Emran, S; (2015) Understanding the mechanisms of dietary restriction to extend healthy lifespan in Drosophila melanogaster. Doctoral thesis , UCL (University College London).

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Abstract

Dietary restriction (DR), defined as a moderate reduction in food intake short of malnutrition, has been shown to extend healthy lifespan in a diverse range of organisms, from yeast to primates. In this work we aim to uncover the mechanism by which DR extends lifespan. The prevailing theory of somatic maintenance by resource reallocation proposes that the balance of nutrient allocation is weighted either towards reproduction, when environmental nutrients are abundant, or towards maintenance of the soma when food is limited, thereby aiding organismal survival during food shortages. This theory has found support in reports that dietary restricted Drosophila melanogaster (fruit fly) benefit from increased lifespan but have compromised reproduction, and that the inverse is true of fully fed flies. It has recently been found that addition of the ten essential amino acids (EAA) to a DR diet is sufficient to decrease lifespan and increase fecundity to the same degree as full feeding, implicating EAAs as the dietary mediators of the responses of lifespan and fecundity to DR. In this thesis I characterise the physiological and metabolic parameters that define DR flies, fully fed flies and EAA-supplemented DR flies, with the aim of identifying candidate factors that consistently correlate with lifespan for the three treatments in order to identify the causes of longer life in response to DR. We also use genetic tools to explore the role of nutrient signalling pathways in mediating the relationship between nutrition and ageing, with special focus on the amino acid sensitive target of rapamycin (TOR) pathway, the insulin/insulin-like growth factor signalling (IIS) pathway, and the general amino acid control (GAAC) pathway. These studies find a role for TOR signalling in mediating the effects of DR on lifespan and this effect appears to be different from those caused by altered IIS and GAAC pathways. These data also implicate accumulation of fat as consistently correlated with, and so possibly causal for, longer life. Finally, I investigated the potential roles that these nutrient sensing/signalling pathways might play in modifying feeding behaviour in response to changes in dietary nutrient quality. Here, the GAAC pathway proved to play an important and specific role in the way single amino acid deficient foods are detected to alter feeding behavior. These data are somewhat consistent with mammalian studies on nutrient-specific feeding alterations and establish the groundwork for detailed studies into the molecular processes involved. As a combined body of work, this thesis outlines important data on the mechanisms of DR to extend life as well as new information about the nutrients and molecular signals involved in shaping feeding choices.

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