Small (Weinheim an der Bergstrasse, Germany)Aug 12, 2026

Attaching enzyme-activated glowing markers to track aging cells over time in lung scarring

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 13, 2026

Abstract

TCFM-Gal achieves over 85% signal retention in lysosomes for imaging senescent cells within 24 hours.

Senescence-associated beta-galactosidase (SA-beta-Gal) is a key biomarker for idiopathic pulmonary fibrosis (IPF).
Current imaging probes for SA-beta-Gal are limited by signal diffusion and rapid clearance.
TCFM-Gal utilizes an enzyme-activated labeling strategy to improve imaging fidelity by covalently anchoring signals within cells.
In senescent cells, TCFM-Gal enables extended imaging by retaining fluorescence in lysosomes.
TCFM-Gal allows for longitudinal tracking of senescent cells in an IPF model and maintains high signal intensity beyond 24 hours.
This imaging tool aids in assessing the progression of fibrosis by quantifying the senescence burden across different disease phases.

Simplified

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease caused by the pathological accumulation of senescent cells. In this fibrotic microenvironment, senescence-associated β-galactosidase (SA-β-Gal) serves as a key biomarker. However, existing SA-β-Gal molecular probes suffer from signal diffusion and rapid clearance due to the extracellular leakage, compromising imaging fidelity. To address this issue, an enzyme-activated covalent labelling strategy is proposed, and as a design paradigm developing TCFM-Gal, a imaging tool integrating β-galactosidic fluorophore with an ortho-difluoromethyl leaving group. Upon SA-β-Gal-mediated hydrolysis, TCFM-Gal generates a quinone methide intermediate that covalently anchors to surrounding nucleophiles, confining fluorescence within lysosomes. In senescent cells, TCFM-Gal achieves extended lysosome-retained imaging, maintaining over 85% signal retention within 24 h. In the IPF model, TCFM-Gal enables longitudinal tracking of senescent cells and maintains a high signal intensity after 24 h. Rapid circulatory washout and high interstitial fluid pressure make conventional probes ineffective in the lungs. TCFM-Gal overcomes this not just by sensing, but by anchoring the signals in situ. Moreover, TCFM-Gal facilitates staging assessments of fibrosis progression by quantifying the senescence burden across disease phases. This study establishes an enzyme-activated covalent labeling paradigm for high-fidelity senescence imaging, advancing the spatiotemporal mapping of senescence in lung diseases.

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Attaching enzyme-activated glowing markers to track aging cells over time in lung scarring

Abstract

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