A Combination of Rapamycin and Trametinib Extended Maximum Lifespan by up to 35%

[nikney]

When we look at intracellular signaling pathways, hyperfunction of almost all of them increases with age, and this causes many cancers. This means that these pathways somehow show hyperactivation during the aging process.

[Joseph_Lavelle]

From X

“ trametinib/rapa. is toxic.

Neither very low doses (longevity) or short treatment (cancer)”

[RapAdmin]

I think Blagosklonny has not read the most current paper and is going off old data. I think the situation with trametinib may be very similar to that of rapamycin a decade or so ago, when everyone just said the longevity research with rapamycin was interesting but not translatable because of the side effect profile.

[desertshores]

Unfortunately very pricey stuff, even from India.

[Cohen]

Regressive changes in epithelial stem cells underlie mammalian skin aging, but the driving mechanisms are not well understood. Here, we report that mouse skin hair follicle stem cell (HFSC) aging is initiated by their intrinsic upregulation of miR-31, a microRNA that can be induced by physical injury or genotoxic stress and is also strongly upregulated in aged human skin epithelium. Using transgenic and conditional knockout mouse models plus a lineage-tracing technique, we show that miR-31 acts as a key driver of HFSC aging by directly targeting Clock, a core circadian clock gene whose deregulation activates a MAPK/ERK cascade to induce HFSC depletion via transepidermal elimination. Notably, blocking this pathway by either conditional miR-31 ablation or clinically approved MAPK/ERK inhibitors provides safe and effective protection against skin aging, enlightening a promising therapeutic avenue for treating skin aging and other genotoxic stress-induced skin conditions such as radiodermatitis.

Trametinib is a specific MEK1/2 inhibitor drug. It strongly suppressed miR-31-mediated ERK activation in cultured MKs and DTG skin epithelium. ERK activation was known to be promitogenic in keratinocytes. Consistently, miR-31 OE in MKs also granted a growth advantage that could be suppressed by trametinib (Fig. 5d). In vivo, trametinib suppressed miR-31 mediated hair growth blockade, HF miniaturization and HFSC loss in DTG mice (Fig. 5e–g and Extended Data Fig. 7g). Similar reversal of miR-31-induced baldness was reproduced using an ERK1/2 inhibitor drug sch772984 (ref. 33) (Extended Data Fig. 7h). By Sox9-CreER;mTmG lineage tracing, we found that trametinib also suppressed miR-31-induced HFSC transepidermal differentiation (Fig. 5h).

MAPK/ERK inhibitors suppress IR-induced premature skin aging

If IR induced premature skin aging by activating the miR-31-MAPK/ERK pathway, a short-term MAPK/ERK inhibition following IR should be sufficient to suppress it. Consistent with this idea, oral feeding of trametinib at 1 mg kg−1 body weight dosage every 3 d for five times after IR (Fig. 6a) drastically suppressed the skin-aging phenotypes in LIR mice. Most notably, it largely abolished hair graying of LIR-Rad skin (Fig. 6a). This was faithfully reproduced by oral feeding of sch772984. The trametinib treatment also suppressed LIR-Rad skin’s in vivo and in vitro wound healing defects, CD34+ HFSC depletion, SG miniaturization and hair regeneration defects. It also suppressed HFSC transepidermal differentiation in LIR-Rad skin based on Sox9-CreER;mTmG lineage tracing (Fig. 6h). Notably, these treatments induced no discernible changes in noRad skin.

The role of CLOCK in miR-31-mediated HFSC aging reconciled well with the tightly intertwined stories of circadian rhythm and aging in mammals. It has been shown that aged individuals often have significantly reduced amplitudes of circadian oscillation45 and ablation of circadian clock in mice can lead to premature skin aging46. It is also known that chronic circadian disturbance such as sleep deprivation, which may dampen CLOCK expression47,48, could lead to aging-like skin symptoms such as hair loss and graying in humans. It would be interesting to examine whether MAPK/ERK inhibitors may also help to relieve these symptoms. That said, it is worth noting that an miRNA often functions by simultaneously fine-tuning a number of target genes. Besides Clock, additional targets of miR-31 likely also contributed to its pro-aging functions. This is consistent with the observation that drastic hair growth inhibition elicited by miR-31 OE far exceeded those from circadian clock machinery ablation in mice.

A stress-induced miR-31-CLOCK-ERK pathway is a key driver and therapeutic...

[nikney]

It seems that the mapk pathway even affects the circadian rate. It is interesting that the circadian rate is also linked to these pathways. We learn new things every day. Gerontology is advancing very quickly. It also says in this article that trametinib reverses gray hair. Trametinib is on its way to becoming the new rapamycin.

[KarlT]

@Gokhan

In 2020 I ran trametinib in 2 separate experiments. I was forced to discontinue quickly due to notable unpleasant side effects.

I figured someone here would be crazy enough to try this.

[RapAdmin]

@Gokhan

Trametinib User Experience

• In 2020 I ran trametinib in 2 separate experiments. I was forced to discontinue quickly due to notable unpleasant side effects.
• Dose: 1mg/day
• This was based on studies showing triple combo of rapa lithium tranetinib extending life close to 50%. I had calculated 4mg/day [based on the fruit fly study] and started light to be safe. Maybe I got it wrong?? Took a few days to feel like shit.
• What were the side effects? feeling poisoned. drained. off

Thanks for posting your experience! Obviously daily dosing at this level is probably not optimal for longevity.

But perhaps 0.5 mg/week or 1mg/week or even 2mg/week may provide the benefit without the side effects. Do you have any of the medication left, and perhaps you could try a dosing schedule more similar to this?

I’m talking to researchers about a phase 1 clinical trial for safety of low dose trametinib in healthy humans, and one person also suggested “you can also consider an observational trial or case series as a first step”.

I checked on pricing from India. Current pricing for Trametinib (2 mg tablets) is $4,500 / 60 tablets (or $37.5 US per mg).

If generics become available quickly after the drug goes generic in the US (Sept/2025), then prices should drop to around rapamycin prices of $1 to $2 per mg.

[AnUser]

@RapAdmin

But perhaps 0.5 mg/week or 1mg/week or even 2mg/week may provide the benefit without the side effects.

The therapeutic index for longevity might be much lower and the dose used in cancer is actually the toxic dose (FYI I don’t know anything about this compound).

[RapAdmin]

Yes - that is what the Partridge lab people are saying (lower doses for longevity).

So - I’ve been digging around trying to find the original dosing studies to see what data we can get on these lower doses and how they translate into blood levels, that we can then compare to the new paper from the Partridge lab.

I’ve found this:

Dose selection for phase II and III clinical trials with trametinib was based on the results from its phase I study in which daily doses ranging from 0.125 to 4 mg were administered to patients with solid tumors.

So - this would seem to be the data we want to look at. We want to see if the lowest level of drug dosing used in this phase 1 dosing study might meet the blood level dosing requirements for longevity that we see in the new longevity study from the Partridge lab, and then check on the side effect profile of these very low doses to see if they might work (be tolerable) for most healthy people.

Looking through the original FDA approval package for the drug, I think the original phase 1 dosing study is of most interest because it covered a range of lower doses.

So I’ve found the original FDA study information filed in 2013 that was generated from this original Phase 1 clinical study.

Here is the original clinical study overview: ClinicalTrials.gov

And the data repositories now: https://www.clinicalstudydatarequest.com/Posting.aspx?ID=519&GroupID=DEFAULT

Which then brought me to this site where the actual reports are:

https://www.gsk-studyregister.com/en/trial-details/?id=MEK111054

At the bottom of the page are two sections under the “Study Documents” section (note the Clinical Study report is a 56MB document with over 2700 pages of information, and the Scientific Results only 5MB):

Clinical Study Report

Scientific Result Summary

I’m very interested in the 0.125mg dosing, the 0.250mg, and the 0.5mg dosing levels and resulting blood levels and curve.

Reviewing the clinical study report, I see the following:

Lots of interesting information here, but a ton of data to dig through, and then compare to the new paper data. I’m working on it.

Feedback and thoughts from the medical professionals that participate here, on this data is of course always greatly appreciated.

[RapAdmin]

Following is the paper that they published on that Phase 1 dosing escalation study. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial - PubMed

The good news is that there doesn’t seem to have been much in the way of side effects seen until they got above the 1.0 mg dosing level (this was a 21 day dosing study, daily dosing). So it’s increasingly looking like low dose longevity use may be viable.

infante2012-2.pdf (245.9 KB)

[tananth]

From the plots it looks like even a single dose of 0.5mg results in plasma concentration of 0.3 ng/mL after 2 days, 3x the targeted level of 0.1ng/mL in the mouse study. This means a dose of 0.25mg once weekly should be more than enough to achieve an average level of 0.1ng/mL.

[RapAdmin]

Yes, but the data seems a little sketchy… the “Cmax” for 0.125 mg is higher than that for 0.25mg dosing, and both are N=1, so it seems there is a high level of interpersonal variability (and I can’t believe they used N=1 at this lower level… really, GSK, this is the best you can do in this phase 1 dosing study?).

So there are going to be some pretty large error bars around those “Cmax” measures.

But overall, yes, its looking like people could get by taking a pretty low dose of trametinib to meet the longevity blood levels suggested in the most recent paper. And, trametinib is sold in 0.5mg tablets as well as 2mg tablets, so it would be easy to split the 0.5mg tablets into 2 or 4 pieces.

[RapAdmin]

I’m trying to pull the key information out of the 2,700 page clinical study file that GSK has helpfully provided. Below I think are some of the key points of information and graphs… I’m hoping that @cl-user might be able to help us and graph the dosing schedule and blood levels given the target blood levels provided in the recent paper (0.1 ng/mL), half-life of around 90 hours, the data I posted earlier, and the data below…

[Gokhan]

Hi! Please note that I was relaying the experience of a Rapamycin Facebook group user. You can go to the linked thread to contact him and ask any detailed questions.

[cl-user]

Here it is. I can make use the model to Make dosage simulations if you want.
That said the quality of initial trial data is very poor and the model is only based on that.

BTW please note that, similarly to rapamycin, the peak height is meaningless as it only shows the difference of speed between GI absorption and distribution to the organs. Reducing the absorption speed will reduce the peak height but end up with more trametinib into the organs.

I can also use other thresholds than 1 and 3ng/dl.

[tananth]

The right bottom plot shows that average plasma concentration from daily dosage of 0.125mg seems to be around 0.7 ng/mL. These daily dosing charts look less noisy than the single dosing charts.

This suggests that to achieve an average level of 0.1ng/mL, you need a weekly dosage of 0.125mg , though the plasma level won’t be as uniform with weekly dosage of 0.125mg as it would with daily dosing of 0.125/7 mg, but it is at least possible to divide a 0.5mg tablet into 4 weekly 0.125mg pieces.

[cl-user]

Here is the simulation for 0.25mg daily

And 0.125mg every other day

[RapAdmin]

In the Glaxo documents, and other studies, they talk about the half-life being around 90 hours. Why is the “blood half life 4.81 h” in your graphs?

The target suggested in the new longevity pre-print paper is a blood level of trametinib of between 0.1 ng/ml, and 0.2 ng/ml. What dosing level and frequency do you think provides roughly that level over longer period of time?

[cl-user]

@RapAdmin

Why is the “blood half life 4.81 h” in your graphs?

It’s 48.1h. In the report table the half-file is 48.8h for 4mg and I used the 10mg data for the model fit as the points are better.

That said the half-life is all over the place and seems to be very long at low doses. For instance they don’t give any half-life for 0.125mg and 0.25mg, 1 individual at 161h for 0.5mg, 291h and 121h for 1mg.
That’s not really actionable. 291 is more than 12 days while 121 is 5 days.
The largest interval is for 2.5mg where the confidence interval goes from 4h to 210h.
If you have some strong feelings about a value for the low dose half-life, I will use it to find the optimal dosage.
Here is what we get with a 161h half-life

Same dosage but 291h half-life ends up with twice the concentration