Elevated DNA damage without signs of aging in the short-sleeping Mexican cavefish.

Lloyd E; Xia F; Moore K; Zertuche Mery C; Rastogi A; Kozol RA; Kenzor O; Warren W; Appelbaum L; Moran RL; Zhao C; Duboue ER; Rohner N; Keene AC

Abstract

Dysregulated sleep has widespread health consequences, including the accumulation of DNA damage. The Mexican tetra, Astyanax mexicanus, provides a powerful model to study the evolution and consequences of sleep loss. Multiple cave-adapted populations of this species have independently evolved reduced sleep compared to surface populations, yet show no obvious decline in healthspan or longevity. To examine whether evolved sleep loss is associated with DNA damage, we compared DNA damage response (DDR) and oxidative stress across populations. Cavefish exhibited elevated γH2AX in the brain and increased gut oxidative stress, consistent with chronic sleep deprivation. Following acute UV exposure, surface fish, but not cavefish, increased sleep and activated the photoreactivation repair pathway. Fibroblast cell lines derived from both populations confirmed diminished DDR and repair in cavefish, supporting an attenuated acute DNA damage response. Transcriptomic analysis revealed that many genes differentially expressed with aging in surface fish remain unchanged in cavefish, suggesting altered regulation of aging-related pathways. Together, these findings indicate that cavefish experience elevated cellular hallmarks of sleep deprivation yet exhibit resilience to its long-term consequences, highlighting an evolutionary model to investigate the mechanisms underlying sleep, DNA repair, and healthy aging.