#47

I don’t believe there is any evidence that low-dose Trametinib has a significant life extending effect which is the main issue for this. Would it be possible perhaps to try a low-dose Trametinib trial in the wormbot?

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#48

See the earlier post by @Cohen

I also just realized I mis-interpreted the 1.44mg/kg as per kg of weight of the mouse, whereas its actually a measure of drug in the food.

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#49

Dosing to match mice plasma levels

  • The lifespan-extending dose of trametinib (1.44 mg/kg diet) resulted in plasma levels of ~0.1 ng/ml in mice. This is significantly lower than the 5.5-7.5 ng/ml peak levels observed in human patients receiving 2 mg daily doses for cancer treatment. [1]

  • Considering trametinib’s long elimination half-life of 3.9 to 4.8 days in humans, an appropriate starting dose for human longevity trials might be 0.25-0.5 mg taken orally once or twice weekly. This weekly dose, approximately 1/8th-1/4th of the standard 2 mg daily dose used in cancer treatment, aims to maintain plasma levels similar to those observed in the long-lived mice (around 0.1-0.2 ng/ml) while accounting for the drug’s extended presence in the body.

  • Trametinib is sold in 0.5mg tablets. A single 0.5mg tablet can be obtained for $21 in a country like Turkey. If one were to use 0.5mg weekly, the yearly cost of the drug would be $1100.

  • We can follow the same principle that Dr Blagosklonny has long proposed for Rapa: The optimal longevity dose is the highest dose without side effects.

  • As an experiment, Trametinib timing can be aligned with intermittent Rapamycin timing to maximize the “fasting-like” effects (two nutrient sensing pathways blocked simultaneously).

[1] A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone, Gkioni et al, 2024 (preprint)

Trametinib user experience (Link)

  • 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

(Not Mine – From another Rapamycin group. Sharing because it’s very interesting!)

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#50

Triple Drug Combination Targeting Nutrient-Sensing Network Dramatically Extends Lifespan in Fruit Flies (2019)

This study investigated the effects of combining three drugs that target different components of the nutrient-sensing network to extend lifespan in fruit flies. The researchers tested rapamycin (an mTOR inhibitor), trametinib (a MEK inhibitor), and lithium (a GSK-3 inhibitor) individually and in combination. They found that double combinations of these drugs produced greater lifespan extension (around 30% on average) compared to any single drug alone (11% on average). Most remarkably, the triple combination of all three drugs extended median lifespan by 48%. The drug combinations did not significantly alter feeding behavior or food intake, suggesting the lifespan effects were not due to dietary restriction.

Importantly, the study also found that lithium was able to counteract some negative side effects of the other drugs. Specifically, lithium reversed the increased triglyceride levels and starvation resistance caused by rapamycin treatment. The researchers conclude that simultaneously targeting multiple nodes of the nutrient-sensing network with drug combinations may be an effective strategy to maximize longevity benefits while minimizing side effects. They suggest this “polypharmacology” approach of combining established pro-longevity drugs could potentially be developed into therapies to improve health in late life.

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#51

Targeting RAS/MAPK Signaling: A Promising Approach for Extending Healthspan and Lifespan (2022)

This review examines evidence that inhibition of the RAS/MAPK signaling pathway can extend lifespan and improve healthspan across multiple model organisms. Genetic studies in yeast, worms, flies and mice have shown that reducing activity of various components of the RAS/MAPK pathway can increase lifespan and enhance resistance to age-related decline. The effects appear to be evolutionarily conserved, as variants in human RAS pathway genes have also been associated with longevity. The RAS/MAPK pathway integrates with insulin/IGF signaling, a well-established aging regulatory pathway, suggesting it may be a key node in controlling the aging process.

Based on these genetic findings, the authors discuss the potential for repurposing existing RAS/MAPK inhibitor drugs as “geroprotectors” to promote healthy aging in humans. Several compounds that directly or indirectly inhibit RAS/MAPK signaling, including trametinib, statins, acarbose, and metformin, have shown lifespan-extending and health-promoting effects in model organisms. However, challenges remain in translating these findings to humans, including potential side effects and the need to determine optimal dosing and timing of interventions. Nevertheless, the authors argue that pharmacological modulation of RAS/MAPK signaling represents a promising avenue for developing interventions to extend healthspan and lifespan in humans.

Trametinib: RAS/MAPK/ERK Signaling Pathways and Mechanism of Action

signaling pathways

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#52

I wanted to add this comment from @Ray1 here, as its relevant. Just as with rapamycin, the general perception of medical professionals (given the typical cancer dosing levels used with trametinib) is quite negative. This suggests that, just as with rapamycin, getting an IRB approval for study in healthy humans may be a challenge… but, we’ll see.

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#53

Warning: mechanistic speculation ahead… :laughing:

Chronic rapa (for 4 mo or 16mo) in male mice can oppose the increased ERK activation that normally occurs during that time frame in liver and kidney. So it’s not actually reducing ERK activation below the level present in young mice—just preventing the age-associated increase.

Even if we can just maintain youthful levels of ERK activation, I think that is huge. Because ERK is one of the primary positive regulators of AP-1 activity. AP-1 is a transcription factor recently shown to be a master regulator of epigenetic remodeling in aging. Presumably more ERK activity->more AP-1 activity->more rapid loss of epigenetic information

To get ERK below even youthful values, you could periodically pulse a bona fide MEK or ERK inhibitor.

Another alternative to trametinib would be function-selective (as opposed to ATP-competitive) ERK inhibitors like SF-3-030, which affects expression of fewer genes than ATP-competitive ERK inhibitors.

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#54

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.

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#55

From X

“ trametinib/rapa. is toxic.

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

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#56

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.

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#57

Unfortunately very pricey stuff, even from India.

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#58

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.

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#60

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.

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#61

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

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#62

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.

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#63

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).

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#64

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.

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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

pdf-iconScientific 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:

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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.

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#65

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.

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Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers
#66

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.

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#67

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?).

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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.

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