Open AccessmTORC 1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts
Author(s) -
Romero Yair,
Bueno Marta,
Ramirez Remedios,
Álvarez Diana,
Sembrat John C.,
Goncharova Elena A.,
Rojas Mauricio,
Selman Moisés,
Mora Ana L.,
Pardo Annie
Publication year - 2016
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12514
Subject(s) - autophagy , idiopathic pulmonary fibrosis , pi3k/akt/mtor pathway , mtorc1 , myofibroblast , cancer research , biology , apoptosis , pulmonary fibrosis , protein kinase b , lung , microbiology and biotechnology , signal transduction , fibrosis , medicine , pathology , biochemistry
Summary Idiopathic pulmonary fibrosis ( IPF ) is a chronic, progressive, and usually lethal disease associated with aging. However, the molecular mechanisms of the aging process that contribute to the pathogenesis of IPF have not been elucidated. IPF is characterized by abundant foci of highly active fibroblasts and myofibroblasts resistant to apoptosis. Remarkably, the role of aging in the autophagy activity of lung fibroblasts and its relationship with apoptosis, as adaptive responses, has not been evaluated previously in this disease. In the present study, we analyzed the dynamics of autophagy in primary lung fibroblasts from IPF compared to young and age‐matched normal lung fibroblasts. Our results showed that aging contributes for a lower induction of autophagy on basal conditions and under starvation which is mediated by mTOR pathway activation. Treatment with rapamycin and PP 242, that target the PI 3K/ AKT / mTOR signaling pathway, modified starvation‐induced autophagy and apoptosis in IPF fibroblasts. Interestingly, we found a persistent activation of this pathway under starvation that contributes to the apoptosis resistance in IPF fibroblasts. These findings indicate that aging affects adaptive responses to stress decreasing autophagy through activation of mTORC 1 in lung fibroblasts. The activation of this pathway also contributes to the resistance to cell death in IPF lung fibroblasts.