Thomas Roeder

Model organisms play a central role in advancing our understanding of human nutrition and physiology. This narrative review highlights the unique advantages of the invertebrate models Caenorhabditis elegans and Drosophila melanogaster for studying biofactors—diet‐derived compounds that modulate biological functions. Both models offer powerful genetic toolkits, short life cycles, and cost‐effective maintenance, enabling high‐throughput and mechanistic investigations. Particular emphasis is placed on the availability of chemically defined diets, which allow precise manipulation of nutrient and biofactor composition. These features make C. elegans and D. melanogaster invaluable systems for dissecting the essentiality, bioavailability, and physiological impact of individual biofactors as illustrated by selected recent studies. Being ethically less problematic substitutes for mammalian models, both invertebrate models offer the possibility of closing the gap that often exists between in vitro and cell culture studies on the one hand and in vivo evaluation in animal experiments in laboratory rodents on the other. By integrating these model systems into experimental research, we can gain critical insights into biofactor‐gene interactions and the molecular mechanisms underlying their health‐promoting properties.

Respiratory organs must balance their primary function of gas exchange with the constant threat of inhaled pathogens. In the Drosophila tracheal system, gas exchange occurs at the tracheal terminal cells (TTCs), the functional equivalents of mammalian alveoli. While bacterial infection triggers a robust innate immune response throughout the broader airway epithelium, we reveal that TTCs are uniquely exempt from this reaction. Mechanistically, TTCs lack expression of the membrane-associated peptidoglycan recognition receptor PGRP-LC. This absence protects these highly susceptible cells from immune deficiency (Imd) pathway activation and subsequent JNK-mediated cell death, establishing TTCs as a distinct, immune-privileged niche. Ectopic immune activation via targeted PGRP-LCx overexpression in TTCs caused a severe reduction in branching, cellular damage, and ultimately cell death, phenotypes that were fully rescued by the depletion of AP-1 or foxo . Because both structural plasticity (in response to nutritional cues and hypoxia) and innate immune responses strictly require the transcription factor FoxO, we demonstrate that potent immune signaling is fundamentally incompatible with dynamic TTC remodeling. Ultimately, the immune-privileged status of TTCs represents an essential evolutionary trade-off, restricting local inflammation to preserve foxo -dependent structural plasticity and vital respiratory function.

Respiratory organs must balance their primary function of gas exchange with the constant threat of inhaled pathogens. In the Drosophila tracheal system, gas exchange occurs at the tracheal terminal cells (TTCs), the functional equivalents of mammalian alveoli. While bacterial infection triggers a robust innate immune response throughout the broader airway epithelium, we reveal that TTCs are uniquely exempt from this reaction. Mechanistically, TTCs lack expression of the membrane-associated peptidoglycan recognition receptor PGRP-LC. This absence protects these highly susceptible cells from Immune deficiency (Imd) pathway activation and subsequent JNK-mediated cell death, establishing TTCs as a distinct, immune-privileged niche. Ectopic immune activation via targeted PGRP-LCx overexpression in TTCs caused a severe reduction in branching, cellular damage, and ultimately cell death, phenotypes that were fully rescued by the depletion of AP-1 or foxo. Because both structural plasticity (in response to nutritional cues and hypoxia) and innate immune responses strictly require the transcription factor FoxO, we demonstrate that potent immune signaling is fundamentally incompatible with dynamic TTC remodeling. Ultimately, the immune-privileged status of TTCs represents an essential evolutionary trade-off, restricting local inflammation to preserve foxo-dependent structural plasticity and vital respiratory function.

Background: Octopamine, the functional equivalent of noradrenaline in invertebrates, is a key neuromodulator that also influences immune functions. However, the receptor‑specific roles of octopamine in regulating innate immunity in Drosophila melanogaster remain incompletely understood. Methods: Using loss‑of‑function mutants for the two major octopamine receptors Octβ1R and Octβ2R, combined with systemic bacterial infection models, bacterial clearance assays, in vivo and in vitro phagocytosis assays, and quantification of antimicrobial peptide (AMP) gene expression, we dissected the contribution of each receptor to distinct immune effector modules. Results: Flies deficient in Octβ1R or Octβ2R exhibited reduced survival and impaired bacterial clearance following systemic infection, which was associated with increased bacterial persistence. This phenotype correlated with reduced phagocytic activity of hemocytes in both in vivo and in vitro assays. In contrast, deficiency of Octβ1R or Octβ2R led to enhanced induction of a subset of essential AMP genes upon infection, indicating that octopamine signaling dampens specific humoral immune outputs. Conclusion: Our data demonstrate that octopamine exerts a decisive influence on the performance of the Drosophila innate immune system by differentially modulating cellular (phagocytosis) and humoral (AMP expression) immune modules in a receptor‑specific manner. These findings establish octopaminergic signaling through Octβ1R and Octβ2R as an important node of neuro‑immune regulation in invertebrates.

The polyamines putrescine, spermidine (Spd), and spermine have essential functions in cell growth and proliferation. Previous research has unveiled a potential link between polyamine metabolism and triacylglyceride (TAG) homeostasis. In this study, we utilized Drosophila melanogaster as a model to study the impact of dietary (Spd) on body TAG stores. We found that food supplementation with 1.0 mM and 2.5 mM Spd prevented the build‐up of TAG stores in female fruit flies monitored for up to 14 days post‐eclosion in a dose‐ and time‐dependent manner, without affecting their total protein content. Notably, a 7‐day treatment with 2.5 mM Spd also counteracted high‐sugar diet–induced obesity and accelerated the breakdown of existing TAG reserves in obese females. Mechanistic analysis revealed that the adipokinetic hormone (Akh) pathway but not the TAG lipase Brummer (Bmm) was required for the TAG‐lowering bioactivity of Spd. Remarkably, this TAG‐reducing activity was completely abolished when flies were fed a high‐yeast diet, which increases dietary protein. Analyses of the polyamine pattern of flies and their excreta revealed that under low dietary yeast conditions, the administered Spd did not result in a rise in the endogenous Spd level. Instead, the Spd metabolites putrescine and N ¹ ‐acetylated Spd were increased, which provides evidence for the induction of the catabolic arm of the polyamine pathway. Together, our data suggest that the administration of Spd at lower mM concentrations, if combined with a low‐protein diet, stimulates Akh‐dependent catabolic processes that facilitate the reduction of fat stores in D. melanogaster . This work uncovers a diet‐dependent metabolic role of Spd in fat storage regulation, which awaits confirmation in mammals and humans, and highlights the importance of nutrient context in modulating polyamine‐mediated metabolic outcomes.

Background/Objectives: Some marine plants and algae are known to exert health benefits. However, the long-term effects and underlying mechanisms of these health benefits are still poorly understood. For this reason, we have investigated an extract from the marsh samphire Salicornia europaea for its life-prolonging potential. Methods: We investigated the effect of an aqueous extract of Salicornia europaea (SEE) on the lifespan of several wild-type strains of Drosophila. In addition, we used deficient flies to elucidate the mechanism of the life-prolonging effects. Finally, we comprehensively phenotyped the treated animals. Results: Supplementing a standard diet with SEE extended the lifespan of different Drosophila laboratory strains by up to a third (37% in w¹¹¹⁸ and 19% in yw). A total of 0.05% of SEE were ineffective, whereas 0.2% induced robust lifespan prolongation. This effect was strictly sex-specific, as the SEE application was completely ineffective in males, while prolonging life in females. We found that the body fat content of SEE-treated female flies was lower compared to controls. The extract also positively impacted the lifespan of flies fed a high-fat diet but not a high-sugar diet. SEE exhibited a lipase-inhibitory activity in vitro. Moreover, SEE counteracted aging-associated loss of intestinal barrier integrity. The sex-specific lifespan extensions induced by the SEE entirely depended on functional Tor signaling in the flies. Tissue-specific silencing of the Tor signaling pathway in different cellular compartments of the intestine reduced, but did not altogether abolish, the lifespan-prolonging effect in females. Conclusions: SEE is a promising candidate for a health-promoting intervention, as it induces lifespan-prolonging and anti-obesogenic effects in a sex-specific manner. These effects depend on functional Tor and partially on FoxO signaling. Future studies should identify the active compounds in the extract.

Background: Long-term disruption of epithelial immune homeostasis plays a key role in the development and persistence of chronic lung diseases. The regulation of immune pathways, especially the NF-kB pathway, is crucial for maintaining this balance. A20 (TNFAIP3) acts as an inhibitor of the NF-kB pathway and has been linked to chronic lung disease.Methods: We investigated the functional role of A20 by studying its Drosophila ortholog, Trabid. trabid-deficient flies were analyzed for immune response activation, susceptibility to various airborne stressors (dehydration, chronic cigarette smoke, and hypoxia), and their cellular adaptation to hypoxia in the tracheal system.Results: trabid-deficient Drosophila exhibited chronically activated immune responses in airway epithelial cells. These animals showed markedly increased sensitivity to dehydration, cigarette smoke, and hypoxic stress. Moreover, the plastic (adaptive) response of terminal tracheal cells to hypoxia, normally present in wild-type animals, was lost.Conclusion: Loss of A20/Trabid leads to disease-associated phenotypes resulting not only from heightened epithelial immune activity, but also from a profound reduction in the organism’s ability to withstand environmental stresses. This highlights the dual importance of immune regulation and stress resistance in epithelial health and chronic lung disease.

Background: Sirtuins are deacetylases that are highly conserved throughout the animal kingdom. They act as metabolic sensors that coordinate cellular responses, allowing an adapted response to various stressors. Epithelial cells, especially those of the intestine, are directly exposed to a wide range of stressors. Together with the microbiota, they form a complex ecosystem with mutual influences. The significance of sirtuins in this complex system is still waiting to be clarified. Results: Here, we show that a protein-restricted diet strongly increases the intestinal expression of sirtuin 4 (dSirt4), the only mitochondrial sirtuin in Drosophila. To elucidate the effects of deregulated dSirt4 expression in the intestine, we analyzed dSirt4 knockout flies. These flies showed substantial changes in their intestinal proteome and physiological properties. One of the most striking effects was the strong induction of lysozymes in the intestine, with a corresponding increase in lysozyme activity. This effect was organ-autonomous, as it was also observed in flies with dSirt4 knocked out only in intestinal enterocytes. The significant increase in lysozyme abundance in response to tissue-specific dSirt4 knockdown did not reduce the total number of bacteria in the intestine. However, it did affect the microbiota composition by reducing the number of gram-positive bacteria. This effect on microbiota composition can be attributed to dSirt4-dependent lysozyme expression, which is absent in a lysozyme-deficient background. dSirt4 knockout in the enterocytes shortened the lifespan of the flies, as did ectopic lysozyme overexpression in the enterocytes. Conclusions: The only mitochondrial sirtuin in Drosophila, dSirt4, is induced by dietary stress in intestinal epithelial cells, which directly regulates the lysozyme activity of these cells. We could associate this altered lysozyme activity with a shift in the microbiota composition, demonstrating a direct link between stress, nutrition, and the host’s microbiota regulation.

Summary: Airway epithelia must maintain barrier integrity while continuously adapting to changing environmental conditions. This requires key signaling pathways in airway epithelia to operate within a tightly controlled functional range. Here, we show that airway epithelial homeostasis in Drosophila depends on balanced JAK/STAT signaling. Basal pathway activity is constitutively present in differentiated epithelial cells and is necessary for cell survival, epithelial integrity and stress resistance. In accordance with this role as a stress responsive regulator in epithelial biology, environmental stressors, including hypoxia, cigarette smoke, and cold exposure, induce JAK/STAT signaling. In contrast, sustained pathway activation is associated with airway remodeling characterized by epithelial thickening, luminal narrowing, and altered cellular organization. Transcriptomic analysis reveals that sustained activation is associated with a coordinated epithelial stress program integrating immune signaling, proteostasis, and metabolic adaptation. Cross-species comparisons with murine and human datasets suggest that key aspects of this response are conserved. Pharmacological inhibition demonstrates that remodeling depends on continued pathway activity and can be partially reversed in vivo . Together, our findings support a model in which airway epithelial homeostasis depends on maintaining JAK/STAT signaling within a defined functional range. This “Goldilocks” principle provides a conceptual framework for understanding how epithelial stress responses are balanced under physiological and pathological conditions. Graphical

Time‐restricted feeding (TRF), a dietary intervention involving daily fasting periods, has been associated with metabolic benefits; however, its long‐term physiological impact remains unclear. Using Drosophila melanogaster as a model, we investigated the effects of a 16:8 TRF regimen on lifespan, reproductive output, gut health, and microbiota composition. TRF significantly extended lifespan, even when applied only during early adulthood. Notably, this longevity benefit occurred without compromising reproductive fitness, as measured by female fecundity in life's most crucial reproductive phase. TRF promoted gut homeostasis in aged flies by reducing intestinal stem cell proliferation and enhancing epithelial barrier integrity. Furthermore, TRF induced a shift in microbiota composition, increasing the prevalence of gram‐negative bacterial taxa. These results show that even short‐term TRF interventions at a young age can have long‐term physiological benefits. Metabolic reprogramming or increased autophagy are the most likely mechanisms mediating the health‐promoting effects of this type of nutritional intervention. TRF is an effective, non‐invasive strategy for promoting healthy longevity without significant adverse effects on other aspects of life.