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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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 so many factors come together to create the perfect storm. My mother is APOE3/4 and until age 90, lived alone and looked after herself. She is now almost 96 and sadly, very close to the end, yet still knows who I am. She also has longevity genes which have likely offset the "4" negative. I'm 4/4 and have recently started taking rapamycin after seeing Dr. Green. While he recommended 6mg, I started a bit lower (4mg). So far, no problems and I'm into week 4.
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BobM Thank you. OMAD is most definitely the toughest mental challenge to overcome. The ghrelin signal is super strong between say 11am until I eat my OMAD dinner at normally 6pm. It requires great fortitude/self control to ignore it.
Per my original post on ghrelin signalling and neuroenergenesis:
Ghrelin-Mediated Hippocampal Neurogenesis: Implications for Health and Disease
https://www.sciencedirect.com/science/article/abs/pii/S1043276019301249
Great question on "how you will measure any change". As an engineer, the old mantra "you cannot manage what you cannot measure" is extremely relevant here. As you can see, I have a pretty detailed monitoring of lifestyle interventions, most recently adding layered brain imaging/cognitive testing. The challenge will be teasing out the Rapamycin effect given I am simultaneously layering so many interventions that boost brain function/cardiovasculature.
And given that I believe AD is a vascular mediated disease, I am currently studying what biomarkers I can track that signal the effect of the rapamycin intervention. Given my metabolic profile, current thinking is perhaps starting with a lower dosage, say 4 mg every 7 days (not settled).
Practically, these Rapamycin tracking markers need to be reasonably accessible vs exotic academic lab tests.
If you review this paper for example (albeit mice):
Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease
https://journals.sagepub.com/doi/pdf/10.1177/0271678X15621575
They used conventional tests of ASL and CMRglc to assess the impact of Rapamycin. The SPECT scan I am scheduled for is really a cerebral blood flow scan. The CMRglc is not readily done and $$, but it's a gold standard for brain functionality and is readily available. Enhanced NO production and NF-κB signalling is also a direct result of Rapamycin intervention. There are a few other markers.
Of course, will also be testing for some of the potential negative effects such as lipids/glucose/insulin/immune system functionality.
Still researching...
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MAC Hi Mac! Since you have researched neuroprotection well, I wonder if you have any personal view on the usefulness of Taurine. I have used it intermittently at 1500 mg at bedtime for improved sleep and for its potential for promoting neurogenesis. But lower dosing has a negative effect on my sleep.
I find this recent review covering the neurological effects of Taurine well. "Taurine and its analogs in neurological disorders: Focus on therapeutic potential and molecular mechanisms"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536745/
Any focus on aptosis in cells other than braincells would be out of line. A link more focusing on taurine as pro apoptosis in some cancers.
https://academic.oup.com/abbs/article/46/4/261/1578
Since preserving brainfunction is one of my main goals, I wonder about your view on this particular substance.
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@ staffan_olsson I have not read much on Taurine, it's not on the mainstream "AD" radar for pharma interventions. From a brief read on the article, it appears that Taurine itself has very low bioavailability, and engineered analogs need are required for enhanced pharmokinetic activity (ie. crossing the BBB). There are some beneficial outcomes in some neurological mouse models reported, but at huge doses, mostly ip injected. Mouse models, unfortunately, have translated extremely poorly to humans when it comes to Alzheimers research (think Amyloid). Btw, IMHO, amyloid and tau are downstream pathological markers of the brain trying to deal with some other underlying upstream chronic dysfunction (e.g. vascular, BBB).
To think that a single pharma molecule could "prevent" neurological disease, when the disease has so many apparent pathways leading to synaptic loss is perhaps wishful thinking. I am not sure your age or neurological state, but prevention with lifestyle interventions that act beneficially on EVERY cell in the body, is still the best protocol.
My sleep is still a work in progress, but a very important component of overall health and well being. Sleep disruption has 2 way associations with AD.
https://www.ncbi.nlm.nih.gov/pubmed/31536750
For a good reference on the importance of sleep, read Matthew Walker (Why we Sleep). Petter Attia has several podcasts with Matthew as abbreviated option. https://peterattiamd.com/?s=walker
It appears that my keto diet, OMAD, supplements, hormone treatments "may" have disrupted my serotonin and/or circadian rhythm, and my sleep is somewhat fragmented (no issue falling asleep, but will awaken during). I just ordered a DREEM2 sleep tracker https://dreem.com/en?p=dreem2 so I can begin to understand my sleep patterns, and then implement lifestyle interventions to monitor improvement.
What are your sleep symptom characteristics, attributable to any lifestyle changes, and does Taurine help?
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MAC hi! My pattern of sleep has been that I can easily fall asleep but might wake up after a few hours Usually 3-5 hours. I need more sleep than that. Melatonin accentuated this issue and I became wide awake after 3-4 hours. Melatonin did not work for me. I am surprised but 200 - 400 mg folic acid makes me sleep better. (I have not had the same sucess with 5-MTHF). Taurine att 1500 mg improves my sleep but lesser dose Taurine disturbs my sleep. Magnesium citrate/bisglycinate improves my sleep.
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Duy noted. My sleep hacking is still a work in progress. The melatonin (various doses) does not seem to impact my waking, although it definitely helps with falling asleep. I tried magnesium L-theronate at night (I normally take it in the day for simple Mg plasma level elevation), but found no improvement. I am not so advanced in my experimentation with sleep interventions. I am hoping that once I start tracking my sleep with the DREEM2, I can baseline, and then start further interventions. If I learn anything, will be glad to share. Even though my sleep is fragmented and I find myself yawning during the day, I still have plenty of energy and there's impact on my daily routines.
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Sorry. I meant mimetic.
