Breaking: 15% Healthy Lifespan improvement via Rapamycin seen in Marmosets

[Olafurpall]

@Jjazz

The conversions are accurate as written for converting based on body surface area (assumed from mass) and do not include a margin of safety or anything else that would distort the values.

You’re right. There is no direct safety margin factor in the formula. I thought there was one based on memory, but there wasn’t. However, the safety margin is still in the formula in a less obvious way. I know it doesn’t look like it, but a safety margin is actually hidden in the formula.

@Jjazz

Here is the formula, for reference:

HED = animal dose in mg/kg x (animal weight in kg/human weight in kg)^0.33.

Yes, that’s the formula the FDA uses to get their scaling factors. This formula is somewhat misleading in that it makes it look like there is no safety factor. But fact is, the use of the exponent 0.33 in the equation, is the safety margin. The more correct exponent is actually 0.25. The 0.33 exponent is derived from the exponent for body surface area of 0.67 while the 0.25 is derived from the exponent for body surface area of 0.75. The latter is more accurate when scaling doses between humans and other animals. The former however is used, despite being less accurate, because it leads to estimations of lower doses for humans, which is safer.

Here is a quote from a study (To scale or not to scale: the principles of dose extrapolation - PubMed) on this:

" The FDA approach uses the exponent for body surface area, 0.67, to scale doses between species. This practice was traditionally rationalized as a means of accounting for differences in metabolic rate. The link between body surface area and metabolic rate, as discussed above, is the evolutionary adaptation of animals to their size, so body surface area is an indirect and imperfect correlate of metabolic rate. There has been debate in the literature about whether the exponent 0.75 would be more appropriate to account for metabolic rate/physiological time (0.75 is the exponent used in veterinary practice). Indeed, better scaling of doses has been demonstrated with the use of the 0.75 exponent (Rennen et al., 2001). On a conceptual level it is more logical to use the exponent that directly accounts for differences in physiological time, rather than an imperfect correlate of metabolic rate, and the proposed fractal origin of the scaling relationship also supports 0.75 as the proper exponent to use (West and Brown, 2005). The justification for using 0.67 is safety related; it provides a more conservative dose estimate."

[RapAdmin]

Thanks for that post, that was the type of explaination I was hoping for as it sounded like you had some some indepth research on the topic.

At a practical level whether the dose is 10mg/day or 18mg/day, the serious side effects will (I suspect) be pretty similar, most concerning of which is some level of immune supression. What I’d like to see are some human clinical studies with different dosing regimens (every 2 days, every 4 days, every 8 days, ever 16 days…) to see whether we might be able to lower the level of mTORC2 inhibition with these different variations on a pulsed dosing strategy, or perhaps with added mTORC2 activators like Acarbose…

As we’ve seen, there are risks with simple 10mg/day approaches:

Below are some examples in a high dose (e.g. 10mg/day) everolimus study for cancer patients (admitedly a serious and complex situation already, but … there was a death due to e-coli sepsis).

Rapamycin is not a risk-free drug, especially as you increase doses above the regular 5 to 8mg dosing once per week level.

The most common Adverse Effects (AEs) of everolimus therapy were laboratory abnormalities (100% of patients) and infection complications (83 episodes in 15 patients). Infectious episodes of pharyngitis (67%), diarrhea (44%), stomatitis (39%), and bronchitis (39%) were the most common infections. They were mostly mild or moderate in severity (grade 1–2).

In two cases, life-threatening conditions related to mTOR inhibitor treatment were encountered. The first was classified as grade 4 pleuropneumonia and Streptococcus pneumoniae sepsis, whereas the second was classified as death related to AE (grade 5) Escherichia coli sepsis.

A 27-year-old woman with TSC was started on everolimus
treatment because of AML of the left kidney
(60 Å~ 48 Å~ 36mm in size). The other signs of TSC were
facial angiofibroma, hypomelanotic macules of the skin,
and shagreen patch. The diagnosis of TSC was made
12 years earlier when the patient underwent nephrectomy
because of a large tumor of the right kidney. The
patient received everolimus at a dose 10 mg/day and the
trough concentrations of the drug ranged from 4.08 to
5.08 ng/ml. After 3 months of everolimus therapy, a
reduction in AML was observed (40 Å~ 31 Å~ 20mm in
size). During treatment, hypercholesterolemia (309 mg/
dl) and transient leukopenia (3.2 Å~ 109/l) with neutropenia
(1.34 Å~ 109/l) was observed. She also reported
oligomenorrhea. After a gynecological consultation, a
functional ovarian cyst was identified and contraceptives
were prescribed. However, 2 weeks later, she was
admitted to the gynecological unit because of subabdominal
pain and an ovarian cyst (64 Å~ 53mm in seize)
on ultrasound examination. Torsion of the ovarian cyst
was suspected. On the day of admission, WBC was
9.2 Å~ 109/l, the absolute neutrophil count (ANC) was
6.6 Å~ 109/l, the hemoglobin level was 10.8 mg/dl, the
PLT count was − 275 Å~ 109/l, and the C-reactive protein
concentration was 8.0 mg/dl (normal < 5.0 mg/dl). The
patient was advised to continue intake of contraceptives
and everolimus. The next day, the general condition of
the patient aggravated. Her blood pressure was low (85-
/50mmHg). Her WBC and ANC decreased (WBC
−2.4 Å~ 109/l, ANC − 1.8 Å~ 109/l), whereas the hemoglobin
level (11.0 g/dl), the PLT count (185 Å~ 109/l), and coagulation
tests were normal. Computed tomography of the
abdomen and pelvis showed AML of the left kidney (size
as in the previous examination), an ovarian cyst measuring
65 Å~ 50 Å~ 40 mm, and fluid in the retroperitoneal
space with density of the blood. Further aggravation of
her general condition was observed. The patient was
transferred to the ICU and she died after 2 h with
symptoms of shock and multiorgan failure. Blood and
urine cultures collected when she was in the ICU were
positive for Escherichia coli.

Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening

https://sci-hub.se/10.1097/CAD.0000000000000207

[Karl92651]

Any idea of why they did such a high dose? If 5mg once weekly inhibits mTor by 50-70% and 10gm once weekly inhibits by 70-90%, I wonder why they went higher. The doses they are using are immunosuppressive. Did all animals receive the same high dose? It would be interesting to see if there is a dose response but maybe that’s the next study. Let me know if you think my mTor inhibition estimates are correct.

[AnUser]

@RapAdmin

which is some level of immune supression

The negative effect on healthspan through increasing infections of shingles, influenza, common cold, etc, can’t be underestimated either especially for the unvaccinated or the anti-vaxxer.

[Vlasko]

The argument over the 3/4 and 2/3 exponents has been ongoing for decades. It isn’t just safety related, although the FDA admits above they factored that in when choosing one over the other. You can also find papers arguing for a split, with 2/3 or 3/4 being chosen depending on animal sizes.

Re-examination of the "3/4-law" of metabolism - PubMed

Edit: I was looking for something more recent that reviews the literature. The following article in Scientific Reports from 2018 has a focused review. Here’s an excerpt:

“ While some of the empirical works seem to comply better to α = 2/3 5,6,7, a great majority took for granted a 3/4 power law8,9,10, raising it to the level of central paradigm in comparative physiology11. This scaling was subsequently elegantly explained by space-filling fractal nutrient distribution network models12,13,14,15 (with possible deviations for small masses due to finite size effects), thus apparently closing the debate on its origin. However, additional statistical evidence challenges the validity of α = 3/416,17,18,19,20,21,22,23 (see also24 for a recent experimental study of the fractal exponents in human vascular networks). For instance Dodds et al .16 found that, for masses under 10 kg, a 2/3 exponent gives a better fit, while 3/4 fits better the whole range.”

Ballesteros, F.J., Martinez, V.J., Luque, B. et al. On the thermodynamic origin of metabolic scaling. Sci Rep 8 , 1448 (2018). On the thermodynamic origin of metabolic scaling | Scientific Reports

[RapAdmin]

@Karl92651

If 5mg once weekly inhibits mTor by 50-70% and 10gm once weekly inhibits by 70-90%

I’ve never seen any numbers like this - where did you get them?

Generally the dose used in the marmoset study seems to be in-line with the range (4.7ppm to 42ppm) used in the ITP studies with mice and rapamycin - so I think they were just following their lead, and perhaps bumping it up a little because unlike the ITP with 300 mice in each arm of each cohort (total of 900 mice), the UT Southwest researchers only had a total of 60 marmosets in this study, so they had to make sure they got a larger effect given the small number of animals in the study (otherwise the “power” of the result would be low).

Yes - the doses they are using are definitely immunosuppressive (though I don’t know how immunosupressive, rapamycin is not a very good/strong immunosupressive drug and thats why its usually bundled with cyclosporine, etc). The dose/response curve “should” be similar to what we seen in the mice I think… though exactly what dose equates to what percent lifespan increase at higher ranges is impossible to know right now in marmosets (and given the 10 year+ length of this type of study, its hard to believe they want to do too many of these studies).

I’ve heard of short-term studies in rats where they’ve gone much higher than 1.0 mg/kg, in fact upwards of 50 mg/kg without significant issues or side effects (these were IP injections). All of which makes me think that research groups need to be investigating injectable delivery of rapamycin for delivery of higher doses of rapamycin with lower side effect profiles, along the vein of what @MAC has done: Intramuscular (IM) + Intranasal (IN) Rapamycin - A new paradigm for human longevity translation

[Karl92651]

I asked chatGPT for the numbers. Here is the response…

Inhibition of mTOR by Rapamycin in a Healthy Adult

The goal of mTOR inhibition in healthy adults, often pursued for potential longevity benefits, is to achieve effective inhibition while minimizing side effects. Here’s a detailed explanation based on available research and expert insights.

Effective Doses for mTOR Inhibition:

1. 5 mg Once Weekly:

   • Effectiveness: Research and anecdotal reports suggest that a weekly dose of 5 mg of rapamycin can inhibit mTOR significantly, approximately around 50-70%.
   • Mechanism: This dose primarily targets mTORC1, leading to increased autophagy and potentially improved cellular function and longevity.
   • Side Effects: At this dosage, side effects are generally mild but can include mouth ulcers and slight immunosuppression.

2. 10 mg Once Weekly:

   • Effectiveness: A dose of 10 mg weekly is more aggressive, with inhibition levels potentially reaching 70-90%.
   • Mechanism: Besides robust inhibition of mTORC1, this dose can also impact mTORC2 over time.
   • Side Effects: Higher doses come with increased risks, such as more pronounced immunosuppression, mouth ulcers, and metabolic disturbances.

Key Points from Research:

• Lloyd Klickstein, M.D., Ph.D. and other experts discuss the use of rapamycin in various dosages for its anti-aging properties and its impact on mTOR pathways. Studies and practical applications have shown different inhibition levels and side effects based on the dose used oai_citation:1,#118 - Lloyd Klickstein, M.D., Ph.D.: Rapamycin, mTOR inhibition, and the biology of aging - Peter Attia .
• Clinical Trials and Studies: Various clinical trials have explored rapamycin dosing, showing that lower weekly doses (5 mg) can achieve substantial mTOR inhibition with manageable side effects, making it suitable for long-term use in healthy individuals oai_citation:2,#118 - Lloyd Klickstein, M.D., Ph.D.: Rapamycin, mTOR inhibition, and the biology of aging - Peter Attia.

Practical Considerations for Healthy Adults:

• Start with Lower Doses: It’s advisable to start with a lower dose (e.g., 5 mg once weekly) and monitor the body’s response. This approach minimizes the risk of side effects while providing substantial mTOR inhibition.
• Medical Supervision: Given the potential for side effects and the need for precise dosing, it is essential to undertake any rapamycin regimen under the guidance of a healthcare professional.
• Regular Monitoring: Periodic blood tests to monitor kidney and liver function, complete blood counts, and other relevant biomarkers are crucial to ensure safety and adjust the dose as needed.

Summary:

In a healthy adult, a weekly dose of 5 mg of rapamycin can inhibit mTOR by approximately 50-70%, providing benefits related to cellular health and longevity with fewer side effects. A higher dose of 10 mg weekly can achieve greater inhibition (around 70-90%) but with a higher risk of adverse effects. Always consult a healthcare provider for personalized advice and regular monitoring.

What do you think of the response?

[RapAdmin]

Ah, I see it in the notes for that podcast, here is exactly what are in the show notes. It was with everolimus (very similar to rapamycin) for a study done at Novartis before they spun the compounds out to ResTOR Bio:

Each of the doses did a different thing to TORC1 inhibition…
The .5 mg dose partially inhibited in a sustained fashion.
The 5 mg once a week fully inhibited TORC1 for a couple days out of the week
The 20 mgs would fully inhibit TORC1 over the dosing interval (i.e., nonstop inhibition of MTORC1 until your next dose)

and about the study:

The drug: RAD001 (aka everolimus–which was already FDA approved for renal cell carcinoma)
-Subjects: 218 patients over 65 with no unstable medical conditions
-Primary endpoint: To determine whether the study worked or did not work, they were looking at the response to a flu vaccination for the seasonal flu -Site: Australia because the timing needed to be right before a population was going to get their flu vaccines
-Four arms in the study:

1. Placebo arm
2. Group that gets 0.5 mgs of RAD001 daily 3) Group that gets 5 mgs once a week
3. Group that’s gets 20 mgs once a week

A “clever design” because…a) the weekly doses 5 mg vs. 20 mg answers both efficacy and toxicity questions as they pertain to that dose, and b) the 0.5 mg daily versus the 5 mg weekly is your closest aggregate dose where you get to see if there is a difference in trough

-Treatment period: Patients were dosed for 6 weeks and then given a 2 week “washout” period before getting the flu vaccinations (they wanted to see if there was a residual improvement to the immune system not just a direct one due to the presence of the drug)

[kbaba]

I think its worth mentioning that we shouldn’t just assume the life extension benefits in Marmosets depends on having such a high dose as it doesn’t seem they studied different doses. At some dose extra might be overkill, so it’s more a data point to consider than a new goal to strive for

[Joseph_Lavelle]

How would the researchers know how much inhibition of mTOR occurred? It’s in every cell in the body. Measure a tiny sample and then assume rapa reached every cell including crossing the BBB… and had the same effect everywhere…

“% inhibition” has to be a wild guess.

[DrFraser]

This study further supports my approach that we should measure levels and have some type target … but with safety being a serious component.
As I see more levels on patients, dosing like 6 mg might have patients with a level >3 ng/mL which logically is a threshold where we can see at least some objective efficacy in a different setting … but 6 mg will get a 70 kg individual just a few hours of levels greater than 3 ng/mL - and that is only while it is redistributing.
I doubt much gets across the BBB in these low levels.
I doubt much of the molecular mechanisms of mTOR inhibition get going to any beneficial level in just a few hours.
I’ve privately (now publicly I guess) told a number of people that the huge benefit to more individuals on the Rapamycin.news board isn’t likely to be the rapamycin they take - but instead all the other stuff they are doing for their health.
My conclusion right now, and what I’m personally doing is to escalate dosing until I have ~ 55 hours per week of a level over 3 ng/mL as I do think cycling in and out of mTOR inhibition is the right move. Doing it continuously will have bad consequences. It will take some time with this approach to gather data to make sure that there isn’t adverse outcome with this.
Are others considering intensifying dosing and measuring?

[Neo]

@RapAdmin

Some very good news on rapamycin was presented today at the American Aging Association Conference in Wisconsin . This is a groundbreaking development as its the first time we’ve seen primate lifespan improvement with rapamycin

That is the same meeting as here right:

If so, there might be a recording that one can access to watch for some from of virtual registration:

[RapAdmin]

Yes - same meeting. Good point. I’m asking David B. if he still has access and if the presentation is available to view still. It might be worth it to register even now and see the full presentation. I did not know this conference was also offered virtually.

[Virilius]

So 20-30mg of rapamycin a day for a grown man, that’s prohibitively expensive and will completely suppress your immune system. I’m starting to wonder whether rapamycin can even be used by humans in realistic scenarios. We need further studies with weekly/biweekly/monthly dosing and lower/higher doses in order to decide that question.

[RapAdmin]

The cost isn’t that prohibitive really, given the low prices that people can get (from India or costplusdrugs, etc.)
10mg/day works out to about $300/month
20mg/day … $600/month
30mg/day… $900/month

The bigger issue is, as you say, dosing studies that need to be done to see how we might get around the side effects / mTORC2 inhibition issues.

[DrFraser]

It won’t end up being a high yearly expense at all, just make sure you have your funeral pre-paid if you select any of these options … all will be incompatible with life. Please … nobody do this.
You’ll be out at a T1/2 of 65 hours and on even the 10 mg - will have levels probably of 80-100 ng/mL … nothing is going to work well with that would be my guess.

[RapAdmin]

No luck on the presentation still being available to view.

From David Barzilai:

I’ve had a personal correspondence with Adam regarding his talk (which streamed during the event but is no longer available via the portal). Given the preliminary nature of the data, it’s not yet ready for more specifics to be posted on my channel beyond the abstract image below. I will keep you and my other aging biology followers up-to-date, as always, following prepublication standards and the author’s wishes.

Here is the full abstract of the talk:

[Olafurpall]

It wouldn’t be equivalent to taking it daily for humans. Marmosets most certainly metabolize rapamycin faster than humans and will therefore have a shorter half life. So taking it daily for the marmosets might be similar to taking it perhaps 1-2 times weekly for humans.

[Virilius]

Fully agreed. I’ve recently had a bacterial infection that may or may not have been related to my high dose of rapamycin. That’s why I’m much more hesitant to use it for now until the relevant facts emerge.
5€ taurine had a similar effect in mice and monkeys and is a lot safer too.

[DrFraser]

I guess I’m much more worried about malignancy and viral infections and optimizing my T cell immunity. This is an argument for Rapamycin. I’m not worried about bacterial infections - because for me, they are obvious to spot and easy to treat. People get into trouble when they don’t recognize the presence of one … or more often, foolishly just watch it get worse day after day, hoping (hope is not a good strategy in fighting bacterial infections, I’d mention) that it’ll get better.
I get exposed to multiple viruses daily in the ER where I still work 3 days per week. Don’t wear masks, and deliberately get exposed. If I do catch something, I might get 24 hours of minimal symptoms, and probably only catch something once every 6 weeks despite all the exposures. I hope my T cells are doing as good of a job surveilling for cancers as they are at taking care of viruses.