Aging, sleep, and kynurenic acid

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Advanced age presents challenges that increase the likelihood of poor quality and reduced duration of sleep. Disruptions in sleep that come with aging may result in effects such as fatigue, irritability, headaches, and deteriorating cognition. These disruptions are presumed to result from alterations in brain regions that underlie endocrine, behavioral and cognitive responses to homeostatic challenges in the organism. Unraveling common molecular mechanisms between aging and sleep disturbances – which may lead to new therapeutic strategies to alleviate these outcomes – is of great importance. Aging pathophysiology points to dysfunctional cholinergic transmission, which may be driven, in part, by altered hypothalamic orexin neurons. We hypothesize that kynurenic acid (KYNA), an endogenous antagonist of cholinergic neurotransmission, plays a mechanistic role in age-related sleep dysfunction and orexin activation. The small molecule KYNA is of particular interest because (i) KYNA and its synthesizing enzymes kynurenine aminotranferases (KATs) are increased in the aging brain and (ii) an excess of KYNA may be especially involved in sleep deficits that are seen with advanced age. We propose the novel hypothesis that accumulated KYNA activates orexin neurons, thereby disrupting sleep, a circumstance that is exacerbated with aging or a homeostatic sleep deprivation (SD) challenge wherein KYNA accumulates in the brain. A specific inhibitor of KAT II, main enzyme responsible for brain KYNA formation, will be used as an experimental tool to mechanistically test the hypothesis. There are two specific aims to test our hypothesis. Aim #1: To examine the relationship of KYNA to orexinergic activation in the lateral hypothalamus of young rats (3-4 months) and old rats (26-28 months). Hypothesis: Accumulation of KYNA, as a result of aging or acute sleep deprivation (SD), in the lateral hypothalamus activates orexin neurons. Aim #2: To evaluate the impact of KYNA synthesis inhibition in improving sleep quality in old rats and young rats with reduced orexin expression. Hypothesis: KAT II inhibition serves as an efficacious strategy to overcome sleep architecture deficits in old rats and young rats with reduced orexinergic signaling.