I was under the impression that the longevity regime for Rapamycin was based on weight and was to be taken for 12 weeks. Is this still the case? If so, how often should the 12 week dosing regime take place? Once a year? Or half year?
2 Likes
Hi- This is Shriya from the Healthspan Clinical Team! We recommend that our patients take rapamycin once a week and continue this consistent protocol paired with a healthy diet and exercise. From a mechanism perspective, Rapamycin at a low-dose leads to temporary inhibition of the mTOR signaling pathway. By inhibiting mTOR, Rapamycin combats cell senescence, a key contributor to aging, leading to increased longevity and healthier cellular function. Rapamycin has a short half life, meaning that its effect in the body is short-lived. Therefore, a consistent doing of once per week will allow for consistent combatting of cellular senescence.
3 Likes
Any human studies on rapamycin inducing autophagy sooner than fasting? MTORC1 will be activated if there is any trace of leucine (usually completly metabolised within 12 hours of intake, (Redirecting)) , so should rapamycin weekly dose be in conjunction with an intermittent fasting period, e.g. 24-40 hours? How long should a fasting period be after taking the weekly rapamycin to continue the MTCOR1 inhibition or does any rapalog inhibit MTORC1 even in the presence of leucine?
Hi - This is Brandon from the Healthspan Clinical Team and thank you for bringing this question forward so we can all continue to learn together! The short answer to your question is no; no human studies provide us with a conclusive pitting of rapamycin versus fasting to land at the end goal of upregulation of autophagy induction. Good news: we can apply some of the things we know about rapamycin and fasting to connect a few dots. The mechanisms of action of rapamycin and fasting converge on the mTOR pathway, which regulates autophagy. Rapamycin inhibits the mTOR pathway, a key regulator that prevents autophagy under nutrient-rich conditions. By inhibiting mTOR, rapamycin promotes autophagy, the process where cells break down and recycle damaged or dysfunctional components. In preclinical studies, rapamycin has been shown to induce autophagy, which is linked to improved longevity and reduced age-related diseases in animal models.
The time it takes for rapamycin to exit the bloodstream is determined by its half-life, which is the time required for the concentration of the drug in the blood to decrease by half. The half-life of rapamycin in most patients ranges from 57 to 63 hours. However, this can vary depending on individual factors such as age, liver function, and concurrent medications. It generally takes about 4 to 5 half-lives for a drug to be mostly eliminated from the body. For rapamycin, this translates to approximately 10 to 14 days for the drug to exit the bloodstream fully.
Fasting naturally induces autophagy by depleting nutrient and energy stores, suppressing the mTOR pathway through AMPK sensing. This process typically takes 24–48 hours of fasting to initiate in humans, though it can vary depending on the individual and the fasting protocol. At this point, there is likely to be an upregulation of the ketone body beta-hydroxybutyrate (BHB), which is far more than what many consider just an alternative energy source to glucose. It acts more like a signaling molecule or hormone than anything in its constellation of benefits (autophagy being one).
If you compare the timelines of rapamycin and fasting, it would make sense (again in the absence of human trials) to pair these two protocols together. The “awakening” of mTORC1 will probably cast a wide net of possibilities: metabolic health, activity level, bolus of food (i.e. Leucine). However, rapalogs, such as rapamycin and its analogs (e.g., everolimus, temsirolimus), can inhibit mTORC1 even in the presence of leucine which as you shared has a shorter half life, although their effectiveness may vary. Leucine and other amino acids typically activate mTORC1 through upstream signaling, but rapalogs can block mTORC1 activity regardless of the presence of leucine or other amino acids, at least partially. However, rapalogs are known to incompletely inhibit mTORC1, and the degree of inhibition can depend on the specific cellular context. They mainly inhibit mTORC1’s role in protein synthesis (via the S6K pathway), but mTORC1’s regulation of other substrates like 4E-BP1 (involved in cap-dependent translation) may remain active even in the presence of rapalogs. Leucine may still partially stimulate mTORC1 activity in these other pathways, which are not fully blocked by rapamycin.
To bring it back to fasting, BHB helps suppress mTOR by mimicking the effects of fasting, reducing the availability of glucose and insulin signaling. This inhibition of mTOR helps trigger autophagy, similar to what happens during prolonged fasting, and as you mentioned, a reduction in Leucine, which would otherwise trigger mTOR activity or anabolism. AMPK is an energy-sensing enzyme activated when cellular energy levels are low (such as during fasting or carbohydrate restriction). AMPK promotes autophagy by inhibiting mTOR and activating autophagy-related genes. BHB activates AMPK, which helps maintain energy balance and triggers autophagy, especially in response to low glucose availability.
BHB has antioxidant properties that help reduce oxidative stress, which is known to damage cells and trigger compensatory autophagy. By scavenging reactive oxygen species (ROS) and enhancing the expression of antioxidant enzymes, BHB creates a cellular environment conducive to autophagy, allowing cells to repair and regenerate more efficiently.
One of my fan-favorite properties of BHB is its action as an HDAC inhibitor, which influences gene expression. HDAC inhibition leads to increased expression of FOXO3A, a transcription factor that regulates autophagy-related genes. By inhibiting HDACs, BHB promotes the expression of genes involved in stress resistance, longevity, and autophagy, helping cells clear out damaged proteins and organelles more effectively.
Finally, there is a specific form of autophagy that targets damaged mitochondria for degradation and recycling. BHB, by promoting overall autophagy and reducing oxidative stress, supports mitophagy, ensuring that only healthy mitochondria remain active, which enhances cellular energy production and longevity.
I hope this helps, and I look forward to any continued dialogue!
1 Like
I watched a youtube video by Thomas Leech PHD
" Time’s arrow: Brief exposure to rapamycin has the same anti-ageing effects as lifelong treatment"
In it he suggests that (your financial interests aside) a finite use in animals was as effective as a consistent cycling. Again this was data from variety of animals & Insects. He does not specifically recommend a dosage or regiment for Humans but the implication is there.
Hey Horace!
Currently, the longevity community doesn’t have a definitive answer on whether Rapamycin is best taken indefinitely or if cycling on and off (or even taking it only for a finite period) might yield the same benefits. Most of the research supporting Rapamycin for longevity has been conducted in animal studies, where long-term use showed extended lifespan and reduced age-related conditions. However, in humans, the long-term effects are still being studied, and some experts suggest intermittent use to avoid potential downsides of chronic mTOR inhibition, such as potential impacts on metabolic health and tissue regeneration.
For those experiencing noticeable benefits, like improvements in joint pain, inflammation, or other age-related symptoms, long-term use may be worth considering, as it could help maintain these gains. Some practitioners prefer intermittent, indefinite dosing (e.g., weekly or biweekly) to balance Rapamycin’s cellular cleanup effects with periods of mTOR “rebound” for muscle repair and metabolic support. Alternatively, some advocate for periodic breaks or finite use, aiming for a cellular reset that may carry benefits even if use is discontinued.
Ultimately, whether it’s finite or lifelong might depend on symptom improvements, individual health goals, and emerging research. We’ll continue to watch for new studies on human longevity to see where the science lands on this!
Any thoughts on the side effect concerns recently raised by Bryan Johnson and his team that led them to discontinue Rapamycin use after 5 years?
https://x.com/bryan_johnson/status/1857131261980270933
It seems there are a number of studies emerging that suggest this would be better used intermittently as a reset rather than as a long term continuous treatment? Bryan references 5 research papers in his decision.
“Additionally, on October 27th, a new pre-print [5] indicated that Rapamycin was one of a handful of supposed longevity interventions to cause an increase/acceleration of aging in humans across 16 epigenetic aging clocks. This type of evaluation is the first of its kind, as most longevity interventions up to date have been tested against one or two aging clocks, leading to invisible biases and potential intended “cherry picking” of favorable clocks for the tested interventions.”
2 Likes
Hi Greg,
Thank you for your question. The Healthspan Clinical Team would love to weigh in on this. As we wrote about previously, the longevity community doesn’t have a definitive answer on whether Rapamycin is best taken indefinitely or if cycling on and off (or even taking it only for a finite period) might yield the same benefits. Most research supporting Rapamycin for longevity has been conducted in animal studies, which can open the door for human studies when a safety profile has been established.
While it is appreciated that people such as Bryan Johnson are active in the longevity space and willing to share their journey, we must also acknowledge that this is an n of 1. We are all vastly different regarding our current health status, health history, and health goals. For example, rapamycin can become nuanced to the point where liver health might make a difference in bioavailability, dosing, and cycling. Liver health plays a significant role in the metabolism of oral rapamycin due to its involvement in drug absorption, distribution, metabolism, and excretion. The liver is the primary organ for metabolizing many drugs, including rapamycin. It contains various enzymes that facilitate drug breakdown, primarily from the cytochrome P450 (CYP) family. Rapamycin is mainly metabolized by CYP3A4, a key enzyme found in the liver. This enzyme’s activity determines how efficiently rapamycin is processed. Conditions such as cirrhosis, hepatitis, or fatty liver disease can impair the function of CYP enzymes. This can lead to a slower metabolism of rapamycin, resulting in higher blood concentrations and prolonged drug activity, which may increase the risk of side effects and toxicity (more on the comparison of mTORC1 and mTORC2 to come). Liver conditions can also alter the expression or activity of CYP3A4. Reduced enzyme function leads to decreased clearance of rapamycin, while hyperactive enzymes (though less common) might cause faster drug breakdown, potentially reducing efficacy. This illustrates that two 50-year-old males, for example, may require vastly different protocols to achieve similar results while maintaining a safety profile that we prioritize with our Helthspan patients.
Bryan Johnson shared that the potential benefits of rapamycin were not worth the side effect profile. He continued that no other underlying causes were identified, concluding that rapamycin was the culprit. Bryan intricately details his Blueprint, sharing that he is in the top 1% of many health markers, including speed of aging, inflammation, cardiovascular, and combined clinical markers. I would be curious what abnormalities exist while remaining in the top 1%. He also shared his daily supplement/medication regimen, totaling about 50 different things. This suggests there may be more confounders worth considering before deducing rapamycin as the root cause of his adverse side effects.
Most importantly, Bryan notes he takes 2,000mg of Metformin, 400mg of acarbose per day, and a myriad of experimental rapamycin dosing protocols as high as 13mg/week, all of which will have profound effects on mTOR, glucose, insulin, lipids, white blood cells/differentials, and more. This is neither low-dose nor cyclical, and doesn’t warrant much further research to know that high-dose, non-cyclical protocols might yield unwanted outcomes. Adding caloric restriction (CR) into this creates a template for the adage that more is not better. Bryan is chronically suppressing mTOR, which is not advisable, and his team should have never advised him to do so. This has been shown in studies that chronic treatment with high doses of rapamycin causes insulin resistance and glucose intolerance, and that acute treatment with rapamycin elicits deactivation of the nutrient-sensing mTOR pathway, and abolishes a feedback block of insulin signaling, resulting in insulin sensitivity [1,2].
The mTOR (mechanistic target of rapamycin) pathway is a critical regulator of cell growth, proliferation, and metabolism, including glucose and lipid metabolism. Understanding how mTOR functions and how rapamycin’s inhibition of this pathway can lead to metabolic changes provides insight into potential side effects such as glucose and lipid abnormalities or changes in heart rate.
Rapamycin inhibits mTOR as a whole, and there are two components of mTOR - mTORC1 (mechanistic target of rapamycin complex 1) and mTORC2 (mechanistic target of rapamycin complex 2). These are two distinct complexes within the mTOR signaling pathway, each with unique roles in cellular and metabolic processes. The rapamycin-mTOR dynamic is a bit like a bank robber: the robber breaks in, steals what he’s after, and gets out before the cops come. We take our low-dose rapamycin - the bank robber - task the medication with inhibiting mTOR (targeting autophagy, senescence, inflammation, pulsing on anabolic processes), and then get out of there before we spill over to processes such as glucose/lipid metabolism or the immune system response - the cops arriving. If the robber gets greedy and hangs around too long, this generally results in undesirable outcomes.
To provide some context on these two complexes, mTORC1 regulates cell growth and proliferation by promoting protein synthesis and cell growth through activation of pathways such as S6K1 and 4E-BP1.mTORC1 also responds to nutrient availability, energy status (AMP/ATP ratio), and growth factors, which makes approaches such as caloric restriction (CR) or intermittent fasting (IF) intriguing adjuvant therapies to low-dose rapamycin.
Any combination of these suppresses autophagy, a cellular process for degrading and recycling damaged components when nutrients are abundant. Finally, mTORC1 controls lipid synthesis and promotes glycolysis by regulating enzymes related to these processes.
mTORC2, on the other hand, influences cell survival and cytoskeletal organization through the regulation of AKT, PKC, and other kinases. It supports insulin signaling and glucose homeostasis by activating AKT, which enhances glucose uptake and lipid metabolism. It plays a role in cellular stress responses and maintaining homeostasis under varying conditions. Unlike mTORC1, mTORC2 is less sensitive to nutrient changes and is primarily activated by growth factors.
This all supports the notion of not only a low-dose approach, but that a personalized cycling protocol can and should be considered. One could even make the case that from a physiological standpoint, a “macro cycle” might be prudent long-term to something like seasonally. In periods of cold, we often endure less physical activity, higher caloric intake, and a need to survive and stay warm, resulting in some weight/body fat gain.
To illustrate, seasonal weight fluctuations have been observed in humans and animals, influenced by changes in temperature, daylight, and behavior. Moreover, hormones such as melatonin and cortisol, affected by light exposure, may play a role in seasonal weight changes. Changes in these hormone levels can influence metabolism and appetite regulation. A study published in the New England Journal of Medicine indicated that weight gain typically peaks around major holidays such as Thanksgiving and Christmas, with people maintaining higher weights through the winter and gradually losing it in the spring and summer [3]. A seasonal oral rapamycin dosing schedule can be aligned with physiological and lifestyle changes that occur across different times of the year, such as weight gain in the winter and weight stabilization or loss in warmer months. This type of schedule could mimic evolutionary patterns of energy storage and use, optimizing mTOR inhibition during times of reduced activity or higher caloric intake. This might look like the administration of higher or more frequent doses (e.g., weekly dosing) to counteract increased mTOR activation associated with caloric surplus, where as the summer might have a reduced dosing frequency or take a “drug holiday” to allow for optimal muscle maintenance and adaptive responses to physical activity.
The negative implications associated with a high-dose, chronic oral rapamycin protocol (i.e., daily or <7 days) have been demonstrated in animal and human studies. For example, daily high-dose rapamycin (8 mg/kg/day injected) in male mice caused significant body weight reduction without changes in food intake. Although lifespan increased, the weight loss and potential effects on metabolism underscore concerns about systemic side effects at high doses [4]. Moreover, long-term rapamycin administration in animal studies has been linked to glucose intolerance and insulin resistance due to persistent mTORC2 inhibition, which disrupts glucose homeostasis (and Bryan also points out) [5].
In transplant patients taking rapamycin for immunosuppression, common side effects included hyperlipidemia, delayed wound healing, and stomatitis. These effects suggest that chronic, high-dose use could produce unwanted metabolic and systemic issues in non-transplant settings [6]. Finally, elevated doses (beyond weekly low-dose protocols for longevity) can cause gastrointestinal discomfort and increase the risk of infections due to immune modulation. The Healthspan Clinical Team requests regular lab draws from our rapamycin patients so that we remain vigilant in your safety and aligning with your health goals.
I hope this has provided some insight and been helpful!
Sources:
[1] Tataranni, T. et al. Rapamycin-Induced Hypophosphatemia and Insulin Resistance Are Associated With mTORC2 Activation and Klotho Expression. American Journal of Transplantation, Volume 11, Issue 8, 1656 - 1664.
[2] Krebs M, Brunmair B, Brehm A, Artwohl M, Szendroedi J, Nowotny P, Roth E, FĂĽrnsinn C, Promintzer M, Anderwald C, Bischof M, Roden M. The Mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes. 2007 Jun;56(6):1600-7. doi: 10.2337/db06-1016. Epub 2007 Feb 28. PMID: 17329620.
[3] Jack A. Yanovski, M.D., Ph.D., Susan Z. Yanovski, M.D., Kara N. Sovik, B.S., Tuc T. Nguyen, M.S., Patrick M. O’Neil, Ph.D., and Nancy G. Sebring, M.Ed., R.D. A Prospective Study of Holiday Weight Gain. New England Journal of Medicine. 2000;342:861-867. Published March 23, 2000. doi: 10.1056/NEJM200003233421206. Vol. 342 No. 12.
[4] Alessandro Bitto, Takashi K Ito, Victor V Pineda, Nicolas J LeTexier, Heather Z Huang, Elissa Sutlief, Herman Tung, Nicholas Vizzini, Belle Chen, Kaleb Smith, Daniel Meza, Masanao Yajima, Richard P Beyer, Kathleen F Kerr, Daniel J Davis, Catherine H Gillespie, Jessica M Snyder, Piper M Treuting, Matt Kaeberlein (2016). Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice eLife 5:e16351. Aug 23, 2016. doi.org/10.7554/eLife.16351.
[5] Vanessa P. Houde, Sophie Brûlé, William T. Festuccia, Pierre-Gilles Blanchard, Kerstin Bellmann, Yves Deshaies, André Marette; Chronic Rapamycin Treatment Causes Glucose Intolerance and Hyperlipidemia by Upregulating Hepatic Gluconeogenesis and Impairing Lipid Deposition in Adipose Tissue. Diabetes 1 June 2010; 59 (6): 1338–1348. https://doi.org/10.2337/db09-1324.
[6] Augustine JJ, Bodziak KA, Hricik DE. Use of sirolimus in solid organ transplantation. Drugs. 2007;67(3):369-91. doi: 10.2165/00003495-200767030-00004. PMID: 17335296.
2 Likes
I would like to compliment you and your team on the thoughtful response.