Background Sleep duration, physical activity, and nutrition (SPAN) are each associated with mortality risk, yet they are usually examined individually or in pairs, with limited attention to their combined associations and differences across physical activity domains. We examined combined SPAN behaviours in relation to all-cause mortality across different physical activity domains (occupational physical activity (OPA), leisure-time physical activity (LTPA) and transportational physical activity (TPA)). Methods We included adults aged 18 years or older from the National Health and Nutrition Examination Survey 2007–2018. Sleep duration was self-reported in hours/day. Physical activity, including moderate-to-vigorous physical activity (MVPA) across domains, was assessed using the Global Physical Activity Questionnaire. Diet quality was estimated from 24-hour dietary recalls using the Healthy Eating Index-2020 (HEI–2020). We created 27 mutually exclusive joint categories using tertiles of physical activity and HEI-2020, and guideline-based sleep-duration groups (<7, 7–8, and >8 h/day), with the lowest combination as the reference. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs for all-cause mortality. To estimate the minimum combined variations associated with lower mortality risk, we used the 5th percentile of each behaviour as the reference. Results Among 31,875 participants (median age 48.0 years; 51.4% female), 2,623 deaths occurred over a median follow-up of 6.75 years. In joint categorical analyses, a combination of optimal sleep (7–8 h/day), high diet quality (HEI–2020: >56.0), and high LTPA (>35.4 min/day) or high TPA (>25.7 min/day) was associated with the lowest all-cause mortality risk (HR = 0.44, 95%CI: 0.29-0.65; HR = 0.54, 95%CI: 0.37–0.77). The lowest HR for OPA was observed for sleep duration (3.–6.5 h/day), moderate OPA (1.4–114.0 min/day), and high diet quality (HR = 0.53, 95%CI: 0.37–0.75). Relative to the reference values (sleep: 5 h/day, MVPA/PA domains: 0 min/day and HEI–2020: 32.29), a combined minimum increment of 15 min/day of sleep, 5 HEI–2020 points, in combination with either 10.8 min/day of total MVPA, 24.0 min/day of OPA, or 5.2 min/day of LTPA, were associated with 10% lower all-cause mortality. For TPA, the 10% lower risk corresponded to 30 additional min/day of sleep, 5 HEI–2020 points, and 5.5 min/day of transport PA. Conclusions Modest combined increments in SPAN were associated with lower all-cause mortality among US adults across physical activity domains, with combinations including higher amounts of LTPA showing the most favourable profile. ### Competing Interest Statement The authors have declared no competing interest. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used ONLY openly available human data that were originally located at: the National Health and Nutrition Examination Survey (NHANES). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at the National Health and Nutrition Examination Survey (NHANES). NHMRC Investigator Grant, GTN2009264

Ultra-processed diets are associated with excessive energy intake, but studies examining the role of alcohol have produced conflicting results, despite the high energy density of ethanol. We constructed a mechanistic-ecological model to explain this inconsistency and tested its predictions using population dietary data. The model builds on experimentally established mechanisms to predict that, whereas alcohol will contribute ethanol calories irrespective of diet, its impact on total macronutrient energy intake varies depending on dietary pattern. Alcohol consumption stimulates FGF21, a hormone that increases savory (umami) preference and reduces sweet preference. In minimally processed food environments-where umami flavor is a relatively reliable indicator of protein in foods-umami-seeking should direct consumers toward satiating, high-protein foods, with limited effect on macronutrient energy intake. In contrast, on diets rich in ultra-processed savory foods and/or high-fat unprocessed meats, the correlation between umami flavor characteristics and protein is broken by umami-flavored low-protein foods (protein decoys), so alcohol instead drives dietary protein dilution and, through attenuated protein satiation, increased food and macronutrient energy intake (protein leverage). Mixture analysis paired with nutritional geometry confirmed these predictions in population data, suggesting the model may generalize to ecological contexts. Our results potentially explain why alcohol has variable effects on energy balance across dietary patterns and suggest that it exacerbates the obesogenic effects of ultra-processed diets-a potentially important interaction given their global rise.

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.

Background:Sleep, physical activity, and nutrition (SPAN) are key determinants of both life expectancy (lifespan) and disease-free life expectancy (healthspan), yet are often studied in isolation. This study aimed to determine the minimum combined SPAN improvements needed for a longer lifespan and healthspan. Methods:This prospective cohort comprised 59,078 participants from the UK Biobank, recruited between 2006 and 2010 (median age: 64.0 years; 45.4% male). Between 2013 and 2015, a subsample of participants was invited to wear a wrist worn accelerometer for 7 days. Moderate to vigorous physical activity (MVPA; mins/day) and sleep (hours/day) were calculated using a validated wearables-based algorithm. Diet was assessed using a 10-item diet quality score (DQS), including intake of vegetables, fruits, grains, meats, fish, dairy, oils, and sugar-sweetened beverages (ranging 0-100; higher indicates better quality). Lifespan and healthspan (free of cardiovascular disease (CVD), cancer, type II diabetes, chronic obstructive pulmonary disease (COPD), and dementia) were estimated across 27 joint tertile SPAN combinations and a composite SPAN score using life tables. Findings:Over an 8.1-year median follow-up, 2458 deaths, 9996 CVD, 7681 cancers, 2971 type II diabetes, 1540 COPD, and 508 dementia events occurred. Compared to the least favourable tertiles, the optimal tertiles (7.2-8.0 h/day of sleep; >42 min/day of MVPA; DQS of 57.5-72.5) had 9.35 additional years of lifespan (95% CI: 6.67, 11.63) and 9.45 years of healthspan (95% CI: 5.45, 13.61). Compared to the 5th percentile, a minimum combined improvement of 5 min/day of sleep, 1.9 min/day MVPA, and a 5-point increase in DQS (e.g., additional ½ serving of vegetables/day or additional 1.5 servings of whole grains per day) was associated with 1 additional year of lifespan (95% CI: 0.69, 1.15). For healthspan, a combined improvement of 24 min/day of sleep, 3.7 min/day of MVPA, and a 23-point DQS increase was associated with 4.0 additional years (95% CI: 0.50, 8.61). Interpretation:Modest concurrent improvements in sleep, physical activity, and diet were associated with meaningful gains in lifespan and healthspan. Funding:Australian National Health and Medical Research Council.

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 micro-nutritional 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 across their lives—a design rarely applied. We found that cholesterol deprivation induced a substantial reduction in lifespan, but only in frequently mating males, indicating that sterols are continuously invested in reproduction, consistent with their known role in sperm and seminal fluid. Conversely, 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 maximised at higher protein–to–carbohydrate ratios than previously estimated, while reproductive performance in aged males was favoured 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 challenges the long-standing assumption that male reproduction is “cheap,” 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/m2). 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.

Nutritional geometry was used to explore the effects of dietary composition on larval developmental traits in Drosophila melanogaster populations that had been subjected to long-term selection under poorer or richer nutritional conditions. When tested across a range of diets varying systematically in the ratio of protein to carbohydrate (P:C) and energy density, larvae that were adapted to the poorer nutritional condition developed faster to a smaller size with greater pupation success rates than did control larvae under a combination of low-protein and low-carbohydrate dietary conditions that were equivalent to the ancestral diet composition, indicating evolutionary tuning to ensure survival on the poor ancestral diet. Results from measurement of haemolymph storage proteins suggested that larvae that were selected under a poor food environment utilized ingested protein for immediate larval growth, rather than for transcribing haemolymph storage proteins in preparation for adult metamorphosis. Our study illustrates the potential for the nutritional environment to induce selection on life-history traits that span across life stages and demonstrates the utility of the fly as a model for studying the mechanisms underlying adaptation to nutrition transitions.

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.

Ageing is a complex process influenced by modifiable factors such as diet, which may accelerate or decelerate physiological decline. While chronological age increases uniformly, biological ageing varies between individuals, reflecting differences in health status and the resilience of biological systems. The Klemera-Doubal Method (KDM), a composite biomarker-based index often used as an estimate of biological age, has been associated with morbidity and mortality in large cohorts. This study examined whether dietary manipulation of protein source and macronutrient composition affects KDM estimates in older adults. We analysed data from the Nutrition for Healthy Living study, a 2 × 2 factorial dietary intervention trial involving 104 participants aged 65-75 years. Participants were randomised to one of four diets: omnivorous/high-fat (OHF), omnivorous/high-carbohydrate (OHC), semi-vegetarian/high-fat (VHF) or semi-vegetarian/high-carbohydrate (VHC). KDM-derived δAge (the difference between KDM- and chronological-age) was calculated before and after a 4-week intervention. The OHF group, most like participants' baseline diets, showed no meaningful change in δAge. Compared to OHF, participants in the OHC group showed a significant reduction in δAge. The VHF and VHC groups showed similar reductions in δAge, relative to OHF, though not all reached statistical significance. KDM-derived δAge appears responsive to dietary change within 4 weeks and may offer a useful proxy for evaluating shifts in physiological status. Caution is warranted in interpreting such changes as evidence of biological age reversal as observed shifts may reflect acute physiological responsiveness to dietary inputs rather than altered ageing trajectories. Longer-term treatment would be needed to assess changes in age-related disease risks.

The essentiality of protein in the human diet is unequivocal. Yet researchers, clinicians, and lay people often believe numerous propositions about dietary protein despite insufficient supporting or refuting data in some instances. To address this disconnect, and to "pressure-test" current beliefs about dietary protein, the Indiana University School of Public Health-Bloomington convened a workshop in February 2025 titled "Human Dietary Protein Needs and Benefits: A Critical Assessment of Postulated Propositions." More than 20 international experts discussed (1) methodologic issues affecting data acquisition and interpretation; (2) "optimal" dietary protein intakes and effects on muscle protein synthesis rates, muscle protein accretion, muscle growth, and muscle repair; (3) protein needs during weight loss; (4) acute protein intake thresholds above and below which protein is no longer related to anabolism; and (5) dietary protein intakes above which protein may be detrimental to health. The experts rated each proposition on a scale from "existing evidence strongly supports the proposition" to "existing evidence seems sufficient to rule out the viability of the proposition." In most instances, the experts believed additional research was warranted. For many propositions the research base was insufficient in terms of quality (rigor), quantity (sample size, study duration), or pertinence (e.g., use of surrogate markers).

The fly gut integrates nutrient-specific appetite control.

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.

Dietary manipulations like ketogenic diets are established interventions for recalcitrant epilepsy. However, it remains unknown whether specific macronutrient exposure through dietary environments could possibly extend to primary preventive qualities, associated with changes in epilepsy disease burden (prevalence and incidence). Here, macronutrient supply, GDP, and idiopathic epilepsy disease burden data were collated from more than 150 countries from 1990 to 2018. Nutritional geometry generalized additive mixed models (GAMMs) modeling unraveled that dietary environments with high-fat and low-carbohydrate supplies were linked to lower epilepsy incidence and prevalence. Our analyses suggested a plausible primary preventive role of dietary manipulations for epilepsy.

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. Older adults can be affected by multiple chronic medical conditions, including liver disease. This Review provides a comprehensive overview of age-related pathophysiological changes in the liver and discusses interventions and treatment options for older patients.

There has been a proliferation of ultra-processed foods (UPF) in the food environment since the 1980s which have newly been linked to growing number of non-communicable diseases (NCD) including cardiovascular disease, cancers, type 2 diabetes, fatty liver disease, depression, frailty, and hypertension (1) . There is intense debate surrounding whether the mechanism for the negative effect on health of consumption of UPF is their nutrition composition or processing (1) . There is growing evidence that macronutrient ratios are important for chronic disease risk, predict longevity and may adversely affect micronutrient intakes (2) . Intake of macronutrients from ultra-processed sources may lead to macronutrient imbalances and higher energy intakes (3) while being deficient in micronutrients, making it difficult to achieve energy balance and meet micronutrient requirements. Using nationally representative nutrition surveillance data on the Australian population, the National Nutrition and Physical Activity Survey, in this paper we employ the Geometric Framework for Nutrition (2) to examine the multidimensional dietary composition of UPF. Diet was assessed for adults (n = 9.341) with two 24-hour recalls. Diets were classified by degree of processing according the NOVA classification system and classified as ultra-processed diets (UPD, > 60% energy from UPF), moderate or low in UPF i.e., minimally processed diets (MPD, < 20% energy from UPF). Outcomes included the nutrient rich food index (NRF 9.3 index) (4) , the Nutri-Score (5) , and macronutrient and micronutrient intakes. Micronutrients were plotted over macronutrient ratios for MPD and UPD to determine whether micronutrient intakes could be met within the acceptable macronutrient distribution ranges (AMDR). Scheffe’s polynomials were fitted to the data for total energy intake, macronutrient intake and micronutrient intake. Vitamin and mineral intakes were higher for MPD compared to UPD (p < 0.001). Overall nutrient density decreased and the NRF 9.3 scores were 399.2 for MPD and 297.7 for UPD (p < 0.001). For the Nutri-Score, MPD diets scored A (highest quality) and UPD scored C (moderate quality). Poor scores were due to higher energy density, saturated fat, added sugar and sodium increased with UPD, while protein, dietary fibre and micronutrient density and fruit, vegetable, nut and legume ratios decreased. Diets met the estimated average requirement (EAR) for all micronutrients within AMDR for MPD but not for UPD. Regardless of processing, in almost all nutritional indicators of health, diets high in UPF were unsatisfactory relative to nutritional recommendations. We conclude that compositional factors alone point to the mechanisms through which ultra-processed dietary patterns could lead to poor health, in the full understanding that processing likely has additional effects over and above composition that exacerbates the problem.

Nutrition often shapes the outcome of host-parasite interactions, however understanding the mechanisms by which this occurs is often confounded by the intimate nature of the association and by the fact that the host and parasite may compete for the same limiting nutrients. One way of disentangling this interaction is to combine in vivo and in vitro approaches. Here, we explore the role of host nutrition in determining the outcome of infections using a model insect-bacterium system: the cotton leafworm Spodoptera littoralis and the blood-borne bacterium Xenorhabdus nematophila. Spodoptera littoralis larvae were reared on one of a series of 20 chemically-defined diets ranging in their protein: carbohydrate (P:C) ratio and caloric density. They were then challenged with either a fixed dose of X. nematophila cells (live or dead) or were sham-injected. Survivorship of larvae challenged with live bacterial cells was strongly dependent on the protein levels of the diet, with mortality being highest on low-protein diets. This trend was reflected in the bacterial growth rate in vivo, which peaked in larvae fed low-protein diets. To determine whether in vivo bacterial growth rates were driven by the direct effects of blood nutrients or by the indirect effects of the host immune response, we used 20 synthetic haemolymphs ('nutribloods') that mimicked the nutritional content of host blood. In vitro bacterial growth rate was negatively impacted by the protein content of the nutribloods, replicating the patterns seen in vivo and suggesting that nutrient availability and not host immunity was driving the interaction. By comparing standardized bacterial growth rates in vivo and in vitro, we conclude that the outcome of this host-parasite interaction is largely driven by the 'bottom-up' effects of nutrients on bacterial growth, rather than by the 'top-down' effects of nutrients on host-mediated immune responses. The outcome of host-parasite interactions is typically assumed to be strongly determined by the host immune response. The direct effects of nutrition have been underexplored and may have broad consequences for host-parasite interactions across taxa.

Background: Sleep, physical activity, and nutrition (SPAN) are major modifiable risk factors for cardiovascular disease, yet the minimum and optimal combined improvements for prevention remain unknown. We examined the multi-behaviour associations of SPAN with risk of major adverse cardiovascular events (MACE) and its subtypes (myocardial infarction (MI), heart failure (HF), and stroke). Methods: This prospective cohort analysis included 53,242 participants from the UK Biobank (median age: 63.0 years; 56.8% male) who wore activity trackers for 7 days and self-reported dietary data. Wearable-measured sleep (hours/day) and moderate to vigorous physical activity (MVPA; mins/day) were calculated using a machine learning-based algorithm. A 10-item diet quality score (DQS) assessed intake of vegetables, fruits, whole grains and refined grains, unprocessed and processed meats, fish, dairy, vegetable oils, and sugary beverages. Cox proportional hazards models were used to estimate hazard ratios (HR) for MACE risk across 27 joint tertile combinations of SPAN behaviours. We examined dose-response associations of SPAN with MACE using a composite score (from 0-100 points). Results: Over the 8.0-year median follow-up time, 2,034 MACE events occurred, including 932 myocardial infarctions, 584 strokes, and 518 HF events. Compared to the combined SPAN referent group (lowest tertiles for all three), the optimal SPAN combination involving high sleep duration (8.0-9.4 hours/day), high MVPA (42-104 mins/day), and a DQS between 32.5 and 50.0 was associated with an HR of 0.43 (95%CI: 0.30, 0.62). Compared to the minimum SPAN score of 17.8, a median SPAN score of 52.8 was associated with a 41% lower risk of MACE (HR: 0.59; 0.49, 0.70). The median SPAN score corresponded to an HR of 0.53 (0.38, 0.75) for HF, 0.65 (0.50, 0.84) for MI, and 0.52 (0.38, 0.71) for stroke. A theoretical minimum combined improvement of an additional 11 min/day of sleep, 4.5 min/day MVPA, and 3 DQS (1/4 cup of vegetables per day) were associated with 10% lower MACE risk (HR: 0.90; 0.88, 0.94). Conclusions: Modest theoretical improvements across SPAN behaviours were associated with clinically meaningful reductions in MACE and its subtypes. These findings support multi-behavioural CVD prevention trials testing the effectiveness of small improvements across multiple behaviours. ### Competing Interest Statement ES is a paid consultant and holds equity in Complement 1, a US-based company whose products and services relate to healthy lifestyles. All other authors disclose no conflict of interest for this work. ### Funding Statement This study is funded by an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (APP1194510) awarded to ES. The funder had no specific role in any of the following study aspects: the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research has been conducted using the UK Biobank resource under application number 25813. All participants completed informed consent, and ethical approval was obtained by the UK National Health Service (NHS) and National Research Ethics Service for the UK (No. 11/NW/0382). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the UK Biobank, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with the permission of the UK Biobank.

Nutrient composition varies greatly across landscapes, influencing the spatiotemporal dynamics of populations. However, few studies have explored this pattern across multiple scales. We tested how nutrient limitation affects herbivore populations, from individual behavior to landscape‐level dynamics, using the Australian plague locust Chortoicetes terminifera . Our study combined field populations and long‐term survey data across their range. At the individual level, juvenile locusts selected a carbohydrate‐biased intake target of 1 protein (p) to 2 carbohydrate (c) and exhibited the highest growth rates and shortest development times when fed artificial diets matching this 1p:2c ratio during their final juvenile instar. In the field, locusts exposed to protein‐biased plants corrected their nutritional imbalance by initially selecting carbohydrate‐heavy diets (up to a 1p:20c ratio). Over a week after removal from the protein‐rich environment, they returned to the 1p:2c intake target once the deficiency was balanced. At the landscape level, locust outbreaks were negatively correlated with soil nitrogen and exhibited a non‐linear relationship with soil phosphorus, peaking at approximately 4% phosphorus content. By disentangling the interaction between mean annual precipitation and soil nitrogen, using comprehensive locust surveys and remotely sensed soil and weather data spanning decades, we show how environmental factors drive population dynamics. This study integrates lab, field and remote sensing approaches, highlighting the importance of nutrient balancing across scales for herbivores. Specifically, we demonstrate that low‐nitrogen environments promote locust outbreaks, likely by reducing plant protein‐to‐carbohydrate ratios. Incorporating soil quality data into locust plague forecasting models could significantly improve prediction accuracy.

Abstract Background Sleep, physical activity, and nutrition (SPAN) are critical behaviours for health, although they have traditionally been studied separately. We examined the combined associations of SPAN and the minimum between-individual variations associated with meaningfully lower all-cause mortality risk. Methods This prospective cohort analysis included 59,078 participants from the UK Biobank (median age: 64.0 years; 45.4% male) who wore trackers for 7 days and self-reported dietary data. Wearable-measured sleep (hours/day) and moderate to vigorous physical activity (MVPA; mins/day) were calculated using a machine learning based schema. A 10-item diet quality score (DQS) assessed the intake of vegetables, fruits, fish, dairy, whole grains, vegetable oils, refined grains, processed and unprocessed meats, and sugary beverages (0–100 for all components with higher values indicating higher quality). Cox proportional hazards models were used to estimate hazard ratios (HR) for all-cause mortality risk across 27 separate joint tertile combinations of SPAN behaviours with the lowest tertile for all three as the referent group. For more granular clinical interpretations, we examined combined incremental dose–response changes of the SPAN behaviours using the 5th percentile of each behaviour as the referent point. Results Over the 8.1-year median follow-up time, 2,458 mortality events occurred. Compared to the referent group of combined SPAN exposure (lowest tertiles for all three), the optimal SPAN combination involving moderate sleep duration (7.2–8.0 h/day), high MVPA (42–103 min/day), and a DQS between 57.5 and 72.5 was associated with an HR of 0.36 (95% CI: 0.26–0.50). Relative to the 5th percentile of sleep (5.5 h/day), physical activity (7.3 min/day), and nutrition (36.9 DQS), a theoretical minimum combined increase of 15 min/day of sleep, 1.6 min/day MVPA, and 5 DQS points (corresponding to e.g., extra 1/2 serving of vegetables per day or 1 less serving of processed meat per week) was associated with 10% lower all-cause mortality risk (0.90; 0.88–0.93). Combined increases of 75 min/day of sleep, 12.5 min/day MVPA, and 25 DQS points were associated with 50% lower all-cause mortality risk (0.50; 0.44–0.58). Conclusions This study highlights the potential health value of subtle combined SPAN modification in relation to mortality risk and expands opportunities for more holistic recommendations.