The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice.
ABSTRACT: The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.
Project description:Nutrition influences both hepatic function and aging, but mechanisms are poorly understood. Here, the effects of lifelong, ad libitum-fed diets varying in macronutrients and energy on hepatic gene expression were studied. Gene expression was measured using Affymetrix mouse arrays in livers of 46 mice aged 15 months fed one of 25 diets varying in protein, carbohydrates, fat, and energy density from 3 weeks of age. Gene expression was almost entirely influenced by protein intake. Carbohydrate and fat intake had few effects on gene expression compared with protein. Pathways and processes associated with protein intake included those involved with mitochondrial function, metabolic signaling (PI3K-Akt, AMPK, mTOR) and metabolism of protein and amino acids. Protein intake had variable effects on genes associated with regulation of longevity and influenced by caloric restriction. Among the genes of interest with expression that were significantly associated with protein intake are Cth, Gls2, Igf1, and Nnmt, which were increased with higher protein intake, and Igf2bp2, Fgf21, Prkab2, and Mtor, which were increased with lower protein intake. Dietary protein has a powerful impact on hepatic gene expression in older mice, with some overlap with genes previously reported to be involved with regulation of longevity or caloric restriction.
Project description:Both caloric restriction (CR) and low-protein, high-carbohydrate (LPHC) ad-libitum-fed diets increase lifespan and improve metabolic parameters such as insulin, glucose, and blood lipids. Severe CR, however, is unsustainable for most people; therefore, it is important to determine whether manipulating macronutrient ratios in ad-libitum-fed conditions can generate similar health outcomes. We present the results of a short-term (8 week) dietary manipulation on metabolic outcomes in mice. We compared three diets varying in protein to carbohydrate ratio under both CR and ad libitum conditions. Ad libitum LPHC diets delivered similar benefits to CR in terms of levels of insulin, glucose, lipids, and HOMA, despite increased energy intake. CR on LPHC diets did not provide additional benefits relative to ad libitum LPHC. We show that LPHC diets under ad-libitum-fed conditions generate the metabolic benefits of CR without a 40% reduction in total caloric intake.
Project description:Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low-protein, high-carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets or to a control diet. Patterns of RNA expression in the hippocampus of 15-month-old mice were similar between mice fed CR and LPHC diets when we looked at genes associated with longevity, cytokines, and dendrite morphogenesis. Nutrient-sensing proteins, including SIRT1, mTOR, and PGC1?, were also influenced by diet; however, the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. Mice fed CR and LPHC diets had modest improvements in the Barnes maze and novel object recognition. LPHC diets recapitulate some of the benefits of CR on brain aging.
Project description:BACKGROUND:Isocaloric manipulation of carbohydrate or fat intake could alter subsequent ad libitum food intake. METHODS:In a controlled inpatient study, we investigated whether isocaloric manipulation of carbohydrate or fat would alter subsequent ad libitum energy intake. Eighteen non-diabetic subjects (age range 19-53 years.; 15 M/3F; % body fat 38.5 ± 9.1 (mean ± SD)) were fed for 3 days an isocaloric high-carbohydrate diet (HC; 60% carbohydrate, 20% fat, 20% protein) and a high-fat diet (HF; 50% fat, 30% carbohydrate, 20% protein) in random order each followed by 3 days of ad libitum food intake. RESULTS:There were no differences in mean daily energy intake (EI) following each diet (HC vs. HF: 4,811 ± 1,190 vs. 4,823 ± 1,238 kcal/d; P = 0.7) or in the percent of weight maintenance energy needs (%EN-WM; 173 ± 41 vs. 173 ± 46%, P = 0.5). However, the individual difference in EI between the HF versus HC diet (ΔEI) both on day one and over the 3 days of each ad libitum period was negatively associated with % body fat (%BF) and waist circumference (day 1: ΔEI vs. %BF, r = -0.49, P = 0.04; mean day 1-3 kcal ΔEI vs. %BF, r = -0.66, P = 0.003, and ΔEI vs. waist, r = -0.65, P = 0.004). CONCLUSIONS:A short-term isocaloric HC diet did not result in overall lower EI compared with a HF diet in the same individuals. However, we did find that increasing body fat was associated with less decline in EI following the HC versus HF diet indicating that increasing adiposity is associated with altered regulation of EI in response to macronutrient changes.
Project description:Low-fat diets and energy restriction are recommended to prevent obesity and to induce weight loss, but high-protein diets are popular alternatives. However, the importance of the protein source in obesity prevention and weight loss is unclear. The aim of this study was to investigate the ability of different animal protein sources to prevent or reverse obesity by using lean or obese C57BL/6J mice fed high-fat/high-protein or low-fat diets with casein, cod or pork as protein sources. Only the high-fat/high-protein casein-based diet completely prevented obesity development when fed to lean mice. In obese mice, ad libitum intake of a casein-based high-fat/high-protein diet modestly reduced body mass, whereas a pork-based high-fat/high-protein diet aggravated the obese state and reduced lean body mass. Caloric restriction of obese mice fed high-fat/high-protein diets reduced body weight and fat mass and improved glucose tolerance and insulin sensitivity, irrespective of the protein source. Finally, in obese mice, ad libitum intake of a low-fat diet stabilized body weight, reduced fat mass and increased lean body mass, with the highest loss of fat mass found in mice fed the casein-based diet. Combined with caloric restriction, the casein-based low-fat diet resulted in the highest loss of fat mass. Overall, the dietary protein source has greater impact in obesity prevention than obesity reversal.
Project description:Background: The effects of meal-specific protein quantity and protein distribution throughout the day on daily food intake are relatively unknown. Objectives: The aims were to test 1) whether the consumption of higher-protein (HP) compared with normal-protein (NP) meals consumed at each eating occasion reduce free-living, daily carbohydrate and fat intakes in overweight women during energy balance conditions and 2) whether the distribution of protein consumed throughout the day affects food intake outcomes. Methods: Seventeen women [mean ± SEM age: 33 ± 1 y; body mass index (in kg/m2): 27.8 ± 0.1] completed the following tightly controlled, crossover design study. Participants were provided with and randomly consumed three 6-d eucaloric diets containing NP or HP (15% or 25% of energy as protein, respectively). The protein content within the NP diet used an even distribution pattern (EVEN; 21 ± 1 g protein/meal) throughout the day, whereas the protein contents within the HP diets used either EVEN (35 ± 1 g protein/meal) or an uneven distribution pattern (UNEVEN; 19 ± 1 g protein/breakfast, 26 ± 1 g protein/lunch, 63 g protein/dinner). On day 7 of each diet, the participants were asked to consume the diet-specific absolute protein quantity (in grams) at each eating occasion but were provided with a surplus of carbohydrate- and fat-rich foods to consume, ad libitum, during each eating occasion. Results: Eating more protein (HP compared with NP) or evenly distributing protein throughout the day (HP-EVEN compared with HP-UNEVEN) did not reduce the consumption of ad libitum fat- and carbohydrate-rich foods throughout the day (NP-EVEN: 2850 ± 240 kcal/d; HP-EVEN: 2910 ± 240 kcal/d; HP-UNEVEN: 3160 ± 200 kcal/d). Despite the lack of differences in daily energy intake, the breakfast meal within the HP-EVEN diet led to lower ad libitum carbohydrate and fat intakes than the breakfast meals in the NP-EVEN and HP-UNEVEN diet conditions (P < 0.05). Conclusion: Providing 30 g protein/meal at each eating occasion throughout the day did not influence free-living, daily intake of highly palatable, carbohydrate- and fat-rich foods in overweight women. This trial was registered at clinicaltrials.gov as NCT02614729.
Project description:BACKGROUND:Although high protein diets have been tested in controlled environments for applications to weight management, it is not understood if adding high protein foods to the diet would impact ad libitum energy balance in the absence of other lifestyle changes. METHODS:This double-blinded randomized crossover trial compared the effects of a protein shake (PS) to a carbohydrate shake (CS), consumed prior to each major meal to equate to 20% of total energy needs over the course of the day, on energy balance over two 5-day treatment periods in healthy adults with BMI 20-30?kg/m2. Tri-axial accelerometers estimated physical activity energy expenditure. Ad libitum energy intake was measured in a laboratory kitchen. RESULTS:Energy balance was positive during both treatment periods but was not different between periods. There were no interactions between treatment and preload caloric dose or treatment and BMI status on energy balance. Satiety ratings did not differ for any pairwise comparisons between treatment and caloric dose. Controlling for gender and basal metabolic rate, thermic effect of food was greater for PS than CS. CONCLUSIONS:Preload periods significantly altered the macronutrient composition of the overall diet. This study found limited evidence that carbohydrate or protein preloads have differential effects on energy balance in short-term ad libitum settings. TRIAL REGISTRATION:This trial was pre-registered on clinicaltrials.gov as NCT02613065 on 11/30/2015.
Project description:Diabetic nephropathy is aggravated by a higher intake of total protein. The effects of diets with different proportions of protein and carbohydrate on diabetic retinopathy in db mice, a type-2 diabetes animal model, were examined, as well as diabetic nephropathy.Control and db mice at 5 weeks of age were fed the diets (% energy of protein/carbohydrate/fat; L-diet: 12/71/17; H-diet: 24/59/17) under ad libitum conditions and pair-feeding conditions for 6 weeks, respectively.Mice fed the H-diet showed significantly greater retinal thickness by optical coherence tomography, and lower mRNA levels of angiotensinogen. Comparing combinations of diets and genotypes, db-H mice showed significantly higher mRNA levels of angiotensin-converting enzyme, advanced glycosylation end product-specific receptor, and cluster of differentiation molecule 11b (a microglial marker) than db-L mice.Dietary protein and carbohydrate proportions influenced retinal manifestations, including retinal thickness and gene expression in control and diabetic mice.
Project description:Paneth cells recide in the intestinal crypt bottom and are part of the innate immunity and of the intestinal stem cell niche. We used microarrays to detail the global changes in gene expression following reduced calorie intake. Mice were kept on ad libitum or calorie restricted (60% of calories of ad libitum) diets for 4-7 weeks and paneth cells were isolated using flowcytometry
Project description:Calorie restriction (CR) increases lifespan and improves brain health in mice. Ad libitum low protein, high carbohydrate (LPHC) diets also extend lifespan, but it is not known whether they are beneficial for brain health. We compared hippocampus biology and memory in mice subjected to 20% CR or provided ad libitum access to one of three LPHC diets, or to a control diet. At age 15 months, patterns of RNA expression in the hippocampus were similar between CR and LPHC diets for genes associated with longevity, cytokines and dendrite morphogenesis. Nutrient sensing proteins including SIRT1, mTOR and PGC1α were also influenced by diet, however the effects varied by sex. CR and LPHC diets were associated with increased dendritic spines in dentate gyrus neurons. CR and LPHC diets led to modest improvements in the Barnes Maze and Novel Object Recognition. LPHC diets recapitulate some of the benefits of CR on brain aging. Overall design: 30 samples, 6 biological replicates in each group.