Aging is associated with a variety of physiological changes originating peripherally and centrally, including within the autonomic nervous system. Sleep–wake disturbances constitute reliable hallmarks of aging in several animal species and humans. Recent studies have been interested in N-acetylmannosamine (ManNAc) a potential therapeutic agent for improving quality of life, as well as preventing age-related cognitive decline. In this study, ManNAc (5.0mg/ml) was administered in the drinking water of middle-aged male C57BL/6J mice (55weeks old) for 7days. Mice were housed under a 12:12h light:dark cycle at 23–24°C. We evaluated bio-behavioral activity using electrocardiogram, body temperature and locomotor activity recorded by an implanted telemetry transmitter. To estimate sleep–wake profile, surface electroencephalogram and electromyogram leads connected to a telemetry transmitter were also implanted in mice. Autonomic nervous activity was evaluated using power spectral analysis of heart rate variability. ManNAc-treated mice spent more time in a wakeful state and less time in slow wave sleep during the dark phase. Parasympathetic nervous activity was increased following ManNAc treatment, then the sympatho-vagal balance was shifted predominance of parasympathetic nervous system. Furthermore, improvement in sleep–wake pattern was associated with increased parasympathetic nervous activity. These results suggest that ManNAc treatment can improve bio-behavioral activity and sleep–wake quality in middle-aged mice. This may have implications for improving sleep patterns in elderly humans.