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Title: Vitellogenesis and senescence in Caenorhabditis elegans
Author: Sornda, Thanet
ISNI:       0000 0004 7970 6996
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Advancing age comes with an increasing risk of developing multiple diseases. For example, a prominent pathology in ageing C. elegans hermaphrodites is the ectopic deposition of yolk in the pseudocoelom. Yolk has a major role in provisioning developing oocytes during reproduction. It mainly consists of yolk lipids and yolk proteins (YP, vitellogenins), existing as three abundant species: YP170, YP115 and YP88. Interestingly, post-reproductive yolk accumulation is accompanied by atrophy of the intestine, the animal's principal metabolic organ and the site of yolk synthesis (vitellogenesis). Studying the aetiologies of these age-related visceral pathologies may help us better understand ageing. The main aim of this thesis is to characterise these pathologies further to better understand the underlying mechanisms of ageing. This thesis demonstrates the validity of the vitellogenic open tap model of yolk accumulation, involving cessation of egg laying due to depletion of sperm, but seemingly futile run-on of yolk synthesis. YP170 levels increase steadily between day 1 and day 14 of adulthood, implying unregulated yolk production after reproduction (a vitellogenic open tap). Vitellogenesis is coupled to intestinal atrophy in an autophagy-mediated process of gut-to-yolk biomass conversion, which is promoted by daf-2 insulin/IGF-1 signalling (IIS). Mutation of IIS or autophagy reduces yolk accumulation and intestinal atrophy and increases lifespan. YP170 is the major yolk protein that causes intestinal atrophy. Blocking YP170 synthesis reciprocally increases YP115/YP88 levels, and vice versa. However, reducing YP170 alone increases lifespan to almost the same extent as reducing both YP170 and YP115/YP88. Moreover, this study shows that increasing YP115/YP88 levels increases resistance to oxidative stress. Overall, this thesis suggests that late-life vitellogenesis is a futile quasi-programme that causes multiple pathologies. This supports the hyper-function model of antagonistic pleiotropy where ageing results from run-on of biological programmes specified by wild-type gene action (here vitellogenesis, promoted by wild-type insulin/IGF-1 signalling), rather than stochastic damage accumulation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available