mTOR Inhibition Improves Immune Function In The Elderly

Research Summary

A randomised, observer-blind, placebo-controlled trial asking whether short-term, low-dose mTOR inhibition can improve immune function in older adults, using the antibody response to influenza vaccination as a way to measure immunosenescence over a short period.

Who Or What Was Studied?

218 volunteers aged 65 and over without unstable medical conditions, enrolled at nine sites in New Zealand and Australia. They were randomly assigned to a placebo or one of three oral doses of RAD001 (everolimus) for six weeks: 0.5 mg daily, 5 mg weekly or 20 mg weekly. After a two-week drug-free interval they received a 2012 seasonal influenza vaccine, and antibody titres were measured four weeks later. 211 of the 218 completed the study and 199 were in the intent-to-treat analysis.

What Did The Research Show?

• The two lower-dose regimens (0.5 mg daily and 5 mg weekly) met the study’s primary endpoint: at least a 1.2-fold rise in the influenza haemagglutination-inhibition geometric mean titre ratio versus placebo for at least two of the three vaccine strains, each with at least 80% posterior probability.
• Modelling predicted that the 0.5 mg daily regimen inhibited mTOR-mediated S6K phosphorylation by about 38% and the 5 mg weekly regimen by more than 50%, yet both still improved the vaccine response, so partial inhibition appeared as effective as the near-complete inhibition seen at 20 mg weekly.
• Pooled RAD001 treatment lowered the percentage of PD-1-positive CD4 T cells by 30.2% (P = 0.03) and PD-1-positive CD8 T cells by 37.4% (P = 0.008) after six weeks compared with placebo.
• RAD001 also raised antibody titres and seroconversion rates against two heterologous influenza strains not contained in the vaccine, and in subjects with low baseline titres (1:40 or less) it increased seroconversion to the H3N2 and B strains.
• Mouth ulcers were the most common RAD001-related adverse event (20 of 218 subjects, mostly mild); overall, RAD001-treated subjects had a similar incidence of severe adverse events to the placebo group.

Limitations And Interpretation

• This was an exploratory proof-of-concept study with a liberal preplanned significance threshold (80% posterior probability of an effect over placebo), and the six-week course was short.
• The trial measured only the immune response to influenza vaccination; it did not test whether mTOR inhibition affects other ageing-related conditions or lifespan in humans.
• The mechanism is not fully explained: no significant difference was found in the percentage of naive lymphocytes between the groups.
• The study was funded by Novartis, which developed RAD001, and several authors held equity in the company.