Emulating the benefits of IL-11

Hi

The original IL-11 discussion ( like so many discussions on the forum) has drifted into other areas and this topic is worthy of keeping on track.

The dimension that was evolving nicely was based on the diagram below furnished by ngorge and the comment/ question raised by Juandaw

‘Do we now take lithium, trametinib, and rapamycin together? ‘

The diagram above suggests it’s possible at some level to emulate the mechanism of IL-11 inhibition utilising a number of readily available compounds all be it that trametinib is on a different level of cost to the remaining three compounds ( including Senolytics).

I would be very interested to know if anybody has the knowledge and experience to translate this diagram into a dosing schedule in both quantum and timing?

For the record I take 10mg of Rapamycin as a single weekly dose, 500mg Metformin daily, and dose with 100mg Dasatinib plus 2000mg Fisetin as a Senolytic on the two days prior to taking Rapamycin.

How would one consider modifying this approach to include Trametinib?

It would appear on the face of it that this would deliver against the reported benefits of IL-11 inhibitors

Am I in the right track people?

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The question in that thread was Joseph’s, in response to the post of CoachHarvey.

Joseph

1

Jan '23

Do we now take lithium, trametinib, and rapamycin together?

As

FWIW in the US a prescription of 2mg of Trametinib {Mekinist] 30 tablet is around $13,050.00 with a discount coupon {17% off the average retail price of $15,826.00

The India version is only ₹72,000 around $870.00 USD

That discussion was based on the paper below.

https://www.pnas.org/doi/10.1073/pnas.1913212116

The discussion was about MEK inhibitors, which trametinib is. A non-drug MEK inhibitor is myricetin, a supplement touted as a hangover remedy.

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Maybe this is a little off topic but am I reading this correctly? You are taking the senolytic cocktail D&F for two days every week? Is there a special situation where such a high frequency is warranted?

Interesting question

When I started out a few years back I had an in person consultation with Dr Green ( caught COVID on the plane on the way home - early adopter :sunglasses:) with the intention of becoming a patient.

At that time a Senolytics cycle was advocated every three months and since then the cycle has moved around but invariably shorter.

It’s difficult to work with doctors in the USA from the UK mainly relating to drug supply so now I work alone but equally attempt to follow Dr Green in my approach ( that is not to say he is advocating a weekly approach - it is my approach based on my best understanding of his current strategy - working alone!) and I believe he currently advocates regular and frequent Senolytics use.

I cannot say if this is optimal Senolytics strategy but I find it well tolerated and not arduous within my regime.

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If you really want to target senescent cells, I think taurine works better. Mouse studies showed taurine supplemented mice had far fewer senescent cells than D+Q treated mice.

Add in Rapamycin and your senescent cells load should be minimal.

Note the blue line (taurine) vs green (D+Q) and red (control)

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That discussion was based on the paper below. https://www.pnas.org/doi/10.1073/pnas.1913212116

I tend to not put much value on Drosophila or C. Elegans results. It suggests that we should test in mice, but I wouldn’t start taking something solely because it extends lifespan in those models.

However see: Dietary and pharmacological interventions to improve mammalian healthspan and lifespan

Trametinib (at 80kg human equivalent dose of 9.4mg) was also shown to increase median lifespan in mice: 7.2% increase in females and 10.2% in males. Also excitingly, combination of trametinib and rapamycin gave additive lifespan extension. Rapa extended median lifespan by 17.4% and 16.6% in females and males, respectively. Whereas trametinib+rapa extended it by 27.4% in males (the female group hadn’t yet reached 50% survival yet upon publishing).

The downside of this results is that the control mice didn’t live very long. Even the median lifetime of rapa+trametinib male mice was only 912 days, which is actually shorter than the reported median lifespan for that strain. On the bright side they did have a large sample size.

Inbred rodent strains vary a great deal in their longevities, aging patterns, and responses to caloric restriction. The median life span for ad lib-fed B6C3F1 hybrids (males and females combined) in the BAP study was 933 days, or about 11% longer than for ad lib-fed C57BL6, one of the parental strains. [ref]

Just trying to guess from the graph it looked like the female rapa+trametinib group median lifespan might end up being around 1,100 days, which would be more impressive. Perhaps the full results will be published in a journal at some point. Definitely seems a combo that should be urgently tested in ITP.

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Relevant preprint: Functional characterisation of rare variants in genes encoding the MAPK/ERK signalling pathway identified in long-lived Leiden Longevity Study participants

They identified two variants (one in a RAS GAP, the other in c-RAF) which inhibit ERK signaling. Also interesting: one of these variants inhibited mTORC1 when expressed in mouse ESCs, while the other actually activated it.

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Trametinib is prescribed for certain cancers (as monotherapy, or in combination with b-RAF inhibitor for cancer with b-RAF mutations). See below clinical trials for dose and associated adverse effects.

We enrolled 206 patients (median age 58·5 years, range 19–92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded. [ref]

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Thank you Destrider - Very interesting and helpful - just the sort of insight one is looking for through an interactive site like this.

To be fair Dr Green advocates Taurine (3mg per day if there is any further comment on dosing) and Taurine is in my daily schedule, what his comments did not relay was the link to Senolytic activity. However that may be a function of being on the outside of his treatment program!

Time for a review! Any reduction in dosing complexity is certainly welcome.

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The dosing I have heard that best mimics the trials is your age/10 of grams of taurine daily rounded up. So for someone who is 51-59 you would take 6 grams of Taurine daily.

Since taurine increases MTOR, I start taking it 3 days after my Rapamycin dose.

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When it comes to managing hungovers, it is DHM, dihydromyricetin that sometimes is used. @John_Hemming should be the expert in this field. I have only used DHM a few times.

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I use DHM every time I drink (aka Raisin Tree) it is another HDAC inhibitor as well.

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