Abstract
Cellular senescence is a complex biological process that plays a pathophysiological role in aging and age-related diseases. The biological understanding of senescence at the cellular and tissue levels remains incomplete due to the lack of specific biomarkers as well as the relative rarity of senescent cells, their phenotypic heterogeneity and dynamic features. This Review provides a comprehensive overview of multiomic approaches for the characterization and biological understanding of cellular senescence. The technical capability and challenges of each approach are discussed, and practical guidelines are provided for selecting tools for identifying, characterizing and spatially mapping senescent cells. The importance of computational analyses in multiomics research, including senescent cell identification, signature detection and interactions of senescent cells with microenvironments, is highlighted. Moreover, tissue-specific case studies and experimental design considerations for individual organs are presented. Finally, future directions and the potential impact of multiomic approaches on the biological understanding of cellular senescence are discussed.
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Acknowledgements
This work was supported by SenNet grants, including U54AG079753 (S.L., W.F.F., R.K., N.R., R.R., P.R.), U54AG075931 (P.A.A.G., J.C., Q.H., A.M., Q.M., M.K., A.M., M.B., J.L.-M., M.R., I.R., L.R., N.V., J.X.), U54AG076041 (C.A., A.C.N., L.J.N., Z.J., E.J.F., E.K., E.L.S., M.D., P.R., S.T.P., M.D.), U54AG075936 (C.G., Z.J.), U54AG079754 (N.K.L., D.B., J.W., S.T.P., A.H., X.Z.), U54AG075932 (C.B., F.D., B.S.), U54AG075941 (C.A.-M., J.C., W.F.F., V.G., S.H., K.I., T.T., J.K., N.M.), U54AG075934 (L.D.), UH3CA268202 (S.W.), UH3CA268091 (J.L.), UG3/UH3CA268096 (L.G., L.S.), UG3CA275669 (M.J.S.), UH3CA275687 (J.K., P.T.C.S., J.S., K.Z.), U54AG079779 (J.M., S.N., B.C., A.N.R.), UG3CA275681 (P.-H.W.), 1UG3CA268103 (A.C.F.), 1U54AG079779 (J.E., E.J.F., J.M., S.N., B.C., A.N.R.), 5UG3CA275681 (P.-H.W.) and 5U54-AG075936-04 (C.G.). S.L. is a recipient of a Career Development Award (1398-25) of the Leukemia & Lymphoma Society (2024–2029). A.B.H. is supported by the NIA IRP, NIH. J.L.K. is supported by the US NIH (grants R37AG013925 and R33AG061456), the Connor Fund, Robert J. and Theresa W. Ryan, the Hevolution Foundation and the Noaber Foundation.
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S.L., P.A.A.G., C.A., M.J.B., J.C., B.D.C., J.E., N.F., E.J.F., C.G., L.G., Q.H., Z.J., M.K., N.K.L., D.L., A.M., Q.M., V.M., J.T.M., A.L.M., S.N., A.C.N., L.J.N., M.R., H.B.T., J.W., S.W., P.-H.W., J.X., M.X., M.Y., X.Z., Y.Z., P.D.A., C.A.-M., D.J.B., C.B., D.A.B., M.B., J.C., B.G.C., J.H.C., D.C., M.D., L.D., M.D., F.D., A.E., W.F.F., A.C.F., D.F., V.G., S.H., A.B.H., A.V.H., K.I., H.J., J.W.K., S.K., J.L.K., R.K., E.K., J.H.L., Y.L., Y.L., J.L.-M., H.M., S.M., N.M., J.F.P., S.T.P., I.R., R.R., A.N.R., P.D.R., P.R., J.R.-L., L.R., N.R., M.J.S., B.S., E.L.S., K.S., K.S., J.S., P.T.C.S., L.S., T.T., M.G.T., N.V., J.W., J.X., S.Y., K.Z., Q.Z. and R.F. wrote and/or edited the manuscript for scientific content. S.L. and H.B.T. proofread the final published version.
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L.G. is a cofounder of TopoGene; N.K.L. and Mayo Clinic have intellectual property related to this research, which has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with its policies; S.W. is a co-inventor of the MERFISH technology patented by Harvard University; D.J.B. has a potential financial interest related to this research as a co-inventor on patents held by Mayo Clinic and patent applications licensed to or filed by Unity Biotechnology and is also a shareholder in Unity Biotechnology, with research reviewed and conducted in compliance with Mayo Clinic Conflict of Interest policies; B.G.C. has similar financial interests as a co-inventor on Mayo Clinic patents and is a Unity Biotechnology shareholder; M.J.S. and Mayo Clinic have intellectual property related to this research, reviewed and conducted in compliance with Mayo Clinic Conflict of Interest policies; J.H.L. is an inventor on a patent and pending patent applications related to Seq-Scope; R.F. is a scientific cofounder and advisor for IsoPlexis, Singleron Biotechnologies and AtlasXomics. J.L.K. and T.T. have financial interest related to this research, including patents and pending patents covering senolytic drugs and their uses held by Mayo Clinic. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic and Cedars-Sinai conflict-of-interest policies. All other authors declare no competing interests.
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Li, S., Agudelo Garcia, P.A., Aliferis, C. et al. Advancing biological understanding of cellular senescence with computational multiomics. Nat Genet 57, 2381–2394 (2025). https://doi.org/10.1038/s41588-025-02314-y
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DOI: https://doi.org/10.1038/s41588-025-02314-y
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