Update of Aging Hallmarks in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is an epithelial-driven interstitial lung disease of unknown etiology characterized by the excessive proliferation of fibroblast populations that synthesize large amounts of extracellular matrix. In this devastating disorder, all aging hallmarks appear prematurely or are altered. This review highlights key findings about IPF characteristics recently recognized as hallmarks of aging, including mechanical alterations, inflammaging, dysbiosis, alternative splicing, and disabled macroautophagy. It also revisits the classic hallmarks of aging, which encompass stem cell exhaustion, cellular senescence, and altered intercellular communication. Enhancing our understanding of the fundamental processes that underlie the altered hallmarks of aging in IPF may facilitate the development of innovative experimental strategies to improve therapeutic outcomes.

Keywords: aging hallmarks; alternative splicing; dysbiosis; idiopathic pulmonary fibrosis; inflammaging; mechanical alterations.

Figure 1

Disabled macroautophagy in pulmonary fibrosis. Evidence from fibrosis animal models and in vitro studies with TGFβ suggests that the PI3K/AKT/mTOR pathway may be activated in IPF, contributing to impaired macroautophagy in both epithelial cells (blue) and fibroblasts (green). Possible consequences of impaired macroautophagy are EMT and fibroblast-to-myofibroblast differentiation, which are considered key processes in the progression of IPF. Upward arrows mean upregulated expression and downward arrow means the opposite. Created in BioRender. Cisneros, J. (2025) https://BioRender.com/u17c477.

Figure 2

Some classic hallmarks of aging. In IPF (right), cells showed shortened telomeres and damaged mitochondria versus the healthy condition (left).

Figure 3

Cellular interplay with altered and premature aging hallmarks in IPF. (Left), healthy conditions. (Right), IPF. In IPF, AECs have changed; some have died by apoptosis, and many have been replaced by AbBa, compromising the alveolar integrity. Telomere attrition, genomic instability, epigenetic changes, and mitochondrial dysfunction have induced cell senescence. Extracellular vesicles are different, not only in protein content but also in the composition of miRNAs, circRNAs, and lncRNAs. Fibroblasts have been activated, proliferating and secreting vast amounts of extracellular matrix. Fibroblast macroautophagy is also altered, and proteostasis is lost. Macrophages are polarized to an M2 phenotype. T cells are not close to fibrotic foci. In the gut, there are pathogenic bacteria that communicate with the lungs through the vascular system. As there are not enough epithelial stem cells, tissue regeneration is complicated. Image by Víctor Oliveros.

Figure 4

Interactions between aging hallmarks in IPF. In orange are the classic hallmarks. In green are the complementary hallmarks. All of them play pertinent roles in the pathology.