Higher Dose Rapamycin - some initial results

So in the morning of 28th July 2024 I took a packet of Zydus (6mg) and a packet of Biocon (10mg). I ate half a grapefruit about an hour before taking the Rapamycin and the rest at around the same time. This has a multiplier effect by inhibiting digestive enzymes. Hence it perhaps equivalent to 50mg of Rapamycin.

Previously I was taking 6mg every 21 days. The only side effect I have noticed is a disruption of sleep previously. However, because of my increase in cytosolic acetyl-CoA my cells have a greater ability to generate cytosolic ROS to fight local infections. I tend, therefore, not to generate a lot of WBCs and even without rapamycin I am leukopenic (short of WBCs).

I do a blood test pretty well every week although because I wanted a baseline from a lab which does a broader range of tests before I took the Rapamycin I did two blood tests that week. (22 and 26 July).

I was away from my normal base so I used a different lab to the two labs I use normally, but I have enough records from that Lab to see any pattern variations.

I am unusual in that although I do not drink every day I do drink on some days and when I do it is quite heavily. Also I take large amounts of melatonin and citrate along with an otherwise pretty standard healthspan orientated stack.

I am 64 with a BMI of around 22. I do not do masses of exercise although I walk around 10,000 steps each day and do some resistance exercise.

There is an interesting challenge with large amount of citrate supplementation (and I mean over 5/10g per day) which is that this provides more work for the kidneys and so kidney biomarkers can go in a bad direction.

I have all my blood test results and am happy to answer questions, but these are the key points I would make.

In terms of side effects in the early morning of Tuesday 30th July at about 2am I was up and a cat stood on my foot (that’s not a side effect of Rapamycin). I was not expecting this and had a shot of adrenalin which caused my heart to race at about 149bpm. Fitbit identified this as an issue of
concern. The problem with this is that I don’t have a control of a cat stepping on my foot when I have not just taken a large amount of Rapamycin. Hence although it was an odd thing it is not clear whether the heart racing as much was an effect of Rapamycin.

I did have sleep disruption for around a week or so. That would be expected from a higher serum level of Rapamycin and hence higher levels of autophagy.

Looking at WCC (putting dates the English way of day/month)
26/7 3.71, 31/7 3.1, 7/8 2.8, 14/8 2.69

The results on 26/7 and 14/8 are from the same lab and show a drop in WBC of a billion cells per litre. That is perhaps the way you would expect Rapamcyin to function. It reduces the production of WBC so although it does not drop immediately it goes down reasonably quickly after that and then pulls back up. My guess is that next week (the blood draw is scheduled for tomorrow) WBC will be either flat or going back up.

C Reactive Protein.
My CRP is normally too low to measure, but pops up every so often when I have an infection then drops down over a period of a week or two.

CRP 22/7 <0.15 26/7 0.31,31/7 <0.3, 7/8 0.6 14/8 <0.3

The lab I used on 26/7 and 15/8 has a minimum threshold of 0.3 (mg/L), as does the one on 31/7 and 7/8. The one I used on 22/7 has a minimum threshold of 0.15mg/L and I will be using that lab again tomorrow and I expect CRP to be below 0.15mg/L.

What I conclude from this is that I had an infection, possibly as a result of Rapamycin reducing the immune function. I did not notice the infection consciously. However, there clearly is a risk from a reduced immune function. This perhaps would discourage me from increasing the dose (even if it were to be less frequent).

HbA1c 16/7 30.98, 22/7 31, 26/7 31.7, 31/7 31, 7/8 28.9, 14/8 31.1
These figures are in mmol/l. 31 is 5% 28.9 is 4.8%. I am going to keep an eye on this. It varies quite a bit ordinarily, but I would hope that as the effect of the Rapamycin fades into the past this will reduce a bit. I have had HbA1c as low as 4.18%, but that requires a same day result from the test as it metabolises a bit in a blood sample.

Lipids
The threshold in the UK for worrying about LDL-C is 3 mmol/L
16/7 3.01, 22/7 2.74, 26/7 2.81, 31/7 3.6, 7/8 3.2, 14/8 2.68
Well that is perhaps what you might expect from Rapamycin. I think the 3.6 figure was exaggerated by a testing delay (I know there was a testing delay because MCV was wrongly high).
Sadly only one of my labs gives an ApoB result. This was, however, really significant.
16/7 91, 26/7 83, 14/7 105
Now I think this is one of the most significant negatives of this particular exercise. Because all the labs give LDL-C I track with that and it floats around a bit. However, this value of 105 is an outlier and I think it is Rapamycin rather than a test artefact.

I do have Lp(a) (from the same lab, not the others) 16/7 5.3, 26/7 6.7, 14/8 6.5 (nmol/l)

Creatinine is interesting
26/7 91.5, 31/7 110 (delay), 7/8 88, 14/8 86.3 (mcmol/l)
I think this points to a real improvement. Creatinine is another biomarker which increases in a sample which metabolises in the post. Hence the 31/7 value is a test artefact.

I am not happy with Cystatin-C which I have managed to get as low as 0.67
26/7 1.07, 14/8 1.13

I think I know what is causing this when you look at creatinine, urea and urate I think between 26/7 and 14/8 kidney function actually improved but because of timing issues Cystatin-C deteriorated. This is, however, one key marker I am looking at getting back to below 0.75.

PSA is interesting
2/7 0.85, 16/7 4.18,26/7 1.93 14/8 0.87.
My PSA is normally below 1 but for some reason shot up on 16/7 (again only the one lab does it by default), but then it gradually came down again. I don’t think this is a Rapamycin issue, however.

So what are my initial conclusions

a) I am not going to increase the dose without running the test again at this level maybe a few times.
b) It does mess up ApoB so I want to see some more ApoB results before doing it again. I will continue tracking LDL-C. I will also aim for more measurements of ApoB when I do it again.
c) It probably does have a greater beneficial effect than the lower dose although the expected side effects do occur. However, I think it may have improved kidney function.
d) I will try again at this level, but I am going to wait for a few more sets of results to see things coming back into line.
e) It is probably best to avoid doing this at a time when you might be exposed to more sources of infection.

Biomarkers, however, are subject to a lot of variation without any of the underlying systems changing so it is hard to be certain. I think the ApoB result is, however, quite significant.

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ApoB only matters long term. Just like a $1000 investment is more worthwhile ticking for 30 years than 1 month. I guess in this case it matters if it is elevated over time with repeated dosing.

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If I get some time I will review the historic ApoB results against Rapamycin dosing.

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I thought I would add this photo from my bald patch. I use a macro camera and I think the large Rapamycin dose may have started off quite a few fine pigmented hair follicles.

The theory is that the mitochondria have been damaged as a result of ROS caused by DHT. Hence if rapamycin improves the quality of the mitochondria the previous minaturisation of hair follices and cessation of the production of hair should reverse.

Its difficult to be certain as yet and because when I was away I was not able to monitor this daily so cannot be entirely certain, but it does appear that Rapamycin has improved the mitochondrial quality.

I have also now looked at all of my ApoB records and Rapamycin records and it appears that the large dose of rapamycin does increase the production of ApoB in the same way as it reduces the production of WBC. What this means is that after the large dose the ApoB level gradually goes up until the effect of Rapamycin fades after which it goes down again.

The next time I do this (I am currently looking at late September) I will make sure I have more ApoB records so it can be more closely tracked.

It varies a bit anyway as do all biomarkers.

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I thought people might like this photo. If you look in the middle you can see a row of 4 follicles starting to produce hair.

This is something i see quite bit of where a row of follicles changes. I think, but have not proven, that they follow some form of blood supply - capillary probably. Hence as the localised biochemical environment changes the cells start producing hair.

This row of four is not unique there are other rows which show similar development where perphaps one follicle is in advance of the others (as is the case for this four).

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I have yesterday’s results now and CRP is now back below 0.15mg/L. HbA1c has also dropped a bit.

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Have you noticed any other side effects?

For instance, I am stuck at 5 mg + GFJ, because if I go above that, I experience widespread itchy hives for a few days. I assume this will increase my CRP as well as being unpleasant.

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I now have results from 27/8. This is from the lab I use which does the broadest range of tests.

Interestingly non-fasting glucose was quite low. (3.63mmol/L, last time 5.49). Last time insulin was really high at 189.6 (pmol.L) and is now back down to a nice level 91.1. Lp(a) has gone down to <5.2 from 6.5 (nmol/L). HbA1c is very slightly up. This may be the sample metabolising (as glucose reacts with haemoglobin thinking about it, it probably is and that may have pushed up ApoB and LDL-C (Which is also on the high side). CRP is below the measurable limit (this lab is not as sensitive). Urea has dropped to a record low on 3.39 (mmol/L) and urate is quite low at 287.7.

What I think I can see is the effect of stopping drinking alcohol for 4 days prior to the test. A record low on Urea (BUN) - which is for my blood tests since 2021 (I had 1 in 2021 and started frequent testing in 2022) either means Urea metabolises a bit in samples and the testing on this one was delayed or it is significantly low.

Because of the understainty about metabolism it is not clear exactly what is happening about lipids and HbA1c. I think what it looks like is that the strong effect of rapamycin was still trackable in the leading indicators (insulin, glucose) on the previous test, but that has now completely faded. Hence Lp(a) has come back down, insulin and glucose are down but the lagging indicators (HbA1c) are still a bit high. Me not drinking for 4 days also will push up HbA1c (oddly enough).

In any event I want to take the same dose again, but I still would like to see ApoB move back down in line with everything else first. Hence I will probably delay Rapamycin until I see that happen. The uncertainty about sample metabolism is irritating, but just part of life.

Lipoprotein(a) is supposed not to change much. Here are my recent values in nmol/L <5.2, 6.5, 6.7, 5.3, 6.1, 5.5, 5.7, 5.7, <5.2, <5.2, 8.2, 7.8, 5.7, 5.3, 13, <5.2, 5.5, 5.8, 5.6, 7.1, 5.8

I think the 13 is when they tested someone else’s blood.

What seems to be in that is a process of gradual change. I have not particularly tried to correlate it with protocol changes, but as it got it at one point to over 8 and now back below the measurable threshold I would argue that it does change.

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Adding some thoughts about what level of Rapamycin was in my system to compare it to these calculations. If you assume 16mg with grapefruit is the equivalent of 50mg and a simplistic effective half life of 60 hours. Then each week reduces rapamycin levels by a factor of 5.7(ish).

So in terms of dose for each week it is equivalent to
wc 28/7 50
4/8 9mg
11/8 2mg
18/8 0.25mg
(then trivial)
The broad blood tests being compared are 14/8 (after a week with an effective starting dose of 2mg and 27/8 without any really in my system).

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I thought people might be interested in seeing some of the insulin figures. These go back from last week, but are not every 2 weeks, but less frequently. I may try some Tuesday/Friday results after the next Rapamycin dose to try to track the movements more closely to the dose.

All in pmol/l.
91.1, 189.6, 104, 131, 27.3, 125, 60.2,121, 65, 129, 158. 171, 102, 65.5, 111, 152. 48.9, 161, 133, 136,93.3, 180, 42.8, 166, 46.5.

If I get a bit of time I will try to track these against Rapamycin dosing.

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Are these all taken at the same time of day? Fasting? How do you account for the range?

Roughly the same time of day. Normally not fasting. I vary a lot of things and it will take aome time to check my records and come to any idea as to cause other than rapamycin.

This is really interesting so please continue to share results.

Did you by any chance happen to check ferritin or do a full iron panel in these tests? Or anything else noteworthy that remained mostly unchanged?

Any differences in RDW or Albumin?

Ferritin has reduced over a period of years quite nicely. RDW is driven by changes in MCV so I don’t worry about it when MCV is going down. Albumin floats around in the 42 territory, but if fasting it goes lower.

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