Sumit, Ahmed Faisal; (2025) Adrenergic signalling in ageing: Role of tyramine and octopamine in Drosophila. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The vertebrate adrenergic signalling system is initiated by the neuronal or endocrine release of the biogenic amines, namely adrenaline and noradrenaline, that controls physiology to ensure survival through a family of related receptors. Such neuroendocrine signalling pathways can profoundly alter the rate of ageing, and adrenergic signalling has been implicated in several age-related diseases. Nonetheless, the potential for adrenergic signalling pathways to modulate ageing has received relatively less attention so far. Insects, such as fruit flies, have a signalling system initiated by the biogenic amines tyramine (TA) or octopamine (OA) that is functionally equivalent, albeit not orthologous to the mammalian adrenergic signalling pathway. In my main PhD project, I aim to examine whether altering such a conserved pathway by manipulating TA and OA in fruit flies could enhance the health and survival of the whole organism. I observe that an increase in neuronal TA production promotes health at older age, such as preservation of neuromuscular function and maintenance of gut health, and is sufficient to extend lifespan in both sexes. Administration of TA through feeding can promote lifespan in females. Administering OA either through neuronal induction or in food has marginal beneficial longevity effects in males. Increased activation of the β-adrenergic like signalling cascades in the female guts, including the activation of protein kinase A (PKA) and its downstream transcription factor, cAMP response element binding protein B (CrebB), can recapitulate the beneficial longevity effects of TA feeding, whereas limiting the activity of CrebB completely abrogates that response. Transcriptional profiling in the gut reveals that TA and CrebB share significant similarities in the transcripts they regulate in females, and assessing the gene ontology (GO) categories enriched within these differentially expressed transcripts identifies several pathways linked to longevity. Promoting β-adrenergic like signalling cascades in other tissues, notably in fat body and neurons, does not confer such longevity benefits. Hence, I successfully show that localised activation of β-adrenergic signalling cascades, specifically in the female gut, can delay the ageing of the whole organism. In my 2nd PhD project, which is only distantly related to the main project, I aim to investigate the functionally conserved role of a long noncoding RNA (lncRNA) from yeast to fruit fly. This lncRNA, which is known as aal1, was recently identified in yeast as reducing total ribosomal contents, inhibiting cellular protein translation, and extending chronological lifespan. Here, I show that aal1 overexpression in adult midguts could promote fruit fly lifespan, indicating that the functional role of lncRNAs may be conserved across the species.

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