How we might evaluate our immune system in the absence of obvious side effects

Doctors
#1

Let me say at the outset of this post that I am not a medical professional. RapAdmin asked me to help with this sub-forum, I suppose since I pushed for it to happen.

As an initial topic, I, along with many others, would like to better understand how and when to adjust my rapamycin dosage.

In this article, What is Rapamycin? Benefits and Side Effects **, the following is of particular interest:

“Some of the more common side effects include lowered potassium levels in the blood, anemia, decreased blood platelets, increased blood pressure, decreased kidney function, increased triglyceride levels, constipation, joint and muscle pain, dizziness, fever, headache, nausea, diarrhea, and abdominal pain….”

Many of the members of the rapamycin.news forum take or are seriously considering taking rapamycin. For various reasons they may do so without having the benefit of physician oversight. The question of dosage is always an issue and so they look to other users for guidance.

The current conventional wisdom is that when you have side effects, you back off. Without side effects, you gradually increase dosage. But when there are no apparent side effects, is then the sky the limit?

There are routine blood test that are associated with immune system performance. What lab tests, customary and those less common that could be added, could one look to for gauging early signs of immunosuppression? And based on very early signs, would it be expedient to first attempt to enhance immune system with ostensibly helpful supplements or to immediately back off to a lower dosage?

For example: | Potential of Mushroom Compounds as Immunomodulators in Cancer Immunotherapy: A Review
“Mushrooms have been shown to have the ability to stimulate the immune system, modulate humoral and cellular immunity, and potentiate antimutagenic and antitumorigenic activity, as well as rejuvenating the immune system weakened by radiotherapy and chemotherapy in cancer treatment.”

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Side Effects of Rapamycin (part 2)
Side Effects of Rapamycin (part 2)
#2

The role of rapamycin as an immunosuppressant is very complex and misunderstood. Much of that is due to the complexity of the immune system itself.

Rapamycin works in a paradoxical manner. On the one hand it supresses the proliferation of naïve T cells, allowing for an alleviation of the host/ graft transplant reaction. Because this is commonly described as immunosuppression, the fear is that it will increase the risk , and severity, of infections.

Renal transplant patients are very prone to a resurgence in cytomegalovirus infections, which can be quite serious. Interestingly, those patients on rapamycin fared much better against CMV than those treated with other agents.

Here’s the paradox. Rapamycin was found to actually increase a subset of T cells known as CD8+ memory cells. This is particularly true in the quality of their functioning. This was very protective against CMV.

Of further interest, rapamycin was found to increase the immune response to viral vaccines in both mice and monkeys. And not just viruses, but also in mice , there was an augmented response to the mycobacterium TB vaccine.

Furthermore, for the first time, Mannick et al showed a similar response in aging humans from just a low dose of everolimus. In this study it was proposed that rapamycin rejuvenated the T cell population by reducing the percentage of detrimental PD1 T cells which accumulate as we age. This lead to a beneficial response to the flu shot.

At present, there seems to be a general sense that rapamycin protects against viruses, but predisposes to bacterial infections. This appears to be mainly from statements made by Alan Green presumably based on clinical experience. There doesn’t seem to be any other evidence for this risk, especially in those using the drug intermittently.

We need to remember that bacterial infections like sinusitis, bronchitis, and cellulitis, are very common and would be highly prevalent in a control group. Also, it’s very likely that in a very elderly population, like those treated by AG, that polypharmacy is in play and would make it difficult to implicate rapamycin.

As an example of this, I recently saw a hospitalized patient with a severe pneumonia at the age of only 52. She took rapamycin 3 mg once weekly for anti aging purposes. It was therefore assumed that rapamycin was a contributing factor, if not the sole factor, in her infection, which was bacterial in origin. However, on further evaluation, she was also on clozapine which is a known risk factor for severe bacterial pneumonias.

So I would say that we need to define rapamycin as an immunomodulator which acts in a paradoxical manner on the immune system and shows no clear evidence of infection risk, either viral or bacterial, at this time. This is especially true in the intermittent usage group for anti aging purposes.

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#3

BTW, of particular interest in this regard, is the speculation that the protection against CMV by rapamycin may be part of its protection against the development of CAD.

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#4

Thank you for the article. Are you aware of any recent studies about possible cardio- protective effect of Rapamycin?

#5

The main ones in humans were the heart and liver transplant studies.

I generally disregard the rodent studies since they die of cancer mainly.

Decent rabbit study:

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#6

@CTStan Thanks for bringing this up! Dose adjustment has been as slippery as picking a starting dose. Since my expertise is more on hormone replacement / optimization, I am at best a poorly qualified guesser - so her we go!

The immune suppression component appears to be related to mTOR2 inhibition that is blocked more with continuous dosing by blocking mTOR as component before it can become mTOR2. Peak and trough levels of Sirolimus maybe a way to give us an indirect way to guess. A direct measure of mTOR2 inhibition, if even possible, could help.

I do understand when people choose to decrease and or stop their Rapamycin based on specific signs and symptoms like, mouth sores, illness and concerning lab changes from baseline. I have less of an understanding of when someone finds a tolerated dose, such as 6mg / week, and decides to increase it. It does seem many end up with immune changes on their higher doses and then they back off.

Thank you for starting this thread!

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#7

It would be nice to have a nice and easy way to monitor our risk of infection. Could this be just looking at the CBC, or the complete blood count test?

Since the concern seems to be the risk of bacterial infections from rapamycin, then one thing we could theoretically look at would be the absolute neutrophil count. This would be part of the differential component of the CBC. Since neutrophils fight off bacterial infections, we don’t want that count to be too low.

If neutrophils drop below 1500 we call that a mild neutropenia, but if they drop below 1000, this would make it more difficult to fight off infections, and below 500 would be quite serious and would put us at risk from even our own bacteria and fungi.

If we look at the Mannick study, there’s no reported neutropenia at the 5 mg per week dose of everolimus. However, at the rather hefty dose of 20 mg per week, the incidence of neutropenia was 3.8%. They didn’t define this at far as I can tell, so I’m assuming that they mean something other than severe , since none of the participants reported severe infections as a side effect. But if you’re on rapamycin approaching 20 mg per week, then it’s a good idea to monitor the neutrophils.

As far as the white blood cell count is concerned, this will generally go up with bacterial infections. Of greater interest to me is how the WB
C count can be a marker of inflammation and even longevity.
Michael Lustgarten did a nice review of this and it appears that the ideal range of the WBC is between 3500-6000, giving an increased life span of 7 years average.

I have found that my WBC’s dropped from 5500 to 4800 on rapamycin. That’s on 5-6 mg per week over 5.5 years. There’s been no significant changes in my neutrophils.

So is the CBC useful in the context of rapamycin usage? Maybe a little, but primarily if you’re on a larger dose than is usual.

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What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity?
#8

Here’s the Lustgarten article

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