Chris Masterjohn: Rapamycin, "The Worst Longevity Idea Ever Conceived"

[Walter_Brown]

I took it to reduce visceral fat and weight management. I paired it with Osterine to maintain muscle mass. Worked brilliantly. Now microdosing for a variety of health benefits: cancer prevention, reduced inflammation etc…

[EenDwaze]

@Walter_Brown are you still taking ostarine? I think you mentioned in the past you cycle it. Have you noticed it lowering your LH and FSH levels?

[Walter_Brown]

Yes, I am still microdosing. My free testosterone levels came back as low.

[snax444]

I have been on 5mg/week sirolimus dose since last 8 months (with wash out periods every few months). When I take this in combination with Rosuvastatin 5mg, I have experienced glucose dysregulation (more pronounced glucose spikes post-meal as seen on my CGM, and HBA1C increased from 5.2% to 5.8%).

Background:

• My activity level is high (12k steps/day, 4x weekly gym,1x weekly cycling, etc)
• Clean diet
• 14 hr daily fasting window
• Good sleep hyegine
• A handful of supplements (which I mostly keep constant)
• Fasting insulin 2, and Fasting glucose 90 mg/dL when last tested, which suggests very low Homa-IR of 0.44
• Sirolimus 5mg/week, with occasional washout periods (chosen at random)
• For lipid management, I currently use Bempedoic Acid + Ezetimibe daily, with which I can achieve Apo(B) level around 65mg/dL, with no impact on liver/kidney function, and no impact to glucose. If I add Rosuvastatin 5mg to this, I can get Apo(B) further down, however it seems to impair my glucose homeostatis.
• I’m not on metformin on a daily basis. However, I did occasionally take metformin, like once a week or during cheat meals (as an experiment), and found that it does nothing for me (which is expected, since you need steady state metformin levels throughout the week, for it to work)

I haven’t quite worked out if sirolimus alone or rosuvastatin alone or this particular combination is causing my glucose dysregulation.

Example below. I had Sirolumus and rosuvastatin in the morning (note I had a 3 week washout period for rosuvastatin prior to this date). The same day, I finished dinner at 6pm (Mexican naked burrito, which includes brown rice and beans). Each time glucose spiked, I walked and it came down, and this zig zag went on for 5 hours!

Analysis 1: When I read Chris Masterjohn’s article, one point resonated with me - Rapamycin inhibits glucose oxidation. So, my speculation is that inhibition of glucose oxidation kept my blood glucose elevated, while my periodic walking/movement was trying to shuttle glucose back into the cells. This conflict between the two was potentially causing this zig zag spike pattern for me.

Analysis 2: I queried chat GPT - Weekly 5mg sirolimus vs daily rosuvastatin 5mg. Which one is more likely to cause hyperglycemia or glucose dysregulation. Below is what I received.

So I guess I need to isolate the drugs one by one and do some more testing. My goal is HBA1C = 5%, Apo(B) < 60mg/dL, and leveraging sirolimus for episodic mTORC1 supression, and trying to achieve these 3 goals without any impact to liver/kidney function.

Would love to hear the forum’s views on this, and any similar personal experiences.

Thanks

[CronosTempi]

@snax444

For lipid management, I use Bempedoic Acid + Ezetimibe daily, and add Rosuvastatin 5mg on an occational basis (for reasons I explain further down below)

Sorry for being thick. But could you explain what your reasons are (“for reasons I explain further down below”). I must have missed the explanation or I’m not understanding.

[John_Hemming]

If you look at my second high dose

Second High Dose of Rapamycin topic for results

On September 23rd I took 1 packet of biocon and 2 packets of zydus with GFJ and a bit of pomegranate. The Grapefruit was half eaten a while before the rapamycin and half with the rapamycin. This time I had been wearing a CGM (One+) for a few days before taking the rapamycin. It fell off and I got another, I then used a third on schedule, but it stopped uploading on Sunday and that got fixed part way through Tuesday. It will take some work to produce useful reports from this, but I have already done an average glucose chart. I have excluded the days with part data as they will not have useful averages. The results are skewed a bit by alcohol consumption. Alcohol takes down the average glucose. The results, however, still show a useful pattern of Rapamycin initially driving up the average glucose figure. Interestingly it appears that it is the baseline that moves up moreso than the peaks. The body adjusts to produce more insulin, but the rapamycin fades and so at a point when…

You will see the effect of an admittedly high dose on the feedback systems for glucose. Because I have long periods between rapamycin I think I see my glucose feedback system stabilising before rapamycin knocks it off balance again. I don’t think it is an immediate thing, but happens after a couple of days and because initially of hepatic insulin resistance and then the other systems over compensate and it ends up with a period of really high insulin responses without the insulin resistance.

I will do another CGM session before I use rapamycin again.

[LukeMV]

I’ve been doing the same combo of rapa and rosuvastatin and it also raises my A1C. I’m taking a hiatus from Rapamycin for the time being to see if it improves the A1C.

[medaura]

Would an SGLT2 inhibitor take care of this issue in principle?

[LukeMV]

I use one and it does not take care of the issue.

[medaura]

How is it all supposed to happen then? Mechanistically? I’d think that if glucose is getting dumped out in urine it shouldn’t be available to wreak havoc on internal systems through dysregulation of its oxidization? Or is this a question for ChatGPT deep research mode? Just trying to think of a plausible mechanism.

[AnUser]

It probably decreases absolute amounts of glucose by about 60 g/day, so it’s not going to prevent any increases in blood glucose on top of that.

[JeffW]

I noticed you’re using Libre. Have you validated the Libre readings with a glucose meter? I found that Libre was consistently off by about 1 mmol/L, so I wouldn’t fully trust the absolute numbers — though the spikes are probably accurate. I’ve since switched to Dexcom, which I find far more accurate, especially since it can be calibrated against a glucose meter.

On a somewhat related note, I started an SGLT2 inhibitor and noticed my A1C rose by 0.4% — despite better glucose control as shown by Dexcom (tight curves, low variability, and 100% time in range). The likely reason? SGLT2s stimulate erythropoietin (EPO), which increases red blood cell lifespan. Since A1C reflects cumulative glucose exposure over the life of a red blood cell, older cells can show more glycation — artificially inflating the A1C, even when actual glucose levels are lower.

[snax444]

@CronosTempi

But could you explain what your reasons are (“for reasons I explain further down below”). I must have missed the explanation or I’m not understanding

Thanks @CronosTempi , I have edited my post to clarify my points. Basically, i noticed that if I take rosuvastatin 5mg daily, along with sirolimus 5mg weekly, I seem to experience glucose dysregulation. So, as an experiment, I’m trying rosuvastatin 5mg only once a week, to see if it makes any difference to glucose, while also seeing if I still get any significant lipid loweing effect (in addition to Ezetimibe + Bempedoic acid, which I continue to take on a daily basis).

[CronosTempi]

Got it, thank you! Out of curiosity, is there a particular reason you settled on rosuvastatin rather than any other statin? I ask because I myself am prediabetic and trying to lower both ApoB and A1c. And to that end, I switched from 10mg/day atorvastatin to 4mg/day pitavastatin. The idea being that atorvastatin - like rosuvastatin - is linked to glucose disregulation and new onset diabetes, meanwhile pitavastatin is not (also there are many other things to like about pitavastatin).

[snax444]

@LukeMV

I’ve been doing the same combo of rapa and rosuvastatin and it also raises my A1C. I’m taking a hiatus from Rapamycin for the time being to see if it improves the A1C.

Thanks @LukeMV, for sharing your similar experience. You did mention in the past that rosuvastatin alone is not causing glucose dysregulation in your case, so it is more likely rapa doing it (or perhaps in combination)

I will run another experiment taking a 3-month break from sirolimus, will also consider taking a break from rosuvastatin, or perhaps take it less frequently… I’m trying not to change too many variables in my experiment… In my case, I’m not dependent on statins as such, since I believe my risk profile is quite low (CAC score zero, very low Triglycerides 45 mg/dL, very low HomaIR 0.44, hsCRP < 0.4), I’m basically taking low-dose lipid lowering meds to keep my lifetime LDL exposure low.

[snax444]

@CronosTempi

is there a particular reason you settled on rosuvastatin rather than any other statin? I ask because I myself am prediabetic and trying to lower both ApoB and A1c. And to that end, I switched from 10mg/day atorvastatin to 4mg/day pitavastatin

Noted @CronosTempi. I didn’t have a hard-science reason for picking rosuvastatin as such. Basically, 1) I followed Dr Brad Stanfield’s research videos, 2) took a note that it is water soluble (which I now know may not necessarily be the case, as it could potentially cross the blood brain barrier in some people), and 3) thought that I can get away with a baby dose of 5mg, 4) More potent than other statins, at low dose.

Sure, at some stage, I’ll experiment with other forms of statins (Pravastatin / Pitavastatin) that have some meta-analysis suggesting lowest risk for new onset diabetes.

[snax444]

@JeffW

Since A1C reflects cumulative glucose exposure over the life of a red blood cell, older cells can show more glycation — artificially inflating the A1C, even when actual glucose levels are lower

Thanks @JeffW , excellent analysis. Yeah, I did think about this one, I understand that HbA1c is not a perfect marker by any means. My Homa-IR is very low at 0.44 when last tested (likely suggesting that my glucose regulation is generally quite good). However, with a combo of weekly rapa + daily rosuva (consistently taken for 4 weeks), I noticed my HbA1c significantly went up (with all other variables largely remaining the same), which prompted me to slap on my CGM (yes, it is Abbott Freestyle Libre 2) to observe the patterns. Sure, will consider using Dexcom at some stage.

[snax444]

@CronosTempi , here is ChatGPT comparison for equilavent of rosuva 5mg (just for general reference, to be viewed with caution)… At low dose 4mg, Pitava seems to make a good case for me to try

[snax444]

@John_Hemming

Because I have long periods between rapamycin I think I see my glucose feedback system stabilising before rapamycin knocks it off balance again

Interesting viewpoint that does resonate with me

[relaxedmeatball]

I don’t really see the issue here, to be honest? Your glucose went up after eating a burrito, which isn’t a surprise. And it never went hyperglycaemic. The movement up and down is quite normal because digesting the food over several hours and it’s being constantly absorbed, and you are also clearing it from the blood. If you add activity like walking, that’s going to accelerate the clearance. That is balanced with increasing and decreasing your hepatic glucose output, all aimed at keeping your blood glucose relatively stable. To me, that “up and down” looks like homeostasis working perfectly.

@snax444

So I guess I need to isolate the drugs one by one and do some more testing. My goal is HBA1C = 5%, Apo(B) < 60mg/dL, and leveraging sirolimus for episodic mTORC1 supression, and trying to achieve these 3 goals without any impact to liver/kidney function.

Pretty ambitious, depending on your genetics. Based on the goals, why not add some fasting, taking the Rapamycin at the start of the fast? I think that would give you better mTORC1 activity reduction, and it’s also a way of lowering glucose area under the curve.