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

  • Simon C. JohnsonEmail author
Chapter
Part of the Subcellular Biochemistry book series (SCBI, volume 90)

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.

Keywords

mTOR Nutrient signaling Ageing IGF-1 PI3K 

Notes

Acknowledgements

The author thanks Dr. Yousin Suh, Dr. Nir Barzilai, and Dr. Derek Huffman for insightful discussions regarding this topic, and Dr. Matt Kaeberlein for his invaluable mentorship. The author was supported by NIH/NIA F32 AG050444 and NIH/NIGMS K99 GM126147.

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Center for Integrative Brain ResearchSeattle Children’s Research InstituteSeattleUSA

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