Zhou Wu, Aiqin Zhu, Shizheng Wu and Hiroshi Nakanishi
Abstract Mitochondrial DNA (mtDNA), which encodes components of the mitochondria electron transfer complexes, is highly susceptible to damage produced by reactive oxygen species (ROS), due to its close proximity to ROS generated through the respiratory chain and the paucity of protective histones. Accumulation of mtDNA damages during aging result in the reduced expression of the mitochondria electron transfer complexes, especially complex I. The resultant reduced activity of complex I further increases the generation of ROS, forming a vicious cycle. During aging, the accumulation of oxidative mtDNA damages is prominently found in the brain resident microglia. Increased intracellular ROS, in turn, drives microglia to provoke excessive neuroinflammation in the aged brain through activation of nuclear factor-κB (NF- κB). Hypoxia activates microglia to induce the generation of mitochondria-derived ROS and the subsequent activation of NF-κB signaling pathway to produce pro-inflammatory mediators, which impairs the cognitive functions. Propolis, a resinous substance produced by honeybees, significantly inhibits the hypoxia-induced neuroinflammatory responses by microglia. Furthermore, propolis and Ratanasampil, a traditional Tibetan medicine, improve the cognitive functions of the people who are living at high altitude. Considering that the daily exposure to hypoxia is one of risk factors for the aging-related cognitive impairments, these pharmacological approaches that prevent and reverse “microglia-aging” may become a most promising future research avenue for preventing the aging-related cognitive impairments.
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