Rapamycin vs Metformin
I've got a supportive MD who runs an aging clinic I'm seeing soon and am considering next steps. So far I've ...
- Fixed all the basics (hormones, glucose, BP, ...)
- Taking 2000 metformin daily
- Did the NAD patches, plus daily booster
Canonically the next step would be Rapamycin, however I've heard rumors that if you're good with Metformin activating AMPK that perhaps Rapamycin isn't necessary. If it's still 'a good idea' or at least not a bad idea, thoughts?
From the March Life Extension magazine page 98
Human Strategies to Suppress Excess mTOR
Rapamycin is being studied in humans to assess its ability to suppress excess mTOR and potentially reverse age-related pathologies.
The most efficient way for people to suppress mTOR today is to activate cellular AMPK.
This can be done with the drug metformin, intermittent fasting/calorie restriction, and/or AMPK activating nutrients like gynostemma and hesperidia.
The interesting thing is that the article is about the Canine Rapamycin project to suppress mTOR, yet at the end seems to be saying that Metformin is the best way to go about it via AMPK
Further in this article from Feb 2018 by Bill, the sequence is
- Living causes cellular waste, which is removed via autophagy
- "Recent discoveries show that almost every intervention proven to extend healthy lifespan involves activation of autophagy (removing toxic cellular waste)"
- "One of the safest and most effective methods to optimize autophagy is by activating an enzyme in our cells called AMPK"
- "AMPK performs its fat-removing process, in part, by regulating a protein called mTOR"
- The most studied mechanism of metformin action is its ability to boost AMPK activity.
So it would seem you can use Metformin to activate AMPK and thereby regulate mTOR. Or you can go after mTOR directly with Rapamycin. Given the track record of Metformin that would seem the better route, and if you're already taking it then, in the absence of other information, adding Rapamycin would seem to be overdoing it.
Addition: OK I found a reference
BF: Most people eat too much and this causes mTOR to be chronically elevated, which may preclude optimal results using the other interventions. Rapamycin directly suppresses mTOR. So we believe that inducing autophagy (removal of accumulated cellular waste), which happens when mTOR is suppressed, is a logical first step. What we are finding, however, is that most of our supporters already take metformin, practice intermittent fasting, and/or ingest nutrients that boost a cellular enzyme called AMPK, which indirectly suppresses mTOR. So we feel they may be able to skip rapamycin at first and proceed to boosting their NAD+ as I next describe. We will know more about the additive benefits of rapamycin when a clinical trial we are helping fund wraps up in a few months.
There you go, if you are taking Metformin, practice fasting, supplements and diet, then the expense and trouble of Rapamycin is probably not necessary.
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I'm actually wondering if the blocking of gluconeogenesis may be a downside to using Metformin in combination with prolonged fasting. I would be curious to learn if combining it with Rapamycin would give the body flexibility to rely on gluconeogenesis when it is needed.
This is interesting:
Anti-aging combinations
Rapamycin (or another rapalog) should be a cornerstone of anti-aging combinations (Figure (Figure1),1), given its universal anti-aging effect and the ability to delay almost all diseases of aging.
Rapamycin and metformin: Both drugs extend lifespan in animals and have non- overlapping effects. In addition, they may, in theory, cancel possible metabolic side-effects of each other. As we discussed here (see rapamycin section) as well as in [31, 130], rapamycin in different settings may either increase or decrease insulin sensitivity. Similarly, calorie restriction increases insulin sensitivity, whereas severe calorie restriction (starvation) decreases it [129, 245]. In any case, rapamycin prolongs life span, indicating that insulin resistance is benevolent [130]. Unfortunately, the fear of this benevolent ‘side effect’ is delaying applications of rapamycin for prevention of age-related diseases. The simplest approach is to monitor glucose levels in individuals taking rapamycin. In addition, metformin, an anti-diabetic drug that reverses insulin resistance, could be combined with rapamycin.
And vice verse, metformin may potentially increase blood lactate levels. Rapamycin decreases lactate production [164]. Each drug prolongs lifespan in mice, prevents cancer, atherosclerosis, and other diseases of aging.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482593/
I have a prescription for Metformin but can maintain a FBG in the low 80's without it. I want to build up the ability to fast to 72 hours. My understanding is that the body relies on gluconeogenesis to maintain glucose when fasting over multiple days. I could really use more information.
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Christine My update, I have not noticed any change in glucose with the small dose of rapa. (My glucometers do each have a bias, so now I don´t really know my baseline, however, the difference is consistent. So if one shows 75, the other shows 93 and the next day one shows 79 and the other 97 and so on.) I have managed to do several longer fasts. Several 48 hours, two 60 our fasts and a 72hour fast. My mother also joined me on a 60 hour fast 🙂
Cyclical keto works great for me, IR is in my family, and I feel much better when I limit high carb foods to a few weekends when my priority is building muscle, building hormones, social life or feeding my microbiome. That said, as I progress, I notice I am more metabolically flexible. I have my cheat days after a HIT, and I feel the same meal is more easily tolerated in a body with near depleted glycogen stores than in one with fully stuffed glycogen stores. (What may have been my body at my highest weight, when following an average diet.) Even a year ago, I´d have highish fbg the morning after eating carbs, while now, glucose clears after an hour mostly. This tells me that glucose can more easily find its way to glycogen stores which seems more likely when there is capacity to store.
I do believe a lot of diets really mainly work because of cutting sugar, starch and fried food. If you take a pound of vegetables, the protein suited for your weight, a few berries and herbs, there is room left for either some fats or some carbs for burning. Some people feel equally good with both, some don´t.
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Christine Dan Hi! Since this thread is about metformin and rapamycin I decided to post this link here.
https://www.aging-us.com/article/101319/text#fulltext
It is a link to research based on AI. The usual question - Which information and what scientific reports should I act upon - makes this research extra interesting for me and my quest for good health, personal wellbeing and long life. The quest for finding optimal interventions that does not have antagonistic effects on each other.
- Should I base my actions on how my interventions make me feel? And how much should I trust those kind of simple loops of biofeedback?
- Should I base action on single research papers? Papers usually investigating one single substance at the time and not in combination with other interventions.
- How much should I read into labtests?
- And also how should I (we) relate to the approach were AI is the base behind selecting strategies for what supplements to use?
I found this report to be an interesting read and I posted it in this thread. And they also push forward natural rapamycin mimic s, which according to AI has a much better profile when it comes to side effects. Maybe someone else can find this kind of information useful.
PS Life extension used this research as a base for one of their supplements. Now I understand more about the research behind it.
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Staffan Olsson great article. Challenging to find these compounds in available supplements. Would like to find a Withaferin A only supplement.
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Karl Withaferin is usually not sold pure. It is usually sold as ashwagandha extracts. KSM-66 and sensoril are well known standardized extracts.
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Staffan Olsson The supplemental table shows the following combinations, and their similarity to Metformin. There is no data on percentages per combination.
Withaferin is ashwagandha.
Combination Similarity to Metformin Gamma.linolenic.acid_Withaferin.A_Apigenin 0.727711449254284 Gamma.linolenic.acid_Withaferin.A 0.723883017206556 Ginsenoside_Gamma.linolenic.acid_Withaferin.A_Apigenin 0.72204610791846 Ginsenoside_Gamma.linolenic.acid_Withaferin.A 0.716558817066117 Ginsenoside_Gamma.linolenic.acid_Apigenin 0.697734278691384 Ginsenoside_Gamma.linolenic.acid 0.69657810489182 Gamma.linolenic.acid 0.695618610909604 Gamma.linolenic.acid_Apigenin 0.691551138691731 Ginsenoside_Withaferin.A_Apigenin 0.578800197550358 Ginsenoside_Withaferin.A 0.567212836102874 Withaferin.A_Apigenin 0.566698876897712 Withaferin.A_Apigenin 0.560287816 Ginsenoside 0.433228884668052 Ginsenoside_Apigenin 0.347933560371095 Apigenin 0.119565220840027 -
Withaferin is also an analogue of rapamycin, second to the antibiotic geldamycin.
With the rapamycin classifier, the most significant hit was geldanamycin (Fig. 2B). Geldanamycin is an antibiotic belonging to Ansamycins family and targets the ADP/ATP binding site of heat shock protein 90 (Hsp90). Similarly to rapamycin, it has been shown to suppress the mTOR pathway through inhibition of the interaction between Hsp90 and RAPTOR [115]. Interestingly, the second most significant hit was withaferin A, which aligned with our subsequent results of gene- and pathway-level scoring for metformin and rapamycin, respectively.
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Juan Daw how is Withaferin an analogue of Rapamycin?
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Karl Sorry. I meant mimetic.
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Juan Daw Have researched this further and summarized Withaferin A (in a constantly updated health-supplement worksheet) along with possible use with Fisetin to supplement (or supplant ?) rapamycin. Am currently supplementing with all-of-the-above until there are clear, reliable tests for efficacy (and because of their other desirable benefits). Here are a few relevant excerpts:
'Withaferin A, directly binds with HSP90 (Heat Shock Protein 90, most abundant protein at 1%-2% total cellular protein content), which acts as a chaperone (protects over 100 known client proteins from premature degradation, as well as assisting in proper protein folding ) e.g. PI3K (which activates mTORC1 via PI3K/AKT/mTORC1 pathway). Inhibiting HSP90 (by directly binding to it) significantly reduces mTORC1 function and, by default, brings on autophagy and (likely, associated) NRF2.'
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'For reference, mTORC1 inhibition as chemotherapy (e.g. rapamycin to control some cancers) can invite a negative feedback loop from AKT (3-protein complex that serves as an upstream activator of mTORC1), which bypasses mTORC1 suppression by signaling downstream IGF-1 (insulin-like growth factor-1, responsible for tumor growth and puberty growth spurt). Fisetin, in sufficient doses, indirectly suppresses AKT (via directly binding with upstream PIK3 i.e. PIK3/AKT/mTORC1 pathway) and directly inhibits MTORC1 (and downstream S6K even more effectively), which explains it's more favorable performance in suppressing cancer growth (besides it's excellent senolytic properties). Withaferin A may synergize with fisetin as an even more effective rapamycin mimetic (than just fisetin alone, see FISETIN notes below) by inhibiting HSP90 protection of PIK3 (& AKT), making Fisetin/PIK3 binding (along with PIK3 ubiquitination) more effective, thus more successfully shutting down mTORC1.'
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'For reference, rapamycin binds with FKBP12 forming FKBP12-RAPA complex, which then binds with the FRB domain of mTORC1 (destabilizing it and may interfere with assembly of mTORC2) with a relatively strong affinity of 12 nM (nanomolar, a measure of concentration). Fisetin binds directly with mTORC1 at a much weaker affinity (~ 11000nM, a much higher concentration required here...almost 1000x more than rapamycin), but at 3 different binding sites. Fisetin also directly inhibits S6K (a.k.a. p70S6K), a downstream effector of mTORC1 ( at ~ 12 times the affinity at 940 nM, or ~ 80x the concentration of rapamycin/mTORC1), whereas, rapamycin doesn't at all. For reference, S6K1 (a phosphorylated version of S6K, by mTORC1) can also participate in a positive feedback loop, stimulating more mTORC1 activity (by dampening upstream mTORC1 inhibitors). Taking sufficient fisetin, therefore, could supplement rapamycin (or supplant it altogether?). Rapamycin has roughly 20 times the half-life (~ 62-74 hours) of fisetin (~ 3 hours) and should be taken once every 7-10 days (by the time it's mostly out of the system). To approximate rapamycin efficacy, sufficient fisetin (80x, a feasible 500mg or more, to inhibit downstream S6K, or 1000x, >6,000mg, to directly bind mTORC1, which seems unfeasible) would have to be taken once every 12 hours (twice a day). If just as effective, mTORC1 inhibition via fisetin could avoid potential inhibition of mTORC2 (?...gradually/indirectly caused by prolonged high rapamycin exposure) and it's immune signaling functions.'
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Updated information. I'm working with a really good aging MD who recommends that since I'm already taking Metformin, exercise and fast, that doing Rapamycin on top of that is probably overkill. And it's expensive.
Again with managing your state you want to achieve homeostasis. This is to find the balance between two extremes, whether it be in exercise, caloric consumption or what have you. Note this is not the same as "moderation", as in "everything in moderation". That is the rallying cry of people who want an excuse to keep eating their meat, cheese, alcohol or whatever vice the have. Some things are definitively bad for you in any quantity so you don't want it in moderation.
But for the things that are good for you - such as exercise - you don't want too little, and you don't want too much. Taking this example, people tend to think that if a little exercise is good then a lot must be better - not true! just one example is that elite athletes have impaired immune systems due to the constant exercise.
Another example is the Ketogenic diet fad. Yes, ketosis is good, in small quantities. Doing a monthly or bi-yearly multi day water only fast does amazing things, but you don't want to try and achieve that 24/7! Your body is designed to work on glucose - carbohydrates! But there again, people consume too many simple carbohydrates, and instead of being sensible and finding balance they go to the other extreme and try to eliminate them. It's madness.
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Dan I've been on 1000 mg Metformin, 3mg/week Rapamycin and do 16 hour fast 6 days a week. Is it overkill? We just don't know. I acknowledge Rapamycin is expensive but I think for me it's worth it. Dr Peter Attia who is on Metformin, Rapamycin also does extensive fasting (7 day water only fasts every 3 months) and IF. He thinks it's worth it with our current knowledge. He also is very skeptical about efforts to boost NAD+.
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Thanks for the information, yes we don’t really know yet.
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Larry Good post. I also follow Attia. He recently listed his bearishness on NAD+ oral precursors as being his biggest change from a year ago. He is getting ready to start NAD+ oral precursors.
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54 yr old male, APOE 3/4. Mom has AD, dad had PD. Made radical lifestyle changes 3 yrs ago (after finding out I was APOE 3/4) to prevent AD. I went strict ketogenic 70/20/5 LCHF (fats come from plant fats, avocado, nuts, EVOO), minimal wild animal protein (salmon/sardines/bison), and whatever carbs in above ground green veggies (very low carb vegetables). No alcohol. I started 18/IF for 2 years (promptly lost 50 lbs), and then went OMAD (one meal a day) 13 months ago. My blood BHB ketones are typically 2.0 mmol/L daily, my fasting insulin and glucose are very low. My hs CRP is almost zero. I also run 5k intense cardio + 30 minutes resistance exercise DAILY. I have a Functional Medicine Doctor, we practice the Bredesen AD prevention protocol, as well as hormonal supplements, and regular supplements (resveratrol, curcumin, DHA/EPA, etc). I've had a Neuroquant volumetric MRI, awaiting SPECT scan (cerebral blood flow), and CCAC, as well as baseline in depth cognitive testing protocol...all to baseline and follow longitudinally.
I want do counter that the "body needs glucose from carbs" is a complete myth. The liver produces ALL the glucose it needs from proteins/fats. The US food guide states the minimum RDV for carbohydrates is...ZERO. There are no "essential carbs"
https://www.dietdoctor.com/have-to-eat-minimum-amount-carbs
I have become super lean and fit, cardio and muscular, lost 50 lbs, and my biomarkers are stellar (all without carbs for 3 yrs).
Ketones and ghrelin hormone are HIGHLY neurobioenergetic for hippocampal neurons: ancestrally conserved pathways in our evolution.
I am seriously looking at Rapamycin now as additional intervention. I've read almost 3,000 papers on AD, and have come to the conclusion that its a vascular mediated disease. It explains all the risk factors (age, APOE, hypertension, diabetes, ischemic stroke, smoking), the science is so powerful showing the causality. Rapamycin can help prevent vascular (including BBB) dysfunction. Rapaymcin is so intriguing, it acts systemically on so many pro longevity pathways. I don't think I need metformin, would go directly to Rapamycin.
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MAC
Excellent post Mac. And congratulations on all of your progress. Excellent discipline!
I’m really interested in what/ how you will do your Rapamycin. And then how you will measure any change.
Thanks!
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MAC apoe4 males don't have to be concerned about Althzeimers. Guess what, I have it too! A few years ago a Stanford researcher did a review of the data and found the gene is only indicative of AD for females. I did a full genome test and had an included session with a genetics advisor, she also knew of the male apoe4 connection and wasn't concerned at all.
Otherwise a correction on glucose is that yes it is produced from carbohydrates. In full ketosis your body switches to burn ketone bodies produced from fat, but this is a non preferential pathway. Have you ever done a water only fast of at least a week duration? I do it twice a year, it's quite enlightening to experience full ketosis versus normal glucose burning.
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Dan Hi Dan, and you actually believe that?? Anyone who tells you you don’t have to worry about AD, especially if you have APOE4, is blowing smoke.
You know that E4 is the “frailty gene”...we are not meant to live a long life. E4 % representation in old age cohorts is extremely low!! AD and longevity is a polygenic risk dynamic.
Yes I’ve read all the literature on the low risk for E4 males. I know non E4 males and AD came out of NOWHERE! 40-50% of AD is NON E4. You can roll the dice, and I respect that. But hell no, I am doing on full prevention warfare. I am taking the reverse hypothesis: I am high risk, shortened lifespan n=1 and will prevent/extend.
Even if AD dosent get you, one of cancer or CVD or some other secondary complication will. This is a long term anti-aging war. My lifestyle interventions are all about lifespan/health span extension. We don’t (sorry I don’t) have the luxury of narrow genetic haplotypes like the Okinawans/Sardinians/Cretans with longevity.
What brain and blood biomarkers are you tracking?
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Yes I stated it, apparently I do believe it, unless I've already got altheizimers and just think that I believe it, or not think as the case may be 🙂
You're quite passionate about your views on this and I want to ensure we continue to have civil discussion on the board. Briefly I'll note I've spent my adult life pursuing superior health and longevity, so there's no rolling dice, but being a scientist my approach naturally is derived from the existing scientific data with a 'holistic' or 'meta' approach to synthesizing it. Backing that up is that I've conducted personal experiments these many decades and have hard results supporting the approach. However it's quite different from yours. Regardless the conversation has wandered off topic so we should probably stop here.
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Dan my apologies if I offended you or anyone. I always try to stick the science as I see it, but always open to other interpretations.
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MAC No offense at all! We're having a healthy discussion here. Actually I'd like to have some debate, perhaps a dedicated forum, for diet and lifestyle, but am cautious because these topics can become contentious.
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Dan we are all self-hackers, otherwise we wouldn't be on these forums! We cannot wait for western medicine to save us from chronic illness. I personally believe we must take responsibility for our own n=1 self well being. I don't have the answers to longevity nor can I say with ANY proof that anything I am doing will delay any chronic disease. The best that I can hope for is somehow/someway I can baseline and track my inner health longitudinally, and show "positive" trends.
My physical/cardio health is now excellent, and I believe this is a huge part of longevity enhancement. In all the human lifestyle intervention literature, cardio respiratory fitness is always associated with longevity (aside from extreme fitness athletes who push the limits of the heart muscle, and elevate risk of AFIB/ ischemic risk).
Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2707428
This is an excellent study, using a standard controlled cardio test, tracking longitudinally, AND it's outcome is ACM (All Cause Mortality, ergo longevity)
Have a look at Figure 2.
Can someone show me a lifestyle intervention study, in HUMANS, showing a better ACM outcome? I don't think I've found one yet.
There is no "pharma" hack here...pure and simple cardio fitness. There are many evolutionary theories abound that associate our bipedalism and running capability to brain size expansion.
Have we lost our ways in a western sedentary society?
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MAC Hi Again !
Since you have serious interest in physical health I'd like to add this link. Muscular strength and cardiovascular. (it can be stretched to whole body health)
I personally will incorporate tougher resistance training in my efforts.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496010/
This link (even though I dont think the reading is great) bring focus on the muscular fitness and the related effects on whole body health. A couple of years ago I had a rewarding conversations with a well renowned heart surgeon. He said that according to his experience and the lab results he had seen his personal interpretation was that persons who, after different kinds of heart surgery, started to do heavy resistance exercise (like in a gym) showed up with a healthier and younger heart. This even though they did not focus their training on cardiovascular fitness. The guess work was that the anabolic/pysiological response in the muscleoskeletal system was transmitted to the cells in the heart (and other parts of the body) so cardiofitness was also improved. This is of course an anecdotal story based on one person’s experience. But I find this being a good idea to have in mind. Especially since we now see how completely different organ systems interact. (Like the environment in intestine and how it can effect the brain)
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Staffan Olsson I practice BOTH in my daily routine, although I do resistance training more for skeletal muscle build, overall physical health, and strength/resiliency to help reduce risk of frailty as I age. I lost 50 lbs, and have become very lean and muscular on my diet/exercise protocol. The muscularity is all from the daily intense resistance exercise.
Investigation of frailty as a moderator of the relationship between neuropathology and dementia in Alzheimer’s disease: a cross-sectional analysis of data from the Rush Memory and Aging Project
https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(18)30371-5.pdf
"Frailty and Alzheimer's disease pathology were independently associated with Alzheimer's dementia. When frailty was added to the model for the relationship between Alzheimer's disease pathology and Alzheimer's dementia, model fit improved. There was a significant interaction between frailty and Alzheimer's disease pathology. People with an increased frailty score had a weakened direct link between Alzheimer's disease pathology and Alzheimer's dementia; that is, people with a low amount of frailty were better able to tolerate Alzheimer's disease pathology, whereas those with higher amounts of frailty were more likely both to have more Alzheimer's disease pathology and for it to be expressed as dementia.
In my readings, cardiorespiratory fitness is FAR more neuroenergetic than resistance training. My main dementia prevention objective is protecting the hippocampus.
Sustained aerobic exercise increases adult neurogenesis in brain
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818598/pdf/TJP-594-1855.pdf
" Our results confirm that sustained aerobic exercise is key in improving AHN. We report a very modest effect of HIT and no effect of resistance training on AHN in adult male rats"
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Dan Some new literature on Rapamycin, including some new rapalogs that are HIGHLY specific to mTORC1! Its' the mTORC2 inhibition and impact on some of the "basic" biological functions such as glucose and lipid metabolism and the immune system that has me still mulling. New compounds that only impact mTORC1 would be hugely beneficial to human uptake.
(In jurisdictions for which access to Sci-Hub is legal, you can search for the papers there. Per the Digital Millennium Copyright Act)
TORwards a victory over aging
https://www.ncbi.nlm.nih.gov/pubmed/31544928
"The continuous expansion of our knowledge regarding how age-related conditions are influenced by mTOR signaling in many species and disease models, and the continued pursuit of safe, efficacious ways to reduce mTORC1 signaling confirm the value that persists in exploring the regulation of aging by mTOR"
A novel rapamycin analog is highly selective for mTORC1 in vivo
https://www.nature.com/articles/s41467-019-11174-0.pdf
"DL001 inhibits mTORC1 signalling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system"
Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters
https://www.sciencedirect.com/science/article/abs/pii/S2451945619301783
"Here we describe the identification, optimization and characterization of a chemical scaffold that demonstrated a profile consistent with the selective inhibition of mTORC1. Surprisingly, target identification revealed that class I glucose transporters, primarily GLUT1, was the primary target for these compounds yielding potent inhibition of glucose uptake. Upon further characterization, we have demonstrated that cellular inhibition of glucose uptake by these compounds leads to selective and potent inhibition of mTORC1 activity even in the presence of growth factors and other nutrients. Therefore, modulating the glucose-sensing mechanism would be an alternative approach to developing therapeutic tools to selectively target mTORC1 in the future."
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We keep coming back to glucose nutrient sensing as a very strong anti-aging signal. We all know the huge association of elevated glucose with chronic disease, implicated in ALL the major diseases of modern society: cancer, CVD, Alzheimers. Thousands of research studies on lesser organisms have consistently shown longevity associated with reduced glucose/essential amino acid nutrition levels and CR. Excess protein intake (especially the BCAA's found in animal protein) causes gluconeogenesis. These nutrition inputs may ALL have a common root molecular pathway: glucose. Just one of the many reasons why I practice a strict ketogenic/OMAD/low animal protein dietary protocol. Eschewing animal protein for high quality plant protein would take me out of ketosis.
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