Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus

•The metabolic mystery highlights the remarkable fact that even moderately excess nutritional resources are broadly toxic, whereas moderately reduced nutritional resources are broadly protective.•Many studies have shown that neurons in the ventromedial hypothalamus (VMH) regulate energy balance and, more recently, glucose homeostasis.•It is increasingly clear that glucose metabolism drives key aspects of the aging process, as well as diabetic complications.•We propose that nutrient-sensing neurons in the VMH also impinge on the aging process by regulating peripheral glucose metabolism, and that dietary restriction is protective by reducing glucose metabolism in these neurons.

We propose that energy balance, glucose homeostasis, and aging are all regulated largely by the same nutrient-sensing neurons in the ventromedial hypothalamus (VMH). Although the central role of these neurons in regulating energy balance is clear, their role in regulating glucose homeostasis has only recently become more clear. This latter function may be most relevant to aging and lifespan by controlling the rate of glucose metabolism. Specifically, glucose-sensing neurons in VMH promote peripheral glucose metabolism, and dietary restriction, by reducing glucose metabolism in these neurons, reduces glucose metabolism of the rest of the body, thereby increasing lifespan. Here we discuss recent studies demonstrating the key role of hypothalamic neurons in driving aging and age-related diseases.