More severe lung disease tied to greater signs of cellular aging in CF
Inhaled corticosteroids also associated with shorter length of telomeres
More severe lung disease and using inhaled corticosteroids are associated with shorter telomere length, a sign of cellular aging, in immune cells from people with cystic fibrosis (CF), a study suggests.
Telomeres are stretches of repetitive DNA that protect the ends of chromosomes, the long strings of DNA that contain genetic information. Telomeres shorten every time cells divide. When they become too short, cells enter a state of senescence, where they’re too old and faulty to continue replicating.
The shorter telomeres were observed in white blood cells called leukocytes and were particularly more pronounced in men and in patients with two copies of the F508del mutation, the most common CF-causing mutation. Also, telomere shortening happened much faster in very young children with the F508del mutation, but the rate declined throughout childhood and adolescence.
“Our data suggest that the [F508del] homozygous genotype, resulting in the full absence of cystic fibrosis transmembrane conductance regulator (CFTR) channels on the cell surface and therefore giving rise to a severe [disease manifestation], exerts its effect on [telomere length] already early in life and maybe even already intra-uterine, resulting in shorter [telomeres] remaining anchored for the rest of the adult life,” the researchers wrote.
The study, “Leukocyte telomere length and attrition in association with disease severity in cystic fibrosis patients,” was published in Aging.
While telomere shortening is associated with aging, people with chronic lung diseases such as chronic asthma, chronic obstructive pulmonary disease, that is, COPD, and idiopathic pulmonary fibrosis have faster telomere shortening than people of the same ages without those diseases.
While this hasn’t been observed in lung tissue from people with CF, evidence suggests telomeres may be shortened in leukocytes from CF patients with more severe disease. This could lead to accelerated aging and a higher incidence of age-related diseases such as osteoporosis and gastrointestinal cancers, meaning people with more severe disease could benefit from earlier screening and treatment for those conditions.
Telomere length and cellular aging in CF
To confirm the link, researchers in Belgium sought to determine leukocyte telomere length (LTL) in 168 CF patients recruited at the University Hospitals Leuven outpatient clinic between April 2014 and September 2015. The participants included 117 adults and 51 children (mean age, 23.8), about half of them male (53%). A total of 85 patients had a previous, or retrospective, assessment of LTL, collected between 1990 and 2013, a mean of 11.5 years before the most recent evaluation.
LTL significantly decreased with age, by 1.22% a year in the retrospective assessment, and by 0.93% a year in the recent assessment. At the early evaluation, LTL for women wasn’t significantly different than men, but the later assessment showed a 10.5% longer leukocyte telomere length in women than men. In the subgroup with the two LTL assessments, data also showed a significant decrease in mean LTL between the two measurements (1.32 vs. 0.83).
Looking at clinical factors, the researchers found that better lung function, as assessed by the amount of air that can be exhaled in one second (forced expiratory volume, or FEV1) and the ratio between FEV1 and forced vital capacity, which is the maximum amount of air that can be forcefully exhaled in one breath, was associated with a longer LTL. This association was only significant in men, however.
Seventy patients (42%) were treated with inhaled corticosteroids as part of their daily maintenance therapy, indicating they had CF asthma. Those patients had 7.19% shorter telomeres than CF patients not using such medications.
Male patients having of two copies of the F508del mutation, a surrogate measure of worse disease severity, also correlated with 10.46% shorter telomeres compared with males carrying only one copy of the F508del mutation. No associations were observed in women.
Finally, in patients with two available LTL measurements, researchers found that LTL shortening was more pronounced in younger patients, an effect that decreased as they became older. This association with age was only present in CF patients with two F508del copies. Those with one copy had a shorter and somewhat steadier LTL shortening throughout their lives.
“In CF patients, characteristics of more severe disease were associated with LTL, possibly resulting in an increased rate of aging affecting their other bodily functions and making them more prone to age-related diseases,” the researchers wrote. “These effects are probably already established during childhood, stressing the need for early diagnosis of CF and appropriate therapy from an early age onward.”
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