🥼Agingdoc1⭐MD, PhD 🔔 Profile picture
Sep 27, 2020 45 tweets 29 min read Read on X
@Blagosklonny The following is for educational purposes only, and not medical advice.
@Blagosklonny is a pioneer in rapamycin research & was the first to propose it has the potential to extend life based on its mechanism of action (keep reading, this discussion & calculations are stacked)..🧑‍🔬 Image
@Blagosklonny his prediction was subsequently confirmed in Saccharomyces (yeast), C elegans (nematode worms), Drosophila (fruit flies), mice, and others.
Rapamycin (sirolimus) has been used off-label for theorized healthspan and/or lifespan by such celebrities as @PeterAttiaMD...(keep reading)
@Blagosklonny @PeterAttiaMD You can see Dr. Blagosklonny practices what he preaches: 10 mg/week: bit.ly/349jlpM. The discussion that follows puts this in some respects very modest dose in perspective and provides a framework for thinking about dosing (more or less– in the 10-30+mg rapamycin range).
@Blagosklonny @PeterAttiaMD In the ITP for 42 PPM, male mice sirolimus concentration=23 ng/mL (23% median LE, 8% max) & for females 80 ng/mL (26% median LE, 11% max) bit.ly/335VZBM.... (keep reading, thread is stacked, calculations follow)...
@Blagosklonny @PeterAttiaMD In one study (mostly males, mean 79.6 kg ~175#) subject Cmax ~23ng /mL with 10 mg of sirolimus (+/- ~7 ng/mL). Cmax varies substantially by person & setting, so measuring and monitoring Cmax & Cmin is far more accurate bit.ly/3mW8uIk (keep reading)...
@Blagosklonny @PeterAttiaMD So, 42 PPM in mice ~10-35 mg of rapamycin for the average 79.6 kg pt (0.125 mg/kg to 0.44 mg/kg).
While the ITP mice mostly sustained the concentrations by daily dosing, in persons Cmax is achieved within 1-2 hrs & washed out to a trough corresponding to its half life (~65 hrs)
@Blagosklonny @PeterAttiaMD in this study; 55-85 in others). So the AUC and sustained dose duration are substantially higher/longer in the mice though the implications of these differences and the validity of any extrapolations represent unknowns that are matters of both....
@Blagosklonny @PeterAttiaMD great speculation (bit.ly/2GgBt8x) and ongoing investigation.

Everything is a tradeoff – of knowns/unknowns, and risks/benefits. For example, a higher dose would achieve a higher Cmax and also a higher AUC and a more sustained dose above a given concentration threshold
@Blagosklonny @PeterAttiaMD Higher doses also have associated greater potential risks, side-effects, and imply less frequent dosing to allow sirolimus wash-outs to diminish potential side effects ( excess mTORC2 inhibition sequela, excess immunomodulation, etc.): there is nothing magic about weekly dosing..
@Blagosklonny @PeterAttiaMD it can be higher doses taken less frequently – but the implications of such tradeoffs are mostly black boxes....(keep reading)...
@Blagosklonny @PeterAttiaMD In 2020, long-term transplant rejection prophylaxis therapeutic drug levels are 12-20 ng/mL and 5-15 ng/mL for lymphangioleiomyomatosis.

@agingdoc1 was created in 2020 in part to broaden geroscience awareness, promote its potential to improve health, & to elevate discussions.
@Blagosklonny @PeterAttiaMD E.g., if someone takes 20 mg per week instead, sirolimus concentration >= the 10 mg dosing level for one full half-life (longer) as it gets eliminated, but OTOH at 7 days the Cmin trough would be higher too....
@Blagosklonny @PeterAttiaMD The frequency of 20 mg can be reduced or the risk of higher trough levels accepted.

Case report: N=1 of a ~120-130# patient definitely taking sirolimus 20 mg/wk, every week, with no problems & perfect biomarkers but less washout (e.g. less dose or frequency) has>risk, so YMMV.
@Blagosklonny @PeterAttiaMD Re: N=1 middle-aged &healthy patient: He had mouth sores when titrating up to 6 mg at the very beginning, but s/p slow titration over >1 yr up to the 20 mg/wk, he has had no additional mouth sores at this much higher dose. Much of mTOR inhibition and sequela remain a mystery.
@Blagosklonny @PeterAttiaMD Rapamycin is serious business with real risks (& potential/theoretical benefits yet to be confirmed), so less anarchy and the cultivation of more systematic approaches - carefully weighing risks versus benefits as clinically appropriate to that situation - would be a good thing..
@Blagosklonny @PeterAttiaMD The thread above may help, & while not medical advice it does provide rudiments of a framework for conceptualizing the variables, knowns, & unknowns for researchers, clinicians & those engaged in conversations with these parties.
@Blagosklonny @PeterAttiaMD One potential implication of the overview provided above: the need to better characterize how long a washout or low a trough corresponds to a given level of risk & side effects for a given clinical & personal setting. This underscores the role of prude& vigilant monitoring.
@Blagosklonny @PeterAttiaMD Monitoring, in turn, has many elements: from symptoms and tolerance of side effects, to biomarker surveillance, to signs and symptoms of serious sequela. Harm is possible with any pharmacological intervention & needs to be carefully risk-stratified (risk/benefits) by patient.
@Blagosklonny @PeterAttiaMD All these metrics require validation; it is particularly vital that surrogate variables reproducibly predict outcome measures of interest, & the implications need to be better understood.
@Blagosklonny @PeterAttiaMD E.g., If TGs, insulin, glucose, etc. rise on sirolimus, is the risk elevation commensurate w/ that in the gen population? In the ITP, the highest dosing had the highest BG & benefitted more but this may not be so for persons.
@Blagosklonny @PeterAttiaMD Likewise, if the TG rise, but they are normalized to baseline on a statin (if their was elevated risk) is the risk completely normalized? In persons, lowering LDL-p via statin does not reduce risk by a commiserate LDL-p reduction via lifestyle alone.
@Blagosklonny @PeterAttiaMD These Qs are nontrivial, w/ more complexity given the mostly favorable data for sirolimus on atherosclerosis (incidentally, used in coronary DES) but even here not 100% of data and while promising not proven in persons.
1) journals.lww.com/transplantjour…
2)
pubmed.ncbi.nlm.nih.gov/24534455/
@Blagosklonny @PeterAttiaMD An additional implication of the above: Non-traditional dosing schemes may be considered & the clinical efficacy of these vs. traditional approaches need to be characterized for a variety of endpoints: LE in rodents may be conceived as possible surrogates for morbidity in persons
@Blagosklonny @PeterAttiaMD One alternative scheme I propose here: Rather than traditional weekly dosing (pioneered by Dr. Green), instead 1st targeting a given Cmax (based on a priori personalized risk/benefit & pt. risk tolerance/aversion) & titrating initial dose via Cmax monitoring to this level.
@Blagosklonny @PeterAttiaMD Even here there is nuance: Going straight to a target Cmax via estimating mg/kg to get there risks both overshooting as well as intolerance/risk. Thus gradual dose-escalation while monitoring Cmax is may be more prudent....
@Blagosklonny @PeterAttiaMD During this stage, another difference from traditional dosing is highlighted: rather than starting by frequency & determining dose, instead initial escalating test doses may be greatly spaced by weeks or longer - gauge Cmax, Cmin and T(1/2) & s.e.'s under standardized conditions.
@Blagosklonny @PeterAttiaMD During slow dose escalation (essentially a series of gradually rising levels approaching target Cmax & complete washout between) obviously explicit criteria (protocol-driven) & subjective appraisal (by pt & provider) to DC or reduce the initial target Cmax to a lower goal.
@Blagosklonny @PeterAttiaMD ....is needed. Adjusting targets can be subjective, objective, laboratory/clinical signs/symptoms, and many more. These should be set a priori & could be incorporated into informed consent dialogue towards a shared vision - the health equivalent of a financial plan & PFS.
@Blagosklonny @PeterAttiaMD Presuming target Cmax is achieved (or a diminished one based on the gradual esacalation), the next step can be increasing the frequency. How much sirolimus Cmax vs. AUC vs. duration above a threshold concentration, etc. impact efficacy (yet unproven in persons!) are unknowns.
@Blagosklonny @PeterAttiaMD Several studies have demonstrated efficacy at 1-2 weeks on & washouts in rodents have yielded life extension but rodents are not people and additionally rodent-time is on a different scale. Work needs to be done understanding the impact of all these parameters on efficacy in man.
@Blagosklonny @PeterAttiaMD Having said that Cmax / peak concentration appears to hold more weight in the regression model of favorable outcomes ( ncbi.nlm.nih.gov/pmc/articles/P… ) though even a x1 very high dose (again, rodents) has been shown to have lasting benefits.
@Blagosklonny @PeterAttiaMD Next as frequency is increased at that dose, a priori benchmarks again should be established: Targets & stop-rules. Hard stop rules are easy, but other criteria such as how low a Cmin is desired prior to scheduling the next sirolimus dose is more subjective.
@Blagosklonny @PeterAttiaMD I provided concen. targets for transplants as refs above b/c while low dose & potentially pulsatile sirolimus are neutral to favorable (skipping the resTORbio controversy here & Joan Mannick's 1st study), b/c the more constitutive the dosing the greater the exposure...
@Blagosklonny @PeterAttiaMD Thus a key question is how high a Cmin trough level (or level of mTORC2 inhibition- which is not assayed outside of research) is too high? Biomarkers & symptoms are inadequate alone: at certain levels ID vulnerability may >potential benefits....
@Blagosklonny @PeterAttiaMD I argue elsewhere perhaps complete washout is not required, & that these variables are 2-edged (e.g., mTORC2-inh may reduce cancer progression risk in esp. in at-risk poplns). The better we characterize risks/benefits on the research side, the better we appraise NNT & targets.
@Blagosklonny @PeterAttiaMD The point here is that regardless whether glucose homeostasis / immune markers should determine dose periodicity (ncbi.nlm.nih.gov/pmc/articles/P…) or other considerations (I argued, in agreement with @Blagosklonny : ncbi.nlm.nih.gov/pmc/articles/P… ....
@Blagosklonny @PeterAttiaMD that OGTT may not matter so much if in practice your insulin is low while your CGM shows low average and s.d. glucose/postprandial levels in practice based on your lower kcal and/or net-CHO diet. Effectiveness>efficacy since OGTT may not recapitulate your actual diet.
@Blagosklonny @PeterAttiaMD ....continuing... regardless of what metrics are embraced, the point is that the frequency can be titrated at that given Cmax down to the greatest periodicity that does not cross them or other stop/titrate branches in the clinical decision tree +/- holiday period protocols.
@Blagosklonny @PeterAttiaMD Obviously implementing a Markov-cycle like decision tree is futile in light of the fuzzy data & art of balancing all the nuances of personalized EBM in the face of this, however, precisely for this reason & the confusion & chaos that abounds this, rigorous thinking imperative.
@Blagosklonny @PeterAttiaMD The proposed framework outlined above: Starting w/ Cmax targets & if tolerated then titrating down frequency to a priori established EBM and personalized precision medicine metrics, has utility navigating these murky and rough waters towards better care
ncbi.nlm.nih.gov/pmc/articles/P…
@Blagosklonny @PeterAttiaMD This outlines rudiments of one model, & there is much to flush out. A multitude of solid models need to be pursued; there is more than 1 road to Dublin, and in medicine, the rubber meets the road at tradeoffs, including matters of practicality, feasibility and other constraints.
@Blagosklonny @PeterAttiaMD For this very reason, in closing, we need to remember that science, research, & competent, caring clinicians are not enough. Even if the geroscience hypothesis is correct, & rapa provides one bridge to compression of morbidity & a dividend of QALY healthy longevity & vitality...
@Blagosklonny @PeterAttiaMD .....this is still not enough. For geroscience-backed translational medicine to achieve this promise, we need systems to ensure that (1) Care so rendered is both safe and ethical, & (2) incentivized, & indeed promoted, at a systems level to ensure translation to actual patients.
@Blagosklonny @PeterAttiaMD Footnote:
1) This rapamycin dosing theory thread (eg 10-30+ mg) is & threadreaderapp.com/thread/1310159

2) The rapamycin mTORC2-inh hypothesis & dosing implications thread is
& threadreaderapp.com/thread/1310948…

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More from @agingdoc1

Jan 21, 2023
SkepDoc's Corner: Deuterium Depleted Water

By @HHSkepDoc

skepticalinquirer.org/exclusive/deut…
Sample of recent publication (which promoted my lit search and identifying Harriet's blog post👆 -@agingdoc1):

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mdpi.com/1467-3045/45/1… (@CIMB_MDPI)
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[posted by @DominicDAgosti2: ]

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I asked chat-GPT to help me write a tweet thread on how it can help accelerate progress in geroscience. Here’s what she came up with… 👇

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Sep 29, 2020
Rapamycin dosing hypothesis:

This is just a hypothesis, needs testing: Severe mTORC2 inhibition is harmful (esp in males), but mild inhibition is ~neutral or possibly mildly beneficial in some settings (eg-cancer). This is a thread, keep clicking on msg to keep reading....
Problems w/ excess mTORC2 inhibition was mostly shown under:

1)Genetic⬇️eg, full/partial KO
2) Strong NON-rapamycin inhibition, eg RNA interference
3) non-WT or genetic eg murine models
4) HFD or kcal overfeeding
5) High rapa dosing➡️⬆️lipids,insulin,gluc, or other lab issues
Read 38 tweets
Sep 25, 2020
Science is tricky: “Of the four main signaling pathways implied to be linked to the impact of CR on lifespan ([IIS, NF-ĸB, mTOR & sirtuins])...the pathways except SIRT were altered in a manner consistent with increased lifespan.” (Cont.).... ncbi.nlm.nih.gov/pmc/articles/P…
...so to what extent does this reflect 1) role of sirtuins in CR (2)(-) extrapolation from C57BL/6 mice 3) assay sensitivity 4) experiment conditions 5) network complexity 6) “other”. This was a great study & trends>individual studies. Every💪 study ➡️ ⬆️ Q’s than A’s, to explore
Also “In our graded CR study, expression levels of mTORC1 and mTORC2 were both strongly negatively associated with the increase in CR.” Recall the latter is one concern for regular rapamycin (⬆️glucose,⬆️lipids.... but not always and not in case of CR)....
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Sep 24, 2020
“The aging organism may also be viewed as a system with chemical fluctuations caused by biological reactions in the organism. This notion takes the whole organism as collected microscopically ordered patterns resembling oscillating chemical reactions.”

5 👍for correct author ID!
“In such reactions, the chemicals involved form a dissipative structure far from the equilibrium, which allowed the raw materials to be transformed to maintain as a certain self‐assembled biological structure that is ordered both spatially and temporally.....
However, it is harder to maintain such structures when the biological organization of an organism is constrained by its own biology and the genome evolution needed to maximize fitness, and is further impacted by age‐related changes...”
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Sep 24, 2020
Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21 -

This relates to a recent themes & trends in the tweet-verse
onlinelibrary.wiley.com/doi/full/10.11…
“Our findings suggest that MR feeding can reverse the negative effects of aging on body mass, adiposity, and insulin resistance through an FGF21 mechanism. These findings implicate MR dietary intervention as a viable therapy for age‐induced metabolic syndrome in adult humans.”
“This could explain the increased lifespan of mice when MR diet was begun at 12 months of age (Sun et al., 2009). In addition, like MR, FGF21 treatment extends lifespan in mice.... and FGF21 could be the basis of the mechanism behind MR's effects...”
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