"Lock In" Rapamycin Gains with Higher Doses

[DeStrider]

After watching this Matt Kaeberlein video here:

Dr. Kaeberlein's Optispan Podcast Series - Rapamycin and More

[Solving the "Lack" of Anti-aging Discovery & Ranking Current Interventions | 42 - Mark McCormick]

It made me think about the section where Matt and his guest debated about the optimal dosage of Rapamycin. Matt and his guest both agreed that Rapamycin is the best thing available right now as long as we can figure out the right dosage. The dosing arguments are as follows:

1. Too low of a dose and Rapamycin does too little (minimal lifespan gain).
2. Too high of a dose and Rapamycin has side effects such as hyperlipidemia, hyperglycemia, and even MTOR2 inhibition.
3. Somewhere in between 1 and 2 is a dose that provides a maximum lifespan extension benefit.

Ok. We (mostly) all agree on this, so what can we do? Well, IMHO #1 is worse than #2, so, to me, that means we should err on the side of too much. Especially when we are young (55 yo and under). Why is that? Well, in the younger crowd, our bodies are healthier and we can handle the side effects of dyslipidemia and hyperglycemia better than someone older. Also, the ITP mouse studies have shown that the benefits of dosing in middle-aged mice extend throughout their lives even if Rapamycin is discontinued in old age. Therefore, this infers that there is a period where we can “lock in” the gains of high-dose Rapamycin and the gains become permanent even if dosing is discontinued. This is a factor that we often forget about. Fortunately, side effects are not “locked in” and will disappear when dosing is lowered or stopped.

So, I would argue that we should all do a period of high-dose Rapamycin to “lock in” longevity benefits. However, we don’t want to go too high. What do we know about high dosages? Well, we (probably) don’t want to inhibit MTOR2.

From the research presented by @McAlister we know that MTOR rebound doesn’t occur at (bi)weekly levels of 20 mg equivalent or less and that at 40 mg, MTOR rebound is only experienced in 50% of people. So, let’s set the ceiling at 20 mg every 2 weeks. I’d assume MTOR rebound is probably one of the best signs that your dosage is too high.

I would argue that if we took a dose of around 20 mg equivalence (6 mg + GFJ), for about 2-3 years every two weeks, we may be able to “lock in” a base level of benefit from Rapamycin for the rest of our lives and then we could reduce our dosage to a more “normal” maintenance dosage of 6-14 mg equivalence (bi)weekly thereafter. However, we may have to deal with diarrhea and aphthous ulcers during high dose periods.

If we take high doses, we have to make sure that our lipids and blood glucose as well as other biomarkers don’t go out of range. However, if you pair Rapamycin with Metformin or Acarbose (glucose), Bempedoic Acid + Ezetimibe (lipids), and an SGLT2i (glucose), you should be able to mitigate the more serious side effects of Rapamycin.

I plan on changing my dosing to 6 mg + GFJ every two weeks. I am interested in what the rest of the community thinks about this…

[Joseph_Lavelle]

@DeStrider I like it. When putting I always go for in or past the hole. To come up short meant I had no chance. Similarly, too low a dose seems like a waste of time to me. On the other hand, I feel beat down when I take too much for too long. So, regardless of a good or bad longevity effect, it’s not worth it to go beyond wha I can tolerate in the short run. So I’m left with aiming high but drifting back to manage symptoms. That’s a fair balance I think. Beside, rapa is not my main tool for healthspan. For me it is exercise supported by sleep and diet.

[DeStrider]

@Joseph_Lavelle What is too much for you? How do you gauge what too much Rapamycin is?

For me, I have experienced dyslipidemia which I control with Bempedoic Acid + Ezetemibe and slightly higher blood glucose which I control with Metformin, Acarbose and Empagliflozin.

I also get some fatigue (initially and sometimes euphoric) and energy (later). Sometimes I will get apthous ulcers, slower wound healing and bacterial infections. These are all manageable by stopping Rapamycin when the side effects get too serious. However, none of these are a game changer for me.

[KarlT]

Go for it. Let us know what happens. I will pass. Like @Joseph_Lavelle i have found that I don’t feel well at higher doses. Even just 12 mg every 2 or 4 weeks wasn’t right.

There are so many unknowns that I doubt anyone can come up with a great argument for or against your plan. It’s all mostly guess work.
Dose? Frequency? Weight based? With GFJ or other meds?
Is it peak dose or area under the curve or both?
Are side effects due to mtorc2 only? Is that bad or just a required negative?
Is elevated blood sugar and lipids worse at older age? Or will it do more harm when your younger?

[DeStrider]

@KarlT As a medical professional, do you feel that controlled (with meds) dyslipidemia or hyperglycemia or other Rapamycin side effects pose a long-term effect if occurring over a 2-3 year period and then stopped?

I tend to find more benefits at higher doses for myself (more energy/euphoric fatigue/feelings of well-being). This could be because I am fairly large (210 lbs, 5’11" male).

Can you see any definitive downside? I’m looking for devil’s advocate arguments here as to why I shouldn’t do this.

[KarlT]

@DeStrider

do you feel that controlled (with meds) dyslipidemia or hyperglycemia or other Rapamycin side effects pose a long-term effect if occurring over a 2-3 year period and then stopped?

I’m not worried about a few years of treated elevated lipids. The hyperglycemia is a little tougher question. How does Rapa cause hyperglycemia? Certainly in diabetics, tight control of blood sugar is important but won’t prevent some of the negative consequences of diabetes. Although I doubt just a few years would not be harmful.

[DrFraser]

I’m not worried about the anticipated adverse metabolic effects of Rapamycin so long as these are addressed up front. In low risk patients who aren’t that keen on more pharmaceuticals, monitor lipids and insulin sensitivity. For those eager to take more pharmaceuticals, then Acarbose, a GLP1, STLT2 and antilipid medicine of one’s preferred flavor all work together, but also each have evidence of a neurocognitive benefit.
It is very rare for me to Rx Rapa by itself … there should be a constellation of drugs … and also some non Rx items offered.

The dosing, I think should have some safety parameters, to not ineffectively dose, which I think is the case with many dosing regimes, but not overdose where we risk adverse outcomes.

[Joseph_Lavelle]

@DeStrider i take 4mg with GFJ (actually I eat several grapefruit in the hours before dosing) every 2 weeks with a one week holiday every 5th week. I do not eat food for 12 hours before or 12 hours after dosing. I aim for a high peak and short AUC. When I use 4mg with GFJ I feel beat up/ sore / fragile for 2.5 days. Actually the first 24 hours I just feel tired (and sleep great). When I did 5mg with gfj I felt terrible for several days. When I did a lower dose every week I felt a ramping up of tiredness and immune issues over time. This feels like the right balance of getting as much of whatever Rapa has to offer without sacrificing my other efforts at health. I don’t seem to experience higher blood sugar or higher apoB. I no longer get side effects aside from an occasional pimple on my neck.

[Bicep]

Point #3 could easily be wrong. Maximum benefit could come from a dose far above what your lipids…all the side effects…far above what you can stand.

I think it’s dumb to tolerate a lot of side effects for an outcome that is unknown. Also you remember all the childhood stories where somebody gets a wish, then the shit hits the fan for any number of reasons.

So I say do what makes you healthy now. Good food, exercise, sunshine and they say you can’t take it with you, but nobody knows maybe you get credit for your accomplishments so work hard.

[DeStrider]

@Bicep If Point #3 is wrong, and we need an insanely high dose to reap the benefits of Rapamycin, then we are all most probably wasting our time. However, if we are having side effects it means the Rapamycin is doing something. And, I’d bet that it’s doing something good. I just want more of the good stuff.

As for tolerating side effects, they’re not that bad, so they’re easy to tolerate. Is it easy to tolerate increased cholesterol which is then lowered by BA? I’d say so.

[LaraPo]

I feel that higher doze side effects may erase the benefit. I am inclined to think that a lower doze taken more consistently and followed by a break brings more benefits. I came to this conclusion by closely watching my monthly labs for years. During 14 years I experimented with many dozes. On a lower doze all blood parameters are optimal. As soon as I increase the doze my WBC go down, and MPV gets too high, in addition to higher BG and lipids.

[RufusDawes]

I use the Dr. B recommendation for finding the upper limit: increase the dose until you start to see side effects then back off a little. Manick has a study that lists many of the common side effects, with mouth sores and headache as the most common.

[KarlT]

If I used acne as a limiting side effect, my max dose would be zero.

[desertshores]

@Joseph_Lavelle

I aim for a high peak and short AUC

Those are my thoughts exactly. The day after taking rapamycin, I increase my protein intake and exercise, both activating mTORC1 signaling.
Because I was late to the game, my personal premise is high peak and moderate AUC. I am hoping that the high peak causes some crossing of the BBB.
I am a believer in Dr. B’s dosing regimen. I.e., older mammals starting rapamycin need a higher dose regime.

When I first started at high doses my lipids and glucose levels rose. As I was over my “ideal” weight by 10 - 15 lbs., losing the extra weight took care of most of the problem. Depending on your viewpoint my lipids are excellent and my fasting glucose levels are always below 100.
At this time I am taking ER Dapagliflozin (10mg) + Metformin (500mg), Bempedoic acid,180mg, Ezetimibe (10mg), and acarbose once daily.

I usually feel tired the day after taking a dose of 5 mg metformin+ GFJ. Other than that, I feel great.

[JazzMann]

The Kaerberlein McCormack conversation had so much potential but they got into many conversational “nested loops” and failed to fully conclude the discussion on all of the most interesting points.

McCormack touched on the holistic benefits of breaking down and rebuilding our bodies systems. Conventional wisdom suggests that 330 billion cells are replaced daily, this is the equivalent to about 1% of all our cells. In less than 100 days 30 trillion cells will be replenished which makes a new you. For me, the magic of Rapamycin is in stimulating our bodies into autophagy and therefore breaking down and destroying our old, damaged and and abnormal proteins and other substances, and recycling these substances for other important cell functions, or to be discharged from our bodies. As McCormack implies, if we don’t purge our bodies of this detritus our body suffers.

There are so many issues that could vary Rapa doses: body composition, weight, health, diet, the interactions of drugs and supplements, exercise, genetics, age and how we enhance the dose ie GFJ.

@DeStrider My feeling is that my Rapamycin 6mg weekly dose only operates effectively for a few days. Have you thought about the idea of taking your safe high dosage then adding smaller daily increments to keep you at an elevated level a little longer? Taking into account the Rapamycin half-life, this could mean a 5 day high of approx. 8mg if you dosed 8mg x2 x2 x2 x2.

[DeStrider]

@JazzMann Very good question, and a daily dosing had crossed my mind. However, I want to use another senomorphic, Taurine, and Taurine cancels out Rapamycins autophagic effects. So I take my large Rapamycin doses on Saturday and start taking Taurine on Tuesday until the end of the week and then repeat. I am hoping for the best of both worlds.

[Curious]

@DeStrider An important thought. This since I take large doses of Taurine and I wonder where to find research indicating that taurine cancel out the effects for rapamycin?

[DeStrider]

The paper is here

Rapamycin and Taurine

I think this has been mentioned before, but it may be best to skip taurine on the first few days after taking Rapamycin. It appears taurine interferes with Rapamycins autophagy effects. That seems like a bad idea. It could also be why Rapamycin and Taurine appears to have no effect on the Ora Biomedical worms. Maybe they cancel each other out. Therefore, I’m going to take Rapamycin and stop taurine for 4 days after my Rapamycin doses. Indeed, induction of autophagy by rapamycin could suppress the inhibitory effect of taurine on OTA-promoted PCV2 replication. Furthermore, taurine supplementation inhibited 5’AMP-activated protein kinase (AMPK) and activated mammalian target of rapamycin (mTOR). Activation of AMPK by acadesine (AICAR) could suppress the effect of taurine.

[John_Hemming]

I start with a mechanistic approach.

Rapamycin helps by encouraging autophagy.

Rapamycin causes difficulties by inhibiting cell division.

We definitely don’t want autophagy all of the time. Hence I conclude to have large doses of Rapamycin at a frequency such that most of the time it is too low to have much of an effect.

At the moment I am using 6mg with an accelerator (last time Pomegranate, and probably next time Pomegranate), but every 21 days.

I may increase the dose and also reduce the frequency, but for the moment I want to have the balance in the direction of Rapamycin being more active.

[JazzMann]

Yes, I also take Taurine but it may be an occasional approach to consider. Good luck!