The rapidly expanding elderly population and obesity endemic have become part of continuing global health care problems. The hypothalamus is a critical center for the homeostatic regulation of energy and glucose metabolism, circadian rhythm, and aging-related physiology. Nicotinamide adenine dinucleotide (NAD+
)-dependent deacetylase sirtuins are referred to as master metabolic regulators that link the cellular energy status to adaptive transcriptional responses. Mounting evidence now indicates that hypothalamic sirtuins are essential for adequate hypothalamic neuronal functions. Owing to the NAD+
-dependence of sirtuin activity, adequate hypothalamic NAD+
contents are pivotal for maintaining energy homeostasis and circadian physiology. Here, we comprehensively review the regulatory roles of the hypothalamic neuronal NAD+
-sirtuin axis in a normal physiological context and their changes in obesity and the aging process. We also discuss the therapeutic potential of NAD+
biology-targeting drugs in aging/obesity-related metabolic and circadian disorders.
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