Report from Kamil (a scientist at NSU in Singapore) on ARDD:
In recent years The Aging Research and Drug Discovery Meeting has ascended as one of the most important aging conferences.
All your ERK are belong to us
This ARDD, Linda Partridge presented her work on the combination of trametinib and rapamycin. Trametinib is a MEK inhibitor that leads to reduced MAPK/ERK signalling and synergistic lifespan extension with rapamycin under some circumstances — even in F1 mice that pass the 900-day rule.
Hopefully they will pursue phase I studies soon, because I know for certain that we and others are interested in proper microdosing of trametinib. At the same time the ITP updated their webpage and announces that trametinib is in the ITP (which we knew through the grapevine). Interestingly, even Widaja et al. 2024 showed that pERK phosphorylation is up with aging and that this can be reduced by an anti IL-11 antibody, although I do not fully trust that data because I have rarely seen such strong anabolic upregulation with aging before. Be that as it may, an MAPK/ERK inhibitor is clearly an excellent choice to inhibit ERK!
Summary of the Kaeberlein video: he doesn’t think the tranetinib + Rapamycin study will replicate because the controls didn’t live very long (700-800 days).
His rule of thumb is mouse studies need controls to have around a median 900 day lifespan in order to trust results showing a lifespan extension.
After seeing Kaeberlein’s video I see no reason to jump on the trametinib bandwagon.
To paraphrase Dr. Blagasklonny, “anything” plus rapamycin appears to be better than “anything” alone.
Yes. When compared to studies with normal-lived controls, the rapa + trametinib male mice did no better than control animals in other studies, and the females did no better than high-dose rapa alone, and substantially worse than strict CR:
I think it’s a good rule of thumb in general but I’ll bet this one replicates. This isn’t a simple test/control, there was a control, trametinib, rapamycin, and the combo. Not only did trametinib and rapamycin outperform the (short-lived) controls, but the combo outperformed rapamycin and trametinib alone. It’s not just a one-off result, it’s a trend. If you don’t believe the control group is valid, you can drop them and still come to the conclusion that the addition of trametinib improves lifespan over rapamycin alone.
Pricing in Mexico is now below US $1500 per 30 x 0.5mg Trametinib (Resultado de tu búsqueda: 1 resultado relacionados a "Mekinist 0.5mg" – Farmacia Santa Rita), so under $50 per tablet. Due to the high cost most smaller pharmacies won’t carry it but larger pharmacies will deliver to any smaller pharmacy in Mexico for pickup, so those living on the US border to Mexico might be able to get it for a reasonable price, without worrying about refrigeration or customs impoundment. Since the dosage would be 0.5mg every 20 days, that is around $2.5/day.
This line of mouse is bred for sensitivity to carcinogens and trametinib is a kinase inhibitor. How much of the longevity outcome is accounted for along those lines of effect?
Probably not and I get it but the drop off of relevance between flies, mice, and men is a really steep curve. As of today, there is no randomized controlled research demonstrating that rapamycin causes a longer life, or much of anything passing a risk/benefit analysis.
There are five experimental trials underway with the following endpoints and stages:
PEARL Study
Endpoints:
Primary: Changes in biomarkers of aging, such as epigenetic age, immune function, and inflammatory markers (e.g., CRP, IL-6).
Secondary: Self-reported measures of physical and cognitive function, frailty, and quality of life.
Stage: Completed (results pending publication).
Vibrant Study
Endpoints:
Primary: Effects of rapamycin on ovarian reserve markers (e.g., Anti-Müllerian Hormone [AMH] levels, follicle count).
Secondary: Impact on menstrual cycle regularity, energy levels, and subjective well-being.
Stage: Ongoing (participant recruitment and preliminary data collection).
Rapamycin and Exercise in Older Adults with Coronary Artery Disease (CAD)
Endpoints:
Primary: Improvements in physical performance metrics (e.g., VO₂ max, muscle strength).
Secondary: Changes in aging biomarkers, inflammation levels, and endothelial function.
Stage: Recruitment phase.
Rapamycin in Periodontal Disease Prevention
Endpoints:
Primary: Reduction in periodontal pocket depth and inflammation markers in gum tissue.
Secondary: Impact on systemic inflammatory markers and oral microbiota composition.
Stage: Early stage (initial safety and efficacy evaluation).
Rapamycin Effects on Muscle and Bone Aging
Endpoints:
Primary: Preservation of muscle mass and bone density measured through DEXA scans and muscle strength tests.
Secondary: Changes in mitochondrial function, markers of oxidative stress, and incidence of frailty.
Stage: Ongoing (data collection phase).
The paper finally published (the first post in this thread was the pre-print version).
Open access Paper:
The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan
Suppression of the insulin–IGF–mTORC1–Ras network ameliorates aging in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signaling, and trametinib inhibits the Ras–MEK–ERK pathway. In this study, we assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. We show here that trametinib treatment extended lifespan in both sexes and that its combination with rapamycin was additive. Combination treatment reduced liver tumors in both sexes and spleen tumors in male mice, blocked the age-related increase in brain glucose uptake and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. We conclude that trametinib is a geroprotector in mice and that its combination with rapamycin is more effective than either drug alone, making the combination a candidate for repurposing as a gerotherapy in humans.
The MEK-ERK proteins are tied to different signaling pathways in different cells types. So it’s not like the only thing a MEK inhibitor would inhibit is the MEK-ERK pathway downstream of growth factor receptors, and associated increases in anabolic metabolism supporting proliferation, in rapidly dividing cancer cells.
For example, immune cells like macrophages use Toll-like receptors (TLRs) to sense Pattern- and Damage-Associated Molecular Patterns, and downstream MEK-ERK signaling kicks of the massively anabolic process of building an proinflammatory response (i.e. making all the new mRNAs, proteins, and lipids needed to propogate inflammation). So there is undoubtedly affects on other cell types that have to be considered when thinking about the holistic effects of MEK inhibition in the context of lifespan extension studies (i.e. this drug is definitely modulating the immune system and chronic inflammation).
I don’t know about you guys, but this is starting to piss me off. I find flies, and fruit flies very irritating. Why are we working so hard to help the little biters live longer? Where’s my swatter?
Sounds interesting, but too much of a blunt tool. It probably shows what’s possible. I’m sure there are more precise ways to target inflammation without hitting essential pathways.
“Human trials for the drug combo could begin relatively soon. Both drugs are already approved for use in humans in the US and European Union, with anti-aging benefits hinted at in previous studies. Rapamycin, for example, seemed to extend the fertility of perimenopausal women by up to five years in one recent study.”
