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

[RapAdmin]

More good news in the longevity field, this time from the Partridge lab at the Max Planck Institute for Biology of Ageing, where they combined two FDA-approved drugs with very good longevity results.

The researchers are, in this new pre-print paper, building on previous studies finding that lithium, trametinib and rapamycin can each extend lifespan in fruit flies (Drosophila), which is supported by other preliminary evidence in mice, worms, and cells, and observational findings in people.

The drugs all act on different cellular signalling pathways that together form the nutrient sensing network, which is conserved across evolution from worms and flies all the way to humans. This network adjusts what the body is doing in response to changes in nutrient levels. The drugs in question act on different proteins of this network to slow the ageing process and delay the onset of age-related death.

For the latest study, the researchers gave mice doses of trametinib and rapamycin, separately and in combination.

Trametinib treatment caused a significant lifespan extension in both sexes, in females, with a median lifespan extension of 7.2% but no significant effect on maximum lifespan, in males with an increase in median lifespan of 10.2% and maximum lifespan by 15.8%.

As previously shown, intermittent rapamycin treatment extended lifespan in both sexes with an increase in median and maximum lifespan of 17.4% and 16.5% respectively in females and 16.6% and 18.3% respectively in males.

Combined treatment with rapamycin and trametinib increased survival more in females than in males. Combined treatment caused a larger increase compared to the single treatment in both sexes, with median and maximum lifespan increased by 34.9% and 32.4%, respectively, in females and by 27.4% and 26.1%, respectively, in males.

“combined trametinib and rapamycin treatment is more geroprotective than treatment with either drug alone, suggesting immediate translational potential for humans”

From the paper:

Combination treatment reduced liver tumours in both sexes and spleen tumours in males, and ameliorated the age-related increase in brain glucose uptake. There was a striking reduction in inflammation in the brain, kidney, spleen and muscle with combination treatment, accompanied by reduced circulating levels of pro-inflammatory cytokines. Trametinib alone is therefore geroprotective in mice, but combined trametinib and rapamycin treatment is more geroprotective than treatment with either drug alone, suggesting immediate translational potential for humans.

Full Pre-print Paper:

A combination of the geroprotectors trametinib and rapamycin is more...

Related:

• Dietary and pharmacological interventions to improve mammalian healthspan and lifespan (Dissertation)

[nikney]

The mapk(braf-mek-erk pathway seems to be a growth and proliferation pathway independent of the mtor pathway. So theoretically, inhibition of the mapk pathway with trametinib will have a synergistic effect with the inhibition of the mtor pathway. Has anyone taken trametinib and rapamycin and have experience?

[RapAdmin]

Its been discussed quite a bit in the past, I wonder if @Joseph ever pursued it?

One note of caution:

Anyone taking Trametinib?

And I support the right of an individual to make his own choices regarding his personal health and the medications he buys. And if you decide to proceed, I hope it works out for you. With that said, this is a discussion forum. And I think most people here would agree that quality of evidence, cost, and risk/benefit ratios are all important considerations before adding a new compound to one’s antiaging regimen. For me, this medication wouldn’t satisfy any of these criteria. At standard dosages, almost half of patients become anemic. Elevated AST and hypoalbuminemia occur in 60 and 42%, respectively, suggesting liver toxicity. Neutropenia occurs in 44% of patients. And leukopenia occurs in 38%. And the list goes on. It’s one of those medications where, if you’re going to take it, you’d better have a damn good reason for doing so. And then careful monitoring and management of these adverse effects if they do occur. Additionally, the primary reason for considering it for longev…

from this thread: Anyone taking Trametinib?

[jnorm]

Canagliflozin was shown to inhibit the MEK-ERK pathway in mice (in liver, kidney, and muscle, at least), so it might be the safest way we currently have to inhibit the MEK-ERK axis. Sadly this effect (and the lifespan increase) was only present in male mice, so further studies are needed to see if different dosing regimens and/or other -gliflozins can produce similar effect in female mice.

If canagliflozin’s inhibition of MEK-ERK is mediated by SLGT2i, then empagliflozin would probably be an even better choice.

Another option might be isoleucine restriction, which in both male and female mice was shown to inhibit MEK-ERK signaling in liver and increase lifespan (although the male lifespan increase was greater).

I guess it’s nice to see evidence that trametinib+rapa is additive , that suggests that ERK inhibition plays nicely with mTOR inhibition (actually, both cana and isoleucine restriction reduced mTOR signaling via pS6K in the above studies). Trametinib+rapa should definitely be tested in the ITP, although I’d be more excited to see empa+rapa.

[Ilya_M]

Wow! That is better, than Aubrey’s RMR study.

[jnorm]

Oh wow, I forgot the entire curves weren’t in the dissertation. 34.9% median lifespan extension in the females for trametinib+rapa, that’s amazing!

[ReppinMycin]

Very promising, the key caveat being cancer is a far bigger mouse killer than human killer so longevity treatments targeting cancer in mice will have disproportionate benefits.

[KarlT]

Trametinib has some really scary side effects, adverse reactions.

[nikney]

Trametinib side effects generally occur with daily continuous doses. Weekly or biweekly trametinib side effects are minimized, right? Rapamycin can also have many side effects if taken every day, but once a week and low doses cause almost no side effects.

[RapAdmin]

A very good point! We’d never have considered rapamycin if all we did was look at the drug monograph.

It seems we should definitely do a deep dive on the side effects, check to see if any pulsed dosing clinical trials have been done, and perhaps do some testing on a pulsatile dosing strategy (perhaps synchronized with the rapamycin dosing, or perhaps to start with not synchronized).

Trametinib

Typical Dosing:

Mekinist is available as tablets (0.5 and 2 mg). The dose of Mekinist is 2 mg once a day taken on an empty stomach (at least 1 hour before or 2 hours after a meal) and at around the same time every day.

At typical dosing schedules:

The most common side effects with Mekinist (which may affect more than 1 in 5 people) are rash, diarrhoea, tiredness, peripheral oedema (swelling, especially of ankles and feet), nausea and acneiform dermatitis (acne-like inflammation of the skin).

https://www.ema.europa.eu/en/medicines/human/EPAR/mekinist

More detail:

Safety Profile

The most frequent (≥ 20%) adverse events of any grade in the trametinib group were rash (57% vs 10% in the chemotherapy group), diarrhea (43% vs 16%), and lymphedema (32% vs 4%). The most frequent grade 3 or 4 adverse events in the trametinib group were hypertension (12%) and rash (8%). The most common laboratory abnormalities of any grade in trametinib patients were increased AST (60% vs 16%), hypoalbuminemia (42% vs 23%), increased ALT (39% vs 20%), and anemia (38% vs 26%); grade 3 adverse events in these categories occurred in 2% to 3% of trametinib patients.

Adverse events led to discontinuation of trametinib treatment in 9% of patients, with the most common reasons being decreased left-ventricular ejection fraction, pneumonitis, renal failure, diarrhea, and rash, and to dose reduction in 27% of patients, with the most common reasons being rash and reduced left-ventricular ejection fraction. Serious adverse events in trametinib recipients included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, and serious skin toxicity.

Trametinib carries warnings/precautions for cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, serious skin toxicity, and embryo-fetal toxicity. Left-ventricular ejection fraction must be assessed prior to treatment and after 1 month and every 2 to 3 months thereafter. Ophthalmologic exams should be performed for any visual disturbance, and patients should be monitored for pulmonary symptoms and skin toxicities and secondary infections. Women should be advised on pregnancy planning and contraception, and men should be advised on potential impairment of fertility. Nursing mothers should discontinue trametinib or discontinue nursing.

Source: Trametinib in Unresectable or Metastatic Melanoma with BRAF V600E or BRAF V600K Mutation - The ASCO Post

and, as an overview, the Mekinist / Trametinib Risk Management document from the EMA:

mekinist-epar-risk-management-plan-summary_en.pdf (85.1 KB)

[RapAdmin]

Some Twitter Commentary on this new development:

From @agingdoc:**

Source: x.com

From Alex Colville of Age1 Ventures:

Source: x.com

From Alex: How these new results compare to other well known interventions:

From Aleksey Belikov

Source: x.com

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state

In search for geroprotectors: in silico screening and in vitro validation of...

[KarlT]

This is a very interesting subject, but I’m not remotely interested in taking Trametinib without knowing a lot more. I’m aware of the adverse effects of Rapamycin, even if taken daily and they’re not horrible. But on Trametinib you have to see Cardiology, Ophthalmology, and Dermatology on a recurring basis to check for adverse reactions.

I’ll wait for other members here to try it, as unfortunately I think it’s likely someone will.

[RapAdmin]

I agree, we need to learn a lot more.

Here is some interesting dose testing from the preliminary paper:

Dose range for oral administration of trametinib in mice combination with rapamycin can extend lifespan

To determine the dose range of trametinib that efficiently inhibited Ras-Mek-Erk signalling without adverse effects on health, young, C3B6F1 hybrid, wild type male and female mice were fed with 0.29, 0.58, 1.44, 2.88 or 11.52 mg trametinib / kg of diet for 4 weeks (Fig 1A), and their plasma levels of trametinib (Fig 1B-C), Ras-Mek-Erk pathway activity (Fig 1D-E), body weight (Fig 1F-G) and spleen weight (Fig. 1H-I), Sup. Fig 1) were measured. Trametinib in plasma increased with dietary concentrations and was higher in females than in males (Fig 1B-C). We measured inhibition of MEK activity by western blot analysis on liver samples using phosphorylation of ERK1/2 as read-out (Fig 1D-E). Erk1/2 phosphorylation was unaffected at 0.29 and 0.58 mg/kg trametinib and reduced at concentrations of 1.44 mg/kg trametinib and above in both sexes, although low sample number and high variability meant that only 11.52 mg/kg in female mice resulted in a significant reduction. Trametinib did not significantly affect water uptake (Sup. Fig 1A-B). Trametinib can cause body weight loss, liver lesions and necrosis, and increased alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels indicative of liver dysfunction [27]. There was no significant effect of any dose of trametinib on plasma levels of AST (Sup. Fig 1C-D) or ALP (Sup. Fig 1E-F). At doses of 0.29 - 2.88 mg/kg trametinib also did not affect body weight (Fig 1F-G) or spleen size (Fig 1H-I). In contrast, animals fed with 11.52 mg/kg trametinib failed to gain body weight in the 4-week measurement period (Fig 1F-G) with a trend for increased spleen weight in both sexes (Fig 1H-I). In summary, dietary trametinib concentrations of 1.44 mg/kg and above were sufficient to inhibit Ras-Mek-Erk signalling, while only the highest dose of 11.52 mg/kg trametinib induced adverse effects on mouse health. We therefore used 1.44 mg/kg in all subsequent experiments.

Converting this dose to human equivalent dosing:

Divide by 12.3 Based on the FDA animal to human dosing conversion guide here.

Dose Equivalent: 0.117 mg/kg for humans
Equivalent dose for 60kg human: Approx. 7mg (correction, these calculations are wrong because the stated dosing of 1.44 mg/kg is with reference to the amount of medication in the food, not the body weight of the subjects). Read this full thread for the corrected calculations.

This is a high dose for humans using trametinib. In the literature I’ve read, they’ve seen a few “overdoses” of trametinib (accidentally) where the person took 4mg (instead of the regular 2mg) with no obvious repercussions, but it seems higher dosing really has not been tested much (from what I’ve read so far).

[mondagai]

This strikes me as something to avoid unless you have a personal or strong family cancer history. I’d take it if I was a mouse.

[Lost]

Hmm. Isn’t the canonical MEK pathway needed for telomerase activity?

[desertshores]

@RapAdmin

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state | Aging

Even I, experimenter and canary in the coal that I am, stay away from interventions that have scary and possibly profound side effects.

[RapAdmin]

There have been 17 clinical trials so far involving Trametinib, usually with other cancer therapies. Here is a full list, and links to more details:

Clinical Trials Using Trametinib

Clinical trials are research studies that involve people. The clinical trials on this list are studying trametinib. All trials on the list are NCI-supported clinical trials, which are sponsored or otherwise financially supported by NCI.

https://www.cancer.gov/research/participate/clinical-trials/intervention/trametinib

This is interesting:

Trametinib

Drug design and preclinical activity

Trametinib (GSK1120212) is a reversible allosteric inhibitor of MEK1 and MEK2 activation and kinase activity, with preclinical evidence of MAPK inhibition and growth inhibition in BRAFV600E melanoma cell lines and xenografts (23).

Clinical trials

Dabrafenib and Trametinib, Alone and in Combination for BRAF-Mutant...

Phase I trial.

The phase I trial commenced in 2008, and of 206 patients, 97 had metastatic melanoma with no restriction of eligibility by somatic mutations, for example BRAF mutations. Thirty-six patients had BRAF-mutant melanoma and 39 had wild-type BRAF melanoma (7 of whom had an NRAS-mutant melanoma), 6 had unknown BRAF status, and 16 patients had uveal melanoma (24, 25). Dose titration commenced at 0.125 mg, with dose-limiting toxicities observed at total daily doses of 3 mg and 4 mg, and the RP2D was 2 mg once daily. At this dose, analysis of biopsies taken early during treatment and compared with baseline samples showed that there was effective inhibition of MAPK signaling as measured by phosphorylated extracellular signal–regulated kinase (ERK; 60% reduction), effective inhibition of proliferation (Ki67 reduced by 80%), and an increase in cell-cycle inhibition (p27 increased by 170%).

The most frequent toxicities included MEK inhibitor class-like toxicities such as an acneiform rash (88%), diarrhoea, peripheral oedema, and fatigue (Table 1). In the trial of 206 patients with solid tumors, ocular toxicities occurred in 15% (n = 31) of patients, including reversible central serous retinopathy (n = 3) and rarely irreversible retinal vein occlusion (n = 1). Transient left ventricular dysfunction was noted in 8% (n = 16) of patients. Twelve percent of patients treated at 2 mg required dose reductions, most commonly due to rash.

Phase III trial (METRIC).

Toxicities were similar to those in the earlier trials, including MEK inhibitor class-like effects such as rash, diarrhoea, peripheral oedema, hypertension, and transient mild cardiac dysfunction. Chorioretinopathy was rare (<1% grade 3), and no cases of retinal vein occlusion were reported. Most toxicities were mild and did not require drug discontinuation; however, 27% of patients underwent dose reduction.

Table 1.

Summary of dabrafenib and trametinib clinical trial results

TrametinibClinicalTrialSummary.pdf (46.6 KB)

[RapAdmin]

A 2022 Phase 2/3 Clinical Trial of Trametinib, and the associated side effects recorded. Daily dosing of trametinib definitely has an ugly side effect profile. The key question is whether periodic (e.g. once weekly) dosing might greatly reduce or eliminate most of these side effect risks.

The Study used oral trametinib 2 mg once daily (trametinib group)

The toxic effects observed in patients in the trametinib group of our study were similar to previous MEK inhibitor studies in patients with other cancer types, such as melanoma. However, clinical management of adverse events can be challenging, with fatigue, skin rash, and gastrointestinal side-effects occurring most commonly, and dose reductions being necessary for many patients. For adverse events of special interest, the incidence of retinal events was 2%, and, although 8% of patients had decreased ejection fraction, they often recovered, and some patients were able to be rechallenged.

Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02175-9/fulltext#tables

2022ClinicalStudySummaryofSideEffects.pdf (56.6 KB)

[RapAdmin]

ChatGPT on other MEK inhibitors:

Please list all the drugs that are classified as MEK inhibitors

ChatGPT

MEK (Mitogen-Activated Protein Kinase Kinase) inhibitors are a class of drugs used primarily in the treatment of cancer, as they target the MEK proteins involved in the MAPK/ERK signaling pathway, which is often dysregulated in tumors. As of my last update, here are some well-known MEK inhibitors:

1. Trametinib (Trade name: Mekinist) - Approved for the treatment of melanoma, non-small cell lung cancer (NSCLC), and certain types of thyroid cancer.
2. Cobimetinib (Trade name: Cotellic) - Used in combination with vemurafenib for the treatment of BRAF V600 mutation-positive melanoma.
3. Binimetinib (Trade name: Mektovi) - Approved for the treatment of BRAF V600E or V600K mutation-positive melanoma, often in combination with encorafenib.
4. Encorafenib (Trade name: Braftovi) - Although primarily a BRAF inhibitor, it’s often used in combination with MEK inhibitors like binimetinib for better efficacy in treating melanoma.