Insulin/IGF-1 Signaling: More than a Metabolic Pathway

Abstract

Background: Dietary intervention and genetic alterations in gene encoding proteins involved in nutrient-sensing pathways can modulate lifespan, influencing longevity. It depends on under/over-expression of regulatory molecules that lead to different expression of homeostatic genes. Insulin/IGF-1 pathway was associated with longevity and lifespan modulation in model organisms. In humans, a key molecule in this pathway is FOXO3A that acts as a TF on homeostatic genes in response to decreased signaling increasing life span. Interestingly, other genes that increase lifespan interact with FOXO3A such as SIRT1, which modulates the oxidative stress response. Methods: We used meta-analytical and candidate-gene approaches to investigate the association of SNPs encoding proteins involved in Insulin/IGF-1 pathway with ageing and longevity. Results: Our study confirmed previous results related to the association between FOXO3A, IGF-1R, KLOTHO and longevity. No association was reported between IGF-1 and SIRT1 although all IGF-1 SNPs could affect its serum levels, known to modulate ageing and longevity. Moreover, we showed a new association between SHIP2 SNPs and longevity. Conclusions: Our results showed that specific SNPs of IGF-1R, FOXO3A, SHIP2 and KLOTHO influence ageing and longevity in different ethnic populations and that FOXO3A could be the most relevant gene in lifespan extension, particularly in males. Moreover, it could be speculated that a reduction of insulin signaling may decrease the activation of NF-kB slowing down inflammatory gene transcription. Thus, the intervention on ageing and longevity should be based both on nutrient-sensing and inflammatory pathways. The first simple step could be represented by the adherence to the Mediterranean diet with low glycaemic index and low animal proteins.