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.

Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT

“…Many of the responses to DR appear to be mediated by neuroendocrine and autonomic responses that are largely regulated by the ventromedial hypothalamus (VMH) (Dacks et al, 2013). We characterized gene expression in the context of HD within the VMH (Figure 3), and analyzed a panel of genes that are largely responsive to energy homeostasis (Poplawski et al, 2010).…”

Metabolic and Non-Cognitive Manifestations of Alzheimer’s Disease: The Hypothalamus as Both Culprit and Target of Pathology

“…Collectively, these and other studies have consistently shown that caloric restriction can reduce AD-like pathology and improve cognitive behavior; however, the mechanisms underlying this beneficial effect are not known, but may include reducing cellular stress, altering systemic metabolism, and changing hormonal balance e.g., increased insulin sensitivity (Mattson, 2012). It has been proposed that the hypothalamus has a vital role in the benefits seen with caloric restriction (Dacks et al, 2013). Evidence to support a hypothalamic role include the loss of caloric restriction-mediated anti-tumor effects in NPY knockout mice and mice with lesions of the hypothalamic arcuate nuclei by monosodium glutamate, suggesting the importance of hypothalamic pathways that regulate appetite and systemic metabolism in mediating the beneficial effects of caloric restriction (Minor et al, 2011).…”

Promoting Health and Longevity through Diet: From Model Organisms to Humans

“…In both C. elegans and Drosophila , altered sensory perception alone may play a role, with specific subsets of sensory, including olfactory and gustatory, neurons influencing lifespan (Alcedo and Kenyon, 2004; Allen et al, 2014; Apfeld and Kenyon, 1999; Ostojic et al, 2014; Waterson et al, 2014). In C. elegans , Drosophila and mice, neural circuits both detect nutrient status and control the responses to it, in mice mediated mainly by the hypothalamus (Dacks et al, 2013). Alterations in the levels of metabolites (Chin et al, 2014), in activity of the nutrient-sensing insulin/IGF signaling network (Johnson et al, 2013; Kenyon, 2010) in C. elegans , of steroid hormone signaling (Thondamal et al, 2014) and, in the mouse, of growth hormone (Johnson et al, 2013; Kenyon, 2010) also play important systemic roles.…”