Stephen James Simpson

Nutrition shapes development, health and risk of disease over the life course and across generations. The predominant approaches to understanding these relationships have either been to consider the effects of single nutrients, one at a time, or to consider associations with food types and dietary patterns. Although, to date, the single-nutrient approach has defined much of the scientific enquiry and public debate on the macronutrients - carbohydrate, fat and protein - there is an emerging appreciation that their proportions and quality matter more than their individual effects. Growing evidence demonstrates that macronutrient interactions operate at multiple biological levels, and research on dietary protein has proven a particularly productive entry point for characterizing these mixture effects. In this narrative Review, we begin by analysing key issues and introducing a framework for navigating the complexity of macronutrient mixtures (nutritional geometry), then consider the role of macronutrient proportions on food intake, systemic physiology, health and the risk of disease across the life course. Finally, we discuss how human nutritional biology has been subverted within the modern, industrialized food environment, contributing to the global burden of obesity and related diseases of unhealthy ageing.

Seminal plasma can have wide-ranging effects on reproductive fitness—from affecting sperm fertilization capacity and female reproductive physiology to influencing offspring viability and health. Seminal plasma can also change in response to environmental conditions including diet, which of itself is known to affect reproductive traits and fitness outcomes. However, an understanding of how paternal diet alters seminal plasma composition and how these effects relate to fetal development remains elusive. Here, we applied the geometric framework for nutrition to systematically manipulate dietary macronutrient balance in male mice and determine dietary effects on the seminal vesicle fluid (SVF; comprising much of the seminal plasma) proteome, as well as relate differences in the proteome to aspects of fetal development. We (i) identified the largest number of proteins in the mouse SVF proteome to date, (ii) determined a set of proteins that were significantly affected by dietary macronutrients, (iii) showed that differences in a protein related to lipid mobilization and metabolism (APOA4) were correlated with fetal development, and (iv) detected dietary effects on aspects of fetal development that were unrelated to SVF protein abundance. This study provides a comprehensive characterization of the male SVF proteome across nutritional space and highlights potential functional ways in which male diet and the seminal plasma may mediate fitness.

Trade-offs between lifespan and reproduction are a central theme in evolution and ecology, often attributed to physiological constraints on the allocation of limiting resources. However, recent work suggests such trade-offs may depend on macro- and micronutritional context. We examined how macronutrient balance and cholesterol availability shape lifespan and reproductive performance in male Drosophila melanogaster , explicitly testing both unmated males and those permitted to mate freely throughout life—a design rarely applied. We found that cholesterol deprivation substantially reduced lifespan, but only in frequently mating males, indicating that sterols play a key role in mediating the lifespan costs of mating, consistent with their known role in sperm and seminal fluid. Conversely, the inclusion of dietary cholesterol reduced lifespan in unmated males maintained on low protein-to-carbohydrate diets, suggesting that male reproductive investment is sufficiently high to generate sterol-dependent costs to the soma. Lifespan was maximized at higher protein-to-carbohydrate ratios than previously estimated, while reproductive performance in aged males was favored by carbohydrate-biased diets, demonstrating a nutritional trade-off. Males preferentially consumed macronutrient ratios that promoted reproductive success rather than longevity and discriminated the presence of cholesterol in food. Together, these findings reveal sterols as a key mediator of male longevity, with effects that depend critically on both diet and reproductive context. More broadly, by integrating sterols, macronutrient balance, and sustained reproductive investment, our study adds to the growing evidence that male reproductive costs can be substantial and refines our understanding of the evolutionary basis of dietary trade-offs.

Background: Branched-chain amino acids (BCAAs) are essential amino acids for protein metabolism. Preclinical research in mice suggested that BCAA intake relative to other amino acids, in the context of a high-carbohydrate diet, was associated with hyperphagia, obesity, and reduced lifespan. These effects were not attributed to BCAAs alone, nor did they manifest through canonical mechanistic target of rapamycin–insulin-like growth factor 1 pathways; rather, they resulted from indirect effects of other amino acids, notably tryptophan, on appetite. As population aging and obesity-related chronic diseases present significant public health challenges, understanding appetite regulation is critical. To date, no clinical trial has examined the effects of BCAAs on appetite regulation in older adults. On the basis of our preclinical results, we hypothesized that, compared to the control diet, a diet supplemented either with BCAA or with BCAAs and methionine would increase appetite and energy intake, whereas supplementation with BCAA and tryptophan would not increase appetite. Objective: We aimed to translate these preclinical findings to humans by examining the effects of BCAAs per se and in combination with tryptophan and methionine on appetite and other health measures in a cohort of older participants. Methods: This randomized controlled clinical trial recruited 110 adults (aged 65-80 y; BMI 20-35 kg/m ² ). Participants were randomly allocated to four 4-week intervention groups: (1) control (no supplementation), (2) BCAAs, (3) BCAAs+tryptophan, or (4) BCAAs+methionine. All participants received a controlled diet, with intervention groups additionally receiving amino acid supplements. The primary outcomes are appetite assessed via self-reports and fibroblast growth factor 21 levels (a marker of protein appetite), and energy intake quantified from dietary intake data. Secondary outcomes include body composition, cardiometabolic health, gut microbiota, blood biomarkers, sleep, and physical performance. Descriptive statistics will be used to summarize participant characteristics. Linear mixed models will assess intervention effects, with and without adjustment for relevant covariates. Diet-specific self-reported appetite and palatability scores will be analyzed using generalized additive mixed models. Results: The trial was registered on April 12, 2021. Recruitment commenced in April 2022 and was completed in November 2025, with 308 individuals screened and 100 completing the study. Data analyses are planned for completion by December 2026, with results expected to be published in 2027. Data cleaning and analysis are currently in progress and are expected to be completed by December 2026, with trial results expected to be published in 2027. Conclusions: This study will clarify the effects of BCAAs, either alone or in combination with tryptophan or methionine, on appetite and related outcomes in an older population. The findings may inform nutritional strategies targeting appetite regulation and metabolic health to support healthy aging.

Background: Total protein intake during pregnancy has been linked to long-term obesity risk in mothers and their offspring, but the role of specific protein sources remains unclear. Methods: Prospective cohort study, including 59,791 women with singleton births from the Danish National Birth Cohort(1996–2002). Maternal diet at gestational week 25 was assessed using a validated food-frequency questionnaire. Relative risks(RRs) were estimated for maternal postpartum weight retention (PPWR)>5 kg at 6–18 months postpartum and offspring overweight/obesity at ages 7–11 years. Findings: Overall, 10,678(22.1%) women had PPWR>5 kg and 8,287(19.0%) children developed overweight/obesity. When comparing the highest with the lowest quintiles of poultry and fish protein intake(% energy) during pregnancy, the multivariable-adjusted RRs of maternal PPWR>5kg were 0.89(95% CI 0.84–0.94) for poultry and 0.91(0.86–0.96) for fish, and the corresponding RRs for offspring overweight/obesity were 0.95(0.89–0.99) and 0.92(0.87–0.98), respectively. In contrast, mothers in the highest versus lowest quintile of red meat and dairy protein intake had higher offspring overweight/obesity risk, with RRs of 1.09(95% CI 1.02–1.16) and 1.11(1.04–1.19), respectively. In substitution models, replacing 5% of energy from red meat, dairy, or grain protein with poultry protein was associated with 18%–25% lower maternal PPWR>5kg risk and 19%–21% lower offspring overweight/obesity risk. Similarly, replacing red meat or dairy protein with fish protein yielded 15%–23% lower risk in mothers and 21% lower risk in offspring. Interpretation: Higher poultry and fish protein intake during pregnancy, particularly when replacing red meat or dairy protein, may reduce risk of PPWR>5kg in mothers and overweight/obesity in offspring.

Pregnancy and lactation are reproductive periods that require major energy and nutrient investment by the mother. Dietary perturbations over reproduction can impair offspring development and increase the risk of metabolic disease for the mother. However, how the intake of specific macronutrients, independent of total calorie intake, influence maternal reproductive investment and metabolic health remains poorly understood. To understand the role of protein, carbohydrate, and fat intake in influencing these parameters, we fed mice one of ten isocaloric diets that differed systematically in their macronutrient make-up. We allowed females to breed and observed striking effects of different macronutrients on fetal development, with protein intake having strong positive effects on offspring survival, accompanied by major shifts in the morphological structure of the placenta and placental lactogen production. However, maternal glucose tolerance was strongly impaired by high protein intake during pregnancy, with reproductive females more susceptible to the effects of these macronutrients than nonpregnant animals. Strikingly, metabolic effects were reversed after lactation, with mothers developing a resilience to the chronic effects of protein and fat intake on glucose tolerance observed in virgin animals. During lactation, we also observed that offspring development was optimized by a different ratio of macronutrients compared to during pregnancy. These results highlight the importance of optimizing macronutrient, particularly protein, intake to specific levels during pregnancy, ensuring a balance that maintains maternal glucose tolerance while providing sufficient nutrients to ensure healthy offspring growth and survival.

Objective: To examine the association between dietary macronutrient composition and 12‐month weight loss maintenance (WLM) in adults who achieved initial weight loss (≥ 5%).Methods: This prospective cohort analysis used 12‐month follow‐up data from the Navigating to a Healthy Weight trial. Macronutrient composition (%) was assessed using a 4‐day, 24‐h dietary recall. Food sources were categorized as discretionary foods, lean meat, vegetables, fruit, grains, and dairy. Primary outcomes included 12‐month changes in body weight, fat mass index (FMI), waist‐to‐height ratio (WHtR), and hip‐to‐height ratio (HHtR). A nutritional geometry approach was used to examine individual and interactive associations of macronutrient intake, visualizing as response surfaces.Results: Among 1518 participants (69.8% women; mean age 45 ± 12 years), mean macronutrient composition was 20.6% protein, 33.8% fat, and 43.1% carbohydrate. Protein energy percentage was inversely associated with energy intake (β: −0.33; 95% CI: −0.39, −0.27). Response surfaces revealed that lower proportional energy from protein, diluted by high fat and/or carbohydrate, was associated with higher total energy intake and greater 12‐month increases in body weight, WHtR, and HHtR, but not FMI. Consumption of discretionary food, not other food sources, increased energy intake by reducing proportional energy from protein.Conclusions: Maintaining dietary proportional energy from protein, particularly by limiting discretionary food consumption, was associated with reduced energy intake and improved WLM.

As the global population ages, research on the biology of ageing and its role in chronic disease is expanding, alongside a growing clinical focus on the unique needs of older adults. In the past, the liver was not thought to undergo substantial age-related changes, nor was there thought to be any liver disease characteristic of older adults. Current studies challenge this perspective, revealing that ageing substantially influences liver pathophysiology at the organ level and within each of the liver cell types. These observations have implications for understanding the pathogenesis of liver diseases common in older adults, including hepatocellular carcinoma, hypoxic hepatitis and metabolic dysfunction-associated steatotic liver disease. Previously, managing older patients with liver disease mostly addressed age-related changes in drug metabolism and liver function tests. However, current clinical practice increasingly emphasizes age-specific issues such as frailty, sarcopenia, multimorbidity and polypharmacy. Given the liver's pivotal role in systemic metabolism, immunity and detoxification, ageing of the liver can contribute to systemic diseases. In the future, interventions that target ageing biology might offer new treatment options for liver diseases. Here, we review those age-related changes in the liver that have substantial biological and clinical consequences for older adults.

Objective: The objective of this study was to reconcile how two landmark mouse studies came to opposite conclusions regarding the relationship between dietary macronutrient composition and energy intake. Hu et al. concluded that dietary fat drives excess energy intake because its hedonic properties override energy homeostasis. Solon‐Biet et al. concluded that energy intake increases with dietary fat owing to the dilution of protein and carbohydrates, with compensatory feeding for these nutrients dominating inhibitory feedback from fat.Methods: Nutritional geometry was used to reanalyze data from Solon‐Biet et al. and Hu et al.Results: Results from the two studies are strongly concordant. Neither was designed to measure hedonics but, in both studies, the positive associations among dietary fat, food, and energy intakes are as predicted by compensatory feeding for dietary protein and carbohydrates without the need to impute hedonic effects of fat.Conclusions: Whereas conclusions cannot be drawn from either study regarding the role of hedonics, there is evidence for homeostatic feedback operating in both. We suggest that hedonic and homeostatic mechanisms likely interact, with homeostasis being more influential over the longer term. Therefore, “hedonic diversion” may be a more appropriate concept than “hedonic override” when considering energy consumption in mice and, perhaps, humans.

Pregnancy and lactation are reproductive periods that require major energy and nutrient investment by the mother. Dietary perturbations over reproduction can impair offspring development and increase the risk of metabolic disease for the mother. However, how the intake of specific macronutrients, independent of total calorie intake, influence maternal reproductive investment and metabolic health remains poorly understood. To understand the role of protein, carbohydrate and fat intake in influencing these parameters we fed mice one of ten isocaloric diets that differed systematically in their macronutrient make-up. We allowed females to breed and observed striking effects of different macronutrients on fetal development, with protein intake having strong positive effects on offspring survival, accompanied by major shifts in the morphological structure of the placenta and placental lactogen production. However, maternal glucose tolerance was strongly impaired by high protein intake during pregnancy, with reproductive females more susceptible to the effects of these macronutrients than non-pregnant animals. Strikingly, metabolic effects were reversed after lactation, with mothers developing a resilience to the chronic effects of protein and fat intake on glucose tolerance observed in virgin animals. During lactation, we also observed that offspring development was optimized by a different ratio of macronutrients compared to during pregnancy. These results highlight the role of distinct macronutrient combinations in optimizing maternal investment over different reproductive periods, and the role of protein intake in mediating a trade-off between offspring development and maternal health.