#49

You can see this in my white blood cell results I posted in the high dose topic, but at a point Rapamycin inhibits the processes that lead towards cell division. Obviously you don’t want to stop all cell division and hence you need to have a period of time (the trough) when Rapamycin is basically at too low a level to have any serious effect.

#50

High-dose rapamycin (~ 5 mg/day) in young (~ 20yo?) females is harmful
Low-dose rapamycin (~ 5 mg/week?) in older (~40yo? pre-menopausal?) females is beneficial

But I’m neither 20 or 40, I’m at the age where fertility becomes sharply declining and I’m the taeget group to trying to slow it down.

#51

Maybe this can be added to the thread which lists all the possible negative effects of rapamycin that we know of so far?

There’s the equivocal data on testes shrinkage and/or fertility suppression in males at some dosage.

Disclaimer: I too am a male, and don’t know much about this aspect of human health.

But my question is whether these negative effects, including disruption of the menstrual cycle can in fact be characterized as accellerated aging of this tissue. I ask, because CR also causes disruption of the menstrual cycle, and in more severe cases, it causes amenorrhea (which can also be caused in extreme athletes). Amenorrhea, or the arrest or cessation of the menstrual cycle is superficially similar to menopause. Which is what characterizes aging. But it’s clearly not aging, at least in CR’d animal models. In fact CR under these circumstances preserves and extends fertility upon cessation of CR (increased calories).

CR represents adaptations away from procreation towards preservation and life cycle prolongation in both males and females. There are corresponding hormonal adjustments, where for example testosterone levels in males drops, although that low level is preserved longitudinally to the point where compared to ad libitum (non-CR) controls, at very advanced age the testosterone levels in CR’d individuals translate into higher levels compared to old ad libitum individuals. This shows the preservation aspect of CR, including preservation of fertility into advanced age (upon refeeding).

If rapamycin is a CR mimetic in some respects, I wonder whether the same thing might not be happening here, hence my question about whether these disruptions can accurately be described as accellerated aging specifically.

Of course it remains true that younger females intending to get pregnant should not be on CR or rapamycin, but I think we already knew this. Still, perhaps this caution should be emphasized as an undesirable side effect for those intent on having kids. YMMV.

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#52

I have my own hypothesis about fertility which is based around the research and my hypothesis on development/aging.

The oocytes (eggs) are created when the woman is an embryo. In the electron transport chain of the oocyte mitochondrion Complex 1 is inhibited. This reduces the rate at which ROS are generated and the mitochondrial DNA is damaged. However, it does not reduce it to zero.

If the mitochondria end up too damaged then even if the eggs get fertilised they are more likely to have damaged mitochondria and hence miscarrry. Hence it is important to do what you can to keep the quality of the mitochondrial DNA.

The ovaries and general somatic cells of the mother are, however, functioning with complex 1 in the mitochondria active. Hence the rate of development/aging is the same as the rest of the body (apart from the CNS which ages at a slower rate).

Hence the tools to be used for that are different.

#53

You’re not in the target group for the VIBRANT trial, as your AMH was high for your age. The benefits (not yet fully published) seem to be only in premenopausal women with lower than normal AMH.

When did you stop rapamycin? When do you plan to retest AMH? Please keep us posted and I hope it will bounce back :pray:

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#54

Maybe it’s not reassuring enough, but my wife was taking rapamycin for a year, from age 34 to 35. She stopped taking it six months before trying to get pregnant, and she got pregnant on the first try, and the baby was born healthy.

We monitored virtually nothing.

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Chris Masterjohn: Rapamycin, "The Worst Longevity Idea Ever Conceived"
#55

It’s obvious that you’re angry and this is a very personal issue for you. But really, this is a drug which is originally authorized for organ transplant patients and is in no way encouraged for young healthy people. No sane doctor in the world would have prescribed this to an otherwise healthy 37 year old without children who still intends to have them. The trial in question seems to have taken this into account, presumably because your demographic (i.e. older but high AMH) was too risky, since you have more to lose and less to gain.

To be honest, I think anybody who isn’t bullshitting you will freely admit that we are indeed absolutely clueless in this field. For those of us taking Rapa, or taking other interventions, it is a gamble based on very limited data and we make our own personal risk:reward calculations. I don’t think it’s fair to blame researchers, or anybody else.

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#56

How drastic this issue is i try to portray in this image.

If Rapamycin can age ovaries in a woman at late stage of fertility (37 is late) what can it do for pro-aging in people in general of young to middle age?

IMG_20250410_182413
IMG_20250410_1824131220×2182 246 KB

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#57

Untrue, Dr Aimee is prescribing it for everyone in my age group to “prolong fertility”
You dont realize that fertility drops from 37 to 40 like it’s 20 years difference. Ovaries age extremely fast in that period. Thus my age is perfect to intervene according to all fertility anti-aging specialists.
Because later it’s too late.

Also, nobody is even discussing the mechanism how can rapamycin age a person. Because if it ages ovaries , ages a whole person. Does anyone have any idea why?

#59

The negative effects of Rapamycin tend to be because Rapamycin inhibits cell division.

However, what ChatGPT says is:
Rapamycin may reduce AMH (Anti-Müllerian Hormone) because it affects the activity of ovarian follicles through its inhibition of the mTOR pathway, which plays a key role in cell growth, metabolism, and reproduction.

Here’s a simplified breakdown:

:brain: What AMH Does:

  • AMH is produced by small growing follicles in the ovaries.
  • It reflects the ovarian reserve (how many eggs are left).
  • High AMH = more follicles; Low AMH = fewer follicles.

:dna: What Rapamycin Does:

  • Rapamycin inhibits mTOR, a key regulator in cell growth and follicle activation.
  • In ovaries, mTOR activity promotes primordial follicle activation—basically, turning dormant follicles “on.”

:test_tube: How This Reduces AMH:

  • By inhibiting mTOR, rapamycin slows down or suppresses the activation of new follicles.
  • Fewer growing follicles → less AMH is produced.

So, paradoxically, AMH goes down, but it might be preserving the follicle pool, rather than depleting it.

:pushpin: Important Context:

  • Lower AMH with rapamycin doesn’t necessarily mean ovarian aging or fertility loss.
  • In some studies (mostly animal models), rapamycin actually preserves fertility longer by slowing down follicle depletion.
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#60

Another question asked of chatGPT

Q: how does rapamycin harm fertility?

Great question — rapamycin’s effects on fertility are a bit of a double-edged sword. While it may preserve the ovarian reserve by slowing down follicle activation, it can also impair fertility in the short term by disrupting key processes required for successful ovulation and reproduction.

Here’s how rapamycin can harm fertility, especially with continuous or high-dose use:

:dna: 1. Inhibits Follicle Growth and Maturation

  • mTOR signaling is essential for follicle development beyond the primordial stage.
  • Rapamycin blocks this, so follicles can stay dormant or fail to grow properly, impairing ovulation.

:egg: 2. Disrupts Ovulation

  • mTOR is involved in the LH surge response and ovulatory cascade.
  • Inhibiting mTOR can blunt or block ovulation, even if the follicles are otherwise healthy.

:seedling: 3. Alters Endometrial Receptivity

  • mTOR also regulates endometrial cell growth and remodeling.
  • Rapamycin may impair implantation by making the uterine lining less receptive to an embryo.

:test_tube: 4. Reduces Hormone Production

  • It may affect granulosa cell function, reducing estradiol production, which is critical for:
    • Endometrial thickening
    • Fertility signaling pathways

:petri_dish: 5. Dose & Timing Matter

  • Chronic or high-dose rapamycin is more likely to disrupt fertility.
  • Some studies in mice show temporary infertility, which reverses after stopping rapamycin.
  • Low, intermittent dosing may be less harmful or even protective long-term, but this is still being researched.
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#61

I spent some time looking at fertility from the perspective of Melatonin. This also has double effects on fertility. It protects the eggs, but reduces ovulation. Hence if the timing is right it can be helpful.

IMO care should be taken propping up mitochondria, however, as there is a danger that eggs with mitochondrial diseases end up being fertilised and going to term.

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#62

Exactly. This tracks with the impact of CR on fertility. It suppresses it, but preserves it longer. The net effect is slower aging and longer lifespan. Which is why I was wondering if calling this suppressive effect “aging” is accurate.

The analogy is to a candle. You need a big flame for it to throw enough light to see - being fertile. When the candle is at the end close to burning out - aging - the light level drops and it’s too low to see - infertile.

But now you find a way to keep the flame low - CR, rapa - even though it’s still the middle of the candle - too low flame to see - infertile. It seems/looks just like the low light at the end of the candle, old age, so it looks like “hey, it’s made it age faster!”. But really what is happening, is that by keeping the flame low - slowing down ageing - the candle lasts a lot longer - longer life - than a candle that is burning fully and so burning out quicker. And so it preserves the potential of going full flame - fertile for much longer, and when you want a bigger flame - fertility - you STOP the CR, rapamycin and now there’s enough light to see, long after the other candle has burned out. CR and rapamycin might preserve fertility longer this way, but of course if you want to reproduce, you must stop the CR, rapamycin.

CR prolongs life, preserves fertility longer, but to achieve reproduction must be stopped at that moment. Which is why we say that CR slows down aging and prolongs life by trading off reproduction. But it would be factually incorrect to say that CR accelerates aging of any tissue - it does the opposite, it slows down the aging, including reproductive capability.

If rapamycin is a CR mimetic in this respect, it’s possible that exactly the same thing is true of the effects of rapamycin on fertility. One way to test this is to see if fertility bounces back after stopping CR/rapamycin. We know it does for CR in animals. Does stopping rapamycin bounce back all the biomarkers associated with fertility in humans? That could be a big clue. Keeping in mind that as we saw in mice, the effects of rapamycin persist for quite some time after stopping use. So it needs time.

That’s the hypothesis. It might be wrong. It might be that in fact rapamycin hastens aging in humans. We don’t know, because unlike in animals, we have no adequate studies. That means we are gambling. Looking at the totality of the evidence and arguments, some of us walk away from rapamycin, and some take it. I’m gambling that it’s slowing aging, so I take it, but I might be wrong. Which is why I have never advised anyone, nor would I advise anyone that they take rapamycin - it’s a gamble. All I can do is explain why I take it. What you do is 100% your decision.

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#63

Thats a fair position to take. I have my own views as to what aging/development is. Obviously I think I am right, but I have to accept I may be wrong.

Hence I come to conclusions as to how best to act in the circumstances. Anyone else can take a different view.

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#64

I was in the Ageless RX Pearl trial that ended last year. To be considered for a candidate you had to be within a certain age group. I’m 77 so was maybe 75 when I first took part in the trial. The idea of taking low dose Rapamycin is to keep a person healthier as they age. Someone at your age wouldn’t have been allowed in the trial. I was taking 15MG of the compounded form of Rapa and was just offered a chance to increase it to 20MG starting next month. I bike ride, and hit Planet Fitness at least five times a week. I do have Arthritis but overall my health is good.

Video of the trial results. It appears to have benefited women a little more then men.

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#65

Hi! I believe 6mg/week of Rapamune is a very substantial dose. Late Dr Green recommended only 2mg/week to people around the age of 40. You might be better off with 1-2 mg every 2-4 weeks in my opinion. At this low dose, you’ll still experience rejuvenation, but won’t necessarily get permanently supressed cell division.

As rapa has ~3-4 day half life, 6mg/week results in very sigificant growth supression. According to a study conducted in Iran, people who’ve had organ transplant only use 8.4mg/week of Rapa on average (spread out daily – Sirolimus Dose Requirement in Kidney Transplant Recipients in Iran - PubMed). People are fooling themselves when they call 6mg/week enteric coated tablets “low dose” – it is not.

We have studies that suggest Rapamycin can interfere with testicular function; naturally it should! But only at high doses.

Same with Brian Johsonson’s experience, he used too high a dose, and stacked too many mTor inhibiting interventions on top of each other (intermetting fasting, vegan diet, CR, Rapa, numerous supplements…). In the end he was looking like a sick cancer patient for the longest time!

So, 1) don’t stack 2) go low dose if you decide to take it at all. Best of luck!!

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#66

ChatGPT also said it will make AMH higher, also you have to keep in mind it also shortened my cycle length which is a typical sign of ovarian age.

#67

I’d be allowed to a trial for ovarian aging, because ovaries die very fast after my age.

#68

Based on your AMH, I understand that you were not in “menopausal transition stage -3a” which was the criterion to be allowed to the ovarian aging trial.

#69

ChatGPT is quite useful at summarising things, but it tends to provide the conventional wisdom. It is probably worth investing some time to find using ChatGPT or a more traditional search engine or another LLM a list of the papers that study this and analyse those.