IRS2 integrates insulin/IGF1 signalling with metabolism, neurodegeneration and longevity.

Understanding how metabolism and nutrient homeostasis integrates with life span and neurodegeneration is a complicated undertaking. Important inconsistencies have emerged recently regarding the role of insulin-like signalling and the progression of neurodegenerative disease. Insulin resistance and type 2 diabetes are associated with clinical Alzheimer's disease, whereas study in lower organisms shows that reduced insulin-like signalling slows the progressive neurodegeneration and increases life span. From a clinical perspective, compensatory hyperinsulinaemia to overcome systemic insulin resistance is thought to be a healthy goal, because it circumvents immediate catastrophic consequences of hyperglycaemia; however, study in flies, nematodes and mice indicate that excess insulin signalling can damage cellular function and accelerate ageing. Maintenance of the central nervous system (CNS) has particular importance for life span and metabolism. A conflict arises because reduced insulin/IGF1 signalling in the CNS is associated with longevity, but can dysregulate glucose and energy homeostasis, and promote overweight. Here, we explore how the genetic manipulation of insulin/IGF1 signalling system can influence systemic metabolism, life span and neurodegeneration.