The role of endocannabinoid system in brain aging

Abstract

Endocannabinoid system has recently been shown to play a role in brain aging. Mice lacking cannabinoid CB1 receptors (CB1 receptor knockout, Cnr1-/- mice) show signs of accelerated aging specific to the brain and cognitive functions. The mechanisms by which the absence of CB1 receptor deficiency induces accelerated brain aging have not been identified yet. The present work shows that CB1 receptor absence can enhance age-related accumulation of aging marker lipofuscin. Knockout of CB1 receptors also leads to a decrease in cathpesin D expression, as well as changes in autophagic pathway. However, the absence of CB1 receptor does not affect age-related oxidative stress or reduction in the rate of neurogenesis. We next asked if the endocannabinoid system itself undergoes age-related changes and assessed the levels of 2-arachidonoylglycerol (2-AG), the major ligand of the CB1 receptor, and the enzymes responsible for its metabolism in the hippocampus. The expression of the enzymes involved in the synthesis and degradation of 2-AG decreases with age, leaving the basal 2-AG levels unaltered. However, this general decrease in the production of metabolic enzymes for 2-AG might be detrimental in some cases, when an increased synthesis of this endocannabinoid is needed (e.g., excitotoxicity). No change in the levels of anandamide (AEA) or oleylethanolamide (OEA) is observed in aging. In addition, an increase in palmitoylethanolamide (PEA) levels is present in aged animals.