Abstract
Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field.
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Acknowledgements
The National Institutes of Health (NIH) Cellular Senescence Network (SenNet) Consortium mourns the loss of J. Campisi, who passed away unexpectedly in January 2024. Judy always enjoyed her science and her interactions with her mentees, collaborators and colleagues. She would actively participate in all our meetings and contribute with her innovative and creative scientific ideas. Over the past 40 years of Judy’s scientific career, she pioneered research related to cellular senescence and cell fate. Judy truly recognized the relevance of senescence in fundamental aspects of ageing and age-related disease, with a major focus of investigating senescent cells both in model organisms and in humans. With our work in the SenNet Consortium, we hope to take forward her legacy of advancing cellular senescence research and eventually improving human health. The authors thank A. Roy for providing valuable suggestions during the manuscript’s preparation. The manuscript was supported by the following grants: UG3CA268202 (N.N., A. Rocha), R01AG050582 (N.N.), F31AG072748 (A. Rocha), T32GM136566 (A.A.), 1RM1HG011014-01 (S.V.), 1U54AG076040-01 (S.V.), 1U54AG079758-01 (M.G.T., P.D.A., Q.Z., S.Y.), 23CDA1056892 (S. Suvakov), Hevloution/AFAR (D.J.), R01AG68048 (J.F.P.), R01AG82708 (J.F.P.), AG068182 (D.J.), UG3CA268103 (J.F.P.), P01 AG062413 (S. Khosla, J.F.P.), P30AG067988 (G.A.K.), R01 AG069819 (D.A.B.), R01 AG076515 (S. Khosla), R33AG061456 (G.A.K.), U19AI089992 (R.R.M.), U24CA268108 (E.M.Q., J.C.S.), U54AG075931-01 (I.R.), U54AG079754 (D.A.B., M.J.S.), U54AG075931 (I.R.), U54AG075932 (B. Soygur, B. Schilling, F.E.D., J.C.), U54AG075934 (A.K., F. Chen, J.W., L.D., L.R., Y. Song), U54AG075941 (G.A.K.), U54AG075941-02 (P.R., R.R.), U54AG076040 (A.D.H., H.P., N. Sloan, O.K., R.P.-L., V.M., Y. Suh), U54AG076041 (L.J.N., E.L.S.), U54AG079753-01 (P.R., R.R.), U54AG079754 (M.J.S.), U54AG079759 (R.R.M.), U54AG079779 (D.J.B., M.J.S., N.B.), U54AG75941 (C.A.-M., E.A.L.E., K.I., P.C., S.S.), UG3CA268096 (R.D., S. Kong), UG3CA268105 (F.E.D.), UG3CA268112 (H.E.D.-L.), UG3CA268117 (N. Slavov, Z.D.), UG3CA275669 (C.M.C., M.J.S., P.T.G.) and UG3CA275686 (A.P., P.V., R.P.-L.).
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N.N., V.S., A.D.H., A. Rocha, A.P., A.K., A.K.D., A.H., A.A., A.Z., B. Soygur, B. Schilling, C.M.C, C.A.-M., D.J.B., D.A.B., D.J., D.B.M., E.M.Q., E.A.L.E., E.L.S., F. Chen, F.E.D., F. Cambuli, G.K., G.A.K., G.L., H.E.D.-L., H.M., H.P., I.M.A.-N., I.R., J.N., J.F.P., J.C.S., J.C., J.W., K.I., K.B., K.M., K.N., L.D., L.J.N., L.W., L.C.A., L.R., M.L.D., M.G.T., M.J.S., M.X., M.H., M.B., N.B., N. Sloan, N. Slavov, O.K., P.R., P.T.G., P.V., P.D.A, P.C., Q.Z., R.R., R.P.-L., R.F., R.D., R.R.M., S. Shaikh, S.V., S.Y., S. Kang, S. Suvakov, S. Khosla, V.D.G., V.M., Y.X., Y. Song, Y. Suh and Z.D. researched data for the article. N.N., V.S., J.F.P. and P.D.A. created the manuscript outline. N.N., V.S., A.D.H., A. Rocha, A.P., A.K., A.K.D., A.H., A.A., A.Z., B. Soygur, B. Schilling, C.M.C., C.A.-M., D.J.B., D.A.B., D.J., D.B.M., E.M.Q., E.A.L.E., E.L.S., F. Chen, F.E.D., F. Cambuli, G.K., G.A.K., L.G., H.E.D.-L., H.M., H.P., I.M.A.-N., I.R., J.N., J.F.P., J.C.S., J.C., J.W., K.I., K.B., K.M., K.N., L.D., L.J.N., L.W., L.C.A., L.R., M.L.D., M.G.T., M.J.S., M.X., M.H., M.B., N.B., N. Sloan, N. Slavov, O.K., P.R., P.T.G., P.V., P.D.A., P.C., Q.Z., R.R., R.P.-L., R.F., R.D., R.R.M., S. Shaikh, S.V., S.Y., S. Kang, S. Suvakov, S. Khosla, V.D.G, V.M., Y.X., Y. Song, Y. Suh and Z.D. wrote the article. N.N., V.S., A.Z., B. Schilling, D.J.B., H.E.D.-L., J.F.P., J.C., L.J.N. and P.D.A. reviewed and/or edited the manuscript before submission. J.C.S., E.M.Q., N.N. and V.S. curated the database. N.N., V.S., S. Khosla, E.M.Q., D.J.B. and J.F.P. worked on the paper revision.
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Competing interests
The authors declare the following competing interests: J.C. is a founder and shareholder of Unity Biotechnology, which develops senolytic drugs. M.J.S., C.M.C. and Mayo Clinic have intellectual property related to this research. Research in the M.J.S. and D.J.B. laboratory is reviewed by the Mayo Clinic Conflict of Interest Review Board and conducted in compliance with Mayo Clinic Conflict of Interest policies. D.J.B. has a potential financial interest related to this research; he is a co-inventor on patents held by Mayo Clinic and patent applications licensed to or filed by Unity Biotechnology and a Unity Biotechnology shareholder. N. Slavov is a founding director and CEO of Parallel Squared Technology Institute, which is a non-profit research institute.
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Nature Reviews Molecular Cell Biology thanks Raffaella Di Micco and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Glossary
- False-positive senescence
-
A cellular phenotype characterized by the presence of senescence markers without the cell being senescent.
- Gene dropouts
-
In single-cell transcriptomics, refers to the failure to detect or quantify certain genes, typically owing low mRNA abundance.
- Immunosenescence
-
The age-dependent functional decline of immune cells, including reduced frequency of naïve cells, increased exhaustion, and dysregulation of innate immunity and signalling pathways.
- Karyomegaly
-
Refers to enlargement of the hepatocyte nucleus, which is associated with liver-weight increase or cellular senescence.
- Long interspersed element-1
-
(LINE-1). A transposition-competent retrotransposable element that is still active in most mammalian genomes.
- Macrophage crown-like structures
-
Clusters of macrophages that surround dead or dying adipocytes.
- Marker prioritization
-
The process of selecting and ranking potential markers based on certain criteria such as specificity, sensitivity, ease of measurement and clinical utility.
- Oncogene-induced senescence
-
A state of cellular senescence triggered by the activation of certain oncogenes (for example, RAS).
- Replicative senescence
-
A type of cellular senescence induced by the progressive shortening of telomeres during cell divisions.
- Senescence-associated β-galactosidase
-
(SA-β-gal). A marker of increased lysosomal activity.
- Senescence-associated distension of satellites
-
(SADS). Observed in senescent cells as a consequence of chromatin rearrangement leading to the loss of integrity of centromeric regions.
- Senescence-associated heterochromatic foci
-
(SAHF). Observed as DAPI-dense foci in senescent cells in culture, particularly in oncogene-induced senescence; represents large-scale heterochromatin formation.
- Senescence-associated secretory phenotype
-
(SASP). Refers to the secretion of pro-inflammatory cytokines, growth factors, chemokines, proteases and other bioactive molecules.
- Senescent cells
-
Cells that have permanently withdrawn from the cell cycle, usually owing to the build-up of DNA damage.
- Syncytial knots
-
Placental syncytiotrophoblast specializations characterized by remarkable accumulation of nuclei with heavily condensed chromatin; a sign of trophoblast maturation and ageing commonly seen post 32 weeks of human gestation.
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Suryadevara, V., Hudgins, A.D., Rajesh, A. et al. SenNet recommendations for detecting senescent cells in different tissues. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00738-8
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DOI: https://doi.org/10.1038/s41580-024-00738-8
