Abstract The hypocretin (Hcrt; also known as orexin) system has been implicated in arousal state regulation and energy metabolism. We hypothesize that age-related sleep problems can result from dysfunction of this system and thus measured messenger RNA (mRNA) levels of preprohcrt in the hypothalamus, and hcrt receptor 1 (hcrtr1) and hcrt receptor 2 (hcrtr2) in eight brain regions of 3, 12, 18 and 24 months old C57BL/6 mice. Expression of preprohcrt and the colocalized prodynorphin did not change with age. Whereas an age-related change in hcrtr1 mRNA expression was observed only in the hippocampus, hcrtr2 mRNA levels declined in the hippocampus, thalamus, pons, and medulla; these reductions ranged from 33 to 44%. Declining trends ( P<0.1) in hcrtr2 mRNA levels were also observed in the cortex, basal forebrain and hypothalamus. These results are consistent with the hypothesis that an age-related deterioration occurs in the Hcrt system that may contribute to age-related sleep disorders.