Molecular regulation of nutrient sensing and immunometabolism by calorie restriction

“‘You'll live longer and you'll be healthier too,’ he answered. ‘Because as we were saying today, there's nothing in the world like eating moderately to live a long life.’ ‘If that's the way things are,’ I thought to myself, ‘I never will die.’ Because I've always been forced to keep that rule, and with my luck I'll probably keep it all my life.”—Anonymous, The Life of Lazarillo de Tormes and of His Fortunes and Adversities 1554. Adaptive mechanisms in response to calorie restriction are evolutionarily conserved and necessary to promote longevity and increase health span. Caloric restriction (CR) without malnutrition, constitutes an effective strategy for weight reduction and ameliorates the chronic inflammatory burden of many chronic metabolic diseases. CR is known to impact nutrient sensing and immuno-metabolic processes in immune cells, but not much is known about skeletal muscle, the largest tissue in the body. We first delve into the literature that describes the interaction of CR and epigenetic mechanisms: DNA methylation, histone modifications, and microRNAs. We explore the impact of CR on nutrient sensing and immuno-metabolic processes and provide a comprehensive view of the adaptive and epigenetic machinery coordinated by CR. In our first study, we aimed to uncover the long-term effect of CR following early-life high fat-diet exposure. We analyzed physiological, biochemical, and transcriptional changes in muscle following chronic CR. Our results indicate that CR activates nutrient sensing pathways, promotes protein recycling, and stimulates myogenesis, possibly due to inhibition of cachexia-inducing inflammatory pathways. Then, our second experiment was designed to titrate the effects of CR by using a novel approach with clinical translatability. We used alternate-day CR (ADCR) in 1-3 days a week and 25-75 % energy restriction to delineate the physiological, biochemical, and transcriptional changes in muscle following chronic ADCR. Effective strategies with high translatable potential, such as 50% CR more than 2 days a week or 75% CR more than 1 day a week, produced similar effects to the gold standard of 25% chronic CR. Finally, on our third experiment we dissected the series of adaptive, epigenetic mechanisms employed by CR to decrease muscle inflammation. Chronic CR activates a series of inhibitors of inflammatory factor NF-kB, while increasing promoter DNA methylation and decreasing transcription factor binding of cytokine Tnf, as well as fine-tuning miRNA expression to prevent inflammation. Here we describe that CR orchestrates a series of adaptive nutrient sensing and anti-inflammatory checkpoints to inhibit inflammation and promote skeletal muscle maintenance.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Nutritional Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2019

Author dc:creator

• Hernandez Saavedra, Diego

Contributors dc:contributor

• Pan, Yuan-Xiang
• Loor, Juan J.
• Kemper, Jongsook Kim
• Liang, Nu-Chu

• epigenetics
• Caloric restriction
• inflammation
• nutrient sensing
• protein recycling

Statement dc:rights

• Copyright 2018 Diego Hernandez Saavedra

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/102889

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/102889