Recently Stuart Cook published impressive lifespan data on an unexplored pathway which is inhibition of an inflammation boosting protein called Interleukin-11 (pubmed: 39020175). The result was median lifespan extension by 25% in female mice and 23% in males. It will be very interesting to see other labs reproduce the results and also see what the maximum lifespan effect of this intervention will be. In a ARDD conference presentation Stuart showed a simplified overview of the proposed mechanism of actions behind why interleukin-11 inhibition works. I really like this simplified relation “ERK inhibition > AMPK activation > mTOR inhibition”. He also listed different pharmaceutical drugs which targeted each part. Again, keep in mind it’s a simplified relation but there is something elegant with it. Because it gives a framework to put some puzzle pieces together around what may be interesting potential combinational therapies. One week after Stuart had published his paper then Linda Partridge published a paper where they discovered impressive lifespan effect when Rapamycin, a mTOR inhibitor, and Trametinib, a MEK/ERK inhibitor was combined (doi: 10.1101/2024.07.25.605097). The result was median lifespan extension by 35% in female mice and 27% in males and maximum lifespan extension was 32% in females and 26% in males. This maps nicely with the simplified overview proposed by Stuart.
There are two things that differ between the two studies.
The treatment in this study started in young mice and not old mice.
It was also a different strain of mice. It’s frustrating that we don’t have standardized ways to do basic initial research because that would improve comparisons of data between labs and also accelerate things forward.
So based on the two studies above and also historical data on other interventions I created a list to try to give a bigger picture of how things may be related to each other. I’m very curious to see research on the combination Rapamycin (42 ppm) + Acarbose (1000 ppm) + Trametinib (1.44ppm) and when treatment is started at 16 months of age in UM-HET3 mice. It would also be very interesting to get safety and beneficial data on low dose of Trametinib in humans because that data will most likely differ from how things are when treating disease with high doses.
Trametinib is an inhibitor of Mek1 and Mek2.
Other drugs and flavonoids inhibit Mek including Myricitin, Fisetin, Quercitin, etc. Fisetin failed the ITP, but what about Fisetin plus Rapa? So many compounds to test.
I did not know that senolytics like Fisetin and Quercetin target the MEK pathway. That is something I need to take a deeper look on. But it would be interesting to do a screening of MEK/ERK inhibitors after the mTOR inhibitor screening project to get a feeling what findings we can do there. I have ordered two experiments recently from Ora Biomedical to test which is the single intervention Trametinib and then the combination therapy with Trametinib and the PI3K/mTOR inhibitor GSK2126458. Maybe the dose of Trametinib needs to be lowered but let’s see what the result will be.
Here is also one interesting comment from Mikhail Blagosklonny on X today.
I had an interesting conversation with a woman who runs a foundation for research into gastric cancer. The foundation had helped find a study in South Korea to test an MEK inhibitor for precancerous lesions of the stomach. The Korean government decided not to authorize the study. It is one thing to give an MEK inhibitor to children with a deadly cancer who have no other hope. Giving a drug with dangerous side effects to people who may not have a terminal disease at all is a whole different matter.
This is why we need testing in creatures other than mice and humans. Some very important questions cannot be answered until we have some other test subjects. I sure hope the dog aging project keeps going.
I fully agree that we need more data on MEK inhibitors before starting with using it. But I think it’s most likely the case that low dose of Trametinib will not have the same side effect profile as high dose. The same applies to Rapamycin. I would for example never start taking 3-5mg/daily of Rapamycin.
I take fucoidan which is also a PI3K/mTOR inhibitor (am always working on this pathway as I have a benign brain lesion and Prof Maruto told me re that fucoidan useful). I also take other things.
Hi I use the Matakana brand and take it every now and then. No side effects. I also take astaxanthin 12 mg and ecklonia cava, melatonin, D3k2 , high dose PEA , magnesium and taurine (very small amt). Looking into lactoferrin at the moment.
Great! One thing you could do is to test a different dose than the one I have ordered. I think that may be interesting data point. I’m currently in a longevity conference in Denmark so I not able to check what the dose was but email Ora and just say you want to test another dose then the one that was ordered.
