Reduced insulin signalling in neurons induces sex-specific health benefits

Abstract Reduced activity of the insulin/IGF signalling (IIS) network extends healthspan(definition) and lifespan in mammals and possibly humans. Loss of the Irs1 gene increases survival in mice and causes tissue-specific changes in gene expression. However, the tissues underlying IIS mediated longevity are currently unknown. Here we measured survival and healthspan in male and female animals lacking Irs1 activity specifically in the liver, muscle, fat and brain. Tissue-specific loss of IRS1 did not increase survival, suggesting that lack of Irs1 in more than one tissue is required for lifespan extension. Furthermore, loss of Irs1 in liver, muscle and fat did not improve health at old age. In contrast, loss of neuronal Irs1 increased energy expenditure, locomotion and insulin sensitivity, specifically in old males. Neuronal loss of IRS1 also caused male-specific mitochondrial dysfunction(definition), activation of Atf4 and metabolic adaptations consistent with an activated integrated stress response at old age. Thus, we identified a male-specific brain signature of ageing in response to reduced IIS associated with improved health outcomes at old age.