DISCUSSION
obesity, overweight or obesity
OBESITY, CARDIOVASCULAR DISEASE, DISEASE, CHRONIC DISEASES, SAID, CHRONIC DISEASE
Research using the GFN suggests that the benefits of CR generated by dietary dilution in ad libitum fed animals cannot be attributed solely to a reduction in calories. These studies indicate that the ratio of dietary macronutrients also plays an important role in reducing age‐related disease in animals, with potential implications in human populations (Ingram & de Cabo, To our knowledge, this is the first analysis linking dietary macronutrient composition in relation to adherence to the CR prescription and to cardiometabolic risk in humans using the state‐of‐the‐art GFN approach in a population of calorically restricted humans without obesity. All previous applications of the GFN have focused on either animal models or humans with ad libitum access to food. The GFN aims to discern the complex relationships among nutrients and their combined effects on chronic disease risk reduction (Raubenheimer & Simpson, Our findings suggest that calorie restriction results in alterations in macronutrient intake with a shift towards greater consumption of protein and carbohydrate and lower fat intake. These shifts in macronutrient intake, however, were not observed in the control group and one could argue that the adaptation to sustaining a CR regimen may have required an alteration in the diet composition. That said, although participants were not provided food or prescribed a specific diet pattern, they had access to diet counselors who provided broad dietary guidance to help facilitate CR adherence, and it is likely that such guidance was supportive of greater protein intake and lower fat intake combined with average daily macronutrient recommendations for carbohydrate, and this guidance may have influenced the observed changes in intake. Furthermore, dietary protein was not an independent contributor to CR adherence both in the short term (at 12 months) and over the longer term (at 24 months). The diet composition that supported the best long‐term adherence was higher than average in protein consumption in the background of higher carbohydrate and lower fat intake. On a relatively high carbohydrate diet (~60%), substituting protein for fat led to big gains in adherence whereas on a more moderate carbohydrate diet (~45%), substituting protein for fat resulted in lower adherence. These findings underscore the complex interplay between macronutrients and suggest that perhaps the role of carbohydrate intake in adherence to CR may warrant further investigation. Future research involving macronutrient substitutions is required to definitively conclude the impact of these observations on long‐term adherence.Epidemiologic studies consistently show that individual nutrients, foods, and food groups are associated with the onset or progression of some chronic diseases. However, despite marked improvements in cardiometabolic outcomes in CALERIE (Kraus et al., It is important to note that in this study, individual macronutrients were not indicative of strong systemic effect on cardiometabolic outcomes. However, foods and nutrients are consumed in combination and have synergistic effects on health. In our analyses, overall dietary patterns were assessed using three widely used indices that capture different components of a healthy diet and revealed consistent short‐ and longer term relationships with cardiometabolic outcomes in this group of individuals without obesity and without chronic disease. Diet‐quality scores are increasingly used in risk prediction for all‐cause mortality, cardiovascular disease, and other chronic diseases as an alternative to single‐food and single‐nutrient approaches (Hodge et al., Strengths of this study include the highly defined and rigorously collected CALERIE data, including for self‐selected diet composition, objectively measured CR, and comprehensive measures of health outcomes. Furthermore, the synergistic effects of dietary determinants on cardiometabolic risk during CR were determined by applying the GFN approach to CALERIE data which allows for the simultaneous examination of multiple nutrients. The diet data nevertheless are self‐reported, and is a limitation which is somewhat mitigated by the high quality of the reported intake in comparison to the objectively measured doubly labeled water assessment of actual caloric intake. At each time point, the average difference in self‐reported energy intake and measured energy intake was well within ±20% (i.e., 14% at baseline, 14.6% at 12 months, and 15.7% at 24 months).Our findings are directly relevant to the design of future dietary interventions aimed at optimizing the benefits associated with CR. In addition, our analysis lends support for the use of GFN as an analytical paradigm for similar data collected in other populations, including in individuals with overweight or obesity in whom the role of diet composition during CR for the promotion of adherence and reducing cardiometabolic risk may likely be more important.In conclusion, in this study of individuals without obesity, CR resulted in a shift toward greater protein and carbohydrate intake; higher protein in the background of high carbohydrate intake was a predictor of higher adherence to CR. Our analyses suggest that dietary patterns, and not individual macronutrients per se, have an impact on cardiometabolic risk in healthy adults without obesity. Further research involving macronutrient manipulations or substitutions is required to examine the impact of intervention‐related impact of macronutrients in humans with and without obesity.