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.
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:
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 . 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 . Each drug prolongs lifespan in mice, prevents cancer, atherosclerosis, and other diseases of aging.
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.
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.
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"
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.