Has anyone experienced weight gain on Rapamycin? The research I’ve been pouring through is troublingly contradictory when it comes to understanding whether Rapamycin is causing insulin resistance or protecting from insulin resistance. Can someone please explain?
I have been on Rapamycin for a month now and have experienced weight gain. Perhaps taking LDN, Metformin, Berberine or Acarbose with along with Rapamycin could help offset this? Thank you!
Hello! This is Brandon from the Clinical Team. Thanks for posting this question, and I’m sorry to hear you are experiencing an adverse and unwanted effect. The nuances of mTOR (and our inherent pathways in general) can get a bit overwhelming when you get into the weeds of its constellation of effects. Case in point, here is an image of human metabolism:
The mTOR pathway is heavily involved in glucose and lipid metabolism, which is evidenced by the fact that AMP Activated Protein Kinase (AMPK) snugly sits at mTOR’s entrance gates, much like TSA airport security or border patrol is equipped to verify your passport. The relationship between AMPK and mTOR is central to regulating cellular energy balance, metabolism, and aging. Oral rapamycin directly influences this relationship by inhibiting the mTOR pathway. AMPK is activated when energy is low (such as when the ratio of AMP/ATP increases), which could be during fasting, exercise, or caloric restriction. Once activated, AMPK promotes catabolic processes (like fat breakdown) to generate energy and inhibits anabolic processes (such as protein synthesis and cell growth) to conserve energy. mTOR is a master regulator of growth and metabolism, promoting anabolic processes like protein synthesis, cell growth, and proliferation when nutrients and energy are abundant. mTORC1 (one of two complexes of mTOR) is particularly sensitive to nutrient and energy levels.
AMPK acts as a natural inhibitor of mTOR. When energy levels are low, AMPK is activated and inhibits mTORC1, halting growth processes and switching the cell into a more energy-conserving mode. This inhibition of mTOR by AMPK helps the body prioritize energy for essential functions during times of stress or low nutrient availability.
Oral rapamycin directly inhibits the mTORC1 complex, mimicking the effects of AMPK activation, even when energy or nutrient levels are high. By inhibiting mTORC1, rapamycin promotes autophagy (the breakdown and recycling of cellular components) and reduces protein synthesis, thereby lowering cellular stress and inflammation. This inhibition of mTOR is a key factor in rapamycin’s ability to promote longevity, reduce inflammation, and improve metabolic health.
Oral rapamycin has a complex relationship with insulin resistance, and its effects depend on factors like dosage, duration, and the specific tissues being targeted. While long-term use of rapamycin has been associated with increased insulin resistance in some studies (usually in animal models), low-dose and intermittent use of rapamycin—as in longevity protocols—can have protective effects against metabolic dysfunctions, including insulin resistance.
There are a few things at play here. Chronic inflammation is a key driver of insulin resistance, and inflammation interferes with insulin signaling, making it harder for cells to take up glucose. As we mentioned, rapamycin inhibits the mTOR pathway, reducing inflammation at the cellular level. By decreasing chronic inflammation, rapamycin can improve insulin sensitivity over time, helping cells respond better to insulin. Autophagy is a process by which cells remove damaged proteins and organelles. When autophagy is functioning well, cells are healthier and more efficient. Rapamycin promotes autophagy by inhibiting mTORC1. Enhanced autophagy can help clear out damaged mitochondria (which are important for energy production) and improve cellular function, thus helping maintain insulin sensitivity and preventing metabolic stress. Mitochondria play a crucial role in energy metabolism and insulin sensitivity. Dysfunctional mitochondria contribute to metabolic diseases like type 2 diabetes, highlighting the dynamic between blood glucose and insulin (and perhaps a poor diet and/or sedentary lifestyle). Rapamycin’s role in promoting mitochondrial health and autophagy can lead to improved energy metabolism, reducing the likelihood of developing insulin resistance. When cells use energy more efficiently, they respond better to insulin, which helps maintain glucose control.
Chronic, high-dose rapamycin has been shown to cause insulin resistance, especially in tissues like the liver and muscle, due to this continuous inhibition of mTORC1, which is essential for some aspects of normal insulin signaling. However, low-dose and intermittent dosing can avoid the negative effects on insulin signaling while still providing benefits in reducing inflammation and promoting autophagy. This method aims to strike a balance between mTOR inhibition for cellular protection and preserving normal insulin signaling.
Dihydroberberine (DHB) and acarbose can potentially offset the weight gain that is sometimes associated with oral rapamycin by targeting the key metabolic pathways, improving insulin sensitivity, and reducing post-meal glucose spikes. DHB is a natural compound known for its powerful effects on metabolism and glucose regulation, which can counteract some of the metabolic changes caused by rapamycin. DHB is known to activate AMPK, which as we mentioned is a key enzyme that improves insulin sensitivity and enhances glucose uptake by cells. By doing so, they help the body use glucose more efficiently, reducing insulin resistance and preventing fat storage as adipose tissue. AMPK activation also promotes fat burning and inhibits fat storage, helping to regulate body weight. This can mitigate any potential weight gain caused by rapamycin’s impact on metabolism.
Acarbose works by slowing down the digestion of carbohydrates in the small intestine, which reduces the sharp rise in blood glucose after meals. It does this through inhibiting the enzyme alpha-glucosidase, which is responsible for breaking down complex carbohydrates into glucose. By slowing this process, acarbose prevents rapid glucose absorption, leading to more gradual insulin secretion through this smoothing of blood glucose excursions. Insulin is a fat-storage hormone, so we can see how the argument could be made about oral rapamycin and its inhibition of the very pathway tasked with metabolizing glucose. This is why it is important to table the idea that “more is better” (i.e. oral rapamycin). Too much can have some of these deleterious effects, and a cyclical, low-dose with regularly scheduled labs is the recommended protocol.
I would also consider your dosing (I know you mentioned its only been a month now), if you have considered a sirolimus bioavailability lab to assess if you are in the therapeutic range, what your weight gain has looked like, and (I’m reaching), but if a DEXA scan would be warranted to get an idea of what the weight gain really looks like in terms of where the gain is and any body composition changes.
I hope this helps steer you in the right direction and clarifies a little bit!
Thank you for all the information, Brandon!
I’m noticing that the weight gain is due to water retention; most noticeable in my limbs, fingers, feet. Nothing major but I’m noticing that my ring and socks are leaving impressions. My left leg has been feeling “heavy” with a dull ache at the bottom of my foot. Are these side effects that warrant discontinuing oral Rapamycin? I’ve had 5 doses so far. Week 6 is in 4 days. Thank you!
Happy to support you any way we can! If you would like to navigate this a bit further, would you mind either messaging us in your patient portal or shooting an email to support@gethealthspan.com? Thank you so much!
Hi - I’ve been on Rapamycin for over six months now. Started on 3 mg/week and slowly worked my way up to 5 mg/week. I have noticed that I have lost weight during this time period (7 pounds) and the only change that I made was adding the Rapamycin. No additional diet or exercise. I do take Metformin as well, but I started that well over a year ago and didn’t notice any weight change on it alone. I’ve been taking LDN for several years now. Did not notice a weight change on it alone.
Hi! This is Kristen from the Clinical Team. As Brandon mentioned above Rapamycin is known to affect several metabolic pathways, including insulin sensitivity and mTOR inhibition, which can impact fat metabolism and overall body composition. There is some evidence to suggest that Rapamycin may influence how the body processes energy and fat storage, potentially leading to changes and reductions in body weight for some individuals.
Since you mentioned that no other lifestyle factors, such as diet or exercise, have changed, the combination of Rapamycin with Metformin and LDN might also be influencing your metabolism. Metformin is known for improving insulin sensitivity and can contribute to mild weight loss, especially when combined with other metabolic-modulating medications like Rapamycin.
If the weight loss is unintended or concerning, you may want to:
*Discuss potential dose adjustments with our clinical team in your patient portal.
*Ensure you’re maintaining adequate nutrient/caloric intake to support your body’s needs.
*Consider monitoring your body composition (e.g., muscle vs. fat mass) with a DEXA scan to see if you’re losing fat or muscle, as this could provide more insight.
I do take berberine, Metformin(now switched to SGLT-2) and occasional use of Acarbose with high carb meals once in a while. It seems to help. Also recommend using a CGM.
Hello ims! Brandon here from the Healthspan Clinical Team. I just wanted to quickly share that we have recently started offering a Continuous Glucose Monitor (CGM), specifically the Dexcom G7 model. We also have a Clinical Account setup through the Clarity platform that allows Healthspan patients to share their data with the our Healthspan Health Coach Team (should they choose to do so). Patients can then talk with the Coach Team in an ongoing basis to assess the CGM data and cater lifestyle/medication protocols toward your specific health goals. If you’d like to learn more, shoot us a message in your patient portal and we’d love to further support your wellness journey!
thanks, already setup CGM Dexcom G7 sync through Clarity
