According to this post, I think Senolytic is also important.
@man_li Taking Rapamycin with a senolytic activator should be fine. If you are going to take a grapefruit product, make sure you take it 1-4 hours before the Rapamycin. However I do not know if your product will work in this regard. Good luck!
Remember that if you experience any unusual side effects, stop what you are doing and reevaluate.
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Unless you can determine that the grapefruit powder has furanocoumarins content equivalent to that in grapefruit juice, you cant expect it to be an equivalent bioavailability enhancer as grapefruit.
Since the bitterness of grapefruit is largely a function of the furanocoumarins, there is a likelihood that it has been reduced in order to make a less bitter juice.
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Its my understanding that you would want to wait for the lowest rapamycin blood level in your rapa dosing cycle before you take a senolytic. This is because you want SASP to be active for the senolytic to work. Rapamycin suppresses SASP.
So if you are looking for a senolytic effect from the âSenolytic Activatorâ you would take it on the last day before your next dose of sirolimus.
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Very useful information. Thanks!
I donât myself have the same view on mechanism.
AIUI Senescent cells issue SASP. I am not aware of any circadian or other variation in the way cells issue SASP.
AIUI Rapamcyin has the effect of making some senescent cells function properly. On that basis they are no longer senescent and donât issue SASP.
Hence I donât think there necessarily is a timing issue for a senolytic. Furthermore I think most senolytics are really senomorphics (Particularly those that are HDAC inhibitors - which many are).
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I didnât mean to imply a mechanism. I think of SASP as a marker of 30-70% of senescent cells.
I believe James Kirkland has said that anything that suppresses SASP will attenuate the effectiveness of senolytics.
It is my understanding that rapamycin can suppress some of the pro-apoptotic pathways that senolytics rely on to selectively eliminate senescent cells.
Therefore maximum effectiveness of senolytics would be at the end of the sirolimus cycle.
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Although this supplement called âsenolytics activatorâ form life-extension company, itâs main compounds are Fisetin/Theaflavin/Quercetin/Apigenin.
I have found Fisetin/Quercetin/Apigenin are all CYP3A4 inhibitors, thus they all have ability to enhance the bioavailability of rapamycin. Theaflavins has on negative nor positive impact on CYP3A4.
So I think I should take this supplement with rapamycin once a week for better bioavailability of rapamycin, despite the supplementâs name is âsenolytics activatorâ.
Right?
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If you are taking the activator to enhance Rapamycin, you should take it an hour before Rapamycin.
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A question that seems best placed here.
GFJ or other product that inhibits 3A4 thereby increased absorption, I get that. So, 1mg + letâs say, 6 ounces of fresh GFJ might = 3.3 to even 7 single one mg doses.
So, what happens if you have zero GFJ on the day you took the 1mg. But then, drank GFJ the following day, and the day after that.
Do you change the rate of removal of the drug by the liver?
So letâs say your graph shows that on day 6 you test to less than 0.5ng/ml without any GFJ. If you love GFJ and drink it on day 2, 3, 4, 5 and 6 do you now have much higher blood level? The activity within the gut is not likely to be affected but what about the liver with its 3A4?
Grapefruit juice only affects initial absorption. It wonât do anything hours or days after you ingest Rapamycin.
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Are there any papers that confirm this?
The original paper, posted on this site showed the graph that after 4 hours the effects drop off a cliff and eventually go to 0. Itâs the same paper that discovered the 3X effect of GFJ on Rapamycin.
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Even if on later days, and you drink it again, day after day? The 3A4 system is partially in the gut, but itâs also the predominant way the body excretes what it doesnât deem necessary.
It appears that GFJ ties up (blocks?) the 3A4 in the gut. But once out of the gut (systemic) the 3A4 is still removing (or perhaps not removing as much?) in the liver. Intuitively I would suspect that the clearance rate would lessen. Just wonderingâŚ
" Cytochrome P450 3A4 (CYP3A4), is the dominant human liver hemoprotein enzyme localized in the endoplasmic reticulum (ER), and is responsible for the metabolism of more than 50% of clinically relevant drugs. While we were studying CYP3A4 expression and activity in human liver, we found that anti-CYP3A4 antibody cross-reacted with a lower band in liver cytoplasmic fraction. We assessed the activities of CYP3A4 and its truncated form in the microsomal and cytoplasmic fraction, respectively. In the cytoplasmic fraction, truncated CYP3A4 showed catalytic activity when reconstituted with NADPH-cytochrome P-450 reductase and cytochrome b 5. In order to determine which site was deleted in the truncated form in vitro , we transfected cells with N-terminal tagged or C-terminal tagged human CYP3A4 cDNA. The truncated CYP3A4 is the N-terminal deleted form and was present in the soluble cytoplasmic fraction. Our result shows, for the first time, that N-terminal truncated, catalytically active CYP3A4 is present principally in the cytoplasm of human liver cells."
I remember seeing a paper which said that the effects are immediate, but then reduce. I donât remember anything saying that you need to eat the grapefruit 1 hour before the rapamycin. I admit that I eat some grapefruit wait a bit (maybe 10-15 mins) and then take the rapamycin.
I think it is quite likely that there is a further effect in terms of serum elimination. However, I found a paper which had a two compartment analysis of half life and we can spent a lot of time trying to identify a model, but it wonât impact that much on what our decisions should be as to ideal dosing and timing.
I think a key mistake made by Matt Kaberlein on dosing is to want an effective zero Rapamycin prior to the next dose. I think people need a period of time when the serum level is effectively zero as we do need mTOR to function properly some of the time.
Incidentally I also looked up the comparative effects of pomegranate vs grapefruit. Chat GPT said grapefruit was better, but I am not sure Chat GPT is right. I found a paper which said they were much the same. Given that I like pomegranate, but donât like grapefruit although I have got used to the grapefruit I may try out pomegranate next time I take Rapamycin (about 18 days from now).
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My understanding is that grapefruit juice potentiates rapa, not by improving its absorption, but by interfering with its breakdown by inhibiting the CYP3A enzyme. This leaves more of the drug in the blood for longer.
In one of the best studies Iâve read on the topic (Ezra 2012), weekly rapa dosing with the antifungal drug ketoconazole can be used for this purpose and has been shown to increase rapa AUC by 500% when taken on the day of rapa dosing and the three following days. Grapefruit juice (240 cc) increased rapa AUC by 350% when started the DAY BEFORE the rapa dose and continued daily until the next rapa dose. The authors explain the grapefruit juice dosing as follows âThis dosing was based on research showing that the half-life of intestinal enzyme inhibition of grapefruit juice is 12 hours, thus providing time for modulation before sirolimus dosing.â While that explains the getting an early start on the grapefruit juice, it does not explain the daily dosing to me, since the enzymes impact is primarily intestinal, I reason that since the rapa would be fully absorbed after a day, it would no longer be needed. Am I missing something here?
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For me the following link worked just fine.
PDF is watermarked.
https://aacrjournals.org/clincancerres/article/18/17/4785/283561/Phase-I-Studies-of-Sirolimus-Alone-or-in
Ketaconazole has liver toxicity issues, so I prefer grapefruit juice.
The chart I saw that impacted me most was that the absorption of Rapa goes up to 3-3.5X in the 1-4 hour range after taking grapefruit juice. Itâs not much before and after that window. So thatâs what I do.
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Do you have a citation for that chart?