The Case for Starting Rapamycin Earlier in Life (e.g. late 20s) vs middle age (e.g. 50s)

We see an increasing number of people in their 20s in our forums who have started using rapamycin, including this 24 year old PHD student who is posting on his personal rapamycin trial. And a 30 year old MD who describes his rapamycin regimen and his rationale behind it. Additionally, women in their early 30s and early 40s are increasingly turning to rapamycin to maintain their health and fertility.

And we see even younger people. Below we see that 21 year old Thiel Fellow Ben Nashman has started rapamycin. Read on to see some of the research that is driving these types of decisions.

One of the leading researchers in the rapamycin area, Dr. Blagosklonny, suggests people should start rapamycin at 25:

Lifespan Benefits of Starting Rapamycin Younger

The scientific evidence suggests that total healthspan and lifespan may be optimized when a person starts rapamycin in their late 20s or early 30s, rather than in their 40s, 50s or 60s; the more common age range among rapamycin users.

In animal studies, rapamycin has been shown to be effective at increasing healthy lifespan when usage is started either in early adulthood (e.g. equivalent to about 30 years in human terms) or middle age (equivalent to about 60 in human terms), but the longest lifespans achieved in studies so far are when rapamycin is started in earlier adulthood.

In the National Institute on Aging’s ITP studies, the longest lifespan improvements have been in young adult mice (who started taking rapamycin at age 9 months, equivalent to about age 30 in people) where they saw a 23% (male) and 26% (female) median lifespan improvement. This compares the study where they did not start giving rapamycin to the mice until middle-age (20 month old, equivalent to about 60 in human terms) and the study saw a median lifespan improvement of only 11% (m) and 15% (f) using the same dose (source). As they state in the research paper “it may be that this Rapamycin dose is more effective when given starting earlier in adult life”. To the best of my knowledge, the 26% median lifespan improvement in female mice are the best results seen to date for a single longevity drug (rapamycin) study by the National Institutes on Aging.

Some researchers are suggesting with optimized dosing schedules determined through rigorous rapamycin clinical studies may be able to increase human lifespan by 30 years. In fact, new 2022 results recently announced in an interview with Richard Miller of the National Institutes on Aging, Interventions Testing Program showed the longest lifespan extension ever achieved in their tests; a 29% lifespan increase for male mice that are fed rapamycin and Acarbose starting in early adulthood.

Aging begins to ramp up when people are in their late 20s and 30s:


Source: Quantification of biological aging in young adults

There are many cases where rapamycin does a better job at protecting functionality from aging if you start it earlier rather than later. It is true that in many research studies we see a reversal of function back to a younger functional state (e.g. ejection fraction in the heart studies - returning to a more youthful profile), but I suspect that if we look more closely and at more functional outcomes we would see rapamycin is better, in general, at “preserving” functionality during aging (and therefore increasing healthspan) compared to the reversal of aging, and improvement of function that has been lost.

If this is the case perhaps the best strategy may be to start a low dose (e.g. 3mg / week) earlier in life - say when people are at their peak physical condition (say 27 years old, for example). And perhaps the argument for earlier young adult use of rapamycin is stronger for females than males because female fertility decreases much faster than male fertility.

Fertility

In terms of female fertility, there is already strong evidence in mice and rats that rapamycin delays (reverses?) reproductive aging in females.

Here are some of the studies that report this benefit:

The inhibition of mTOR signaling can also prolong ovarian lifespan. Compared to that in control rats, rapamycin-treated rats have a 2-fold increase in the number of primordial follicles after 10 weeks of treatment with rapamycin (5 mg/kg every other day, i.p.) (17, 111). These results indicate that rapamycin can protect the ovarian reserve and extend ovarian lifespan. An interesting experiment also showed that a transient 2-weeks regimen of rapamycin facilitates the sufficient extension of ovarian lifespan in mice regardless of the age at treatment initiation. Source: Frontiers | Role of mTOR Signaling in Female Reproduction

[Note: other compounds like Ca-AKG, NMN and Resveratrol seem to also help with preservation of fertility (sources: 1, and 2 and 3 (resveratrol)). Here, a couple of anti-fibrotic drugs (pirfenidone and BGP-15) restored ovulation in reproductively old mice. So perhaps an ideal approach would be to combine these supplementation approaches.]

There are researchers who argue that rapamycin effectively “slows down time” from a biological growth and development perspective - while maintaining that potential for growth in the future. I’ve spoken to some academics at major US universities that are planning more studies focused on rapamycin and human fertility so its an area ripe for more research, but the preliminary evidence is very encouraging. It was announced in mid-2022 that researchers at Columbia University in New York have initiated a human clinical trial to duplicate the rapamycin fertility trials done in mice and rats, but now in women. It seems to me that preservation of fertility is easier and more likely than reversal of fertility loss, but of course, I could be wrong.

There would, however, be some unique risks I think, associated with being a younger female using rapamycin. Probably the biggest concern would be if a woman were to get pregnant when they are on rapamycin. There is not much research on this - but since rapamycin shuts down mTOR, which is a key growth signal in the body, there could be serious and very negative impacts on any developing fetus (see this study for example) - so a woman would want to work closely with her doctor on this, and really want to be careful about being sure they are off rapamycin for a few months (or more) before thinking about having babies.

I would also argue that the medical profession has been dealing with the risk of rapamycin use / mTOR inhibition and potential pregnancy for the past 20+ years with rapamycin in transplant patients (as long as rapamycin has been used in this application) and there is not that much difference with it going forward in an anti-aging application with people of this age group. Something like 20% of organ transplant patients are under the age of 40 and a significant number (I believe) have had children, so this is a challenge that the medical profession seems to have managed for the past 20+ years already.

If the results in humans are as good as the studies in animals, the cost/benefit for rapamycin is very compelling. The typical cost of rapamycin for anti-aging doses is approximately $40 to $120 per month (for the years of use) vs. the cost for a woman to freeze her eggs (in addition to the hassle and pain of doing so) is approximately $7,000 plus ongoing long-term storage costs.

Menopause

If rapamycin is slowing fertility declines, then it suggests that it might also delay or prevent menopause. And while there is no research on this published that I can find, there are annecdotal reports that people are seeing this:

One Report:

I have been taking rapamycin for 6 months on and off. It has improved my hdl and ldl ratio to the point where my hdl is now higher than my ldl. I have also been giving it to my mother who is 63 years of age. She rather unwillingly told me that she has been having her period again for the first time in 14 years.

Another report:
RapaMenopause

Age-related Erectile Dysfunction

Rapamycin has been shown in several studies (mice and humans) to delay, and reverse erectile dysfunction. A study has even been done that identifies the mechanism of action (see: Rapamycin Improves Erections).

pevalence_of_erectile_dysfunction_at_different_ages

In the ResTORbio clinical studies of their mTOR inhibitor in healthy older humans, it has been reported that “one of the strongest reported “side effects” of the mTOR inhibitors from the resTORbio RCTs was an increase in morning erections”.

Several studies accessed the prevalence of erectile dysfunction (ED). The Massachusetts Male Aging Study reported a prevalence of 52%.2 The study demonstrated that erectile dysfunction is increasingly prevalent with age: approximately 40% of men are affected at age 40 and nearly 70% of men are affected at age 70. The prevalence of complete erectile dysfunction increased from 5% at age 40 to 15% at age 70.2 Age was the variable most strongly associated with ED.

Muscle Function

Additionally, studies indicate that rapamycin can preserve muscle function (important for men and women) much longer if you start earlier rather than later.

Here are some such studies that report this benefit:

I’ve seen some estimates that muscle function starts to decline in sedentary people in their late 20s.

Obesity Prevention

Another argument for rapamycin earlier in life is the trend for people (especially in the USA, but increasingly all around the world) to gain excessive weight as they get older, and it really starts ramping up after age 25, as this graph below shows (this graph is for only one state, but it seems likely to be representative for most states in the USA).

Age+Group+Bar+Chart

Two studies have shown that rapamycin can prevent obesity in mice fed high fat diets. Matt Kaeberlein stated in a recent twitter post: “we show in this paper that rapamycin prevents diet induced obesity in mice and activates CEBP/b target genes”.

Even in people that are not gaining a lot of weight, rapamycin may be of significant value. After age 25 people also start to gain visceral fat, the fat that wraps around your abdominal organs deep inside your body. You can’t always feel it or see it, but it contributes significantly to many health problems. Visceral fat is more likely to raise your risk for serious medical issues. Heart disease, Alzheimer’s, type 2 diabetes, stroke, and high cholesterol

In unpublished data, it has been stated that the reason the PEARL trial for rapamycin in humans chose visceral fat loss as the primary endpoint is because one of its collaborators, Dr Watson, had previously done a very small Rapamycin trial and the biggest effect he saw was a reduction of visceral fat on DEXA scan.

Stem Cell Aging

In this MIT Blood Stem cell study the rapamycin prevented the blood stem cells from aging if they started treatment early in life but it did not rescue them if started later.

When the researchers treated mice with rapamycin, beginning at a young age, they were able to prevent blood stem cells from enlarging as the mice got older. Blood stem cells from those mice remained small and were able to build blood cells like young stem cells even in mice 3 years of age — an old age for a mouse.

Our data indicate that rapamycin prevents the enlargement of HSCs and thereby protects them and potentially other stem cells from aging. However, rapamycin does not restore HSC function once they are large.

Hearing

Similarly - there is research suggesting that rapamycin can stop hearing loss almost completely if you start it early, but it can only slow down hearing loss if started later in life. Here is that study on rapamycin and hearing loss.

Here is some information on how people’s hearing declines with age:

Oral Health

There is also the issue of dental and oral health. Having your teeth is really important - and rapamycin can do a lot to improve oral health and even bone growth, but there is no research suggesting it will grow your teeth back. However, it seems potentially realistic that rapamycin may help people keep their teeth and maintain their oral health much longer if they start rapamycin before they develop any teeth / oral health issues. A good article related to rapamycin and oral health is here: Longevity probably starts with a nice smile. A story about rapamycin and gum disease, an age-associated disorder

A new study has been funded with approximately $300,000, and initiated at the University of Washington, to see if direct application of rapamycin on teeth and gums can prevent periodontal disease, see: New Study Funded: Towards reversing periodontal disease using Rapamycin

Here is a graph showing how oral health (tooth loss, specifically) is seen around the world (I’d like to know what Sweden is doing with their teeth - impressive!):

Spinal Health

Also - when you look at spinal disc degeneration that comes with age you see that rapamycin reverses some of the effects of age on the spinal disc, but only about 50% (very roughly). While this study was done in older monkeys and looked at spinal disc regeneration, I suspect that the results for preservation of the discs would be much better if rapamycin was started earlier. As with all these areas, more research needs to be done.

Osteoarthritis

Osteoarthritis is a leading cause of disability and source of societal cost in older adults. With an ageing and increasingly obese population, this syndrome is becoming even more prevalent than in previous decades (see this review paper on osteoarthritis).

New research on rapamycin suggests that treatment with Rapamycin may compress severe osteoarthritis pathology to late life. See this: “rapamycin delays osteoarthritis” research report and news story.

Problems taking Rapamycin When Older

Other issues arguing for younger rather than older for initiation of rapamycin might be:

  1. The older you are, the more sensitive you are likely to be to any side effects. Generally people are stronger, more fit, healthier and more resilient when they are younger - so they are more able to handle any medication side effects or any illnesses, etc. Therefore rapamycin may be less risky for younger rather than older people. I haven’t looked closely, but I suspect older people have to go off medications more frequently due to bothersome side effects than people in their 30s and 40s, just because they have a healthier body.

  2. The issue of “Polypharmacy”. I look at my parents and their friends and I see people who take a lot of different medications for a lot of different conditions… and adding rapamycin into the mix makes things even more complex and difficult to manage for the medical professionals, and more likely to be problematic. When people are young, they typically aren’t taking any medications - or a minimal amount, and mostly periodically - when they are sick - so it would be much easier to manage integrating rapamycin into their lives and any of the medication the person may be using if they are young. (A group in the UK are struggling with this issue: Video: Safe set of drug candidates for aging - John Overington)

Risks

And, of course - all this has to be weighed against the risks of taking rapamycin at whatever age the person is at. Those risks are still being determined, and will likely be dose dependent.

At high, continuous doses there is evidence that rapamycin can negatively impact the male gonads/ spermatogenesis - and ability to have children. This problem is generally believed to go away after a male stops taking rapamycin, (similar to the case in caloric restriction) - and that has been documented in younger male transplant patients who go on to have children after initially being unable to while on high doses of rapamycin) - but there is some lower level risk there that has to be considered.

There is also risk of cataracts (seen in mice at high doses, not in people), and also possible immune system reduction - which can result in serious problems. So these would also need to be factored in, though again, the risk is likely much lower for younger people, especially at lower doses of Rapamycin dosed periodically.

What are your thoughts? What research have you seen and what do you think might be the best age to start rapamycin?

8 Likes

I would have started in my 30s if I had had this information and an available source. Even though we still need the RCTs on dosage and frequency, the case seems overwhelming.

By the time we hit our 30s, we have passed our peak growth and fertility years, and further chronic increases in IGF-1 are dysfunctional. Tamping down growth factors and encouraging autophagy seems a healthier way.

4 Likes

I am in late 20s, and just started rapamycin 1 month ago

I got my first white hair 2 years ago, and the progression is faster and faster, it made me nervous
( about 10% of the whole hair become gray)
So I did some researches, and found rapamycin is currently the most robust aging intervention in lots of animal models

I wish the hair greying progression will become slow, stop, or even reverse

2 Likes

Hi LeeJohn, It sounds like rapamycin might help with the grey hair, but I haven’t head much about this.

Are there any doctors in Taiwan that prescribe this or are you going solo on this? What dose are you on per week?

I would definitely recommend you tell your doctor and try to get them to work with you whether they are writing you a presciption or not - so you can do and track regular blood testing to see how things are going.

Its highly unusual to hear of people getting grey hair at your young age. Did you experience some significant stress that might have contributed to the grey hair? It does seem that rapamycin, by protecting your stem cells - might help reduce the stem cell aging and grey hair.

You do have some unique risks I think, as a younger female using rapamycin. Probably the biggest concern would be if you were to get pregnant when you are on rapamycin. There is not much research on this - but since rapamycin shuts down mTOR, which is a key growth signal in the body, there could be serious and very negative impacts on any developing fetus - so you really want to be careful about that - and make sure you are off rapamycin before you think about having babies…

3 Likes

Here is the research on pregnancy and rapamycin - in short, its highly NOT recommended. The offspring turn have many problems (suggest mouse studies):

and the recommendations and a review for humans. Rapamycin is not recommended during pregnancy and likely harmful to fetus:

3 Likes

Thanks for the advice

I haven’t found doctors in Taiwan prescribing rapamycin yet
And I am planing to take regular blood testing once a year, after hearing your advice, thank you

Yes I have been under constant stress for years, that probably the biggest factor for my grey hair
In the middle of this year, I began to take Sulforaphane 60mg/day, hoping that can lower my inflammaging state

Lastly, sorry for the confusion, I am actually a boy
www.rapamycin.news automatically updated my Gmail profile here by default
I change profile now, hoping that will not confuse you, and still appreciate the information about the rapamycin side effects

2 Likes

When I read the literature above, it seems like there is an arc that begins at birth and reaches its apogee at some point in late 20s or early 30s when the GROWTH phase of development begins to slow down, creating a down slope all the way to death. Mtor is absolutely crucial in the growth phase and problematic in the decline phase. SO the question is: where is the apex of the curve when starting rapamycin would be beneficial? I don’t think we know that in humans yet, so it could be dangerous to start too soon. As you cite the pregnancy paper above, I think there are very strong lingering concerns about inhibiting mtor in people who are of an age likely to produce offspring. Secondarily, I doubt that a healthy 30 year old is beginning to suffer from inflammation of the bad kind that impeding mtor can help. They are still building muscle and mtor is needed for that. Aiming to start after chilld rearing at age 40-45 makes more sense.

4 Likes

First of all - I think your view is the dominant view of many of those in the medical profession who are at all familiar with rapamycin (if they are at all supportive of people taking rapamycin), and given the nascent state of the rapamycin clinical trials for aging that may be entirely appropriate.

Also - Its absolutely true that Mtor is critical during growth - so you don’t want to experiment with rapamycin until you stop growing. I’m not a biologist - so I will deign to their expertise if they want to weigh in on this, but all that I’ve read suggests that most if not all human development is complete by age 25 to 27. For example this article talks about 25 for the completion of brain development.

I have a cardiologist friend who says the only thing that keeps growing after that are your nose and your ears - and thats why they seem so large on old people. Perhaps the lack of infinite growth of the nose and ears would be another benefit of taking rapamycin I haven’t mentioned :smile:

I agree there are lingering concerns about the risks of inhibiting mTOR in people of reproduction age and that rapamycin use / mTOR inhibition is definitely not recommended (and the risk, of course, is that someone is taking Rapamycin and doesn’t realize they are pregnant) - so definitely extra caution is required during those age periods.

But - I would argue that given that perhaps something like 25% of organ transplants happen to patients under the age of 40 (see graph below), and virtually all of these patients probably take sirolimus (I believe taking it with cyclosporine is the typical medication protocol used in transplant patients), and I suspect that most of these people also go on to have children (or at least a significant portion). So - I would argue that the medical profession has been dealing with the risk of mTOR inhibition and potential pregnancy for the past 20+ years with rapamycin (as long as rapamycin has been used in this application) and there is not that much difference with it going forward in an anti-aging application with people of this age group. But yes, the anti-aging doctors would need to learn about this and implement these educational programs in their clinics if they treat this age group.

Also - you are correct I think that the typical healthy 30 year old is not going to see much benefit immediately from taking rapamycin in terms of inflammation reduction, etc. and still needs mTOR to grow.

But - we all need mTOR for our muscles to grow, we just don’t need mTOR on all the time for our muscles to grow, and rapamycin for anti-aging protocols are all about periodic dosing, to allow mTOR to return to higher levels periodically to help in muscle growth, etc. when its needed. So - a 30 year old would get that on the periodic dosing schedule just as a 60 year old would too.

Maybe there are a number of factors that will ultimately evolve to drive the medical profession’s thinking on this, and consumer’s thinking.

  1. Current concerns with fertility. This is a common concern of professional women in their late 20s and early 30s who place a high priority on their careers. One strategy they pursue right now is freezing their eggs, but that is an expensive, painful and risky medical process too. While still to be proven, rapamycin may simplify this process. I suspect most women of this age would prefer to take rapamycin at a cost $50 a month or so, than the $6,000 to $20,000 for egg freezing - and all that that entails.

  2. Concern about, and Risk of, Obesity (and how well the research on rapamycin in preventing obesity is progressing). The sooner you can stop the problem of obesity, the better. This is definitely one area where a large percentage of people are still growing during their 30s and 40s - but would probably prefer to not be growing.

  3. Risk / Reward Perception - the science around rapamycin is changing every year, and people all have different risk/reward perceptions and profiles. So I think you’ll see the adoption rate of rapamycin vary as research progresses and the risk / reward profile of taking rapamycin becomes better understood by people.

3 Likes

You are on the right path here, I think. There are a number of biomarkers that show when a human has embarked on the aging down slope and as testing technology becomes more sophisticated, we’ll know with more accuracy when that occurs.
For example: https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8002905/pdf/CTM2-11-e372.pdf shows that older adults produce less gluthathione than younger adults. When does that start to happen?
This study shows that a protein called CD38 begins to degrade NAD+ as people age, which may be responsible for many age-related illnesses. https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5885288/pdf/nihms947957.pdf When does that process start?
For females, there is a clear demarcation with menopause. For males it is less clear: when does the level of testosterone begin to decline as DHT increases, causing male pattern baldness and prostate issues? the cause is an increase in 5-alpha reductase that may be the result of a decline in production of progesterone, a natural 5-alpha reductase inhibitor. When does that decline begin?
Another key biomarker is when cells start becoming senescent. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs There are now senolytic drugs that can help remove them, but a better approach would be to start rapamycin therapy as the process begins.
As it becomes easier to plot these turning points, I think the answer to your question will become clearer.

1 Like

Here’s another reason younger men probably would not want to take rapamycin:
“Treatment with TOR-I results in a decrease in testosterone level, and an oppos-
ite increase in LH. Moreover, spermatogenesis seems to be disrupted by TOR-I
and FSH levels are increased.”

1 Like

Yes - we cover that in the animal study risks section. In organ transplant patients taking rapamycin daily it has been shown to be reversible when they stop taking rapamycin.

Regarding the impact of sirolimus on sperm, there was a recently published a case report on a 36-year-old male kidney-transplant recipient treated by an immunosuppressive regimen that contained sirolimus. He presented with dramatic, reversible sperm impairment. He initially (for 3 months) 2 mg/day of sirolimus associated with 10 mg/day of prednisone, 200 mg/day of cyclosporine, and then for 33 months 7 mg/day of sirolimus and 10 mg/day of prednisone. During this time he could not get his wife pregnant. When he stopped taking sirolimus, he could and did get his wife pregnant.

I haven’t seen any people reporting this issue with pulsed, periodic dosing of rapamycin.

1 Like

The reason may be that most of the people taking rapamycin on a pulsed basis, i.e. for anti-aging, have already reached an age where they no longer care about sperm counts. But the decline in testosterone would be unacceptable to many younger men.

2 Likes

We cover a review of all the papers on this topic on the Risks page. The impact on gonads/spermatogenesis is seen in higher dose, continual dosing of rapamycin as is used in organ transplantation and cancer treatment. In the review (the same review that you posted) focused on organ transplant use of rapamycin it states:

The authors confirmed that total testosterone was lower and FSH and LH higher in the group of patients treated with sirolimus than in those from the control group, and in multivariate analysis, only the use of sirolimus was significantly correlated with decrease of testosterone (age, race, etiology of renal failure, transplant and dialysis durations, antihypertensive and non-mammalian target of rapamycin-I immunosuppressive treatments not significant). However, even though the IIEF score was slightly lower in the sirolimus group, there was no significant difference in sexual score between the two groups (mean IIEF score: 49/75 in the sirolimus group; 52/75 in the control group). Moreover, free testosterone levels did not differ significantly between the two groups.

1 Like

@LeeJohn are you seeing any significant issue with rapamycin and testosterone levels at your current dosage of rapamycin (I think you’re taking around 6mg / week - is that correct)? And you’re in your late 20s, correct?

1 Like

I realize this is anecdotal and N=1, but i tested 1092 total testosterone 8/15, 482 on 10/28 after 10 weeks 6 mg sirolimus intermittently, and 649 12/3 after a four-week washout. So while reversible, it’s a significant decline, nonetheless. You might add that test to your Life Extension regimen. On the other hand, my calculated bio age was 40 years younger.

4 Likes

Ah - that is actually really interesting. Its the first time I’ve seen testosterone numbers from people using rapamycin for anti-aging. Thanks for sharing.

Yes - definitely something people might want to consider testing to track over time.

https://www.lifeextension.com/lab-testing/itemlc140103/testosterone-free-with-total-blood-test

Yes I am in late 20s, and plan to take 6mg+grapefruit / bi-week, now I am taking 2mg+grapefruit / week

For the testosterone levels, I only have the basal data before the rapamycin usage, I will have blood test few months later to see if rapamycin increases/decreases my testosterone level

1 Like

Regardless of the actual measure of testosterone - how are you feeling? Do you notice any of these symptoms below, and are they at a level where they bother you?

What are the symptoms of low T? Regardless of your age, low T symptoms can include:

  • erectile dysfunction, or problems developing or maintaining an erection
  • other changes in your erections, such as fewer spontaneous erections
  • decreased libido or sexual activity
  • infertility
  • rapid hair loss
  • reduced muscle mass
  • increased body fat
  • enlarged breasts
  • sleep disturbances
  • persistent fatigue
  • brain fog
  • depression

From here:

1 Like

I do weight training 3 times a week, my muscle mass didn’t decrease after rapamycin
However, My Body Fat Percentage was from 12% to 8%

I did have decreased libido, but I think that’s because it’s getting cold, I generally have lower libido in winter
Thanks for the T symptoms checklist, I will keep monitoring it to see if rapamycin influences my testosterone level

1 Like

That is a pretty amazing biological age reduction. Have you tested it over time? Did rapamycin seem to have any effect or was it other things you are doing or taking?