Exploring the Therapeutic Potential of Decanoic Acid and Methyl Jasmonate in Ageing and PLA2G6-Associated Neurodegeneration Using Drosophila melanogaster

Ageing is a complex biological process that increases vulnerability to age-related diseases, including neurodegenerative diseases (NDs). As the ageing population grows, both ageing and NDs represent significant global health challenges, highlighting the need for innovative therapeutic strategies. PLA2G6-associated neurodegeneration (PLAN) is a group of rare genetic disorders caused by a loss-of-function mutation in the PLA2G6 gene. This project utilises Drosophila melanogaster, a well-established model for ageing and NDs, to investigate the longevity-promoting and neuroprotective effects of two plant-derived compounds, decanoic acid (DA) and methyl jasmonate (MeJA). The first data chapter investigated DA and MeJA in wild-type flies, reporting lifespan extension and improved oxidative stress resistance, with DA uniquely conferring greater starvation resilience. Molecular results indicated that DA primarily modulates mTOR signalling, while MeJA specifically targets IIS, sirtuin, and heat shock pathways. Both compounds modulated immune responses, autophagy initiation, and mitochondrial dynamics, with metabolomics highlighting age-dependent, tissue-specific metabolic responses. The second data chapter demonstrated that DA significantly extends lifespan, reduces bang sensitivity, and enhances heat shock resistance in PLAN models. Molecular analyses revealed that DA modulates pathways including IIS/TOR signalling, sirtuin activity, autophagy, mitochondrial function, and induces metabolic shifts, particularly in gut tissues. The third data chapter focused on MeJA in PLAN models, showing lifespan extension, reduced bang sensitivity, and enhanced stress resistance. Gene expression analysis also revealed changes involving IIS/TOR signalling, heat shock proteins, sirtuins, autophagy, and mitochondrial function. Together, these studies indicate that DA and MeJA enhance longevity and stress resilience through overlapping yet distinct mechanisms involving stress response, autophagy, mitochondrial maintenance, and metabolic modulation. This thesis discusses and critically evaluates the effects of DA and MeJA on ageing and neurodegenerative diseases. Although further investigation is required for clinical translation, these studies collectively demonstrate the therapeutic potential of DA and MeJA in slowing ageing and serving as pharmacological interventions for PLAN.