21 Year Old Female on Rapamycin for 7 months

I was looking at the rapamycin dosing in this article. This article said that 14ppm in food = 2.4mg/kg/day. They list various studies, one study even used 42ppm, which is 6.72mg/kg/day.

According to this article, bone density reaches peak around 30.

“Your bones are continuously changing — new bone is made and old bone is broken down. When you’re young, your body makes new bone faster than it breaks down old bone, and your bone mass increases. Most people reach their peak bone mass around age 30. After that, bone remodeling continues, but you lose slightly more bone mass than you gain.”

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Ah - I think the issue and discrepancy here is how they are measuring the rapamycin. Matt K. is the author on both the papers, so the papers are fine, but I think they are talking about different types of measures.

When they say 14ppm, they are measuring the portion of the mouse chow/food that is rapamycin.

demonstrated that UMHET3 mice fed a diet containing encapsulated rapamycin at 14 ppm (∼2.24 mg/kg/day)

In the injections they are measuring the dose as measured per kg of weight of the mouse - so a different reference point. Its easy to get confused on this because they are clearly not equivalent measures; one being food based, one being animal weight based.

Analysis of rapamycin levels in blood suggests that daily i.p. injection of 8 mg/kg yields blood levels of around 1800 ng/mL one hour after injection and 45 ng/mL 24 hours after injection (Johnson et al., 2013c). For comparison, blood levels of 3-4 ng/mL rapamycin were measured following dietary delivery at 14 ppm in the same mouse strain (Zhang et al., 2014) and studies from the ITP have reported between 9-16 ng/mL at this dose and 23-80 ng/mL in animals receiving the 42 ppm rapamycin diet (Miller et al., 2011). Thus, daily i.p. injection of 8 mg/kg rapamycin, which appears to be well tolerated in wild type mice (Johnson et al., 2013c), yields circulating levels of the drug that are at least 20-fold higher than the highest concentration that has been carefully tested for effects on normative aging.

My understanding for reducing the risk of osteoporosis in old age is that you want to build as much bones as you can when you’re young (before 30). And the way to do that is by doing resistance training. Once we reach peak bone density, we start to lose some bones every year. So the higher the peak density, the more of a buffer you have for bone losses over the years. Of course, one should continue to do resistance training (after 30) to maintain as much bones as possible and slow the losses.

The authors of the mice study specifically designed the study to investigate the timing of the initiation of rapamycin treatment and it’s impact on bone health.

A key aspect to evaluating the clinical utility of rapamycin as an anti-aging therapy is determining the differential effects of rapamycin throughout the lifespan, and in particular, understanding how the age or ‘life phase’ of rapamycin treatment initiation influences health and longevity.

In the present study, we chose to initiate rapamycin treatment at 16–20 weeks of age – an interval shortly before termination of skeletal growth – to establish the effects of rapamycin on development of peak bone mass, a major determinant of bone health during aging.

Based on our findings, we conclude that rapamycin treatment has adverse effects at this critical stage of skeletal maturation.

The study also mentioned that rapamycin seemed to be beneficial to bone health in older rodents.

In contrast to our findings, the few studies examining rapamycin or rapamycin analogs in older rodents have reported moderate protective effects of rapamycin against bone loss, suggesting the impact of rapamycin on skeletal health may be age-or context-specific.

The paper also mentioned that the reason for choosing relatively young mice was to account for the differences in bone development between mice and humans.

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I think its good (and important) to bring up issues of side effects with regard to rapamycin as its still relatively new in terms of its application in healthy human populations for longevity applications. So thank you for posting all of this research, and I appreciate the discussion.

I don’t want to come across as being critical of your efforts - I just want to try to tease out the details so that everyone has a better understanding of possible reasons why a given study may or may not translate to humans, and to help us all accurately understand risks and how to monitor them.

As in all our interactions on this forum - I want to emphasize that its important that we put as much focus/effort/analysis on the science as we can, but at the same time these criticisms are never personal (I’m not being critical of @Kandice as a person (and I really hope its not coming across like that), but I do want to question and evaluate the scientific paper that was referenced and conclusions it draws, and its relevance to healthy people taking rapamycin according to the current longevity protocols).

Our discussions here should never degrade to personal attacks. At the same time I think we all benefit when we focus on the strengths, weaknesses and applicability of any of the research papers we come across relevant to this area of longevity.

There is a long history of what I would call “alarmist” and negative reviews of rapamycin due to its history of use at higher doses, and daily dosing, in organ transplant patients who are typically taking many other medications and frequently have many pre-existing medical conditions that precipitated the need to replace an organ. The side effects documented in these patient populations can be very bad, and this is what many doctors and professionals who first research rapamycin come across and form a negative opinion from. It is for this reason there has been a great deal of push back from the medical community on rapamycin.

So, I just ask people that when they are posting possible side effect information related to rapamycin to try to accurately characterize the information and compare it and contrast it to what healthy people are actually doing in terms of longevity protocols here.

The study mentioned by Kandice was this paper on bone growth and rapamycin: Rapamycin impairs bone accrual in young adult mice independent of Nrf2 - ScienceDirect

Possible caveats as to this study’s relevance to 20 to 30 year olds taking rapamycin include:

  1. Dosing: The dosing used in this study is very high (mice were given 4mg/kg by injection, equivalent to 200+mg rapamycin for a 50kg/120lb human), given every two days. So, on a weekly basis (7 days) it would be on the order of over 600mg+ per week of rapamycin. This is approximately 120 times the weekly dose that is typically used in Longevity applications of rapamycin. I also think its important to put things in perspective. If a person were to take 120 Times the Recommended Dose of any over the counter drug (e.g. Aspirin) I suspect you would likely end up sick and in the hospital. By comparison - they did that in this mouse study and the dose was well tolerated with only minor implications. The simple truth is that Rapamycin is a very safe drug, as outlined here: How Safe is Rapamycin (part 2)
  2. This is a small study - 15 mice were used of the WildType.
  3. How large are the effect sizes? I don’t have time to evaluate this paper in great depth right now - but my questions would be around the issue of significance of the findings. If a mouse, or human, is starting rapamycin (hypothetically just before “the latter stage of linear growth and bone accrual”, I would wonder what percent of remaining bone growth and accrual we are talking about here - if a mouse or person’s bone growth/accrual is at the 95% or 98% level at age of initiation - then we’re talking about the last few percent of growth. At doses of rapamycin 120 times higher than what people are taking, perhaps there is an absolute reduction in bone density of 1% (?). Also noted in the paper was “Rapamycin treatment did not affect bone length and there was no difference in bone length between wild type and Nrf2−/− mice.” If someone has the science background, time and interest - I’d encourage them to investigate this more, but from a cursory review it seems that this works out to quite low probability (at the current level of the data presented) as being very applicable to our population of healthy younger people taking rapamycin.
  4. For people concerned about the risk, Dexa scans can be done and compared to age-matched populations to see if this is in fact an issue for any specific person.
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Hey Jade! Great to have 20 year old perspective on the site:)

I would personally not use Rapamycin at 21 :slight_smile:

I know this is contrary to what most are posting, but it is always nice to have a balance of opinions to chose from. Since we all are guessing based on our limited studies then differing opinions are not unreasonable. Depending on multiple factors, I think aging really starts to change around 25. In females that is when fertility rates are optimal and some suggestion that immune system and cancer risks are at there best. With that being said, but may be disputed, I would wait for a few years while hopefully we have more data. In the hormone replacement world, the concept of “optimizing” hormones translated for many to replace hormones back to the level of a 25 year old with some clinics even naming themselves - Forever 25.

The aging process is still poorly defined by clear markers, but we do seem to be gaining ground. With so much new information on the horizon, just waiting a few years if I were 21 and focusing on sleep, diet and exercise would be my advice. After 25 or even 30, I think the argument is starting to push in favor of Rapamycin as an option.

I do think your risk is minimal and your educated decision to use Rapamycin is not unreasonable. Since the chances of you noting any changes on Rapamycin as a positive are probably small, I am very interested in your journey.

Suggested supplements. Vitamin D, Fish Oil, magnesium night, B-Complex ( especially if using a oral contraceptive.

Good Luck!!!

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I read that the brain is not fully developed until 25.

I used the formula in the paper below to convert the mouse dose to human dose. Basically, the conversion is not based on body weight alone, body surface area (BSA) is included as well.

The formula for conversion of dose is:

animal dose (mg/kg) x animal Km / human Km = human dose (mg/kg)

Km = body weight (kg) / BSA (m squared)

The paper lists the Km values for different animals.

Here’s the conversion:

4mg/kg mouse dose x 3 (mouse Km) / 37 (human Km) = 0.324mg/kg human dose

At 0.324mg/kg human dose, it’s 19.44mg for a 60kg human.

To simplify the formula, the conversion is mouse dose x the ratio between mouse Km and human Km. The ratio is 3/37 = 0.081. Therefore, multiply mouse dose by 0.081 converts to human dose in mg/kg.

https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.07-9574LSF

27 y/o male here. Started 5ish months ago. Not sure I’d be taking it at 21 simply because you likely wouldn’t lose anything waiting until your late 20s, at which point we’ll have a lot more data from Dog Ageing Project etc.

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There are a number of different models for coverting mouse dosing to humans.

In your calculations above it sounds like the 19.4mg would need to be multiplied by the dosing schedule (every two days in the bone density study) , so 3X19.4mg = approx. 60mg per week. Still extremely high, and not something I think anyone of any age is even thinking about in a longevity context right now.

And again, I would posit that if you took 10X the recommended dose of any medication - e.g. Aspirin, for any length of time you’d probably also run into medical problems. Dose makes the poison.

Yes, agreed. This issue is not unique to this study.

This article says women peak physically in their late 20s. Anti-aging may be akin to applying the brakes on peak physical development.

By its own terms, anti-aging means countering aging. Is a 21 year old already aging? Is there anything to slow down? Or is peak maturation being slowed down?

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The worry here is that you won’t reach your optimal development. You may hinder your development so that your muscles aren’t quite as strong or your brain isn’t fully matured, etc… But, to be honest, most of that development should be completed by the time you are 21. Maybe you are retarding the last 10-20%.

Would you sacrifice 5-10% of your peak muscle gain and brain development for an unknown longevity gain of maybe 0-5%? I wouldn’t.

For me personally, I would wait until 25. But that’s my take.

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There are still a lot of different competing theories on aging. Vadim Gladyshev of Harvard believes aging starts shortly after conception…

Yes, if we consider that aging is damage accumulation, we need to ask the question, when does it begin to accumulate? We know it accumulates late in life, but what about earlier times? Does it accumulate at the age of 30? Yes. At the age of 20? Yes. At the age of 10? Again, yes. At birth? Yes! And even before birth.

First, we published a paper where we demonstrated that damage begins to accumulate already early in life. At that point, we didn’t know exactly if it happens at conception or a bit later.

Interestingly, rapamycin is also the only molecule that was found to extend lifespan similarly when the treatment started in early adulthood or much later in life.

Yes, it’s a nice discovery, and rapamycin is a very promising molecule, for sure.

More details here…

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Blockquote Yes, if we consider that aging is damage accumulation, we need to ask the question, when does it begin to accumulate? We know it accumulates late in life, but what about earlier times? Does it accumulate at the age of 30? Yes. At the age of 20? Yes. At the age of 10? Again, yes. At birth? Yes! And even before birth.

I do agree with him. I believe aging begins from the start. Even at 5 years old. It just doesn’t accumulate and show until we’re much older. Even at 21 years old, I would have aging accumulated up to some extent. It just doesn’t show yet. In my opinion its safe to start anti aging regimes as soon as you’re fully developed to slow the accumulation of aging as much as possible.

The key should be to slow aging much as possible and its make sense to do this when you’re young before the accumulation builds up to a critical point which is see in a lot of elderly people with chronic health conditions , dementia, arthritis, cancer.

There is some talk about our brain not developing until we’re 25 but I don’t think rapamycin will halt this process. It’s not like rapamycin completely pauses/halts everything to a complete 100% stop.

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I’ll most likely continue a small dose of rapamycin. Once I’m 25 I’ll increase my dose by a little bit. I feel like at 21 I’m fully grown now. When I look back when I was 18 and now at 21 not much has changed. I’m still the same weight, height etc.

I do resistant training 3-4 times a week so hopefully this supports my bone/muscle health.

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Interesting article. I feel like at 21 I’m aging. It just hasn’t shown yet. What would you do if you were 21? good to hear everyone’s opinion.

Ageing is hard to be reversed, rapamycin, as a geroprotective drug in many animal models, I believe we should take geroprotective therapy as early as possible, because it’s hard to reverse aging but relatively easy to slow it down.

Spot on! Its more easier to prevent/slow something then reverse it. That comes to a lot of things, not just aging, cancer etc is the same with certain types of cancers. Prevent smoking lung cancer from not smoking, don’t smoke get to the point of getting lung cancer and then try to reverse/cure it, while possible to reverse the lung cancer, its more difficult & dangerous.

Same with wrinkles/sun spots caused from the sun. Wear sunscreen & prevent your time in the sun on very hot days. I’ve seen some folks at the beach tanning and they sure have lots and lots of wrinkles/sun spots.

I believe David Sinclair , a well respected Harvard scientist in the field of aging once said “Its easier to prevent wrinkles & grey hair, rather than reversing it”. I totally agree.

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All the interventions now, are just slowing the progress of aging. There is no age-reversal intervention yet.

Since aging, if any, in a 21 year old is slow (like a slow moving car), you do not need to step too hard on the brakes. Hard stopping is needed for a fast car; same with a fast aging body. So I will do other interventions. Those are:

  1. Intermittent fasting - there is a lot of evidence that IF provides similar benefits to the gold standard, caloric restriction.
  2. Exercise - the other gold standard
  3. Reduce inflammation - there is a lot of material on that too.
  4. Supplements - just check the stacks of other people. They seem to converge as to what people take.
  5. Glycine

Rapa and metformin are, to me, like hard braking. Your rate of aging is like a car running at 20 mph. A 60 year old is aging like a car running at 60 mph.

At your age, you may not turn 40 before science discovers age-reversal. Science is advancing now, at a wonderfully fast rate.

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