Make your arguments for Rapamycin dosed weekly vs. biweekly

To each his own, you seem to have way more experience than most of us with your dosing sortees and n=1 side effects.

Cholesterol and glucose has been tossed around as benevolent dysregulation…is it? Perhaps a slight rise with good starting markers is acceptable in return for possible longevity benefits?

Lipids and lymphocytes are typically the biggest human side effects. Some people might bail on some components of CBC going below lab range.

Dr B dosent define “tolerable” re side effects re max dosing. We all have our own risk calculus, which he is saying implicitly.

Not side stepping your legitimate question, but if longevity is the prime objective, then the science says to maximize mTOR inhibition.

Uncharted territory.

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I like your detailed breakdown. Thank you!

I am very interested in MOA since I think that can help guide the dosing dilemma. I think that mTOR1 inhibition is only our preliminary finding and that as we get more information that there is much more involved. I respect Dr G and Dr. B for being true pioneers, but the highest dose you can handle seems to be the trend and this seems to be missing the other moving parts of what Dr. Kennedy is referring to as reseting the modulation and not completely blocking mTOR, but helping to reset its flexibility more similar to what occurs in youth.

Biomarkers and subjective feedback are what we have. I don’t know if improvement in markers always means “good” and that a slide of markers always means “bad”. This creates an issue if you have conflict of a subjective good or bad in oposition with a biomarker that is good or bad…I feel great, but my markers look awful and or I feel like crap, but my markers look great and I should live to 130 :slight_smile:

Always appreciate your detailed insights!

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LOL I haven’t always had good markers, but I felt zero correlation with my markers as to how good I have felt. I’ll bet there are many among us that occasionally had great markers but didn’t feel that great and vice versa.

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Hmmm…I’m haven’t actually bought into this “we shouldn’t shut off mTOR” thinking, it’s just conjecture, and I think related to some acute TOR inhibition experiments, not at all relevant for translation.

Why does anyone think we are shutting off mTOR in humans with constant, high as tolerable pittance weekly dosing? Where is the tissue mTOR DATA? Are people falling like flies, completely immobilized?

In pretty much all the rapamycin/rodent studies, they were giving these mice massive daily doses, regardless of the intervention duration. Mice had very high blood levels of rapamycin, and these were happy go lucky mice. Yet when they went to look at the various tissues for mTOR inhibition…what did they find? ONLY PARTIAL MTOR INHIBITION. Yes, severe acute mTOR inhibition is detrimental, but that is such an extreme regime, not used in typical rodent longevity practice, just longevity model end posts.

So in translating to humans for longevity…show me where it’s proven that the highest dosing tolerable completely shuts down mTOR such that it actually impacts healthspan (putting aside the side effects)?

Galvan, in her seminal cognitive study on rapamycin/WILD type mice, showed that hippocampal brain tissue showed only 30% mTOR reduction, and NO mTOR2 reduction at all. Yet, these rapamycin treated mice showed far superior cognitive ability in older age vs. control? So I am to accept that the pittance of dosing we are taking is going to ABOLISH mTOR1, and I’m all of a sudden going to stop breathing and collapse or shrink in size?

Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice

"Our studies show that feeding encapsulated rapamycin in chow at 14 ppm for at least 16 weeks is sufficient to improve cognitive outcomes in both adult (8 month-old) and in old (25 month-old) C57BL/6 mice compared to control-fed littermates. Rapamycin concentration in the chow results in an average dose of 2.24 mg rapamycin per kg body weight/day. To determine whether rapamycin treatment inhibited mTOR in brain, we examined the phosphorylation status of the mTORC1 targets p70 S6 kinase (p70) in brains of control- and rapamycin-fed mice.

Our results suggest that an approximate 30% reduction in TOR activity in brain for 16 weeks or longer improves performance of C57BL/6 mice in tasks that involve long-term plasticity and are dependent on hippocampus or on hippocampus and prefrontal cortex chronically decreased TOR activity (in our studies, approximately 30%) can improve learning and retention of a spatial task in young mice and improve memory of an aversive event in old animals.

Thus, it is conceivable that long-term, partial reduction of mTOR activity by rapamycin administered in the chow mimics the effect of calorie restriction, enhancing cognitive outcomes in young mice and maintaining intact cognitive performance in older animals.

Of note, cognitive effects of rapamycin feeding were observed when mice were fed for 16 weeks or as long as 40 weeks, suggesting that the effect of chronic rapamycin treatment is sustained for protracted lengths of time. We observed no differences in the phosphorylation of mTORC2 targets in whole brain and in hippocampi of mice treated chronically with rapamycin"

Only 30% brain mTOR reduction at massive doses? Sure, our metabolism is far slower than mice, there’s a huge translation gap…but I don’t think we have even come close to triggering significant mTOR inhibition.

We are at the castle walls trying to get in, but the moat (side effects) is blocking our entry. We need to find a way to get more Rapamycin into the cells/brain and bypass the liver (side effects) to try and scale the walls!

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Not exactly making an argument, but I believe the first dosing schedule I read of for aging prevention/therapy was five days on and two days off, perpetually repeating. Does this ring any bells? Does it seem reasonable? Thanks.

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Hi - and welcome to the forum. Thanks for joining the conversation.

I’ve never heard that (the 5 days on, 2 days off) and it doesn’t really make much sense from the animal (daily dosing) or human studies (daily or weekly dosing) that have been done. I think what you may be referring to is the Mannick study where they did weekly dosing for 6 weeks, then 2 weeks off before testing (their immune response).

The weekly dosing is based on the long half life of rapamycin (from 60 hours to 90 hours), and the issue that if you dose frequently (i.e. daily) for a long period of time (without week or longer “off” period) you eventually start getting mTORC2 inhibition which can lead to immune system suppression.

More details here: How long after you receive your moderna booster vaccine can one resumed taking your Rapamycin dose? - #5 by RapAdmin

Also - see here: Rapamycin Clinical Studies in Healthy People (part 2)

More dosing info here: What is the Rapamycin Dosing / Dosage for Anti-Aging or Longevity, and Life Extension?

@owen5819 Welcome to the forum.

I like this question because it makes us all go back to the mechanism that we are trying to influence. 5 days on and 2 days off I have not heard of, but it I were to make an argument for it, assuming we are using a 1mg per day dose, would be that it is just high enough to slow down the aging effect on mTOR1C, but may not be so high that mTOR2C is inhibited.

Most of the anecdotal information that Dr.G and Dr. B are reporting seem to suggest that bigger doses spaced further apart in a pulse manner are getting the best subjective response and with possibly more potential for more brain activity.

The interest I have in your question is it better to use low doses more regularly to not completely block, but more mimic a more youthful modulation. The idea of taking a ‘holiday’ off Rapamycin is also interesting due to some of the short term use in mice that found long term improvement. The mTOR modulation video with Dr. Kennedy that @RapAdmin posted in this thread is really good.

Good luck!

“bigger doses spaced further apart in a pulse manner are getting the best subjective response”
I started on a weekly dosing regimin for a few months, then switched to bi-weekly high doses as per Dr. B.
I definitely felt much better overall taking the high bi-weekly doses except on the 2 or 3 following days after overdosing using grapefruit. A few times I even felt euphoric for a day or two after taking a high dose.
I don’t know about mTORC1 suppression, but in the beginning when I was on weekly dose rapamycin definitely caused minor wounds, paper cuts, and accidental small cuts to take a much longer time in healing. I can’t make a comparison to the bi-weekly healing because I haven’t had any minor or major wounds.
Subjectively I like the bi-weekly dosing.

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The mTOR modulation effect Dr. Kennedy talked about in the video was new to me. Many of us, meaning me, may have simplistically pictured our rapamycin regimens inhibiting mTOR1, letting it creep back, then hitting it again with another dose, the pulsing helping avoid interference with mTOR2. The modulation aspect brings more questions, among them: how long does it last before old age locks mTOR1 back at a high level and it’s time for another dose to regain its youthful flexibility?

Aside from that, there’s another thing that caught my attention recently. In one of the discussions about topical applications, a linked study suggests that very low doses may have an effect that higher doses don’t. So, how about taking a high dose and waiting three weeks or a month for the next one. You’d get whatever benefits the high dose brought, then as it fades away, the benefits of a medium dose, then the benefits of an extremely low dose. Of course, the study is on topical application, not oral, but it’s still the action of rapamycin on an organ.

Here’s the paragraph: “A notable aspect of this study is the use of such a low dose of rapamycin (10 μM, or 0.001%) for topical application. Topical treatment with higher concentrations (0.1–1%) has been employed for the treatment of tuberous sclerosis complex (TSC) in adults and children and has shown efficacy in the inhibition of the benign growths associated with the disorder without serious adverse events (reviewed in Darling, 2018) (Darling 2018). We chose to use rapamycin at a ten-fold lower dose because the concentrations used in TSC patients are intended to inhibit cell growth, while our aim was to improve cell function while maintaining proliferative potential and preventing senescence similar to our in vitro studies (Bitto et al. 2010; Lerner et al. 2013). This reduced dosing would be expected to pose even lower risk than the doses used for treatment of TSC. The positive impact of our treatment regimen suggests that age-related therapy with rapamycin may be feasible at doses far below those associated with side effects (Nguyen et al. 2019); however, this possibility will require careful evaluation in each specific clinical setting.”

And the study it came from: Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial | SpringerLink

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Many thanks. I have an appointment with my primary care doc tomorrow and will fail to talk him into prescribing rapamycin for “old-age related disabilities.” Then I will begin looking for someone else to take care of it.

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Many thanks. I intend to begin using it soon, so this is a critical issue for me.

You are right, BTW. I remember it as being 1mg.

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Two reasons I’ve switched from weekly to biweekly:

  1. I wanted to move to a higher dose, etc., as discussed by lots of people already.
  2. I found that I had noticeable fatigue for a day or two after my rapamycin dose. Moving to biweekly means I had fewer compromised workouts.
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If you assume Rapamycin’s half life is 62 hours then blood levels drop to 15.3% after 7 days and 2.3% after 14 days. So biweekly dosing would produce a higher peak and 4 days with a lower trough:

6mg > 0.92 after 7 days
12mg > 0.82 after 10 days and 0.28 after 14 days

Though who knows whether this is good or bad!

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In the clinical setting, AUC is the therapeutic dosing target, typically using trough as proxy, all things being equal. Side effects also typically associate with AUC. Without looking at n=1 intra person curves, hard to say which protocol delivers the higher AUC, but it seems on this forum, people have fewer side effects bi weekly, same total dose as 2x weekly. Lower AUC?

Agreed…who knows!

You put that nicely. Anything you have come across based on low daily doses? I Dr B likes higher to get more brain exposure. Dr. Kennedy seem to suggest that it may not be a full inhibition of mTOR 1, but more of a regulation. I was just thinking of a daily 1 mg x 6 days and one day off vs. our typical pulsed dose of 6mg x 1/week. I believe the mice were fed daily in their chow? @tongMD - Any thoughts?

We cannot dismiss the higher peak on biweekly or longer frequency dosing as not being detrimental over time. Tissue dysregulation is sensitive to a peak signal, and depending on kinetics/tissue distribution/clearance etc, this may be a negative, even though, you could mathematically get a lower AUC on biweekly vs splitting same total dose into weekly or daily. People report fewer side effects…but is this the optimal longevity strategy?

It’s quite plausible that more frequent/lower dose to lower peak and keep AUC within a target “might” give you better efficacy/less side effects. Certainly in the vast majority of clinical trials I’ve read, albeit cancer/transplant, dosing is daily at minimum, not less frequent.

But when we change paradigm to prophylaxis, why not replicate…but just lower from cancer therapy trough target via micro frequent dosing? Just keep a low level signal to consistently blunt cancer signalling? Since few people are doing blood monitoring, it’s quite possible many members on weekly/biweekly are actually having trough blood levels below some min?

Don’t let up on the signal, but keep it muted…

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@MAC - you just said in words what has been going through my brain. Back to the mechanism of aging - mTOR1 stuck in the “on” position resulting in inflammatory / age related disease potential vs. other pathways? We have studies that suggest by inhibiting mTOR1 significantly increases life span in mice and others with human trials pending. Is it better to just apply gentle brakes with low dose daily, but NOT reach a therapeutic immunosuppressant level or is more aggressive pulsed doses to create short rest the right answer.

Thanks for your valuable insights!

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We will never get the answer to this re human longevity, but I am leaning this way. Sorry, I haven’t bought into the “rest” phase…cancer does not rest.

I go back to this animation MK posted back in 2016.

I am suggesting that we consider changing the standard playbook…the rapalog, the route, and the formulation. We need new exploratory models.

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Didn’t I hear recently that Blagosklonny have moved to a low dose, daily protocol for their rapamycin? Can anyone confirm they heard this also…

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Did they read my posts? LOL

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