Hungry for life: How the arcuate nucleus and neuropeptide Y may play a critical role in mediating the benefits of calorie restriction

Abstract

Laboratory studies consistently demonstrate extended lifespan in animals on calorie restriction (CR), where total caloric intake is reduced by 10-40% but adequate nutrition is otherwise maintained. CR has been further shown to delay the onset and severity of chronic diseases associated with aging such as cancer, and to extend the functional health span of important faculties like cognition. Less understood are the underlying mechanisms through which CR might act to induce such alterations. One theory postulates that CR's beneficial effects are intimately tied to the neuroendocrine response to low energy availability, of which the arcuate nucleus in the hypothalamus plays a pivotal role. Neuropeptide Y (NPY), a neurotransmitter in the front line of the arcuate response to low energy availability, is the primary hunger signal affected by CR and therefore may be a critical mechanism for lifespan extension.

Fig. 1

Central integration of satiety signals. The two main central targets of peripheral cues regarding energy status are the brainstem and the hypothalamus. Afferent nerves carry sensory information about feeding status directly from the gut to the brainstem while circulating factors derived from metabolism, adipose tissue, the pancreas and the gut signal through the hypothalamus. The appetitive state is determined by the balance of hunger- versus satiety-inducing cues, depicted above in green (pro-hunger) and purple (pro-satiety). PYY, peptide YY.

Fig. 2

Neuroendocrine manifestations of CR through the hypothalamic-pituitary axes. CR increases NPY expression which alters hypothalamic output to the pituitary and ultimately leads to decreased reproductive function, increased glucocorticoid expression, and reduced energy expenditure. ACTH, adrenocorticotrophin hormone; LH, luteinizing hormone; T3, triiodothyronine; TSH, thyroid-stimulating hormone.

Fig. 3

Physiological parallels between the effects of CR and centrally-administered NPY. CR and intracerebroventricular injection of NPY both result in reduced body temperature and increased glucocorticoid secretion, for example, but only CR has been shown to extend the lifespan of mammals.