Alistair M. Senior’s research while affiliated with The University of Sydney and other places

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Publications (171)


Global association of macronutrient supplies and multiple sclerosis (MS) disease burden. A,B) Age‐standardized MS prevalence (blue) and incidence (red) of both sexes A), global GDP per capita (U.S. dollar, black) and supplies of carbohydrate (blue), fat (light yellow) and protein (red) as functions of year B). C,D) Predicted effects of macronutrient supplies on MS prevalence rate C) and incidence rate D) (See Supporting Information for statistics and interpretation and Figure S1 and Tables S1–S4).
High carbohydrate (HC) feeding aggravated CNS autoimmunity while high fat (HF) was protective. A) Study timeline. Mice were fed on high protein (HP), high carbohydrate (HC) and high fat (HF) diets for 6–7 weeks before experimental autoimmune encephalomyelitis (EAE) induction and were kept on the same diet throughout the EAE clinical course. B) EAE clinical course for HP (red), HC (blue) and HF (light yellow) groups (n = 10/group). C) Histological analysis of neuroinflammation and demyelination of the spinal cord from HP, HC and HF mice isolated on D28 of EAE, paraffin‐sectioned and stained with H&E and Luxol fast blue (LFB) and their corresponding quantification results. Scale bars = 20 µm. D) Heatmap comparisons for the gene expression of Ifng, Tnfa, Nlrp3, Ccl2, and Cd68 in the spinal cord of HP, HC and HF mice isolated on D28 of EAE analyzed by qPCR. E) Representative flow cytometric plots of CNS‐infiltrating T cells of HP, HC and HF mice on D28 of EAE. F) Proportions of infiltrating immune cells and activated microglia (MHChi Mic) within the CNS of HP, HC and HF mice on D28 of EAE determined by flow cytometry. G) Representative flow cytometric plots of splenic Th1 (IFNγ‐producing CD4⁺ T cells) and Th17 (IL‐17‐producing CD4⁺ T cells) cells of HP, HC and HF mice on D28 of EAE. H) Proportions of pro‐inflammatory cytokine‐producing T cells in the spleens of HP, HC and HF mice were determined by cytometry. I) Total number of Treg in draining lymph nodes (dLNs) of HP, HC and HF mice on D7 of EAE determined by flow cytometry. J) IL‐10 production in immune cells from dLNs of HP, HC and HF mice quantified by flow cytometry. K,L) Representative flow cytometric plots K) and scattering dot plots L) of dLN Th1 and Th17 cells. M–O) Proliferation of dLN Th1 M), Th17 N), and IFNγ‐producing CD8⁺ T cells O) of HP, HC and HF mice, with (filled dots) and without (hollow dots) stimulation, quantified by Ki67 staining. P–R) IFNγ production in dLN CD4⁺ P), CD8⁺ Q) and γδT cells R) of HP, HC and HF mice upon MOG antigen stimulation. S,T) Proliferation of dLN Treg of HP, HC and HF mice, with (filled dots) and without (hollow dots) stimulation S) and their corresponding proliferation indices T), quantified by Ki67 staining, with the dashed line denoting proliferation index of 1. N = 6‐10, data are represented as mean ± S.E.M., with *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, by one‐way ANOVA for most analyses; # p < 0.05 by unpaired t‐test; two‐way ANOVA for the clinical curve analysis, and paired t‐test for the proliferation assay analysis. (See also Figures S2–S6, Supporting Information).
High fat feeding modulated immunometabolism to induce tolerance during CNS autoimmunity. A) Violin plots of the gene set scores for glycolysis and fatty acid metabolism for CNS‐infiltrating immune cells in Ctrl (cyan) and EAE (red) mice analyzed by scRNA‐seq. B) Gene set enrichment analysis (GSEA) showing the enrichment of glycolysis pathway in the peripheral blood mononuclear cells (PBMCs) from MS patients versus Ctrl. C,D) Violin plots of the gene set scores for glycolysis and fatty acid metabolism of T cells in PBMCs (C) and cerebrospinal fluid (D, CSF) from Ctrl (pink) and MS patients (blue) analyzed by scRNA‐seq. E–G) Levels of HK1 (E), CPT1A (F) and lipid‐staining BODIPY 493/503 (G) in dLN T cells and conventional dendritic cells (cDC) of HP, HC and HF mice on D7 of EAE were quantified by flow cytometry. H) IL‐10 production (IL‐10⁺% of cells) in different immune cell subsets (CD4⁺ T cells (green), CD8⁺ T cells (brown), Treg (cyan) and cDC (dark green)) was significantly correlated with their corresponding lipid content (BODIPY⁺% of cells), as quantified by BODIPY 493/503 staining. (See also Figures S5, S7–S9, Supporting Information). N = 6‐10, data are represented as mean ± S.E.M., with *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, by one‐way ANOVA.
High fat feeding preconditioned T cell toward Treg differentiation. A) Experimental design. Mice were fed on HP, HC and HF diets for 6–7 weeks before sorting splenic naïve CD4⁺ T cells for RNA‐sequencing (RNA‐seq) and reduced‐representation bisulfite sequencing (RRBS‐seq). B,C) GSEA showing the enrichment of mTORC1 signaling pathway comparing HF naïve T cells with HP (B) and HC (C). D–F) GSEA showing the enrichment of signals upregulated in Treg versus conventional T cells comparing HF naïve T cells with HP (D,E) and HC (F). G,H) Venn diagrams showing the hypo‐methylated (G) and hyper‐methylated (H) regions comparing HF naïve T cells with HP (red) and HC (blue) and their overlapping genes Map3k11 (hypo‐methylated) and Ube2q1 (hyper‐methylated), and the violin plots for the expression of Map3k11 and Ube2q1 analyzed by RNA‐seq. I) Proportions of Treg differentiated from splenic naïve CD4⁺ T cell from HP (red), HC (blue) and HF (light yellow) mice quantified by flow cytometry. J) Proportion of splenic Treg from HP, HC and HF mice. K) Proportion of splenic Treg from mice fed on HF diet and mice first fed on HF diet and then switched to HC diet (HF→HC), and mice fed on HP diet and mice fed on HP diet then switched to HF diet (HP→HF). L) Visualization of the compositions of diets used in this study. Each circle represents one diet and their relative locations on the x, y and hypotenuse axes denote the proportion of protein, fat and carbohydrate (carb). The proportions of carbohydrate are also reflected by the color range. M–O) Contributions of macronutrient compositions to Treg proportions in mesenteric lymph node (M, mLN) and thymus (N) and to in vitro Treg differentiation experiment (O), were modelled by mixture modelling and mapped on right‐angled mixture triangles, consisting of protein (x‐axis), fat (y‐axis) and carbohydrate (hypotenuse). (See Supporting Information for statistics and interpretation and Table S5–S8). N = 6‐8, data are represented as mean ± S.E.M., with *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, by one‐way ANOVA for most analyses and unpaired t‐test for the Treg dynamics analysis.
Overview of the potential mechanisms underlying the multifaceted anti‐inflammatory effects of an isocaloric high fat (HF) diet. HF reprogrammed the immunometabolism, reducing the pro‐inflammatory glycolysis while promoting the anti‐inflammatory lipid storage in T cells and dendritic cells (DC), which led to a more tolerogenic phenotype as reflected by higher IL‐10 production. HF also modulated naïve CD4⁺ T cell at epigenetic and transcriptomic levels. HF reduced the promoter methylation of Map3k11 and increased the gene expression, which was linked to dampened T cell activation and reduced Th1 and possibly Th17 responses. Higher Map3k11 expression might associate with increased IL‐10 production and enhanced Treg generation, via activation of AP1/JunD signals, which warranted future investigations. HF also upregulated the mTORC1 signaling in naïve CD4⁺ T cells and skewed them toward a transcriptomic profile more similar to Treg, promoting Treg generation. Together, through these multi‐factorial mechanisms, HF feeding was linked to protection against experimental autoimmune encephalomyelitis (EAE).
High Fat Low Carbohydrate Diet Is Linked to CNS Autoimmunity Protection
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March 2025

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56 Reads

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Julen Reyes

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Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) believed to be driven by autoimmune mechanisms. Genetic and environmental factors are implicated in MS development, and among the latter, diets and nutrients are emerging as potential critical contributors. However, a comprehensive understanding of their impacts and the underlying mechanisms involved is lacking. Harnessing state‐of‐the‐art nutritional geometry analytical methods, it is first revealed that globally, increased carbohydrate supply is associated with increased MS disease burden, while fat supply has an opposite effect. Furthermore, in a MS mouse model, experimental autoimmune encephalomyelitis (EAE), it is found that an isocaloric diet high in carbohydrate aggravated EAE, while a diet enriched in fat (HF) is fully protective. This is reflected by reduced neuroinflammation and skewing toward anti‐inflammatory phenotypes. The protective effects from the HF diet are multifaceted. Metabolically, HF increased lipid storage in immune cells, correlating with their increased anti‐inflammatory IL‐10 production. Transcriptionally and epigenetically, HF feeding preprogrammed naïve T cells toward a less activated but more tolerogenic phenotype. It is showcased that manipulating diets is a potentially efficient and cost‐effective approach to prevent and/or ameliorate EAE. This exhibits translational potentials for prevention/intervention of MS and possibly other autoimmune diseases.

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Global associations of macronutrient supplies and idiopathic epilepsy disease burden. (A) Global age‐standardized prevalence (black) and incidence (red) of idiopathic epilepsy of both sexes as functions of years. (B) Global gross domestic product (GDP) per capita (in US dollars, black), and macronutrient supplies (carbohydrate: green, protein: blue, fat: cyan) as functions of years. (C) A global overview of the age‐standardized idiopathic epilepsy incidence of both sexes in 2018. (D) Modeled effects of macronutrient supplies on age‐standardized idiopathic epilepsy incidence rate of both sexes, with 2018 results shown as representative (see Supporting Information S1 for statistics and interpretations). (E) Modeled effects of macronutrient supplies on age‐standardized idiopathic epilepsy incidence rate of both sexes in 1990 (left), 2000 (middle), and 2010 (right).
Modeled effects of macronutrient supplies on age‐standardized idiopathic epilepsy prevalence rates of both sexes, with 2018 results shown as representative.
High‐Fat and Low‐Carbohydrate Dietary Environments Are Linked to Reduced Idiopathic Epilepsy Incidence and Prevalence

February 2025

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23 Reads

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.


Interpreting prediction intervals and distributions for decoding biological generality in meta-analyses

February 2025

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31 Reads

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1 Citation

Despite the importance of identifying predictable regularities for knowledge transfer across contexts, the generality of ecological and evolutionary findings is yet to be systematically quantified. We present the first large-scale evaluation of generality using new metrics. By focusing on biologically relevant study levels, we show that generalization is not uncommon. Overall, 20% of meta-analyses will produce a non-zero effect 95% of the time in future replication studies with a 70% probability of observing meaningful effects in study-level contexts. We argue that the misconception that generalization is exceedingly rare is due to conflating within-study and between-study variances in ecological and evolutionary meta-analyses, which results from focusing too much on total heterogeneity (the sum of within-study and between-study variances). We encourage using our proposed approach to elucidate general patterns underpinning ecological and evolutionary phenomena.


Interpreting prediction intervals and distributions for decoding biological generality in meta-analyses

February 2025

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7 Reads

Despite the importance of identifying predictable regularities for knowledge transfer across contexts, the generality of ecological and evolutionary findings is yet to be systematically quantified. We present the first large-scale evaluation of generality using new metrics. By focusing on biologically relevant study levels, we show that generalization is not uncommon. Overall, 20% of meta-analyses will produce a non-zero effect 95% of the time in future replication studies with a 70% probability of observing meaningful effects in study-level contexts. We argue that the misconception that generalization is exceedingly rare is due to conflating within-study and between-study variances in ecological and evolutionary meta-analyses, which results from focusing too much on total heterogeneity (the sum of within-study and between-study variances). We encourage using our proposed approach to elucidate general patterns underpinning ecological and evolutionary phenomena.


Dietary macronutrients modulate the proteome of brown adipose tissue in males and their female offspring

February 2025

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15 Reads

Brown adipose tissue (BAT) dissipates energy as heat, not only under cold exposure but also in the dissipation of excess ingested energy. Therefore, enhancing BAT activity is a potential avenue to combat weight gain. Dietary macronutrient composition influences BAT size and has recently been shown to influence BAT size of daughters through the patriline of C57BL/6J mice. However, the effects of macronutrient composition and any paternal effects on BAT function have yet to be characterised. Using the Geometric Framework for Nutrition, we investigated the effects of macronutrient composition on the BAT proteome in male mice and intergenerational effects in their offspring. In fathers, >50% of the proteome was affected by macronutrient composition, with distinct clusters of proteins that responded in similar ways. We identified two clusters with inverse patterns that correlated with BAT mass. Notably, UCP1 was reduced on low fat diets that promoted increased BAT mass, while there were increased levels of proteins involved in protein turnover on those same diets. The same diets also led to a reduction in proteins involved in purine biosynthesis (often UCP1 inhibitors). We did not find any effects of paternal diet on the BAT proteome in sons, but paternal protein intake negatively affected basigin expression in daughters - a protein that regulates UCP1 transcription. Our results highlight that dietary macronutrient composition in males remodels the protein expression landscape of BAT, and pre-conceptionally reprograms BAT expression profiles of female offspring.



Dietary macronutrient composition and cardiometabolic health markers for females. The mixture triangles show the model predictions of the cardiometabolic health markers with a significant association with macronutrient composition. Predictions were made at mean caloric intake of females (1811 kcal/day) across the sex-specific range of macronutrient percentages in this dataset. Percentage of fat can be inferred as decreasing moving away from the origin, such that each point on the triangle can be summed to equal 100%. Response values are colored such that warm colors display higher values and cooler colors display lower values. Response surfaces were adjusted for age, household income, race/ethnicity, education level, smoking, alcohol, physical activity, BMI, and the Healthy Eating Index
Dietary macronutrient composition and cardiometabolic health markers for males. The mixture triangles show the model predictions of the cardiometabolic health markers with a significant association with macronutrient composition. Predictions were made at mean caloric intake of males (1890 kcal/day) across the sex-specific range of macronutrient percentages in this dataset. The x and y-axis show protein and carbohydrate respectively. Percentage of fat can be inferred as decreasing moving away from the origin, such that each point on the triangle can be summed to equal 100%. Response values are colored such that warm colors display higher values and cooler colors display lower values. Response surfaces were adjusted for age, household income, race/ethnicity, education level, smoking, alcohol, physical activity, BMI, and the Healthy Eating Index
Associations between dietary macronutrient composition and cardiometabolic health: data from NHANES 1999–2014

December 2024

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45 Reads

European Journal of Nutrition

Purpose Dietary macronutrients significantly impact cardiometabolic health, yet research often focuses on individual macronutrient relationships. This study aimed to explore the associations between dietary macronutrient composition and cardiometabolic health. Methods This study included 33,681 US adults (49.7 ± 18.3 years; 52.5% female) from the National Health and Nutrition Examination Survey during 1999–2014. Dietary data was derived from 1 to 2 separate 24-hour recalls and cardiometabolic health included lipid profile, glycemic control, blood pressure, and adiposity collected in a mobile examination center. Associations between dietary macronutrient composition and cardiometabolic health were examined using generalized additive models adjusted for age, socio-demographics, lifestyle, and diet quality. Results In females, triglycerides (P < 0.01) and HDL cholesterol (P < 0.01) were the least optimal in diets containing lower fat (10%) and higher carbohydrate (75%). In males, HDL cholesterol was positively associated with fat (P < 0.01) and no association with triglycerides was detected. Total-C associations were male specific (P = 0.01) and highest in diets composed of 25% protein, 30% carbohydrate, and 45% fat. In both sexes, systolic blood pressure (P ≤ 0.02) was highest in diets containing lower fat (10%) coupled with moderate protein (25%). Diastolic blood pressure associations were female specific (P < 0.01) with higher values in those consuming the upper range of fat (55%). There were no associations of macronutrient composition with glycemic control or adiposity. Conclusion This study revealed sex-specific relationships between macronutrient composition and cardiometabolic health. Future research is needed to explore these relationships across age groups.


eNODAL: an experimentally guided nutriomics data clustering method to unravel complex drug-diet interactions

November 2024

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12 Reads

Briefings in Bioinformatics

Unraveling the complex interplay between nutrients and drugs via their effects on “omics” features could revolutionize our fundamental understanding of nutritional physiology, personalized nutrition, and, ultimately, human health span. Experimental studies in nutrition are starting to use large-scale “omics” experiments to pick apart the effects of such interacting factors. However, the high dimensionality of the omics features, coupled with complex fully factorial experimental designs, poses a challenge to the analysis. Current strategies for analyzing such types of data are based on between-feature correlations. However, these techniques risk overlooking important signals that arise from the experimental design and produce clusters that are hard to interpret. We present a novel approach for analyzing high-dimensional outcomes in nutriomics experiments, termed experiment-guided NutriOmics DatA cLustering (‘eNODAL’). This three-step hybrid framework takes advantage of both Analysis of Variance (ANOVA)-type analyses and unsupervised learning methods to extract maximum information from experimental nutriomics studies. First, eNODAL categorizes the omics features into interpretable groups based on the significance of response to the different experimental variables using an ANOVA-like test. Such groups may include the main effects of a nutritional intervention and drug exposure or their interaction. Second, consensus clustering is performed within each interpretable group to further identify subclusters of features with similar response profiles to these experimental factors. Third, eNODAL annotates these subclusters based on their experimental responses and biological pathways enriched within the subcluster. We validate eNODAL using data from a mouse experiment to test for the interaction effects of macronutrient intake and drugs that target aging mechanisms in mice.


Citations (63)


... replying to: A. Senior et al.; Scientific Reports https://doi.org/10.1038/s41598-025-90267-x (2025. ...

Reference:

Reply to: A caveat about the use of trigonometric functions in statistical tests of Nutritional Geometry models
A caveat about the use of trigonometric functions in statistical tests of nutritional geometry models

... The prevailing evolutionary hypothesis to explain the life-extending effects of CR is that it reflects an optimal resource-allocation strategy in which animals redirect metabolic resources away from reproduction to somatic maintenance during periods of food scarcity, thereby increasing the chances of surviving to reproduce when resource availability permits (129). However, accumulating evidence implicates the restriction not of calories per se, but specifically of protein and certain amino acids, as a proximate nutritional link between dietary restriction and lifespan (107,(130)(131)(132). Whether this is consistent with the resource-allocation theory depends on the extent to which protein (or specific amino acids) versus energy is more likely to have limited reproduction and somatic maintenance within the evolutionary environment of a species. ...

The Geometric Framework for Nutrition and Its Application to Rodent Models
  • Citing Article
  • November 2024

Annual Review of Animal Biosciences

... Therefore, it would be of interest to inspect which threshold levels of ketosis are required for epilepsy treatment or prevention. In addition, a high-fat, low-carbohydrate diet is likely to influence the gut-brain axis [20] and immunometabolism [21], which are also critical for the physiology and pathology of the CNS system. ...

High fat low carbohydrate diet is linked to protection against CNS autoimmunity

... Following model construction, effect sizes and associated variance were calculated using the escalc function (39,40) as both response ratios and standardized mean change, since the effect size calculation choice may influence model selection (41). Response ratios were calculated as the sum of the natural logarithm of the ratio of post-test and pre-test means, which were later exponentiated (i.e., e x ) to convert them to percentage change scores to make practical interpretation more intuitive. ...

Bivariate multilevel meta-analysis of log response ratio and standardized mean difference for robust and reproducible environmental and biological sciences

... Dietary fibre plays a key role in regulating the gut microbiota and promoting the production of short-chain fatty acids, such as butyrate, which exhibit anti-inflammatory and antiproliferative effects (Koemel et al., 2024;Stolzenberg-Solomon, 2023;Vetrani et al., 2022;Yarmand et al., 2024). Whole grains, fruits, and vegetables, which are rich in fibre, folate, and antioxidants, are consistently linked to lower risks of colorectal and gastrointestinal cancers (Shah et al., 2023;Tammi et al., 2024;Zhao et al., 2022). ...

Macronutrient composition of plant-based diets and breast cancer risk: the E3N prospective cohort study

European Journal of Nutrition

... One clinically important, but under-recognized, complication in men with type 2 diabetes (T2D) is dysfunction of the reproductive system, including erectile dysfunction, hypogonadism, and infertility [2]. Moreover, emerging data in rodents indicate that paternal diet, hyperglycemia, and obesity may affect sperm epigenetics and impact health and development of offspring [3][4][5]. ...

Paternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring

... Especially, a decrease in the dietary content of essential amino acids such as tryptophan, threonine, methionine, and cysteine strongly increases calorie intake and modulates the associated metabolic profile. [61][62][63] Therefore, the interpretation of data F I G U R E 4 Percentage adiposity data from Wali et al., Nature Metabolism, 2021. [48] Response surfaces show the relationship between the intake of glucose-, fructose-, and protein-derived energy (kJ/mouse/day) and the percentage of fat mass of male mice measured after being fed on diets for 12-14 weeks. ...

Mice Regulate Dietary Amino Acid Balance and Energy Intake by Selecting between Complementary Protein Sources
  • Citing Article
  • April 2024

Journal of Nutrition

... Here, we leveraged nutrient supplies, a proxy for diet and nutrient environments, to interrogate the potential associations between nutrient exposures and epilepsy incidence and prevalence, harnessing the powerful tool, nutritional geometry generalized additive mixed models (GAMMs), we previously conceptualized [8,9]. We found that dietary environments, high in fat and low in carbohydrate supplies, are associated with reduced idiopathic epilepsy prevalence and incidence, indicative of its protective effects. ...

Global associations of macronutrient supply and asthma disease burden

... Previous studies have identified total energy intake as an important factor driving weight gain [26], while others have focused on the contributions of specific macronutrients [27,28]. In addition to total energy intake, the macronutrient composition, namely the percentage of energy intake from carbohydrates, proteins, and fats, potentially have an important influence on energy balance [29]. There is a long history of debate on the effects of fat, carbohydrate, and protein on body weight management [30][31][32]. ...

Dietary macronutrient composition impacts gene regulation in adipose tissue

Communications Biology