Vitamin D Promotes Protein Homeostasis and Longevity via the Stress Response Pathway Genes skn-1, ire-1, and xbp-1

Cell Rep. 2016 Oct 25;17(5):1227-1237. doi: 10.1016/j.celrep.2016.09.086.

Abstract

Vitamin D has multiple 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 (D3) induced expression of SKN-1 target genes but not canonical targets of XBP-1. D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented toxicity caused by human β-amyloid. Our observation that 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 vitamin D deficiency.

Keywords: Alzheimer’s disease; Ceanorhabditis elegans; IRE-1; SKN-1; XBP-1; insoluble protein; lifespan. aging; protein aggregation; proteostasis; vitamin D.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / physiology
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Calcitriol / metabolism
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cholecalciferol / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Homeostasis / drug effects*
  • Longevity / physiology*
  • Protein Aggregates
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Solubility
  • Stress, Physiological / genetics*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Unfolded Protein Response / drug effects
  • Vitamin D / pharmacology*

Substances

  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • DNA-Binding Proteins
  • Protein Aggregates
  • Transcription Factors
  • XBP-1 protein, C elegans
  • Vitamin D
  • skn-1 protein, C elegans
  • Cholecalciferol
  • Protein-Serine-Threonine Kinases
  • IRE-1 protein, C elegans
  • Calcitriol