a lot of room to maneuver my diet due to above-average amounts of total lean mass and exercise with what would be considered âmild CRâ an overwhelming majority of the time (only a very occassional heavy restaurant meal on a rest day will put me over and thatâs alright with me). Muscles are a pretty large glucose sink. This can vary by individual.
I love salmon and eat it regularly, but the numbers Iâm seeing suggest it would take a lot of salmon to get 1 gram of astaxanthin per day.
Given the 12% median lifespan increase achieved by the ITP recently with astaxanthin, Iâm thinking of in the near future doing my bloodwork (a pre-test), and then ramping up my astaxanthin uptake to a relatively high number for a few months (say 1 gram / day) and retest to see any impact on blood biomarkers. Iâve taken up to 240mg daily for weeks at a time in the past as a test, with no ill effects - so it seems like a pretty safe effort to move up to 1 gm/day for a few months.
@tongMD Iâd appreciate your input - thoughts pro and con to this idea and test approach. Any input greatly appreciated.
Trying to do this with salmon seems like a challenge given the numbers below.
Ah 240 mg to 1 g a day would be difficult to get with salmon.
I was merely assuming 4 mg, which is typically the dose in supplements. You can tell roughly how much is in it by the color of the flesh and whether it is ânaturalâ or âsyntheticâ depending on what it typically feeds on and wild vs farmed.
As for my views on megadosing it to match ITP extrapolated levels - I thought about it - I have no idea for or against whether it would work or not - as you know, there isnât enough human data.
My diet already consists of other carotenoids - beta-carotene, zeaxanthin, lutein, etc which has related and similar biological activities. While none of these are tested in ITP - I donât feel comfortable taking any individual âantioxidantâ type of intervention as megadose supplementation for a long period of time without more data on humans.
âAntioxidantâ supplementation has shown to lead to potentially slightly increased mortality in several cases - we saw that with megadose beta carotene supplementation in smokers that was supposedly expected to be long-term safe and a promising treatment has significantly much higher mortality - the opposite of what was expected.
On the other hand, we could potentially mitigate any individual âantioxidantâ agentâs potential toxicity by combining different ones at lower levels ie what Protandim does as seen in the ITP. It would be interesting to see if Protandim + astaxanthin would interfere with each other or not.
Ultimately, Iâm not sure how much extra potential benefit I would derive from these megadosed amounts over what has been consumed if I have a mix of most of these antioxidants tested in the ITP but at lower than extrapolated doses from food on top of a diet that already has a good amount of dietary âantioxidantsâ and a sizable amount of dietary NRF2 activators that go on the higher level of endogenous antioxidant regulatory factors.
The only study Iâm aware of that suggests long-term safety is roughly 8-12 mg. I suspect one might even push it a bit more to 20 mg or so but much beyond that I would be far less comfortable based on the issues so far until more human trials are done at least for a longer term. Now some people will have much higher risk tolerance. Thatâs just not me.
When i spoke with Richard Miller about 6 months ago about the astxanthin study he mentioned that he would like to do a lower dose follow-up study with astxanthin to see what sort of response they could get with less extreme doses, so I think we may see that in the future.
I agree with you. Many supplements such as Vitamin C, Glycine + NAC, Astaxanthin, etc⌠are providing antioxidant support. I take about 3 g of Glycine + NAC daily to replenish GSH and human studies support that this is good for longevity (Baylor). However, once you start mixing in more antioxidants, is it possible to have too much of a good thing or does your body self-regulate and allow you to literally piss out the excess?
Supplementing with high doses of beta-carotene may increase the risk of lung cancer in smokers. Supplementing with high doses of vitamin E may increase risks of prostate cancer and one type of stroke.
Endogenous antioxidant activity is tightly regulated. I doubt one would piss out most of it and render the effect useless, if you add a bunch of exogenous antioxidants. The issue is what the effect would actually be, if any.
As for Vitamin C, it is pro-oxidant when megadosing and the kidney stones side effect is real yet itâs never mentioned in the marketing. Pro-oxidants arenât necessarily âbadâ - just look at tetrahydrobiopterin. Not to mention, exercise initially induces oxidative stress. Overdo the antioxidants and one might interfere with exercise. The oversimplification of antioxidants = âgoodâ should be thrown away in the garbage - itâs already way past that but the misconception wonât die. Itâs partly used to sell antioxidant supplements. âAntioxidantsâ are like all these other buzzwords often repeated like autophagy or senescent cells - oversimplifying a complex situation.
I also spoke to Richard Miller last year and asked about the dose which I told him I thought made no sense being so high. I donât know what the people that recommended that dose were thinking because itâs way above anything that can be achieved trough diet or has been tested on animals before.
I believe that the people that recommended that dose are the scientists at DSM, the company that produces the synthetic astaxanthin (AstaSana 5%) that they used in the study. Generally Richard Miller has said that the ITP team asks either the team submitting the proposal for what they think the optimal longevity dose is, or they ask experts in the field. I think them, and in fact most of the scientists who submit these proposals, are suggesting a dose that they think maximizes the probability of a longevity effect. How well that translates into practical usage is a secondary concern.
I have been experiencing with Astaxanthin for well over a year now. I find it to put a lot of pressure on my eyes when my dosage goes above 12mg. I am not sure why, anyone have this issue?
Super interesting that you suspect an interaction with rapamycin because I spontaneously stopped taking astaxanthin (low dose 4mg per day for over 20 years) after starting rapamycin.
