Interconnections of Hypoxia and Aging in Long-Lived Species

Abstract Hypoxia is traditionally considered harmful to cells, yet emerging evidence suggests it may promote longevity through unclear mechanisms. Two evolutionarily distant but ecologically similar species, the naked mole-rat (NMR) and blind mole-rat (BMR), exhibit exceptional longevity and hypoxia tolerance, making them ideal models for studying the molecular links between hypoxia and lifespan. Our previous work indicated that hypoxia is associated with several longevity interventions like calorie restriction at the transcriptomic level. This study explored whether hypoxia tolerance pathways overlap with longevity mechanisms, particularly within the nutrient-sensing axis. To investigate, we exposed NMRs, BMRs, and mice to normoxia and severe hypoxia (0% O2 for species-specific survival times) and assessed survival rates. We analyzed AMPK/mTOR signaling, autophagy, mitochondrial function, and inflammation in heart tissue, alongside metabolomics and oxidative phosphorylation (OXPHOS) assays. Our results demonstrated that long-lived species survived hypoxia significantly better than mice. Notably, enhanced AMPK signaling, elevated autophagy-related protein levels, and reduced oxidative stress in these species suggest a strong link between longevity and hypoxia resilience. Moreover, long-lived species preserved mitochondrial health under hypoxia, likely contributing to their extended lifespan. These findings highlight hypoxia’s potential role in longevity and suggest new therapeutic avenues for age-related diseases.