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.
Highlights
Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare fatal pediatric disorder characterized by segmental severe premature aging and early death for which no cure exists [1].Patients suffering from HGPS show clinical features resembling physiological aging, including vascular disease, lipodystrophy, alopecia, progressive joint contractures and stiffness, and osteoporosis, that lead to shortened life span and death at approximately 14.7 years of age [1,2]
Text Mining Analysis to Identify Genes Altered in Vascular Disease, Arthritis, Alopecia and Lipodystrophy
In total 157 genes were associated with alopecia, 67 genes were associated with lipodystrophy, 1049 genes were associated with arthritis, and 1560 genes were associated with vascular disease (Table S1)
Summary
Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare fatal pediatric disorder characterized by segmental severe premature aging and early death for which no cure exists [1].Patients suffering from HGPS show clinical features resembling physiological aging, including vascular disease, lipodystrophy, alopecia, progressive joint contractures and stiffness, and osteoporosis, that lead to shortened life span and death at approximately 14.7 years of age [1,2]. The genetic basis of HGPS is linked to mutations in the LMNA gene [3]. In the majority of HGPS cases, a single de novo mutation (LMNA 1824C >T, G608G) activates a cryptic splicing site, causing the production of a truncated prelamin A protein with a 50 amino acid deletion called progerin. Among all of the traits that characterize HGPS patients, we focused on the four conditions typically recognized, namely, vascular disease, arthritis, lipodystrophy, and alopecia. These pathologies are not specific to HGPS, as these conditions develop in patients suffering from other progeroid
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