Show Notes
Sengstack J et al., Proc. Natl. Acad. Sci. U.S.A - TRDP with Perturb-seq in human fibroblasts found that manipulating TFs (EZH2, E2F3, STAT3, ZFX) reversed aging hallmarks, and EZH2 overexpression rejuvenated aged mouse livers.
Study Highlights:
The study used passaged human neonatal dermal fibroblasts and aged mouse liver as model systems and applied the Transcriptional Rejuvenation Discovery Platform (TRDP) with Perturb-seq and CRISPRa/CRISPRi screens. Overexpressing E2F3 or EZH2 and repressing STAT3 or ZFX reversed global gene expression toward earlier passage states and ameliorated cellular aging hallmarks including increased proliferation, proteasome activity, and mitochondrial function. In aged mice, AAV8-mediated liver-specific EZH2 overexpression (log2fc ≈ 2.9) reversed thousands of age-associated gene changes (R_rej = -0.42), reduced steatosis and fibrosis, and improved glucose tolerance. Downstream transcriptional programs converged across perturbations, suggesting shared molecular requirements for cellular and tissue rejuvenation.
Conclusion:
Single transcription factor perturbations identified by TRDP can reverse cellular aging hallmarks in human fibroblasts and, in the case of EZH2 overexpression, partially rejuvenate aged mouse liver with improved histology and glucose tolerance.
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Reference:
Sengstack J, Li H, Aghayev T, Bier G, Mobaraki M, Zheng J, Lin J, Deng C, Villeda SA, et al. Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation. Proc. Natl. Acad. Sci. U.S.A. 2026;123:e2515183123. Published January 9, 2026. https://doi.org/10.1073/pnas.2515183123
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/
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