A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues

Dominik Saul; Robyn Laura Kosinsky; Elizabeth J. Atkinson; Madison L. Doolittle; Xu Zhang; Nathan K. LeBrasseur; Robert J. Pignolo; Paul D. Robbins; Laura J. Niedernhofer; Yuji Ikeno; Diana Jurk; João F. Passos; La Tonya J. Hickson; Ailing Xue; David G. Monroe; Tamara Tchkonia; James L. Kirkland; Joshua N. Farr; Sundeep Khosla

doi:10.1038/s41467-022-32552-1

A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues

Dominik Saul, Robyn Laura Kosinsky, Elizabeth J. Atkinson, Madison L. Doolittle, Xu Zhang, Nathan K. LeBrasseur, Robert J. Pignolo, Paul D. Robbins, Laura J. Niedernhofer, Yuji Ikeno, Diana Jurk, João F. Passos, La Tonya J. Hickson, Ailing Xue, David G. Monroe, Tamara Tchkonia, James L. Kirkland, Joshua N. Farr, Sundeep Khosla

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Abstract

Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

Original language	English (US)
Article number	4827
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32552-1
State	Published - Dec 2022
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by the German Research Foundation (D.F.G., 413501650) (D.S.), National Institutes of Health (NIH) grants P01 AG062413 (S.K., J.N.F., N.K.L., R.P., P.D.R., L.J.N., Y.I., J.P., D.G.M., T.T., J.L.K.), R01 AG076515 (S.K., D.G.M.), R21 AG065868 (S.K., J.N.F), K01 AR070241 (J.N.F.), R01 AG063707 (D.G.M.), R37 AG 013925 (J.L.K., T.T.), R33AG 61456 (J.L.K., T.T., R.P., P.D.R., L.J.N., S.K.), 1R01AG068048-01 (JFP), R56 AG 60907 and R01 AG55529 (N.K.L.)., the Connor Fund (J.L.K., T.T.), Robert P. and Arlene R. Kogod (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K., T.T.), the Noaber Foundation (J.L.K., T.T.), and Mildred Scheel postdoc fellowship by the German Cancer Aid (R.L.K.). X.Z. is supported by the Robert and Arlene Kogod Center on Aging Career Development Award. The authors thank SA Johnsen and FH Hamdan for inspiring discussions.

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© 2022, The Author(s).

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Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., Pignolo, R. J., Robbins, P. D., Niedernhofer, L. J., Ikeno, Y., Jurk, D., Passos, J. F., Hickson, L. T. J., Xue, A., Monroe, D. G., Tchkonia, T., Kirkland, J. L., Farr, J. N., & Khosla, S. (2022). A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nature communications, 13(1), Article 4827. https://doi.org/10.1038/s41467-022-32552-1

Saul, D, Kosinsky, RL, Atkinson, EJ, Doolittle, ML, Zhang, X, LeBrasseur, NK, Pignolo, RJ, Robbins, PD , Niedernhofer, LJ, Ikeno, Y, Jurk, D, Passos, JF, Hickson, LTJ, Xue, A, Monroe, DG, Tchkonia, T, Kirkland, JL, Farr, JN & Khosla, S 2022, 'A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues', Nature communications, vol. 13, no. 1, 4827. https://doi.org/10.1038/s41467-022-32552-1

@article{401f2ab2a0be440bbb1f04173b75f0e2,

title = "A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues",

abstract = "Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.",

author = "Dominik Saul and Kosinsky, {Robyn Laura} and Atkinson, {Elizabeth J.} and Doolittle, {Madison L.} and Xu Zhang and LeBrasseur, {Nathan K.} and Pignolo, {Robert J.} and Robbins, {Paul D.} and Niedernhofer, {Laura J.} and Yuji Ikeno and Diana Jurk and Passos, {Jo{\~a}o F.} and Hickson, {La Tonya J.} and Ailing Xue and Monroe, {David G.} and Tamara Tchkonia and Kirkland, {James L.} and Farr, {Joshua N.} and Sundeep Khosla",

note = "Funding Information: This work was supported by the German Research Foundation (D.F.G., 413501650) (D.S.), National Institutes of Health (NIH) grants P01 AG062413 (S.K., J.N.F., N.K.L., R.P., P.D.R., L.J.N., Y.I., J.P., D.G.M., T.T., J.L.K.), R01 AG076515 (S.K., D.G.M.), R21 AG065868 (S.K., J.N.F), K01 AR070241 (J.N.F.), R01 AG063707 (D.G.M.), R37 AG 013925 (J.L.K., T.T.), R33AG 61456 (J.L.K., T.T., R.P., P.D.R., L.J.N., S.K.), 1R01AG068048-01 (JFP), R56 AG 60907 and R01 AG55529 (N.K.L.)., the Connor Fund (J.L.K., T.T.), Robert P. and Arlene R. Kogod (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K., T.T.), the Noaber Foundation (J.L.K., T.T.), and Mildred Scheel postdoc fellowship by the German Cancer Aid (R.L.K.). X.Z. is supported by the Robert and Arlene Kogod Center on Aging Career Development Award. The authors thank SA Johnsen and FH Hamdan for inspiring discussions. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-32552-1",

language = "English (US)",

volume = "13",

journal = "Nature communications",

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TY - JOUR

T1 - A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues

AU - Saul, Dominik

AU - Kosinsky, Robyn Laura

AU - Atkinson, Elizabeth J.

AU - Doolittle, Madison L.

AU - Zhang, Xu

AU - LeBrasseur, Nathan K.

AU - Pignolo, Robert J.

AU - Robbins, Paul D.

AU - Niedernhofer, Laura J.

AU - Ikeno, Yuji

AU - Jurk, Diana

AU - Passos, João F.

AU - Hickson, La Tonya J.

AU - Xue, Ailing

AU - Monroe, David G.

AU - Tchkonia, Tamara

AU - Kirkland, James L.

AU - Farr, Joshua N.

AU - Khosla, Sundeep

N1 - Funding Information: This work was supported by the German Research Foundation (D.F.G., 413501650) (D.S.), National Institutes of Health (NIH) grants P01 AG062413 (S.K., J.N.F., N.K.L., R.P., P.D.R., L.J.N., Y.I., J.P., D.G.M., T.T., J.L.K.), R01 AG076515 (S.K., D.G.M.), R21 AG065868 (S.K., J.N.F), K01 AR070241 (J.N.F.), R01 AG063707 (D.G.M.), R37 AG 013925 (J.L.K., T.T.), R33AG 61456 (J.L.K., T.T., R.P., P.D.R., L.J.N., S.K.), 1R01AG068048-01 (JFP), R56 AG 60907 and R01 AG55529 (N.K.L.)., the Connor Fund (J.L.K., T.T.), Robert P. and Arlene R. Kogod (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K., T.T.), the Noaber Foundation (J.L.K., T.T.), and Mildred Scheel postdoc fellowship by the German Cancer Aid (R.L.K.). X.Z. is supported by the Robert and Arlene Kogod Center on Aging Career Development Award. The authors thank SA Johnsen and FH Hamdan for inspiring discussions. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

AB - Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

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A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues

Abstract

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