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Devin Wahl,1,2 Sean CP Coogan,1,3 Samantha M Solon-Biet,1,2 Rafael de Cabo,4 James B Haran,5 David Raubenheimer,1,6,7 Victoria C Cogger,1,2 Mark P Mattson,8 Stephen J Simpson,1,2,7 David G Le Couteur1,2 1Charles Perkins Centre, University of Sydney, Sydney, 2Aging and Alzheimers Institute, ANZAC Research Institute, Concord Clinical School/Sydney Medical School, Concord, NSW, Australia; 3Department of Renewable Resources, University of Alberta, Edmonton, AB, Canada; 4Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA; 5Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA; 6Faculty of Veterinary Science, 7School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, Australia; 8Laboratory of Neurosciences, National Institute on Aging’s Intramural Research Program, National Institutes of Health, Baltimore, MD, USA Abstract: Evaluation of behavior and cognition in rodent models underpins mechanistic and interventional studies of brain aging and neurodegenerative diseases, especially ­dementia. Commonly used tests include Morris water maze, Barnes maze, object recognition, fear ­conditioning, radial arm water maze, and Y maze. Each of these tests reflects some aspects of human memory including episodic memory, recognition memory, semantic memory, spatial memory, and emotional memory. Although most interventional studies in rodent models of dementia have focused on pharmacological agents, there are an increasing number of studies that have evaluated nutritional interventions including caloric restriction, intermittent fasting, and manipulation of macronutrients. Dietary interventions have been shown to influence ­various cognitive and behavioral tests in rodents indicating that nutrition can influence brain aging and possibly neurodegeneration. Keywords: calorie restriction, intermittent fasting, aging, memory, macronutrients

We present and apply to data for insects, chickens and rats a conceptual and experimental framework for studying nutrition as a multi-dimensional phenomenon. The framework enables the unification within a single geometrical model of several nutritionally relevant measures, including: the optimal balance and amounts of nutrients required by an animal in a given time (the intake target), the animal's current state in relation to these requirements, available foods, the amounts of ingested nutrients which are retained and eliminated, and animal performance. Animals given a nutritionally balanced food, or two or more imbalanced but complementary foods, can satisfy their nutrient requirements, and hence optimize performance. However, animals eating noncomplementary imbalanced foods must decide on a suitable compromise between overingesting some nutrients and underingesting others. The geometrical models provide a means of measuring nutritional targets and rules of compromise, and comparing these among different animals and within similar animals at different developmental stages or in different environments. They also provide a framework for designing and interpreting experiments on the regulatory and metabolic mechanisms underlying nutritional homeostasis. [ABSTRACT FROM AUTHOR]

An abstract of and comment on the article "Serotonin Mediates Behavioral Gregarization Underlying Swarm Formation in Desert Locusts," by M.L. Anstey and colleagues is presented.

Dieting is a potent risk factor for eating disorder (ED) symptoms and development, which typically occur in late adolescence. However, as diets are often motivated by body image concerns (another core ED risk factor), dieters may already carry heightened ED risk. Thus, the current study aimed to document ED risk among young people starting a diet in the community. Young people (16-25 years) starting or intending to start a self-initiated diet (N = 727) provided data via a screener questionnaire, assessing containing sociodemographic factors, past and current ED symptoms and behaviours. Over a third (36.9%) screened using a validated instrument were found to be at-risk of a current ED, with 10% above the clinical cut-off. Consistent with this finding, over 10% of the sample self-reported experiencing a lifetime ED, while nearly a quarter reported symptoms consistent with an ED diagnosis with no reported formal diagnosis. Findings suggest a high level of ED risk among young people starting a diet in the community and point to the need for more proactive measures targeted at this cohort (e.g., screening, monitoring). Further education on the risks of dieting and encouragement for help-seeking in young people is indicated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rodents have been the primary model for mammalian nutritional physiology for decades. Despite an extensive body of literature, controversies remain around the effects of specific nutrients and total energy intake on several aspects of nutritional biology, even in this well-studied model. One approach that is helping to bring clarity to the field is the geometric framework for nutrition (GFN). The GFN is a multidimensional paradigm that can be used to conceptualize nutrition and nutritional effects, design experiments, and interpret results. To date, more than 30 publications have applied the GFN to data from rodent models of nutrition. Here we review the major conclusions from these studies. We pay particular attention to the effects of macronutrients on satiety, glucose metabolism, lifespan and the biology of aging, reproductive function, immune function, and the microbiome. We finish by highlighting several knowledge gaps that became evident upon reviewing this literature.

The global obesity epidemic results from a complex interplay of genetic and environmental factors, with diet being a prominent modifiable element driving weight gain and adiposity. Although excess intake of energetic macronutrients is implicated in causing obesity, ongoing debate centers on whether sugar or fat or both are driving the rising obesity rates. This has led to competing models of obesity such as the "Carbohydrate Insulin Model", the "Energy Balance Model", and the "Fructose Survival Hypothesis". Conflicting evidence from studies designed to focus on individual energetic macronutrients or energy rather than macronutrient mixtures underlies this disagreement. Recent research in humans and animals employing the nutritional geometry framework (NGF) emphasizes the importance of considering interactions among dietary components. Protein interacts with carbohydrates, fats, and dietary energy density to influence both calorie intake ("protein leverage") and, directly and indirectly, metabolic physiology and adiposity. Consideration of these interactions can help to reconcile different models of obesity, and potentially cast new light on obesity interventions., (© 2024 Wiley Periodicals LLC.)

Plant-based diets reduces the risk of chronic conditions. The interaction between protein source and other macronutrients-fat (F) and carbohydrate (C)-has yet to be investigated. The aim was to assess the main and interactive effects of protein-source (plant vs. animal) and F:C (high or low) and the transition from an Australian diet to a whole food diet on various health markers in older individuals. This single-blinded, parallel, randomised experimental trial used a 2 × 2 factorial design to compare pro-vegetarian (70:30 plant to animal) versus omnivorous (50:50 plant to animal) diets at 14% protein and varying fat-to-carbohydrate ratios (high fat ~40% vs. low fat ~30%) over 4 weeks. Study foods were provided, alcohol consumption was discouraged, and dietary intake was determined through food records. Analysis included both RCT and observational data. Changes in appetite, palatability of diets, and dietary intake were assessed. Body composition, muscle strength, function, gut microbiome, and cardiometabolic health parameters were measured. Data from 113 (of the 128 randomised) individuals aged 65-75 years were analysed. Pro-vegetarian diets reduced diastolic blood pressure, total cholesterol and glucose levels. Moreover, the overall sample exhibited increased short-chain fatty acids and FGF21 levels, as well as improvements in body composition, function, and cardio-metabolic parameters irrespective of dietary treatment. Transitioning to a diet rich in fruit, vegetables, fibre, and moderate protein was associated with improved health markers in older age, with added benefits from pro-vegetarian diets. Further research on long-term effects is needed., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Not all wheeze is "asthma" in those born very preterm. Further work is needed to better understand the aetiology of prematurity-associated lung disease and the best treatments for this population. https://bit.ly/3Tko3vi., Competing Interests: Conflict of interest: None of the authors have a conflict of interest to disclose., (Copyright ©The authors 2024.)

Background: A 2-stage revision remains the standard for managing chronic periprosthetic joint infection. Despite multiple spacer options, whether a particular one better resists biofilm formation remains unclear. Prefabricated polymethylmethacrylate (PMMA) articulating spacers containing antibiotics and a proprietary pore structure were developed to increase antibiotic elution characterized by a rapid burst phase for the initial one to two days and an extended slow-release phase for > 28 days. This in vitro study determined whether biofilm formation is prevented during the initial rapid burst phase and/or the slow-release phase., Methods: S. aureus-Xen36 was incubated in 1.5 mL of Luria-Bertani broth with PMMA discs with the proprietary pore structure either with or without gentamycin and vancomycin or with 'Hoffman style' positive-control discs (ultra-high molecular weight polyethylene or cobalt-chrome). Nonadherent bacteria were removed by three phosphate buffered saline rinses every 20 to 24 hours. Planktonic bacterial growth in the culture broth and biofilm formation on the discs were measured by colony forming unit (CFU) counting and resazurin reduction assays. Experiments were repeated > four times., Results: No detectable planktonic bacterial growth or biofilm formation occurred in cultures containing PMMA with antibiotics (≤ 15 CFUs/disc), whereas biofilms formed on PMMA without antibiotics, ultra-high molecular weight polyethylene, and cobalt-chrome (1 × 10 7 to 4 × 10 8 CFUs/disc, P < 0.0001). Biofilm formation was confirmed by a 100-fold decrease in sensitivity to vancomycin. To determine whether the antibiotic slow-release phase is sufficient to block biofilm formation, PMMA discs with antibiotics were preeluted for 14 days with multiple saline changes prior to bacterial inoculation. After antibiotic elution, still no detectable biofilms formed on PMMA discs with antibiotics (≤ 15 CFUs/disc, P < 0.0001)., Conclusions: Antibiotic release during both the initial and slow-release phases prevented biofilm formation on PMMA with the proprietary pore structure. This may translate into improved infection eradication rates clinically., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Recent evidence suggests that plant-based diets may reduce the risk of breast cancer (BC). However, the macronutrient composition of plant-based diets and its potential impact on BC risk has not been well explored. This analysis investigated the association of macronutrient composition with BC risk across a spectrum of plant-based diet indexes using a multidimensional approach., Design: This study followed 64,655 participants from the Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale (E3N) cohort from 1993 to 2014. Diets were evaluated using validated 208-item diet history questionnaires at baseline (1993) and follow-up (2005), to calculate adherence to the overall plant-based diet (PDI), healthful plant-based diet (hPDI), and unhealthful plant-based diet (uPDI). The association of macronutrient composition with BC risk was assessed via generalized additive time-dependent Cox models across different levels of these indexes. Response surfaces were generated to visualize compositional associations at the 25th, 50th, and 75th percentile of each index (low, moderate, and high)., Results: A total of 3,932 incident BC cases were identified during the 21-year follow-up. There was a significant association between macronutrient composition and BC risk for hPDI, uPDI, and PDI (all P < 0.001). Akaike information criterion favored the hPDI model for characterizing the association between macronutrients and BC. BC risk was highest for individuals with a lower hPDI score who also consumed a diet containing lower protein (10%), lower carbohydrate (35%), and higher fat (55%). The lowest risk of BC was observed in those with higher hPDI scores with the lowest intake of protein (10%). At higher PDI and uPDI, diets containing higher protein (30%) and fat (45%) had the highest BC risk., Conclusion: These results demonstrate a complex relationship between macronutrient composition, plant-based diet quality, and BC risk. Further research is needed to examine specific foods that may be driving these associations., Registry: The protocol is registered at clinicaltrials.gov as NCT03285230., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Many survivors of preterm birth (<37 weeks gestation) have lifelong respiratory deficits, the drivers of which remain unknown. Influencers of pathophysiological outcomes are often detectable at the gene level and pinpointing these differences can help guide targeted research and interventions. This study provides the first transcriptomic analysis of primary nasal airway epithelial cells in survivors of preterm birth at approximately 1 year of age. Methods: Nasal airway epithelial brushings were collected, and primary cell cultures established from term (>37 weeks gestation) and very preterm participants (≤32 weeks gestation). Ex vivo RNA was collected from brushings with sufficient cell numbers and in vitro RNA was extracted from cultured cells, with bulk RNA sequencing performed on both the sample types. Differential gene expression was assessed using the limma-trend pipeline and pathway enrichment identified using Reactome and GO analysis. To corroborate gene expression data, cytokine concentrations were measured in cell culture supernatant. Results: Transcriptomic analysis to compare term and preterm cells revealed 2,321 genes differentially expressed in ex vivo samples and 865 genes differentially expressed in cultured basal cell samples. Over one third of differentially expressed genes were related to host immunity, with interferon signalling pathways dominating the pathway enrichment analysis and IRF1 identified as a hub gene. Corroboration of disrupted interferon release showed that concentrations of IFN-α2 were below measurable limits in term samples but elevated in preterm samples [19.4 (76.7) pg/ml/µg protein, p = 0.03]. IFN-γ production was significantly higher in preterm samples [3.3 (1.5) vs. 9.4 (17.7) pg/ml/µg protein; p = 0.01] as was IFN-β [7.8 (2.5) vs. 13.6 (19.5) pg/ml/µg protein, p = 0.01]. Conclusion: Host immunity may be compromised in the preterm nasal airway epithelium in early life. Altered immune responses may lead to cycles of repeated infections, causing persistent inflammation and tissue damage which can have significant impacts on long-term respiratory function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Evans, Hillas, Iosifidis, Simpson, Kicic and Agudelo-Romero.)

Background: A balanced intake of protein and constituent amino acids (AAs) requires adjustments to total food intake (protein leverage [PL]) and food selection to balance deficits and excesses (complementary feeding). We provided mice with choices of casein and whey, 2 protein sources that are complementary in AA balance, across a range of protein concentrations (P%) of digestible energy (DE)., Objectives: We aimed to determine if: 1) PL operates similarly for casein and whey; 2) one protein source is preferred at control P%; 3) the preference changes as P% falls; and 4) AA intakes under control and low P% levels identify AAs that drive changes in protein selection., Methods: Food intake and plasma fibroblast growth factor-21 (FGF21) concentrations were measured in mice at various P% (P7.5%-P33%). For direct comparisons, defined diets were used in which the protein source was either casein or whey. In food choice studies, mice had access to foods in which both casein and whey were provided at the same P% level at the same time., Results: PL operated at different P% thresholds in casein (13%)- and whey (10%)-based diets, and the magnitude of PL was greater for casein. Although mice preferred casein under control conditions (P23%), a pronounced preference shift to whey occurred as P% fell to P13% and P10%. At low P%, increases in food intake were accompanied by increases in plasma FGF21, a protein hunger signal. Among AAs deficient in casein and enriched in whey, the intake of Cys was the most invariant as P% changed between P23% and P10%, appearing to drive the switch in protein preference., Conclusions: Mice selected between complementary protein sources, casein and whey, achieving stable total energy intake and regulated intake of AAs as P% varied. Supplementation of low P% casein diets with one whey-enriched AA, Cys, suppressed plasma FGF21 and total food intake., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Increasing evidence suggests that the pre-conception parental environment has long-term consequences for offspring health and disease susceptibility. Though much of the work in this field concentrates on maternal influences, there is growing understanding that fathers also play a significant role in affecting offspring phenotypes. In this study, we investigate effects of altering the proportion of dietary fats and carbohydrates on paternal and offspring body composition and anxiety-related behavior in C57Bl/6-JArc mice. We show that in an isocaloric context, greater dietary fat increased body fat and reduced anxiety-like behavior of studs, whereas increased dietary sucrose had no significant effect. These dietary effects were not reflected in offspring traits, rather, we found sex-specific effects that differed between offspring body composition and behavioral traits. This finding is consistent with past paternal effect studies, where transgenerational effects have been shown to be more prominent in one sex over the other. Here, male offspring of fathers fed high-fat diets were heavier at 10 weeks of age due to increased lean body mass, whereas paternal diet had no significant effect on female offspring body fat or lean mass. In contrast, paternal dietary sugar appeared to have the strongest effects on male offspring behavior, with male offspring of high-sucrose fathers spending less time in the closed arms of the elevated plus maze. Both high-fat and high-sugar paternal diets were found to reduce anxiety-like behavior of female offspring, although this effect was only evident when offspring were fed a control diet. This study provides new understanding of the ways in which diet can shape the behavior of fathers and their offspring and contribute to the development of dietary guidelines to improve obesity and mental health conditions, such as anxiety., Competing Interests: Declaration of competing interest We declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: Protein leverage (PL) is the phenomenon of consuming food until absolute intake of protein approaches a 'target value', such that total energy intake (TEI) varies passively with the ratio of protein: non-protein energy (fat + carbohydrate) in the diet. The PL hypothesis (PLH) suggests that the dilution of protein in energy-dense foods, particularly those rich in carbohydrates and fats, combines with protein leverage to contribute to the global obesity epidemic. Evidence for PL has been reported in younger adults, children and adolescents. This study aimed to test for PL and the protein leverage hypothesis (PLH) in a cohort of older adults., Methods: We conducted a retrospective analysis of dietary intake in a cohort of 1699 community-dwelling older adults aged 67-84 years from the NuAge cohort. We computed TEI and the energy contribution (EC) from each macronutrient. The strength of leverage of macronutrients was assessed through power functions ( TEI = μ * EC L ). Body mass index (BMI) was calculated, and mixture models were fitted to predict TEI and BMI from macronutrients' ECs., Results: In this cohort of older adults, 53% of individuals had obesity and 1.5% had severe cases. The mean TEI was 7673 kJ and macronutrients' ECs were 50.4%, 33.2% and 16.4%, respectively for carbohydrates, fat, and protein. There was a strong negative association (L = -0.37; p < 0.001) between the protein EC and TEI. Each percent of energy intake from protein reduced TEI by 77 kJ on average, ceteris paribus. However, BMI was unassociated with TEI in this cohort., Conclusions: Findings indicate clear evidence for PL on TEI, but not on BMI, likely because of aging, body composition, sarcopenia, or protein wasting., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Macronutrient intake impacts physiology, behavior, and gene expression in a wide range of organisms. We used the response surface methodology to compare how life history traits, lifespan, and reproduction differ as a function of protein and carbohydrate intakes under choice and no-choice feeding regimens in the fruit fly, Drosophila melanogaster. We found that when offered a choice of nutritionally complementary foods mated female flies regulated toward a protein to carbohydrate ratio (P:C) that was associated with shortened lifespan and maximal egg production when compared to response surfaces derived from flies fed 1 of a range of fixed diets differing in P:C (no-choice regimen). This difference in lifespan between choice and no-choice feeding was not seen in males or virgin flies, reflecting the fact that increased protein intake is triggered by mating to support egg production. However, whereas in mated females a higher P:C intake was associated with greater egg production under both choice and no-choice feeding, contrary to expectations, choice-fed mated flies laid fewer eggs than no-choice flies on equivalent macronutrient intakes, perhaps reflecting that they had to ingest twice the volume of food to attain an equivalent intake of nutrients than no-choice flies on a diet of equivalent P:C ratio., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Paternal diet can influence the phenotype of the next generation, yet, the dietary components inducing specific responses in the offspring are not identified. Here, we use the Nutritional Geometry Framework to determine the effects of pre-conception paternal dietary macronutrient balance on offspring metabolic and behavioral traits in mice. Ten isocaloric diets varying in the relative proportion of protein, fats, and carbohydrates are fed to male mice prior to mating. Dams and offspring are fed standard chow and never exposed to treatment diets. Body fat in female offspring is positively associated with the paternal consumption of fat, while in male offspring, an anxiety-like phenotype is associated to paternal diets low in protein and high in carbohydrates. Our study uncovers that the nature and the magnitude of paternal effects are driven by interactions between macronutrient balance and energy intake and are not solely the result of over- or undernutrition., (© 2024. The Author(s).)

Objective: Exposure in utero to maternal diet can program offspring health and susceptibility to disease. Using C57BL6/JArc mice, we investigated how maternal dietary protein to carbohydrate balance influences male and female offspring appetite and metabolic health., Methods: Dams were placed on either a low-protein (LP) or high-protein (HP) diet. Male and female offspring were placed on a food choice experiment post weaning and were then constrained to either a standard diet or Western diet. Food intake, body weight, and composition were measured, and various metabolic tests were performed at different timepoints., Results: Offspring from mothers fed HP diets selected a higher protein intake and had increased body weight in early life relative to offspring from LP diet-fed dams. As predicted by protein leverage theory, higher protein intake targets led to increased food intake when offspring were placed on no-choice diets, resulting in greater body weight and fat mass. The combination of an HP maternal diet and a Western diet further exacerbated this obesity phenotype and led to long-term consequences for body composition and metabolism., Conclusions: This work could help explain the association between elevated protein intake in humans during early life and increased risk of obesity in childhood and later life., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)