Breaking: 15% Healthy Lifespan improvement via Rapamycin seen in Marmosets

[Jjazz]

You are absolutely correct that there is likely batch to batch variability in this or any unstandardized grapefruit supplement. These are “consistent” for me in the sense that I can buy ten bottles from the same lot, this will last for a year or two, and the effects should be similar until I buy from a new lot.

Regarding the furanocoumarin content of peel, other references show that grapefruit peel has higher concentrations than the flesh. It probably depends on many factors, like the specific variety, ripeness, storage, etc. From this paper:

“Similar to the diversity of compounds, higher compound concentrations were generally found in peel than in pulp (Figs 2 and 3).” Note the difference in y-axis scales for Figures 2 and 3.

Figure 2:

Figure 3:

Overall, even without standardization, I believe a grapefruit peel supplement can be a more consistent way to inhibit CYP3A4 vs. juice or fresh fruit. Once you have found a dose regimen that achieves your desired blood concentration or effect, you can expect it to be relatively consistent the next time you use the same product from the same lot.

[RapamycinCurious]

@Olafurpall

As far as rapamycin increasing glucose in ways that are independent of mTORC2 such as by damaging beta cells, …organ transplant patients will get a lot more mTORC2 inhibition than the people taking weekly doses for longevity, yet they don’t seem to be getting type II diabetes left and right due to beta cell destruction.

One study showed that tacrolimus to rapamycin conversion in renal transplant recipients was associated with a 30% increase in impaired glucose tolerance ([9](javascript:;)). Furthermore, a study of renal transplant recipients from the U.S. Renal Data System showed that patients treated with rapamycin in combination with either tacrolimus or cyclosporine had the highest incidence of NODAT [New Onset Diabetes After Transplantation] ([10](javascript:;)). Other studies have found sirolimus, on multivariate analysis, to be a risk factor for NODAT in kidney transplant recipients ([11](javascript:;)–[15](javascript:;)). Furthermore, in a large-scale randomized control trial of immunosuppressive regimens in renal transplantation, sirolimus was associated with the highest incidence of hyperglycemia (5 vs. 4.7% low-dose tacrolimus vs. 4.4% high-dose cyclosporine vs. 2.9% low-dose cyclosporine), although the incidence of NODAT was higher in the tacrolimus group ([16](javascript:;)).

However, as patients in these studies also received other immunosuppressants, including corticosteroids, it is not possible to determine the exact influence of rapamycin on the development of NODAT. However, as part of their U.S. Renal Data System study, Johnston et al. ([10](javascript:;)) analyzed the risk of NODAT in renal transplant recipients receiving tacrolimus in combination with mycophenolate mofetil (MMF) or azathioprine versus those receiving tacrolimus and sirolimus. This demonstrated a hazard ratio of 1.25 (95% CI 1.03–1.52), suggesting an increased risk for NODAT from sirolimus independent of any effect of tacrolimus.

The data on the risk of NODAT with sirolimus use after liver transplantation are more sparse. However, in one study the incidence of NODAT in liver transplant recipients receiving sirolimus without CNIs was 10.5% compared with 29.4% in a historical control group receiving only CNIs ([17](javascript:;)).
Evidence for Rapamycin Toxicity in Pancreatic β-Cells and a Review of the Underlying Molecular Mechanisms Rapamycin