Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile

Evi M Mercken,Claudio Franceschi,Dennis T Villareal,Lellean Jebailey,Susan Krzysik‐Walker,Yongqing Zhang,Luigi Fontana,Kevin Becker,Dudley W Lamming,David M Sabatini,Miriam Capri,Rafael De Cabo,Seth D Crosby

doi:10.1111/acel.12088

Abstract

Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore, our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans.

Highlights

Caloric restriction (CR) without malnutrition and inhibition of the insulin/IGF-1 signaling are the most robust and reproducible interventions for extending lifespan and preventing or delaying agerelated disease in a variety of species (Anderson & Weindruch, 2007; Kennedy et al, 2007; Piper & Bartke, 2008)
As one of the primary metabolic tissues, skeletal muscle is extremely vulnerable to the effects of aging, and decreases in muscle mass and strength have been associated with increased mortality (Cesari et al, 2009)
We hypothesized that the impressive metabolic changes previously described in these individuals on long-term CR would result in several molecular adaptations, including a down-regulation of the insulin/IGF-1/FOXO pathway, a key nutrient sensing pathway, shown to slow aging in several experimental animals (Kenyon et al, 1993; van Heemst et al, 2005; Kennedy et al, 2007; Piper & Bartke, 2008)

Summary

Accepted for publication 12 April 2013 inflammation. our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans.

Introduction

Results and discussion

Experimental procedures

Conflict of interest