I could not get the NEJM article to copy, but this repeats the findings.
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I always thought it was weird that Brenner was so into selling NR without addressing NMNT. If you address that, Iâd presume cheap niacin (USP) + Trp would be the easy way to NAD+. Flush sucks but NMN is not too shelf stable so itâs hard to source.
One could try a ânaturalâ NMNT inhibitor for NAD+ until small molecule inhibitors are developed.
Hereâs the theory:
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I have tweeted David Sinclair and Brenner about this subject of NNMT inhibition as I would imagine they are quite familiar with it in their research. Never received reply or seen them speak about it. It makes more sense to me versus just putting more precursor (NMN or NR) into the system. 5 Amino 1MQ and the molecule in the paper you posted (JBNSF) are two that have some initial research as being viable.
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AFAIK, they have not really addressed it. I am certain they know about it with their backgrounds since they put so much stock into it.
I would have presumed either would have by now, but I suppose many of their fans are not quite equipped with biochem literacy
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I am currently once again trying to ramp up my niacin intake to 1 gram a day so that I can quit my statin and if it raises my NAD+ levels, so much the better, and yes, the flush sucks. Things that reduce the flush may be counterproductive. I have also read that time-release niacin may be hard on the liver.
I wonât pretend I actually understood the article, but thanks
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I think Sinclair called it exercise in a pill. I wish I felt that effect. No difference that I can tell.
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I think I would call it the benefits of calorie restriction in a pill. If anything I have lost some muscle mass, but also have lost the aches and pains/ inflammation as well. Expectations are so important when trying a therapy to improve an outcome. Good luck!
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Not sure who you are responding to, but âcalorie restriction in a pillâ, are you referring to Rapamycin?
Hereâs the thingâŚCR in mice results in MASSIVE weight loss. So if Rapamycin is CR in a pillâŚwhy hasnât human translation resulted in massive weight loss? Dosing translation orders of magnitude off?? Are we REALLY anywhere signalling the lifespan promoting effects of CR with rapamycin? I donât accept this equivalency, even though CR and rapamycin have different signalling pathways.
On rapamycin? Ok that is definitely NOT goodâŚyou must preserve muscle mass, you must add resistance exercise to maintain/build.
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CR =/= rapamycin
Can be additive for muscle though!
As a âblunter of mTORâ, agreed. As a physiological body translation, only partially in mice, and certainly not in humans.
Look at red delta vs blue delta, and the absolute % weight loss of both interventions.
Every longevity study in mice given âlifespanâ rapamcyin protocols (even those newborn which seemed cruel btw), there is significant weight loss. Itâs a signature phenotype response.
So why arenât we getting these levels of % weight loss in translation if Rapamycin is a CR equivalent?
Even the seminal cancer/Rapamycin/GFJ study, cohorts on VERY high trough/AUC doses (will venture to say nobody on this forum is anywhere near these dose levels or duration)âŚweight loss was only a side effect in 11% of the cohort, and only 1 person of the n=118 had a level 3/4 DLT of weight loss. And this was only at 60 mg/week.
I would hardly call this CR = Rapamycin.
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I can understand.
I believe I have lost the appearance of muscle size on Rapamycin. My biceps seem about half the size they were before I started on rapamycin. However, my arm strength is the same⌠so more shredded⌠or jacked looking. No extra fat, so toned as opposed to muscle looking.
It initially bothered me⌠but realize it is healthier to have nothing to hamper flow of nutrition in the body and waste out.
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Wow you were that much bigger? All went to your hair.
Wish you had a pre and post DEXA.
But seems to me you have an amazing reserve for a 64 yr oldâŚand you continue to maintain. 
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Oops! I forgot to tag who I was answering. Some saying that they thought Rapa was suppose to be like exercise in a pill and I was just trying to suggest that from a longevity standpoint it was close to CRâŚas far as outcomes, not mechanisms of action.
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Maybe less intramuscular fat (ie marbling)?
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Noted, but I still argue that although they do have different mechanisms of action, they BOTH induce significant weight loss in extended lifespan mice. So putting aside alternate mechanisms of action, if rapamycin is NOT inducing a significant weight loss in humansâŚhow can it possibly enhance lifespan (at current human oral, low, non therapeutic doses)?
2019 (very good review paper)
"While dietary restriction and rapamycin may have similar effects on some pathways and processes; overall, they affect many pathways/processes quite differently. Therefore, rapamycin is likely not a true dietary restriction mimetic. Rather dietary restriction and rapamycin appear to be increasing lifespan and retarding aging largely through different mechanisms/pathways, suggesting that a combination of dietary restriction AND rapamycin will have a greater effect on lifespan than either manipulation alone.
The recent nature article on RM + CR confirms:
âOur results conclusively demonstrate that CR and RM exert distinct, non-overlapping and frequently additive effects in aging skeletal muscle. The striking failure of RM to recapitulate the effects of CR and more surprisingly, the failure of CR to recapitulate the effects of RM raises the exciting prospect of multiple, additive interventions to counteract sarcopeniaâ (ME: and extend lifespan)
So Iâm hedging for maximum possible benefit (along with other stacked interventions), combining rapamycin with quasi CR mimetic (keto/OMAD). My brain thinks I am starving, constant hunger signal throughout the day, depressed fT3, but yet Iâm not. If I look at the calories I consume daily vs my build and exercise regiment and 24 hr fasting regiment, I should be eating a lot more to keep my weight stable. And the apparent preservation of muscle on relatively low protein (there is likely an additional mechanistic pathway, as keto mechanistically spares muscle). There is definitely some type of positive steady state CR âsignalâ at play. Even people on full on CR, they eventually reach a steady state weight and signal.
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@MAC interested to understand your broader philosophy.
Reading your posts across multiple threads my interpretation is that you think we are not going far enough with weekly dosing of 6 to 10mg?
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I am under that impression that 6mg to 8 mg is not enough and I am now using 6mg with Grapefruit Juice to aim for a 20 mg a week dose.
Been on this about 2 months already - next dose tonight⌠I am not seeing muscle change. As I am consistent in my workout routine for the past 6-years â even subtle changes are very obvious. I think even at that dose (20 mg) the MTOR 2 is still functioning fine. I tend to get a bit of diarrhea. However, if I take peto bismol diarrhea pill - post dosage 12 hours and then again at 18 hours post dosage of rapa. Nothing happen - no diarrhea and I stay regular.
I am not seeing a muscle or strength change in arms, chest , legs or ass - ;). I plan to take Glycan and methylation test in 6-months to see how my biological age changes â reverses - maintains or moves forward - using the higher dosage. Will stick to it as long as I donât see physiological issues or other negative side effects.
Maybe less intramuscular fat (ie marbling)?
That is my belief that my bigger, solid arms were not just muscle - marbled fat.
Now smaller but very defined - shredded. Just as strong.
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Which brand/source of Rapamycin are you using?