Inhibition of JAK-STAT Signaling with Baricitinib Reduces Inflammation and Improves Cellular Homeostasis in Progeria Cells

Cells. 2019 Oct 18;8(10):1276. doi: 10.3390/cells8101276.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke, is caused by mutations in the LMNA gene. Nearly 90% of HGPS cases carry the G608G mutation within exon 11 that generates a truncated prelamin A protein "progerin". Progerin accumulates in HGPS cells and induces premature senescence at the cellular and organismal levels. Children suffering from HGPS develop numerous clinical features that overlap with normal aging, including atherosclerosis, arthritis, hair loss and lipodystrophy. To determine whether an aberrant signaling pathway might underlie the development of these four diseases (atherosclerosis, arthritis, hair loss and lipodystrophy), we performed a text mining analysis of scientific literature and databases. We found a total of 17 genes associated with all four pathologies, 14 of which were linked to the JAK1/2-STAT1/3 signaling pathway. We report that the inhibition of the JAK-STAT pathway with baricitinib, a Food and Drug Administration-approved JAK1/2 inhibitor, restored cellular homeostasis, delayed senescence and decreased proinflammatory markers in HGPS cells. Our ex vivo data using human cell models indicate that the overactivation of JAK-STAT signaling mediates premature senescence and that the inhibition of this pathway could show promise for the treatment of HGPS and age-related pathologies.

Keywords: Baricitinib; JAK-STAT; Progeria; Progerin; Senescence; age-related disease; inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Alopecia / metabolism
  • Arthritis / metabolism
  • Autophagy / drug effects
  • Autophagy / genetics
  • Azetidines / pharmacology*
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cells, Cultured
  • Cellular Senescence / drug effects
  • Child
  • Child, Preschool
  • Data Mining
  • Etoposide / pharmacology
  • Female
  • Humans
  • Immunohistochemistry
  • Inflammation / metabolism*
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / metabolism
  • Lamin Type A / genetics
  • Lamin Type A / metabolism
  • Lipodystrophy / metabolism
  • Male
  • Mutation / genetics
  • Progeria / metabolism*
  • Reactive Oxygen Species / metabolism
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • Sulfonamides / pharmacology*
  • Vascular Diseases / metabolism

Substances

  • Azetidines
  • LMNA protein, human
  • Lamin Type A
  • Reactive Oxygen Species
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Sulfonamides
  • Etoposide
  • Adenosine Triphosphate
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • baricitinib