Let's Talk About Rapamycin!

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Sirolimus (rapamycin) has not demonstrated life extension in humans to date (it has not been so evaluated). These protocols are not endorsements and have substantial risks, including & not limited to opportunistic infection & death. The narrative is for research purposes only. Sirolimus use should always be under the medical management and surveillance by qualified prescribing medical providers, and only used when suitable for the patient. Ketoconazole also has risks including liver failure.

In this and subsequent series I describe, with reliably sourced US pharmacy dispensed generic Rapamune N=1 experiment. All interventions were performed under intense medical and laboratory surveillance. (1) & (2) have been recorded (unreleased).

Highest validated sirolimus dose in a human to date 180 mg sirolimus: 10/27/22
2nd trial by N1: 100 mg sirolimus preceded by ketoconazole. Estimated equivalent dose of 500 mg sirolimus. Highest laboratory confirmed rapamycin concentration in humans to date, exceeding 200 ng/mL in this middle aged male patient, "N1." 2/20/23.
Higher dose than #1: Subsequent 200 mg generic Rapamune preceded by higher dose ketoconazole: estimated minimum dose equivalent: >1,000 mg of US pharmacy dispensed generic Rapamune. 11/16/23.
Setting: N1 on weekly doses up to 30 - 40 mg + / week average > year by 2024.

Purpose: Proof-of-principal

1) >= One individual (N1) can survive without acute AE a one-time bolus rapamycin bolus.

2) Sustained weeks of prolonged substantial sirolimus elevation with optimal lipid & blood glucose control under medical management (N1 at baseline is on pharmacotherapy).

Unresolved:

Probability of adverse events, including across a diverse population.
Influence of genetics, environment.
Long-term reliable safety and efficacy data for long-term use (N1 has been on 30 mg weekly for over 1 year as of 2024).
Off-label efficacy in humans, if any.
No hard inferences can be made except for proof-of-principal this scenario is possible for at least one individual/circumstance: "The exception breaks the rule."

[This case report is not discussed below, but elements are addressed on YouTube Agingdoc Podcast, beginning with Epsidode 7 with Matt Kaeberlein Part 3, Part 4 & beyond].

Enjoy! -Agingdoc🧑‍⚕️

#7 Matt Kaeberlein

Part 3 Episode:

Let’s talk Rapamycin!

00:00:01 Rapamycin fed late in life extends lifespan in genetically heterogeneous mice (2009)

This is required reading,” for this Agingdoc Podcast; the first major ITP study with synopsis of some of the data prior to testing].

See also the raw data here:

00:02:33 Rapamycin and aging: When, for how long, and how much? (2014)

[Excellent discourse by Matt on unknowns around rapamycin dosing. While I explore this subject with some of my thoughts below, key issues are unresolved. This reading is just as pertinent today as when it was written].

00:02:39 Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction (2014)

[Interventions Testing Program testing at 4.7 PPM, 14 PPM, and 42PPM with a dose-response, note as dose rises the male mice survival catches up with female survival]

Figure 1: Survival curves at varying doses of rapamycin. Tabular format follows.

Note that while median survival increases ranged from 3% (males, 4.7 PPM) to 23 & 26% (males and females given 42 PPM), that maximum survival, as reflected by 90th %ile increase was no more than 8-11%. While the former reflect reducing premature death (vs species specific maximum lifespan), the latter is more reflective to discourse around whether rapamycin can increase lifespan beyond naturally occurring variation.

In 2000, I performed and posted here (and on what became called X) a detailed back-of-the-envelope calculation of allometric conversions between mice and humans. Rather than focusing on strict mouse vs. human weight allometric conversion, I felt it may be more accurate to utilize serum concentration as the markers of comparison between rodents and humans. The objective of my calculation was to make a best estimate [read: "best guess"] for what dose for could hypothetically have some geroprotective therapeutic effect in humans.

My assumption for these purposes was that the ITP average serum level of rapamycin with daily dosing should ideally be the minimum peak levels arrived at by intermittent dosing of rapamycin in humans. A third assumption is "high" dose in the mouse translates to 42 PPM sinc this was the highest dose seen in the rapamycin ITP study through the the centers of the Interventions Testing Program in genetically heterogeneous mice, at their highest average dose of 42PPM [As noted above, other work has increased lifespan up to a full 9x higher then that 42PPM highest ITP dose, with only slight decrease in lifespan that was nonsignificant in the females] to be a minimum level for human peak blood levels following PO sirolimus. The reader should note these calculations are based on hypotheses, and "best gueses," no authority knows the true answer including whether rapamycin is efficacious as geroprotector in humans (I define "know" as justified to arrive at said conclusion).

Having made the arguments for higher dose, it should be noted lower doses are better tolerated with a lower risk and side-effect profile, and suggestive work [using rapalog everolimus] by Joan Mannick suggests potential efficacy.

See: mTOR inhibition improves immune function in the elderly (2014).

While detractors state subsequent work has contradicted the study, this is not true: No study his truly recapitulated the original design. Among issues were not using rapalog in favor of another mTOR inhibitor with a different mechanism and a shifting of goalposts by the FDA towards nonspecific markers of URI symptoms.

Full discussion beyond the scope of this brief document, but suffice to say Joan's original study cited above was suggestive of greater immunity in older adult vaccine recipients even at the 5 mg per week dose of everolimus. Moreover 20 mg per week was not more effective but with significantly greater aphthous ulcers. As the focus is the interview I am not presenting my views on optimal dosing here, only bringing in pertinent literature and arguments.

Other promising subsequent data include "upregulation of antiviral gene expression was associated with a decrease in the incidence of laboratory-confirmed RTIs" though this applies strictly to RTB101 (another mTOR inhibitor, not closely related [to rapamycin] rapalog everolimus).

These are not recommendations, and are extremely crude; there is no way to evaluate models except testing them against reality, which is far more complex.

The former is desirable as it curtails early death, and at least in rodents, appears to improve some functional markers of robustness and health. The untested hope is that rapamycin may extend human healthspan in a comparable manner.

Please refer to the Agingdoc Podcast with Aubrey de Grey, in particular I can't recommend enough watching Part 2 & Part 3 from that series where this was explored further. (They both also featured lively debates and controversy; I believe these should be required listening for any longevity themed curriculum.

The connection to my material with Matt is that I expressed in the interview my feeling that in the absence of better data, that being more optimized at baseline species is for longevity (such as humans), the less the likely benefit from agents such as rapamycin compared with shorter lived ones like rodents (ie effect sizes of this magnitude, if there are any).

This perspective is supported by the rapamycin literature in model organisms whereby rapamycin exerts less benefit moving from yeast, to nematode worms, to drosophila, to verebrates including rodents (I will spare the reader a plethora of publication references there).

For this reason I believe rapamycin has more potential for healthspan and normalizing shorter lifespan than drastically affecting maximum lifespan in humans. Debate won't settle this, however, only better data will, and Matt and I both very much hope to see this happen over our lifetime, without delay (there's a whole other matter of assessing whether a geroprotector works, I'll leave reference to that discussion to a subsequent Agingdoc Podcast interview with Morgan Levine).

00:03:02 mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome (2013)

"Doses up to (8 mg/kg) daily by intra-peritoneal injection starting at P10…. resulted in blood levels ranging from >1800 ng/ml immediately after injection to 45 ng/ml trough levels (fig. S3). For comparison, an encapsulated rapamycin diet that extends life span in wild-type mice by about 15% achieves steady-state blood levels of about 60 to 70 ng/ml…."

00:03:48 I report levels of rapamycin appeared to be at least 9-fold the 42ppm (which in turn is 3x the “average” rapamycin dose) highest dose group in the ITP reference above (Matt jokes I remember this detail better than him for this old study; of course I have the benefit of reviewing these periodically for myself and my longevity clients). This is based on estimates discussed by Alessandro Bitto and Matt in naturally aged mice here: Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice whereby “we estimate that this treatment regimen [They are discussing here 8 mg/kg rapamycin – Agingdoc] is comparable to dietary delivery of eRapa at approximately 378 ppm… or 27-fold higher levels than initially shown to extend lifespan in mice when continuous treatment is initiated at either 9 months or 20 months of age.”

And the raw data in tabular format:

Above Table 1: Sex-segregated comparison of median and mean post-treatment life expectancy for mice receiving rapamycin by injection (8 mg/kg/day) or feeding (128 ppm). M: males, F: females

Note, once more, different routes of administration (PO vs. IP) are not directly comparable and require experimentation to infer impact on lifespan and measures of health. There was a lot more to this study including novel observations on the microbiome but these are outside the scope of these Agingdoc Podcast shownotes.

Also of interest:

In context of their statement that 8 mg/kg [of rapamycin -Agingdoc] appears "comparable to dietary delivery of eRapa at approximately 378 ppm… or 27-fold higher [than 14 ppm standard dose]:

Their source for this was (Johnson et al., 2015): (Dose-dependent effects of mTOR inhibition on weight and mitochondrial disease in mice). I am referencing here the part of our interview where Matt jokes that he thinks I remember the details of the dosing better than him; readers should note the equivalency between the dosing statement made in Matt’s original 2016 study with Alessandro Bitto (ie 27-fold higher than initially shown to extend lifespan in mice…) versus my statement “at least 9-fold” higher than the 42 PPM.

They also details impact of dietary rapamycin on Ndufs4 KO mice (a mitochondrial disease)

So back to my comment to Matt on dosing the ITP publication Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction (2014) used up to 42 PPM was exactly three times the standard (14PPM) dose used in the original 2009 rapamycin ITP study, hence at least 9-fold” higher than 42 PPM (highest ITP tested dose) is equivalent to 27-fold higher than 14 PPM ("standard dose" used in 2009)

00:04:22 Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice (2016); Here I share some specific details including you will note in these tables the impact of the dermatitis observed in this study in the rapamycin group (I concur with Matt these may be strain specific; rapamycin presents a complex GxE picture puzzle necessitating empirical experimental data; we're just scratching the surface in rodents, lets of all personalized precision 3.0 medicine in humans).

00:05:00 Here I discussed the same study as we brought up at 00:03:02, however here I am now referencing my observation of Figure 1A (displayed immediately above) revealing markedly greater life extension for the daily versus every other day rapamycin group. However it must be noted that this was a Leigh Syndrome mouse model, so the impact on normative aging in wildtype mice was not directly tested here. Direct link to the figure here:

I would have also liked to add that while Dudley Lamming in the study cited at 00:04:22 suggested lifespan extension with intermittent dosing of rapamycin, this study examined versus controls not on rapamycin. It did not compare the intermittent rapamycin group with a (same cohort/study) lifespan extension of daily rapamycin dosing. Hence there remain significant unknowns regarding the efficacy curve for intermittent rapamycin (more data regarding other protocols follow).

00:08:30 Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects (2020)

[Context: discussion of different rapamycin regimens; this one from the ITP. The intermittent dosing regimen was one month off for the protocol and was compared with temporary (late life) for 3 months vs. continuing (starting late life) life-long rapamycin therapy without interruption). See abstract for details, results were sex-specific: “Rapa exposure were also effective in both sexes, though this approach was less effective than continuous exposure in female mice.” More subtlety embedded in the paper.]

At ~ 00:08:30 I reference work by Anisimov with lifespan extension with intermittent doing. However it should be noticed he used a particularly cancer prone murine model: “Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice (2011).”

Pertinent reading with regard to transient rapamycin therapy:

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice (2016)

In more recent years, a presence of a nutritional, potentially epigenetic memory may account for some of the lifespan extension when rapamycin is introduced in earlier years. The first study I cited above (2009 ITP) was remarkable in that the UMHET3 genetically heterogeneous mice were already ~ 60 years old in human equivalents when rapamycin was introduced. This was an artifact of technical challenge encapsulating rapamycin in a form that was adequately bioavailable for target serum rapamycin levels. Despite skepticism [as articulated by Rich Miller and others] that a putative geroprotector could have significant lifespan extension in a mammalian (rodent) model, rapamycin delivered with statistically and materially significant lifespan extension introduced in those years. The following two references pertain to a potential lifespan "bonus" in early life administration:

Long-lasting geroprotection from brief rapamycin treatment in early adulthood by persistently increased intestinal autophagy. (2022, Linda Partridge Lab),

Rapamycin treatment during development extends life span and health span of male mice and Daphnia magna (2022, Gladyshev Lab).

These work suggest overlap with caloric restriction, with both associated with developmental delay and slowing of development; CR studies showing greater life extension than rapamycin data available to date (up to about 60% life extension at 50-60% CR in at least one well done study) but with less efficacy than rapamycin when introduced in late-life.

There is also data, as we have seen, that to a lesser extent sufficiently high dose short-term rapamycin may extend lifespan even if discontinued. Seet Bitto & Kaeberlein Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice , and further ITP work detailed below.

[Let's unpack metformin a bit here before returning back to rapamycin as it came up a bit in our conversation; this segment only scratches the surface though, and deserves separate coverage another time.... fortunately a future Agingdoc Podcast to be released will feature Nir Barzilai

-Agingdoc ]

00:12:07 A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021)

[vs.]

Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) and Geroscience‐guided repurposing of FDA‐approved drugs to target aging: A proposed process and prioritization

00:12:12 I note here that metformin when tested by itself did not extend lifespan in the ITP study. Contrast this with the combination of rapamycin + metformin with historical controls (there was no direct comparison). See the following: Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer (2016)

The study found: “Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone.”

As the authors appropriately qualify: “Our evidence is inconclusive, however, in that the comparisons are to historical rather than to simultaneous cohorts, the effect seen in males is not statistically significant by our standard site-stratified log-rank test (P = 0.12), and the effect in females is small.”] .

I will not reproduce their literature review here but I direct the reader to their discussion where they briefly overview prior work with varying results, and the rationale for testing metformin given some of the more favorable results. A full discussion of potentially short-lived controls, metabolically challenged settings etc. is beyond the scope here. Suffice to say in my estimation the matter of metformin is unsettled and warrants further investigation particularly to test whether it is an effective gerotheropeutic in non-diabetic humans. Stay tuned for my interview with Nir Barzilai for elaboration on rationale for the TAME study and other investigation intended to help resolve these questions.

The authors do an excellent review of prior work, their strengths and limitations (eg, shorter-lived controls) such as Alejandro Martin-Montalvo and de Cabo's 2013 Metformin improves healthspan and lifespan in mice. Much of the literature was subsequently detailed in Taming expectations of metformin as a treatment to extend healthspan (2019), which reads along the lines of A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan.

I will only note, before a few additional references is complex, and I strongly support the TAME trial, which can help settle uncertainty. There is reason for caution, and there is reason for optimism specifically for metabolically vulnerable populations, which may include segments of the naturally aged population. I should hasten to alert the reader while I share the same last name as Nir Barzilai, we met through his reaching out to me from my work in geroscience on X - Nir of course being well known for decades in geroscience as a leader especially with respect to metformin and genetic contributions to aging and capitalizing that biology towards gerotheropeutics. We are both medical doctors too, but at the point of this post neither of us know whether or not we are distantly related.

Since the reviews detailed above, there has been data in humans suggesting a potential (on average) blunting of muscle hypertrophy gains following resistance exercise (but notably without statistically significant loss of muscle strength, and with a follow-up study suggesting this may be due to a potentially more youthful (appearing) transcriptome in metformin users) and a blunting in gain of VO2max with training in some populations (though notwithstanding the strong association between this measure of aerobic capacity we do not know whether this effect in the context of metformin is deleterious or represents a protective metabolic shift).

David Barzilai MD PhD

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