ORCID

0000-0001-6575-9729 (Sanders)

Document Type

Article

Publication Date

2026

DOI

10.3389/fragi.2026.1816071

Publication Title

Frontiers in Aging

Volume

7

Pages

1816071

Abstract

Aging is a major risk factor for many chronic lung diseases, including Idiopathic Pulmonary Fibrosis (IPF), a fatal and incurable disease characterized by progressive fibrotic remodeling. Age-associated structural alterations, impaired regenerative capacity, and dysregulated cellular signaling collectively create a pro-fibrotic microenvironment. A central driver of this pathological shift is the accumulation of senescent cells, which undergo irreversible growth arrest and develop a robust pro-inflammatory senescence-associated secretory phenotype (SASP). Emerging evidence identifies senescent lung fibroblasts as critical mediators of IPF pathogenesis. These cells promote excessive extracellular matrix deposition, myofibroblast differentiation, and tissue stiffening, while simultaneously impairing epithelial regeneration. Together, these effects create self-reinforcing feedback loops that perpetuate fibrotic remodeling and disease progression. To therapeutically target this process, strategies to use senolytics and senomorphics have been developed to eliminate senescent fibroblasts or attenuate their pathogenic secretory programs. However, significant translational challenges remain, including senescent cell heterogeneity, the lack of definitive and cell-specific biomarkers, and the need for targeted delivery approaches to enhance precision and minimize off-target effects. In this review, we delineate the mechanisms by which cellular senescence reprograms fibroblast function and disrupts normal lung repair to drive fibrosis, evaluate emerging therapeutic strategies, and discuss the key obstacles needed to be addressed to advance senescence-targeted interventions for IPF.

Rights

© 2026 Palega, Borengasser and Sanders.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Original Publication Citation

Palega, S. B., Borengasser, A. Y., & Sanders, Y. Y. (2026). Senescent fibroblasts in aging and pulmonary fibrosis. Frontiers in Aging, 7, Article 1816071. https://doi.org/10.3389/fragi.2026.1816071

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