Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes SKN-1, IRE-1, and XBP-1

Vitamin D is a secosteroid that has multiple regulatory roles including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitamin D, the major circulating form of vitamin D, is associated with an increased risk of age-related chronic diseases including Alzheimer's disease, Parkinson's disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that Vitamin D3-induced lifespan extension requires the stress response pathway genes SKN-1, IRE-1, and XBP-1. Vitamin D3 induced expression of SKN-1 target genes, but not canonical targets of IRE-1/XBP-1. Vitamin D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented the toxicity caused by human ß-amyloid. Our observation that vitamin D3 improves protein homeostasis and slows aging highlights the importance of maintaining appropriate vitamin D serum levels, and may explain why such a wide variety of human age-related diseases are associated with a vitamin D deficiency. Overall design: The experimental design consisted of contrasting gene expression data derived from RNA extracted from pools of synchronized aged worms. L4 worms were placed on either vehicle (DMSO) or Vitamin D (100uM) for 44 hours prior to extraction. A pool of 50 worms was considered a single biological replicate. For the Vitamin D treated group, there were 6 independent biological replicates, and were compared with a group of untreated (vehicle) wild-type N2 animals, also using 6 biological replicates.

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Mark KA, Dumas KJ, Bhaumik D, Schilling B, Davis S, Oron TR, Sorensen DJ, Lucanic M, Brem RB, Melov S, Ramanathan A, Gibson BW, Lithgow GJ