Preprint: elexacaftor/tezacaftor/ivacaftor treatment associated with decelerated epigenetic ageing in cystic fibrosis

A preprint deposited on bioRxiv presents findings from a pilot longitudinal study examining whether treatment with the CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI, marketed as Kaftrio in the UK) influences epigenetic ageing trajectories in people with cystic fibrosis (CF).

The study enrolled eight modulator-naive individuals with CF. Blood DNA methylation was profiled before ETI initiation and after 12 months of treatment, with epigenetic age acceleration estimated using the DNAmGrimAge2 clock — an established methylation-based surrogate for biological ageing derived from longitudinal mortality data. The authors report that ETI treatment was associated with deceleration of epigenetic age acceleration, and that this change correlated with reductions in inflammatory markers.

CF is caused by pathogenic variants in the CFTR gene, and ETI substantially improves lung function and clinical outcomes in individuals with at least one copy of the F508del allele. The hypothesis explored here — that the systemic inflammatory burden of CF may contribute to accelerated biological ageing, and that modulator therapy reverses part of this — is biologically plausible given ETI's documented effects on systemic inflammation.

The study is limited by its very small sample size (n = 8) and pilot design, and has not yet undergone peer review. DNAmGrimAge2 clocks provide population-level associations rather than individual biological-age readouts, and effect sizes and confidence intervals should be interpreted cautiously in a sample of this scale. Researchers in CF biology, epigenomics, and ageing will find the mechanistic framing of interest. Genetic counsellors working with CF families may note the emerging evidence base on long-term modulator effects.