Anti-aging and immunomodulatory role of caffeine in Drosophila larvae

Abstract

Drug repurposing is a promising approach to identify new pharmacological indications for drugs that have already been established. However, there is still a limitation in the availability of a high-throughput <i>in vivo</i> preclinical system that is suitable for screening and investigating new pharmacological indications. The aim of this study was to introduce the application of <i>Drosophila</i> larvae as an <i>in vivo</i> platform to screen drug candidates with anti-aging and immunomodulatory activities. To determine whether <i>Drosophila</i> larvae can be utilized for assessing anti-aging and immunomodulatory activities, phenotypical and molecular assays were conducted using wildtype and mutant lines of <i>Drosophila</i>. The utilization of mutant lines (<i>PGRP-LBΔ</i> and <i>Psh[1];;ModSP[KO]</i>) mimics the autoinflammatory and immunodeficient conditions in humans, thereby enabling a thorough investigation of the effects of various compounds. The phenotypical assay was carried out using survival and locomotor observation in <i>Drosophila</i> larvae and adult flies. Meanwhile, the molecular assay was conducted using the RT-qPCR method. <i>In vivo</i> survival analysis revealed that caffeine was relatively safe for <i>Drosophila</i> larvae and exhibited the ability to extend <i>Drosophila</i> lifespan compared to the untreated controls, suggesting its anti-aging properties. Further analysis using the RT-qPCR method demonstrated that caffeine treatment induced transcriptional changes in the <i>Drosophila</i> larvae, particularly in the downstream of NF-κB and JAK-STAT pathways, two distinct immune-related pathways homologue to humans. In addition, caffeine enhanced the survival of <i>Drosophila</i> autoinflammatory model, further implying its immunosuppressive activity. Nevertheless, this compound had minimal to no effect on the survival of <i>Staphylococcus aureus-</i>infected wildtype and immunodeficient <i>Drosophila</i>, refuting its antibacterial and immunostimulant activities. Overall, our results suggest that the anti-aging and immunosuppressive activities of caffeine observed in <i>Drosophila</i> larvae align with those reported in mammalian model systems, emphasizing the suitability of <i>Drosophila</i> larvae as a model organism in drug repurposing endeavors, particularly for the screening of newly discovered chemical entities to assess their immunomodulatory activities before proceedings to investigations in mammalian animal models.

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