Aging is usually accompanied by mitochondrial dysfunction, reduced energy levels, and cell death in the brain and other tissues. Mitochondria play a crucial role in maintaining cellular energy through oxidative phosphorylation (OXPHOS). However, OXPHOS is impaired as the mitochondrial oxygen supply decreases with age. We explored whether pharmacologically increased oxygen diffusion by crocetin can restore OXPHOS and help delay the aging of the brain and other vital organs. We found that aged mice treated with crocetin for four months displayed significantly improved memory behavior, neuromuscular coordination, and ATP and NAD+ levels in the brain and other vital organs, leading to an increased median life span. The transcriptomic analysis of hippocampi from crocetin-treated mice revealed that enhanced brain energy level was caused by the upregulation of genes linked to OXPHOS, and their expression was close to that in young mice. The chronic treatment of aged astrocytes also showed improved mitochondrial membrane potential and energy state of the cells. Moreover, chronic treatment with crocetin did not cause any oxidative stress. Our data suggest that restoring OXPHOS and the normal energy state of the cell can delay aging and enhance longevity. Therefore, molecules such as crocetin should be further explored to treat age-related diseases.
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