Telomere dysfunction is associated with exacerbated intermittent hypoxia-induced cognitive deficits and nerve damage.

Abstract

Cognitive impairment associated with obstructive sleep apnea (OSA) is more prevalent and severe in the elderly, possibly due to age-related increases in neuronal susceptibility to intermittent hypoxia (IH). As telomere dysfunction is a key driver of cellular aging, this study aimed to characterize the interaction between telomere dysfunction and IH, and to explore the associated molecular alterations. Using telomere-damaged PC12 cells and G3 Tert -/- progeria mice exposed to IH, we assessed cellular stress responses, apoptosis, cognitive function, and hippocampal structural changes. The effects of the senolytic agent fisetin ( in vivo ) and the mTOR inhibitor rapamycin ( in vitro ) were evaluated. Transcriptomic analysis was performed on cells. IH-exposed G3 Tert -/- mice displayed exacerbated cognitive deficits and hippocampal atrophy compared to wild-type controls, which were significantly ameliorated by fisetin treatment (vs. IH-G3 Tert -/- : cognitive deficit, p = 0.028; hippocampal atrophy, p < 0.01). Correspondingly, telomere-damaged PC12 cells exhibited a heightened stress response to IH, manifested by increased p21, SA- β -gal and apoptosis upon IH, an effect also mitigated by rapamycin. RNA sequencing of these cells revealed a distinct inflammatory signature under IH, with enrichment in pathways like TNF and IL-17 signaling and identification of IL-6, CXCL10, and ICAM1 as key hub genes. Our findings indicate that telomere dysfunction is associated with exacerbated IH-induced cognitive deficits and nerve damage. We identify a corresponding inflammatory transcriptomic signature and provide preliminary evidence that interventions targeting these senescence-associated pathways can confer protection. This provides a new mechanistic perspective on aging-related susceptibility and outlines a translational roadmap for future investigation into OSA-related cognitive decline.