# Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGFβ1

## TL;DR

This study shows that aging reduces autophagy and mitophagy in the lungs, contributing to pulmonary fibrosis, and suggests that improving these processes could help treat age-related fibrotic diseases.

## Contribution

The study identifies age-related defects in autophagy and mitophagy as key contributors to pulmonary fibrosis and highlights TGFβ1's role in this process.

## Key findings

- Older mice show reduced autophagy and elevated oxidized proteins after lung injury.
- TGFβ1-induced FMD is associated with reduced autophagy flux and mitochondrial dysfunction.
- PINK1 expression is reduced in fibrotic lung tissue and IPF patient biopsies.

## Abstract

Aging constitutes a significant risk factor for fibrosis, and idiopathic pulmonary fibrosis (IPF) is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to pulmonary fibrosis. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to lung injury in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to lung injury are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy (mitophagy). Fibroblast to myofibroblast differentiation (FMD) is an important feature of pulmonary fibrosis in which the profibrotic cytokine TGFβ1 plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts’ fate. On the contrary, FMD mediated by TGFβ1 is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a TGFβ1-adenoviral model of lung fibrosis. PINK1 expression is also reduced in the aging murine lung and biopsies from IPF patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to lung injury may contribute to the promotion and/or perpetuation of pulmonary fibrosis. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases.