A cystic fibrosis drug reversed epigenetic clock aging over one year in eight patients
A cystic fibrosis drug reversed epigenetic clock aging over one year in eight patients
In eight patients with cystic fibrosis who had never previously received CFTR modulators, a preprint from researchers at the University of British Columbia, published on September 18, documented the following: over one year of therapy with elexacaftor/tezacaftor/ivacaftor, the median acceleration of biological age on the DNAmGrimAge2 epigenetic clock shifted from +1.92 years to −1.70 years. Within those same patients, faster clock pace coincided with higher levels of blood inflammatory markers: interleukin-6, interleukin-1β, and calprotectin.
Cystic fibrosis is a hereditary disease. Because of a defect in the CFTR gene, cells fail to produce a functional channel protein that should transport chloride across the membrane, and mucus in the lungs becomes thick. In the mid-twentieth century the disease killed most children before school age. With the advent of drugs that repair the protein itself, median life expectancy in Canada, the United States, and the United Kingdom has risen to approximately 65 years.
The most potent of these modulators is the triple combination elexacaftor/tezacaftor/ivacaftor (ETI), marketed as Trikafta and Kaftrio. It was approved in 2019 and is suitable for roughly 90% of people with cystic fibrosis. In the pivotal trial it reduced the rate of pulmonary exacerbations by 63% and lowered sweat chloride from 102 to 58 mmol/L, close to the diagnostic threshold for cystic fibrosis (60 mmol/L).
A new preprint tests a less expected effect of the same therapy: the rate of biological aging. Cystic fibrosis is a near-natural experiment because restoring the CFTR protein removes the cause of chronic inflammation. The DNAmGrimAge2 clock is a newer version trained to predict the risk of death and chronic disease; the same group previously showed, in COPD, that this clock best captures lung aging. Over one year of therapy, lung function rose from 64.5% to 90% of the predicted value, and sweat chloride fell from 98 to 41 mmol/L. Before treatment, the median age according to the clock exceeded chronological age by 1.92 years; after one year it lagged behind chronological age by 1.70 years (p=0.008).
Epigenetic age acceleration was also linked to inflammation: the higher a patient's acceleration, the higher the levels of interleukin-6 and interleukin-1β (signals of the innate immune response) and calprotectin, a protein released by neutrophils, the first-line defense cells. In people with cystic fibrosis these cells are chronically activated by thick mucus and infection. This inflammation damages cells and accelerates the aging that epigenetic clocks detect. Higher lung function was associated with less age acceleration, and higher sweat chloride with more.
"The profound clinical effect of restoring CFTR protein function may extend to the biological processes of aging, and this may be accompanied by a reduction in chronic inflammation," the authors of the preprint write.
More than a year ago, an Italian group studying 52 adults with cystic fibrosis using the older Horvath clock showed that in patients whose epigenetic age was initially accelerated, one year of the same therapy reduced it alongside improvements in lung function. The new preprint replicates this finding with a different instrument and, for the first time, links the effect to inflammatory markers.
In a pilot study without a control group, four independent measures shifted in parallel within the same eight patients: sweat chloride, lung function, inflammation, and epigenetic age. This convergence turns a single observation into a testable hypothesis: epigenetic aging in cystic fibrosis can respond to the removal of its cause as rapidly as sweat chloride and lung function do. It is precisely the speed of such a shift that proves meaningful: a 24-year follow-up of 699 Italians showed that the pace of change in GrimAge matters more for mortality than a single time-point measurement, especially for the second version of this clock.