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.

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:

• Anyone taking Trametinib?

• 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!

[Curious]

I would really like the ITP to test Myricetin. Since it is a MEK inhibitor.

[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

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).

[justaguest]

Myricetin inhibits MEK-1 (ref, ref) and parsley is a major source. I have no idea how much weaker the effect is though.

Quercetin too (ref).

[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.

[jnorm]

Your 1st source isn’t loading for me, but I’d say the 2nd source isn’t that useful. Docking scores are useful for motivating further study, but they don’t give a quantitative measure of potency or affinity (e.g IC50, Ki).

Myricetin does get mentioned in the study above (In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state):

The effects of the test substances on the senescent fibroblasts are summarized in Table 2. As can be seen from the table, NDGA had almost no effect on senescent phenotype, but decreased both short- and long-term survival. Myricetin had mild rejuvenating effect as judged by cell phenotype, but severely compromised long-term survival.

and

To investigate the mechanism of action of these compounds we performed pathway analysis. For this purpose we utilized transcriptional response data provided from Library of Integrated Network-based Cellular Signatures (LINCS) L1000 dataset. After data processing (see Methods) we obtained pathway activation scores for 97 age-related pathways ( Supplementary Table S4). EGCG showed strong upregulation of cAMP pathway and inhibition of mitochondrial apoptosis and Ras pathways. Myricetin was found to upregulate ILK, DNA repair, cAMP and Hypoxia pathways. On the other hand, it severely suppressed PAK, IL-6, MAPK, Cellular senescence, p38, mTOR and several chemokine pathways. NAC showed strongly inhibition of pro-proliferative pathways like MAPK, AKT, p38, RAS, PAK, ERK and in turn activated p53, EGFR1, SMAD and Caspase signaling.

Myricetin also extends lifespan in C. Elegans: IJMS | Free Full-Text | Myricetin-Mediated Lifespan Extension in Caenorhabditis elegans Is Modulated by DAF-16

[Cohen]

The present study is the first proof-of-concept of using U0126, an inhibitor of ERK1/2 phosphorylation, to increase elastin synthesis in a rat model deficient in aortic elastin content. Using vSMCs isolated from the aorta of the BN rat, we have shown that the marked increase in intracellular Ca2+ mediated by A23187 decreases the steady-state levels of several mRNAs encoding for proteins implicated in elastic fiber formation. We also showed that A23187 decreases both the transcription of the elastin gene and the stability of elastin mRNA. Furthermore, we provide evidence that the decrease in elastin gene transcription mediated by an increase in [Ca2+]i requires the phosphorylation of ERK1/2 and the recruitment of AP1 transcription factors. Our study specifically demonstrates for the first time that inhibition of ERK1/2 phosphorylation increases elastin synthesis both in vitro, in vSMCs, and in vivo, in the BN aorta, suggesting that inhibition of ERK1/2 phosphorylation might be a potential therapeutic strategy in vascular pathologies due to a deficit in elastin, such as SVAS.

Among molecules described to regulate elastin synthesis, we note that the downregulation of the elastin gene in rat fibroblasts by both bFGF and EGF is mediated by activation of the ERK1/2.13–15 ERK1/2 activated by bFGF and EGF translocates to the nucleus where it accumulates, resulting in phosphorylation of Elk-1, which then induces c-fos expression that upregulates fra1.14,15 Both fra1 and c-fos can be heterodimerized with c-jun to form the complex AP1. In the human elastin gene promoter, an AP1-like site located at −564 to −558 bp has been described to repress elastin gene transcription mediated by recruitment of AP1 transcription factors.

Inhibition of ERK1/2 phosphorylation: a new strategy to stimulate...

In the present study we show that pharmacological inhibition of pro-proliferative pathways including H-Ras activation, Mek/Erk signaling, or cyclin D-cdk4 complex formation coincides with the recovery of normal deposition of elastic fibers in cultures of CS fibroblasts. To inhibit the initial proliferative signals induced by the hyperactive mutated H-Ras in CS cells, we used the antibiotic radicicol that emerged as a potent inhibitor of heat shock protein 90, the ubiquitous chaperone of numerous oncogenic proteins that ensures their proper folding and activation. It has been shown that the radicicol-dependent inhibition of heat shock protein 90 results in degradation of Raf and the consecutive inhibition of the Ras/Raf-Mek/Erk signaling cascade.

We found that experimental inhibition of H-Ras activity with radicicol not only quenched the heightened proliferation of CS fibroblasts but also induced recovery of their normal elastogenesis. Our finding encourages the use of this non-toxic macrolidic antibiotic in the future therapy of CS patients that would combat tumorigenesis as well as phenotypic abnormalities resulting from impaired elastogenesis. This claim can be endorsed by the fact that radicicol, in addition to inhibition of cancer cells proliferation, has also been shown to quench proliferation of activated inflammatory leukocytes and endothelial cells, thereby reducing inflammatory responses in atherosclerosis and experimental pneumonia. Radicicol has been also proposed as a potential drug for treating different angiogenesis-dependent diseases, such as solid tumors, psoriasis, rheumatoid arthritis, and diabetic retinopathy. Importantly, we have also established that treatment with PD0332991 that inhibits the growth of solid tumors can also stimulate elastogenesis in cultures of normal and CS fibroblasts after Rb phosphorylation on Thr-821. Thus, this cdk4 inhibitor should also be considered in future therapies of CS patients.

Retinoblastoma protein modulates the inverse relationship between cellular...

To assess potential to address or slow the increasing burden of disease we investigated the potential of repurposing Trametinib as an anti-fibrotic and anti-inflammatory compound in a preliminary in vivo study using a mouse model of JEB. We found that over half of the mice treated with Trametinib experience a more severe phenotype, marked by a thinner epidermis, an increase in fibrotic marker αSMA, and a non-significant decrease in the CD4 T cell infiltrate. In a combination treatment of Losartan and Trametinib, however, we found that Losartan ameliorated Trametinib’s adverse effects and restored epidermal thickness to the control phenotype, decreased αSMA expression compared to Trametinib-only treatment, and CD4 expression steadily increasing in response to greater ear damage severity. Losartan is able to modulate some of Trametinib’s effects, potentially opening new lines of investigation to consider in terms of Losartan’s role in inflammatory conditions in EB research.

The effect of Trametinib on epidermal thickness is intriguing, and logic would dictate that inhibition of MEK in a highly proliferative tissue such as the epidermis would lead to a reduction in cellular content (in this case keratinocytes) and subsequent thickening. In the context of JEB, it is known that human patients have a stem cell defect, with laminin 332 contributing to stem cell maintenance [36,37], and this may well be compounded through the inhibition of proliferation. Indeed, it has been demonstrated that Trametinib inhibits dermal stem cells as well. Losartan on the other hand has demonstrated the ability to improve stem cell niches derived from adipose tissue and muscle, which provides another potential mechanism of action to explore in epidermal stem cells. Furthermore, the effects could be accelerated by environmental triggers leading to a worsening of the disease phenotype in the context of Trametinib treatment.

Trametinib-Induced Epidermal Thinning Accelerates a Mouse Model of Junctional...

[Curious]

Myricetin is a novel natural inhibitor of neoplastic cell transformation and...

Myricetin is a novel natural inhibitor of neoplastic cell transformation and...

A mechanistic discussion about Myricetin’s potential as MEK inhibitor.

[Lost]

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