“YOLO”
-Bryan Johnson
Anyone know or have thoughts on the rationale for the
13mg then 6mg then 13, then 6 and so on?
Its all focused on trying to balance the benefits of mTORC1 inhibition (more inhibition the better, suggest mouse studies), while minimizing mTORC2 inhibition, and the side effects (lipid / glucose disregulation( that are thought to come from the mTORC2 inhibition.
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I know this is mentioned in several articles
whereas the negative effects of rapamycin on glucose and lipid metabolism are mediated by inhibition of mTORC2.
https://www.nature.com/articles/s43587-023-00416-y
For example, the negative effects of rapamycin on glucose homeostasis have been attributed to the inhibition of mTORC2 in the liver
But how does this compare to Blagosklonny?
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I had read something which implied that continual inhibition of mTORC1 has the effect over time of inhibiting mTORC2, but I don’t have a source for that. (much that one may be available from searching).
However, as I am probably the least frequent Rapamycin doser it is not my priority for study or research.
I think Dudley Lamming is the key proponent (at least from my reading) of the idea that long-term, high dose, rapamycin tends to inhibit mTORC2 and thus cause the lipid and glucose disregulation.
Some references:
Here: Evidence that mTORC2 inhibition is detrimental, by Dudley Lamming
and
We have demonstrated that chronic, long-term administration of rapamycin results in inhibition of not only mTORC1, but also mTORC2, in vitro in cancer cell lines as well as in vivo in mice (Sarbassov et al ., 2006; Lamming et al ., 2012). Long-term rapamycin treatment results in glucose intolerance in humans, rats, and C57BL/6 mice as well as genetically heterogeneous HET3 mice (Houde et al ., 2010; Gyurus et al ., 2011; McCormack et al ., 2011; Lamming et al ., 2013). We found that this effect is mediated in part by decreased hepatic insulin sensitivity, an effect that can be reproduced by depletion of RICTOR, an essential protein component of mTORC2, in the whole body (Lamming et al ., 2012) or specifically in the liver (Hagiwara et al ., 2012; Lamming et al ., 2012; Yuan et al ., 2012). We have recently shown that Rictor deletion specifically in the liver has significant effects at both the mRNA and phosphoproteomic level that are distinct from those seen with acute rapamycin treatment (Lamming et al ., 2014).
https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12256
and
but there is some research that suggests a little mTORC2 inhibition may not be a bad thing: Ideas on Protocols for Testing Higher Rapamycin Doses - #13 by brandy111
I’m not at all familiar with the data behind blagosklonny’s comment regarding mTOR2 inhibition in humans.
But I did talk to Adam Salmon who is running the long-term marmoset rapamycin study at UT Southwestern in Texas and they are dosing at 1mg/kg (which does not raise blood/sirolimus levels anywhere near 100 to 500 ng/ml of rapamycin) and he said they definitely see mTORC2 inhibition. if this is true in primates, I suspect its also true in humans.
Also, see this paper by Dudley Lamming:
preprints202102.0491.v1-6.pdf (391.7 KB)
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I eat super veggie blended daily and really enjoy it. Very filling and yummy. Nutty pudding I haven’t tried fully prepared because i haven’t found detailed prep instructions - I am the type the needs step by step with food, so I just eat the nuts as an afternoon snack.
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Would be nice to calculate his amount of Rapa concentration in blood per day for this “6mg/13 mg” schedule after a month on such schedule. It looks like there are no breaks from R and he’s trying to achieve a permanent concentration of it in blood. If so, why not to take just .5 or 1 mg per day for a week and have 3 day break before starting again?
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I haven’t seen Bryan publish his apoB @Oliver_Zolman_MD and there is a clinically significant reduction in MI’s in the short term with PCSK9 inhibitors from Bryan’s level’s of LDL. Rapamycin has the side effect of hyperlipidemia for some. So it isn’t out of the question that his apoB might be high/become high. And you’re potentially missing compounded benefits from apoB reduction from his (probably) already low levels? According to Thomas Dayspring ASCVD cannot develop from having very low apoB levels (akin to neonatal levels).
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https://twitter.com/bryan_johnson/status/1683855033425866755?s=20
More /Video: My Complete Anti-Aging Workout - YouTube
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I actually don’t know of Profile and Google couldn’t elucidate me either. Care to share?
I microneedle so in that sense I am familiar with mesotherapy but I’m a bit hung up on injectables. I did do a bit of hyaluronic acid filler via the pressure pen (needle free, Google hyaluron pen) and it looked good but honestly felt like cheating. I don’t want to look filled either, want to have naturally great skin. At present my texture and color are close to perfect glass skin but I find some structural things like nasolabial folds developing, mostly from rapid weight gain and loss from 4 pregnancies back to back, that will require some aggressive intervention if I’m serious about winding back the clock. Getting myself worked up for plasma fibroblast as the likeliest solution.
he is not that depleted - I would do nano-fat if I were him
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108 under the condition that he continues his insane protocol? It’s very likely that he won’t. I predict that he’ll be mentally exhausted in couple years if not sooner.
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What do you believe is most mentally exhausting part of his routine?
I personally think that with some minor adjustments and less obsessiveness it is a completely doable and achievable…
Maybe. But he might also end up benefitting from some cutting edge therapy in the not too distant future that allows him to take his foot off the gas.
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I’d be happy to put money on it because odds are really against it happening, but all he has to do is outlive me and I’m almost 63. I’ll never collect.
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As long as he has enough money to hire people to prepare all the food and pack all of his supplement boxes, I think he can probably stick with most of it
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