As the global population ages, cellular senescence contributes increasingly to the burden of age-related diseases. Hallmarks of this process include telomere shortening and loss of proteostasis, frequently linked to DNA damage-associated transcriptional stress. Although telomere dysfunction-induced foci (TIF) have been well documented in lungs from patients with idiopathic pulmonary fibrosis (IPF), their occurrence and role during physiological lung aging remain unclear. Analysis of senescence markers in lung tissue from organ donors aged 16-88 years showed a linear decline in telomere length with age; however, TIF frequency increased significantly in the airway epithelium only in individuals older than 75 years. Similarly, senescence markers such as p16 tended to rise with age but did not reach the levels observed in IPF lungs. To better delineate the early events driving senescence in the human respiratory epithelium and to expand the cohort size, we collected nasal epithelial cells by brushing from 213 healthy volunteers aged 2-97 years. As in the aging lung, telomere shortening was evident, yet TIF were rare and detected almost exclusively in individuals over 80 years of age. In contrast, indicators of impaired proteostasis, including increased senescence-associated β-galactosidase activity and lysosomal content, were apparent from the age of 40 in nasal epithelial cells and correlated with olfactory decline. Together, these findings suggest that telomere dysfunction is unlikely to be the primary driver of cellular senescence in the human respiratory tract, where proteotoxic stress may instead play a more prominent role.
Coquette et al. (2026) studied this question.