Senescence cell induction methods display diverse metabolic reprogramming and reveal an underpinning serine/taurine reductive metabolic phenotype

Tools

Berardi, Domenica and Farrell, Gillian and AlSultan, Abdullah and McCulloch, Ashley and Hall, Nicole M. and Pereira Sousa, Rui Pedro and Jimenez, Melanie and Selman, Colin and Bellantuono, Ilaria and Johnson, Caroline H. and Rattray, Zahra and Rattray, Nicholas J. W. (2025) Senescence cell induction methods display diverse metabolic reprogramming and reveal an underpinning serine/taurine reductive metabolic phenotype. Aging Cell. e70127. ISSN 1474-9726 (https://doi.org/10.1111/acel.70127)

[thumbnail of Berardi-etal-AC-2025-Senescence-cell-induction-methods-display-diverse-metabolic]
Preview
 Text. Filename: Berardi-etal-AC-2025-Senescence-cell-induction-methods-display-diverse-metabolic.pdf
Final Published Version
License: Creative Commons Attribution 4.0 logo
Download (5MB)| Preview

Abstract

The relationship between in vitro senescence cell induction and intracellular biomolecular dysregulation is still poorly understood. In this study, we have found that a range of metabolic subphenotypes exists and is dependent on the induction method that is used. To develop understanding of these subphenotypes, we developed and employed a novel bioanalytical pipeline integrating untargeted metabolomics, label-free proteomics, and stable isotope tracing alongside cellular deformability measurements and established senescence biomarkers. Initially, standard senescent markers indicated all induction methods were consistent by showing elevated SA-β-Gal expression, p21 levels, and γH2AX DNA damage markers alongside a decrease in Ki67 and an increase in shape, volume, and deformability. However, when probed at the metabolic and protein levels, all senescence models indicated both shared and unique biomolecular responses. A metabolic shift toward reductive pathways (driven by serine and taurine rewiring) and impaired proteostasis was an observed shared response. These findings suggest that targeting metabolic redox circuits, alongside serine and taurine metabolic processes, presents novel therapeutic strategies for addressing senescence and aging. But importantly, alongside this general shift, we found that significant metabolic and proteomic heterogeneity also exists across different senescence induction methods. This demonstrates that the method of senescence induction significantly influences cell metabolic and proteomic profiles. Critically, methods of senescence induction are not interchangeable, and careful consideration is needed when choosing between different induction methods and when comparing cellular phenotypes across different in vitro senescence experiments.

ORCID iDs

Berardi, Domenica, Farrell, Gillian, AlSultan, Abdullah, McCulloch, Ashley, Hall, Nicole M. ORCID logoORCID: https://orcid.org/0000-0001-8328-8094, Pereira Sousa, Rui Pedro ORCID logoORCID: https://orcid.org/0000-0002-3305-1504, Jimenez, Melanie ORCID logoORCID: https://orcid.org/0000-0002-4631-0608, Selman, Colin, Bellantuono, Ilaria, Johnson, Caroline H., Rattray, Zahra ORCID logoORCID: https://orcid.org/0000-0002-8371-8549 and Rattray, Nicholas J. W. ORCID logoORCID: https://orcid.org/0000-0002-3528-6905;
CORE (COnnecting REpositories)