Nutrient Sensing, Signaling and Ageing: The Role of IGF-1 and mTOR in Ageing and Age-Related Disease.

Abstract

Nutrient signaling through insulin/IGF-1 was the first pathway demonstrated to regulate ageing and age-related disease in model organisms. Pharmacological or dietary interventions targeting nutrient signaling pathways have been shown to robustly attenuate ageing in many organisms. Caloric restriction, the most widely studied longevity promoting intervention, works through multiple nutrient signaling pathways, while inhibition of mTOR through treatment with rapamycin reproducibly delays ageing and disease through specific inhibition of the mTOR complexes. Although the benefits of reduced insulin/IGF-1 in lifespan and health are well documented in model organisms, defining the precise role of the IGF-1 in human ageing and age-related disease has proven more difficult. Association studies provide some insight but also reveal paradoxes. Low serum IGF-1 predicts longevity, but IGF-1 decreases with age and IGF-1 therapy benefits some of age-related pathologies. Circulating IGF-1 has been associated both positively and negatively with risk of age-related diseases in humans, and in some cases both activation and inhibition of IGF-1 signaling have provided benefit in animal models of the same diseases. Interventions designed modulate the nutrient sensing signaling pathways positively or negatively are already available for clinical use, highlighting the need for a clear understanding of the role of nutrient signaling in ageing and age-related disease. This chapter examines data from model organisms and human genetic association studies, with a special emphasis on IGF-1 and mTOR, and discusses potential models for resolving the paradoxes surrounding IGF-1 data.