Calorie restriction, eating up to 40% fewer calories while maintaining optimal micronutrient intake, improves health and reliably extends life in most species. In humans it produces robust improvements in health, but we experience a much lesser degree of life extension than short-lived species such as mice. Calorie restriction research has given rise to a number of lines of work in which specific dietary components (such as individual essential amino acids) are restricted, to try to identify which of these components are responsible for the benefits. A sizable fraction of the calorie restriction response is thought to be triggered by low dietary intake of the essential amino acid methionine, for example. In contrast to that body of work, researchers here restrict threonine, another essential amino acid, in laboratory mice, and observe an interesting set of benefits.

The current classification of essential amino acids (EAA) is based on the nutritional requirements for growth and vitality under nil dietary supply of an amino acid. However, humans rarely face dramatic protein/amino acid insufficiency, and for the first time in human history, nutritional excesses mean the amount of overweight people outnumber the amount of underweight people on a global scale. This calls for a reconsideration of amino acid functions in nutrition, now based upon health-related criteria.

One approach is dietary protein dilution (DPD), where protein is reduced and replaced by other nutrient sources, and is distinct from caloric restriction. Unlike severe protein/amino acid restriction, which is not compatible with vitality, moderate DPD promotes longevity in multiple species including flies, rodents, and perhaps humans. Furthermore, DPD also affects health-span and preclinical studies have demonstrated that DPD can retard age-related diseases such as cancer, type 2 diabetes, and dyslipidemia/fatty liver disease. Notably, dietary protein intake rates are positively related to type 2 diabetes risk as well as all-cause mortality in humans.

Here, by mimicking amino acid supply from a casein-based diet, we demonstrate that restriction of dietary EAA, but not non-EAA, drives the systemic metabolic response to total amino acid deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total amino acid supply, are both adequate and necessary to confer the systemic metabolic response to amino acid restriction.

Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.