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Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming

Lu, Jinlong Y., Tu, William B., Li, Ronghui, Weng, Mingxi, Sanketi, Bhargav D., Yuan, Baolei, Reddy, Pradeep, Rodriguez Esteban, Concepcion, Izpisua Belmonte, Juan Carlos·2025·Cell
DOI 10.1016/j.cell.2025.07.031
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Abstract

The loss of cellular and tissue identity is a hallmark of aging and numerous diseases, but the underlying mechanisms are not well understood. Our analysis of gene expression data from over 40 human tissues and 20 diseases reveals a pervasive upregulation of mesenchymal genes across multiple cell types, along with an altered composition of stromal cell populations, denoting a "mesenchymal drift" (MD). Increased MD correlates with disease progression, reduced patient survival, and an elevated mortality risk, whereas suppression of key MD transcription factors leads to epigenetic rejuvenation. Notably, Yamanaka factor-induced partial reprogramming can markedly reduce MD before dedifferentiation and gain of pluripotency, rejuvenating the aging transcriptome at the cellular and tissue levels. These findings provide mechanistic insight into the underlying beneficial effects of partial reprogramming and offer a framework for developing interventions to reverse age-related diseases using the partial reprogramming approach.

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  • Partial epigenetic reprogramming leverages transient expression of Yamanaka factors to rejuvenate cells and reverse senescence markers without inducing cell death, offering a route toward cellular restoration rather than removal.

    “An emerging, conceptually transformative frontier is partial epigenetic reprogramming, which leverages transient expression of Yamanaka factors to rejuvenate cells and reverse senescence markers without inducing cell death, offering a route toward cellular restoration rather than removal143–145.”

    From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [145]

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Metadata

Authors
Lu, J. Y., Tu, W. B., Li, R., Weng, M., Sanketi, B. D., Yuan, B., Reddy, P., Rodriguez Esteban, C., & Izpisua Belmonte, J. C.
Venue
Cell
Publisher
Elsevier BV
Published
2025-10
Volume
188
Issue
21
Pages
5895-5911.e17
ISSN
0092-8674
DOI
10.1016/j.cell.2025.07.031
Cited by
68
References
18
Language
en
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