Role of the hypothalamus in mediating protective effects of dietary restriction during aging

Abstract

Dietary restriction (DR) can extend lifespan and reduce disease burden across a wide range of animals and yeast but the mechanisms mediating these remarkably protective effects remain to be elucidated despite extensive efforts. Although it has generally been assumed that protective effects of DR are cell-autonomous, there is considerable evidence that many whole-body responses to nutritional state, including DR, are regulated by nutrient-sensing neurons. In this review, we explore the hypothesis that nutrient sensing neurons in the ventromedial hypothalamus hierarchically regulate the protective responses of dietary restriction. We describe multiple peripheral responses that are hierarchically regulated by the hypothalamus and we present evidence for non-cell autonomous signaling of dietary restriction gathered from a diverse range of models including invertebrates, mammalian cell culture, and rodent studies.

Figure 1

During DR, neurons in the hypothalamus may respond to changes in glucose, other fuel substrates, and hormones such as leptin and insulin. In response, hypothalamic metabolites, transcription factors, and other proteins may alter their activity and interact to regulate hypothalamic activity and output.