Vitamin D Metabolism and Lifespan Determination

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DESCRIPTION (provided by applicant): Vitamin D has a critical role in bone mineral homeostasis but also has a broad range of other physiological effects. Deficiency of 25-hydroxyvitamin D, the major circulating form, is associated with increased risk of age-related chronic conditions including Alzheimer's disease, Parkinson's disease, cognitive impairment and a wide range of cancers. However, the mechanism that links vitamin D deficiency to diverse chronic diseases is unknown but it is suspected that elderly populations are vitamin D deficient. We have discovered that exposure of adult Caenorhabditis elegans (C. elegans) to D3 prevented the accumulation of a diverse range of insoluble proteins during aging and extended lifespan. It also prevents the aggregation of Abeta peptide. We have preliminary data that suggests that these beneficial effects require the endoplasmic reticulum unfolded protein response (ER UPR) and a nuclear hormone receptor (NHR-226) which may be acting as a vitamin D receptor. We aim to uncover the mechanism at play with a view to understanding the role played by vitamin D in human health. We propose to establish whether the effects of vitamin D are through a nuclear or a non-nuclear mechanism and establish how vitamin is affecting protein homeostasis. To do so, we must first understand vitamin D metabolism in C. elegans so we can manipulate vitamin D action. We expect our results could be influential how vitamin D is studied in relation to human chronic disease.