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.
1 Like
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?
2 Likes
This research group saw the same benefits from the combination of drugs in their earlier studies with drosophila, so that doesn’t seem very relevant.
3 Likes
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.
3 Likes
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).
4 Likes
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?
1 Like
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.
I agree, but I’d really like to see a result in a different strain of mice.
1 Like
This article hints that there may be human studies forthcoming.
4 Likes
“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.”
5 Likes
I wanted to be more precise on the median lifespans, but have found the only way I think I can work them out is from the chart and I used an image editor to try to draw lines on the chart to give a more accurate result. I am still not pleased with this, but thought people might like it for themselves so link it here.
I have written to the authors of the paper to ask for the actual values. I always wonder on how much the figures are adjusted by the mice being euthanased at different points by different animal welfare people.
4 Likes
a coming new paper:
Regulation of Enzymes of De Novo Lipid Metabolism by Chaperone-Mediated Autophagy: Effects of the Lifespan-Extending MEK1 Inhibitor Trametinib
The availability of multiple slow-aging mice allows a search for possible shared mechanisms that affect the rate of aging. Previous work has shown down-regulation of the MEK1-ERK-MNK kinase cascade, which regulates protein translation through eIF4E, in response to four anti-aging drugs. Here we show that decreased protein abundance of enzymes involved in hepatic de novo lipogenesis (DNL) is characteristic of mice exposed to two anti-aging drugs that modulate glucose homeostasis (acarbose and canagliflozin), as well as in calorically restricted mice and in two long-lived mutant models. The same pattern of changes in the de novo lipogenesis enzymes can be produced, in cultured cells or in intact mice, by trametinib, a drug that inhibits the MEK-ERK kinase cascade, and which has been shown to extend mouse lifespan. The trametinib effect on DNL enzymes is, unexpectedly, not related to transcriptional changes, but depends on selective protein degradation through chaperone-mediated autophagy. Our data support models in which chaperone-mediated proteomic alterations, triggered through the MEK1-ERK-MNK kinase pathway, may collaborate with mTORC1 changes to slow aging and extend mouse lifespan.
3 Likes
I am considering adding Trametinib to my stack (currently primarily Rapamycin, Acarbose, Lithium). What doses and frequency are people taking?
I have seen the theoretical 0.5mg every 20 days mentioned above. I’m just wondering, is that what people are actually doing? Or have you decided upon a different regime?
I don’t think anyone is yet taking trametinib yet. Its a hard drug to get; it needs to be refrigerated so you can’t just order it from the regular indian online pharmacies that many people here get their rapamycin from. No regular doctor is going to prescribe it to anyone for longevity yet because it can have some toxic side effects (read the entire thread carefully, and some of the related threads on using this drug). So the only way to get it would seem to be by flying to India and buying it locally and making sure it stays refrigerated on the way home. This is a pretty high hurdle for most biohackers.
The dosing in humans for longevity is still far from being a well understood thing at all (even worse than with rapamycin, which is also an open issue in this regard).
So I think its still early days with regard to use in longevity. I’ve heard some talk that there may be a healthy human trial planned for trametinib but I’ve seen no details yet.
5 Likes
Side Effects
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
More common
- Bleeding from the rectum or bloody stools
- bleeding gums
- blemishes on the skin
- blistering, crusting, irritation, itching, or reddening of the skin
- bloating or swelling of the face, arms, hands, lower legs, or feet
- bloody nose
- blurred vision
- chest discomfort, pain, or tightness
- cracked, dry, or scaly skin
- coughing up blood
- decreased urine output
- diarrhea
- difficulty in moving
- difficulty with breathing or swallowing
- dilated neck veins
- fast, slow, irregular, or pounding heartbeat
- headache
- increased menstrual flow or vaginal bleeding
- irregular breathing
- joint pain
- lightheadedness, dizziness, or fainting
- muscle aches, cramps, pain, or stiffness
- nervousness
- nosebleeds
- paralysis
- pimples
- pounding in the ears
- prolonged bleeding from cuts
- rapid weight gain
- rash
- red or black, tarry stools
- red or dark brown urine
- redness, swelling, or pain of the skin
- scaling of the skin on the hands and feet
- swelling of the hands, ankles, feet, or lower legs
- tingling of the hands and feet
- ulceration of the skin
- unusual tiredness or weakness
- unusual weight gain or loss
Less common
- Cough
- fever
Rare
- Change in vision
- seeing flashes or sparks of light
- seeing floating spots before the eyes, or a veil or curtain across part of your vision
- stomach cramps, pain, or tenderness
- watery or bloody diarrhea
Incidence not known
- Blistering, peeling, loosening of the skin
- chills
- itching
- red skin lesions, often with a purple center
- sore throat
- sores, ulcers, or white spots in the mouth or on lips
- swollen glands
- unusual bleeding or bruising
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
More common
- Acne, pimples
- burning, itching, and pain in hairy areas, pus at the root of the hair
- canker sores
- change in taste
- dark urine
- dry eyes
- dry mouth
- dry skin
- itching, pain, redness, swelling, tenderness, or warmth on the skin
- loosening of the fingernails
- loss of taste
- redness or soreness around the fingernails
- sores, ulcers, or white spots on the lips or tongue or inside the mouth
- swelling or inflammation of the mouth
- thirst
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
4 Likes
Thanks. I have seen this - my impression was that it’s similarly scary to the Rapamycin list of side effects.
BUT if you’re taking an infrequent and low dose, then your odds of experiencing these side effects would be very low…?
FWIW - I am still considering adding this to my stack. As some further context for those scratching their heads, my Doctor recently informed me he is retiring in 1 1/2 months. If I am already prescribed something, a colleague at his practice will likely issue renewals without much scrutiny. But if I ever try asking those colleagues for new prescriptions of some of our more funky chemicals, let’s just say they’re not as liberally minded…. So for me, it’s essentially now or never…
The dose I am considering asking for is 0.5mg every 20 days.
1 Like
As posted numerous times…
“If you wait until you are ready, it is almost certainly too late.”
~ Seth Godin
2 Likes
The sealed bottle of 30 tablets is supposed to be stable at up to 25C/77F for 36 months including up to 30 days at 30C/86F. Accordingly, ordering from India in Jan (when average daily highs are around 77F for New Delhi, or around 86F for Nagpur where many of the Indiamart sellers are located), might be a possibility. Of course, you need to verify that the seller is sourcing from a wholesaler that uses AC or refrigeration for long term storage (25C/77F is not achievable in India otherwise).
On the other hand, the opened bottle has to be refrigerated at 2C-8C (36F-46F) for up to 24 months (OR used within 30 days if stored at or below 25C/77F). Since the single bottle of 30 tablets of 0.5mg taken every 20 days would last almost 2 years, it would definitely need to be refrigerated once opened.
India seems to have 2 versions of Trametinib, a cheaper “Generic” Meqsel (by Novartis, India) around $600 per 30 tablets of 0.5mg and the “Brand” version of Mekinist by GSK, around $1500 for the same 30 tablets of 0.5mg. In reality Novartis bought the rights to Trametinib from GSK (Glaxo Smith Kline) in 2015, so both versions in India are actually sold by Novartis!
5 Likes