Only if you just assume without evidence that lower dosing would be useful in humans. They did a pilot study to identify a dose that inhibited mTOR and was sufficient to stimulate autophagy, but didn’t lead to hyperlipidemia or glucose dysregulation in most animals. They tested five doses ranging from 0.01-1.0 mg/kg/day and found:
The higher doses of 0.2–0.4 mg/day (roughly 0.5–1.0mg/kg/day) resulted in a measureable and reproducible decrease in phospho-rpS6 indicating downregulation of mTORC1 in marmoset PBMCs as expected. In tissues, the phosphorylation of rpS6 appeared to be suppressed by the treatment of RAPA. However, the two obese subjects (with relatively low circulating RAPA concentrations) showed no decrease in phosphor-rpS6 in PBMCs at 2 weeks of dosing and had ratios that overlapped that of the controls in liver and adipose tissue taken at 14 months. These results indicate that consideration may have to be given to altered concentrations of RAPA dosing in obese subjects, including humans.
Testing Efficacy of Administration of the Antiaging Drug Rapamycin in a Nonhuman Primate, the Common Marmoset | The Journals of Gerontology: Series A | Oxford Academic
So 1 mg/kg wasn’t enough for the obese subjects — and since this was the top dose they tested, it’s possible that a higher dose would have been better even in the normal-weight animals.
Here’s the critical point:
Circulating trough rapamycin levels (mean = 5.2ng/mL; 1.93–10.73 ng/mL) achieved at roughly 1.0 mg/kg/day was comparable to those reported in studies of rodents and within the therapeutic range for humans. …The trough levels observed in both the short-term and the long-term studies that were achieved at the dose of 0.4 mg/day (roughly 1.0 mg/kg/day) were comparable with those reported in studies of C57BL/6 mice being fed a diet containing e-RAPA at a concentration of 14 ppm. Zhang and colleagues (4) report blood concentrations averaging 3–4 ng/mL and Fok and colleagues (5) report a range of 2.0–10 ng/mL. Harrison and colleagues (1) and Miller and colleagues (18), in contrast, report significantly higher circulating concentrations in the genetically heterogeneous UM-HET3 mice used in the NIA Intervention Testing Program.
By comparison, the marmoset blood concentrations averaged 5.2ng/mL with a range from 1.93 to 10.73 ng/mL. The among-subject variance in trough blood concentrations, as evidence by coefficient of variation, was similar in marmosets receiving 0.40 mg/day and humans receiving 4–5mg/day (11)—marmoset c.v. = 0.667, human c.v. = 0.673–0.778.
And in this lifespan study, per Salomon’s interview with @RapAdmin , the trough levels were even higher:
In our previous pilot study, we showed that the delivery of a dose similar to this produced trough concentrations (24 hr since last treatment) of rapamycin of ∼5 ng/ml (Tardif et al., 2015). This previous report also details the pharmacokinetics Here, with approximately double the number of animals, the average trough concentration of rapamycin for all animals 24 hr after dosing was 6.4 ± 1.0 ng/ml
we found that rapamycin concentrations in male marmosets were significantly higher than those in females (Figure 2). Rapamycin concentrations in the blood averaged 8.4 ± 1.7 ng/ml for male marmosets and 4.4 ± 0.6 ng/ml for female marmosets.
IMO, this puts all gymnastics around half-life to one side: these animals, similar to the mice in nearly all LS studies, were dosed every day and never had plasma levels below 6.4 ± 1.0 ng/mL. This seems to put weekly dosing out the window for an effect size in this range.
Exactly. Conversely, if they had used the kinds of doses most people here use and it had failed (as the dose-ranging study suggests it would have), you would be left wondering if it meant the dose was too low or if rapa just doesn’t work in primates — including hairless primates.
