Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging

Daniel I Benjamin; Jamie O Brett; Pieter Both; Joel S Benjamin; Heather L Ishak; Jengmin Kang; Soochi Kim; Mingyu Chung; Marina Arjona; Christopher W Nutter; Jenna H Tan; Ananya K Krishnan; Hunter Dulay; Sharon M Louie; Antoine de Morree; Daniel K Nomura; Thomas A Rando

doi:10.1016/j.cmet.2023.02.001

Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging

Daniel I Benjamin, Jamie O Brett, Pieter Both, Joel S Benjamin, Heather L Ishak, Jengmin Kang, Soochi Kim, Mingyu Chung, Marina Arjona, Christopher W Nutter, Jenna H Tan, Ananya K Krishnan, Hunter Dulay, Sharon M Louie, Antoine de Morree, Daniel K Nomura, Thomas A Rando

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

18 Citations (Scopus)

Abstract

With age, skeletal muscle stem cells (MuSCs) activate out of quiescence more slowly and with increased death, leading to defective muscle repair. To explore the molecular underpinnings of these defects, we combined multiomics, single-cell measurements, and functional testing of MuSCs from young and old mice. The multiomics approach allowed us to assess which changes are causal, which are compensatory, and which are simply correlative. We identified glutathione (GSH) metabolism as perturbed in old MuSCs, with both causal and compensatory components. Contrary to young MuSCs, old MuSCs exhibit a population dichotomy composed of GSHhigh cells (comparable with young MuSCs) and GSHlow cells with impaired functionality. Mechanistically, we show that antagonism between NRF2 and NF-κB maintains this bimodality. Experimental manipulation of GSH levels altered the functional dichotomy of aged MuSCs. These findings identify a novel mechanism of stem cell aging and highlight glutathione metabolism as an accessible target for reversing MuSC aging.

Original language	English
Journal	Cell Metabolism
Volume	35
Issue	3
Pages (from-to)	472-486.e6
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2023.02.001
Publication status	Published - 7 Mar 2023
Externally published	Yes

Keywords

Aging/physiology
Animals
Cellular Senescence
Mice
Multiomics
Muscle, Skeletal/metabolism
Stem Cells/metabolism

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10.1016/j.cmet.2023.02.001

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Benjamin, D. I., Brett, J. O., Both, P., Benjamin, J. S., Ishak, H. L., Kang, J., Kim, S., Chung, M., Arjona, M., Nutter, C. W., Tan, J. H., Krishnan, A. K., Dulay, H., Louie, S. M., de Morree, A., Nomura, D. K., & Rando, T. A. (2023). Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging. Cell Metabolism, 35(3), 472-486.e6. https://doi.org/10.1016/j.cmet.2023.02.001

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title = "Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging",

abstract = "With age, skeletal muscle stem cells (MuSCs) activate out of quiescence more slowly and with increased death, leading to defective muscle repair. To explore the molecular underpinnings of these defects, we combined multiomics, single-cell measurements, and functional testing of MuSCs from young and old mice. The multiomics approach allowed us to assess which changes are causal, which are compensatory, and which are simply correlative. We identified glutathione (GSH) metabolism as perturbed in old MuSCs, with both causal and compensatory components. Contrary to young MuSCs, old MuSCs exhibit a population dichotomy composed of GSHhigh cells (comparable with young MuSCs) and GSHlow cells with impaired functionality. Mechanistically, we show that antagonism between NRF2 and NF-κB maintains this bimodality. Experimental manipulation of GSH levels altered the functional dichotomy of aged MuSCs. These findings identify a novel mechanism of stem cell aging and highlight glutathione metabolism as an accessible target for reversing MuSC aging.",

keywords = "Aging/physiology, Animals, Cellular Senescence, Mice, Multiomics, Muscle, Skeletal/metabolism, Stem Cells/metabolism",

author = "Benjamin, {Daniel I} and Brett, {Jamie O} and Pieter Both and Benjamin, {Joel S} and Ishak, {Heather L} and Jengmin Kang and Soochi Kim and Mingyu Chung and Marina Arjona and Nutter, {Christopher W} and Tan, {Jenna H} and Krishnan, {Ananya K} and Hunter Dulay and Louie, {Sharon M} and {de Morree}, Antoine and Nomura, {Daniel K} and Rando, {Thomas A}",

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year = "2023",

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doi = "10.1016/j.cmet.2023.02.001",

language = "English",

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pages = "472--486.e6",

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Benjamin, DI, Brett, JO, Both, P, Benjamin, JS, Ishak, HL, Kang, J, Kim, S, Chung, M, Arjona, M, Nutter, CW, Tan, JH, Krishnan, AK, Dulay, H, Louie, SM, de Morree, A, Nomura, DK & Rando, TA 2023, 'Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging', Cell Metabolism, vol. 35, no. 3, pp. 472-486.e6. https://doi.org/10.1016/j.cmet.2023.02.001

TY - JOUR

T1 - Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging

AU - Benjamin, Daniel I

AU - Brett, Jamie O

AU - Both, Pieter

AU - Benjamin, Joel S

AU - Ishak, Heather L

AU - Kang, Jengmin

AU - Kim, Soochi

AU - Chung, Mingyu

AU - Arjona, Marina

AU - Nutter, Christopher W

AU - Tan, Jenna H

AU - Krishnan, Ananya K

AU - Dulay, Hunter

AU - Louie, Sharon M

AU - de Morree, Antoine

AU - Nomura, Daniel K

AU - Rando, Thomas A

N1 - Published by Elsevier Inc.

PY - 2023/3/7

Y1 - 2023/3/7

N2 - With age, skeletal muscle stem cells (MuSCs) activate out of quiescence more slowly and with increased death, leading to defective muscle repair. To explore the molecular underpinnings of these defects, we combined multiomics, single-cell measurements, and functional testing of MuSCs from young and old mice. The multiomics approach allowed us to assess which changes are causal, which are compensatory, and which are simply correlative. We identified glutathione (GSH) metabolism as perturbed in old MuSCs, with both causal and compensatory components. Contrary to young MuSCs, old MuSCs exhibit a population dichotomy composed of GSHhigh cells (comparable with young MuSCs) and GSHlow cells with impaired functionality. Mechanistically, we show that antagonism between NRF2 and NF-κB maintains this bimodality. Experimental manipulation of GSH levels altered the functional dichotomy of aged MuSCs. These findings identify a novel mechanism of stem cell aging and highlight glutathione metabolism as an accessible target for reversing MuSC aging.

AB - With age, skeletal muscle stem cells (MuSCs) activate out of quiescence more slowly and with increased death, leading to defective muscle repair. To explore the molecular underpinnings of these defects, we combined multiomics, single-cell measurements, and functional testing of MuSCs from young and old mice. The multiomics approach allowed us to assess which changes are causal, which are compensatory, and which are simply correlative. We identified glutathione (GSH) metabolism as perturbed in old MuSCs, with both causal and compensatory components. Contrary to young MuSCs, old MuSCs exhibit a population dichotomy composed of GSHhigh cells (comparable with young MuSCs) and GSHlow cells with impaired functionality. Mechanistically, we show that antagonism between NRF2 and NF-κB maintains this bimodality. Experimental manipulation of GSH levels altered the functional dichotomy of aged MuSCs. These findings identify a novel mechanism of stem cell aging and highlight glutathione metabolism as an accessible target for reversing MuSC aging.

KW - Aging/physiology

KW - Animals

KW - Cellular Senescence

KW - Mice

KW - Multiomics

KW - Muscle, Skeletal/metabolism

KW - Stem Cells/metabolism

UR - http://www.scopus.com/inward/record.url?scp=85149739793&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2023.02.001

DO - 10.1016/j.cmet.2023.02.001

M3 - Journal article

C2 - 36854304

SN - 1550-4131

VL - 35

SP - 472-486.e6

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging

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Keywords

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