Translational analysis of a novel intervention to promote healthy aging.

Project Summary Advancing age is associated with an increased risk of type 2 diabetes, which is exacerbated by the high prevalence of obesity in the aged. These disorders are risk factors for age-related diseases associated with significant morbidity and mortality, including cancer, cardiovascular disease, and Alzheimer’s disease. New approaches to maintain glucose homeostasis in the aged are therefore urgently needed. The objective of the proposed study is to test the ability of diets with reduced levels of isoleucine, valine, or histidine to reverse diet induced obesity and insulin resistance. We have shown that specifically reducing levels of either isoleucine, valine, or histidine can rapidly reduce adiposity in diet-induced obese mice, restoring normal body composition and enhancing insulin sensitivity. Further, we have shown that diets with lower levels of isoleucine or histidine are associated with reduced body mass index in humans. Here, we will determine the degree of restriction of these three amino acids that optimally promotes metabolic health in diet-induced obese mice and test an optimized amino acid restricted diet for the ability to reduce adiposity and restore glycemic control in a non-human primate. We will also gain insight into the molecular mechanisms induced by reduced levels of these dietary amino acids through integrative transcriptomic and metabolomic analyses of blood, adipose, and skeletal muscle samples from nonhuman primates and from young and aged mice. Additionally, we will collect samples for future analysis of the role of the epigenome and microbiome in the response to dietary amino acids. These studies are urgently needed to understand if manipulation of specific dietary amino acids is a translatable intervention to promote metabolic health and increase healthspan.