TORC1 Inhibition Enhances Immune Function And Reduces Infections In The Elderly

Research Summary

A phase 2a randomised, double-blind, placebo-controlled trial asking whether low-dose mTOR inhibitor therapy can improve immune function and reduce infections in older adults, at doses low enough to avoid the immune suppression seen at transplant or cancer doses.

Who Or What Was Studied?

264 volunteers aged 65 and over, without unstable medical conditions, enrolled at 12 clinical sites. They were randomly assigned to one of four once-daily oral regimens for 6 weeks — RAD001 0.5 mg, RAD001 0.1 mg, BEZ235 10 mg, or RAD001 0.1 mg plus BEZ235 10 mg — or a matching placebo. After a two-week drug-free interval they received a seasonal influenza vaccine and were followed for about a year in total. Rats treated for 7 days were used separately to confirm which doses actually inhibited TORC1 in liver tissue.

What Did The Research Show?

• The combination of RAD001 0.1 mg plus BEZ235 10 mg was associated with a significant reduction in the annualised rate of infections reported by participants (P = 0.001): 1.49 infections per person per year versus 2.41 in the placebo group.
• BEZ235 alone also significantly reduced reported infections (P = 0.008, 1.61 per person per year); the two RAD001-only arms showed a trend that was not statistically significant.
• Only the combination improved the antibody response to the influenza vaccine, meeting the study’s primary endpoint of a 1.2-fold rise in geometric mean titre ratio versus placebo for at least two of the three vaccine strains.
• Gene-expression analysis of whole blood after the combination showed up-regulation of type 1 interferon-stimulated antiviral genes (for example IFI27, IFIT1, MX1 and ISG15); the average size of that increase was small, about 17.8%.
• The regimens were generally well tolerated during the 6 weeks of treatment — no deaths occurred, and serious adverse events were reported in 26 of 264 participants over the 12 months, with no significant differences between the arms.

Limitations And Interpretation

• Infections were self-reported rather than laboratory-confirmed, although the trial was blinded and placebo-controlled and the authors argue misclassification should be similar across arms.
• The study tested a specific low-dose combination of two mTOR inhibitors, not rapamycin (sirolimus) alone, and treatment lasted only 6 weeks.
• It measured immune response to vaccination and reported infection rates, not lifespan or ageing itself; the drugs were developed by Novartis, which also funded the study.