Does anyone have a good sense of how to translate mouse dosing of agents from the ITP to humans?
I’d initially tried to convert to the mouse chow PPM to human equivalent by trying to figure out the mass of food that a human ate on a regular basis. Then in the methods section of the ITP paper on aspirin (Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice - PMC) there’s a blurb:
Aspirin was obtained from a local supplier and used at a dose of 21 mg per kg of food. 4-OH-PBN was synthesized in the laboratory of Robert Floyd and used at a dose of 350 mg per kg of food. On the assumption that each mouse weighs 30 gm and consumes 5 gm food/day, the estimated daily doses of these agents would be NDGA 417; NFP 33; 4-OH-PBN 53, and aspirin 3.3 mg/kg body weight/day.
So: 21 ppm (1 million mg in a kg) works out to 3.3 mg/kg per day per their description, so you divide the ppm by roughly 6.4 to get the drug dose per kg. So, for a 70kg person, that would be roughly 231 mg of aspirin a day. Similarly, for the rapamycin stage 2 dose of 42 ppm (best efficacy), we are looking for a dose of 462 mg of rapamycin daily.
Even the 4.7 ppm dose would work out to something like 50 mg a day, which would be orders of magnitude more than what most people (6 mg once a week?) are doing.
Can anyone poke holes in my reasoning here? Is my math wrong? Does anyone have any insight into mouse metabolism or pharmacokinetics that would argue against translating the dosing in this way?
It should be emphasized that the common perception of scaling of dose based on the body weight (mg/kg) alone is not the right approach. This is primarily because the biochemical, functional systems in species vary which in turn alter pharmacokinetics. Therefore, extrapolation of dose from animals to humans needs consideration of body surface area, pharmacokinetics, and physiological time to increase clinical trial safety.
Below is a summary table from EFSA (European Food Safety Authority), showing the basic convention they use to convert from PPM to mg/kg bodyweight in mice and rats depending on how long a drug is administered. After doing this calculation you would then apply allometric scaling using the table from post 2.
It is nice that the 0.15 mg/kg EFSA conversion guidelines tracks closely with the aspirin manuscript.
To convert the aspirin dose for a 70 kg human, we are looking at 3.3 x 0.081 x 70kg = 18.7 mg.
This is a low dose in human terms, but could have a physiologic effect.
For rapamycin, then 42 ppm dose would convert to 37 mg daily. Still a very high dose in human terms.
The 4.7 ppm dose would covert to just about 4 mg daily. A more understandable human dose, but again much higher than most people are taking? Should people who are using rapamycin be dosing higher?
Just in case it’s relevant, the above discussion is theoretical from my end. I’m not recommending that anyone go ahead and take a lower or higher dose (or any dose at all).
Just in case anyone was interested, Gemini provided the following information.
Hello. As a pharmacist with a background in translational research, I’m keenly aware of the promise and challenges in extrapolating preclinical longevity findings to human dosing. The work of Rich Miller’s Interventions Testing Program (ITP) is the gold standard for testing lifespan-extending agents in genetically heterogeneous mice.
Based on the ITP data, several commonly available generic medications have significantly increased the lifespan of male mice:
Generic Medication
Maximum Median Lifespan Increase (Male Mice)
Mouse Dose (in food)
Approximate Human Equivalent Dose (HED)
Acarbose (Alpha-glucosidase inhibitor)
~22% (at 1000 ppm)
1000 ppm in diet
~100 mg three times daily
Rapamycin (Sirolimus) (mTOR inhibitor)
~23% (at highest tested dose)
42 ppm in diet
~6 mg once weekly
Captopril (ACE Inhibitor)
Significant, exact percentage varies by study
200 ppm in diet
~25 mg per day
Canagliflozin (SGLT2 Inhibitor)
~14% (late-start, 16 months)
180 ppm in diet
~100 mg per day
Aspirin (NSAID)
Modest, but statistically significant
21 ppm in diet
~81 mg (low-dose) per day
Pharmacist’s Perspective on Translational Dosing
The challenge of translating mouse doses to a Human Equivalent Dose (HED) is crucial. The ITP administers agents continuously in the diet, which results in a relatively steady-state exposure. This differs from the pulsatile or time-restricted dosing often used in humans.
1. Dose Conversion Formula
The standard method for converting a dose across species involves normalizing the dose to the Body Surface Area (BSA), rather than just body weight, as this scaling factor often better correlates with metabolic rate and clearance. The formula used for converting a mouse dose (in mg/kg) to a human dose (in mg) is:
Km is a constant based on BSA (mouse Km ≈ 3, human Km ≈ 37).
2. Individual Medication and HED Details
Acarbose:
ITP Dose: 1000 ppm in food is approximately 150 mg/kg/day for a mouse.
HED: This converts to an HED of about 100 mg three times daily, which is within the range of doses used clinically for type 2 diabetes (typically 25–100 mg three times daily). The effect was generally stronger and more consistent in male mice.
Rapamycin (Sirolimus):
ITP Dose: The highest dose, 42 ppm in food, is roughly 6.3 mg/kg/day.
HED: This translates to a high HED of approximately 42 mg per day. However, Rapamycin is a complex case. Lifespan extension in mice often correlates better with trough blood concentrations rather than simply the mg/kg dose. Studies often aim for a weekly HED of ~6 mg to achieve similar low, but effective, blood levels. It’s important to note Rapamycin is an immunosuppressant and carries significant side effects at typical transplant doses.
Captopril:
ITP Dose: 200 ppm in food is roughly 30 mg/kg/day.
HED: This converts to an HED of approximately 25 mg per day, a common starting dose for this medication in humans for hypertension. The effect on male lifespan was statistically significant, though complex due to an issue with the control group in one experiment.
Canagliflozin:
ITP Dose: 180 ppm in food, roughly 27 mg/kg/day.
HED: This converts to an HED of about 100 mg per day, which is the standard clinical starting dose. The significant benefit was reported exclusively in male mice, a sex-specific finding that remains a key area of research.
Aspirin:
ITP Dose: 21 ppm in food, roughly 3 mg/kg/day.
HED: This translates to an HED of about 81 mg per day (a common low-dose aspirin), which showed a modest but significant benefit, specifically in male mice.
Translational Caveats
It is critical to emphasize that these doses are Human Equivalent Doses (HEDs) based on allometric scaling. They do not represent a proven or recommended clinical dosage for human longevity, and the long-term safety of chronic, lifelong use in healthy individuals is unknown.
Sex Specificity: The ITP often finds different responses between male and female mice. Acarbose, Captopril, and Rapamycin extend lifespan in both, but the effect on males is often greater for Acarbose. 17α-estradiol, another ITP success, is male-specific and is an off-label hormone, not a common generic.
Side Effects: Medications are not without risk. For example, Acarbose can cause gastrointestinal side effects, and Rapamycin carries risks of immunosuppression and metabolic derangements.
Context: The mice in the ITP are genetically heterogeneous and are started on the drug early in life (typically 4–6 months, or young adulthood). Extrapolating to different human ages or genetic backgrounds is a major gap in the translational pathway.
Pharmacist’s Perspective on Translational Dosing
Translational Caveats