Crocetin Delays Brain and Body Aging by Increasing Cellular Energy Levels in Aged C57BL/6J Mice

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.