Understanding how metabolism integrates nutrient homeostasis with life span is a complicated undertaking. The insulin pathway coordinates growth, development, metabolic homoeostasis, fertility and stress resistance, which ultimately influence lifespan. From a clinical perspective, compensatory hyperinsulinemia to overcome systemic insulin resistance is thought to be a healthy goal, because it circumvents to immediate catastrophic consequences of hyperglycemia; however, work in flies, nematodes and mice indicate that excess insulin signaling ultimately damages cellular function and accelerates aging. Maintenance of the central nervous system (CNS) has particular importance for lifespan. Depending upon the exact site, reduced insulin/IGF1 signaling in the CNS can dysregulate peripheral energy homeostasis and metabolism, promote obesity, and extend lifespan. In this review, we explore how genetic manipulations of insulin/IGF1 signaling components are beginning to reveal neuronal circuits which might resolve the central regulation of systemic metabolism from organism longevity.
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