NAD                         +                          metabolism governs the proinflammatory senescence-associated secretome

Timothy Nacarelli; Lena Lau; Takeshi Fukumoto; Joseph Zundell; Nail Fatkhutdinov; Shuai Wu; Katherine M. Aird; Osamu Iwasaki; Andrew V. Kossenkov; David Schultz; Ken ichi Noma; Joseph A. Baur; Zachary Schug; Hsin Yao Tang; David W. Speicher; Gregory David; Rugang Zhang

doi:10.1038/s41556-019-0287-4

NAD ⁺ metabolism governs the proinflammatory senescence-associated secretome

Timothy Nacarelli, Lena Lau, Takeshi Fukumoto, Joseph Zundell, Nail Fatkhutdinov, Shuai Wu, Katherine M. Aird, Osamu Iwasaki, Andrew V. Kossenkov, David Schultz, Ken ichi Noma, Joseph A. Baur, Zachary Schug, Hsin Yao Tang, David W. Speicher, Gregory David, Rugang Zhang

Research output: Contribution to journal › Article › peer-review

162 Citations (SciVal)

Abstract

Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD ⁺ metabolism influences both tissue ageing and cancer. However, the role of NAD ⁺ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD ⁺ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA–NAMPT–NAD ⁺ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD ⁺ -mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD ⁺ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD ⁺ augmentation should be administered with precision.

Original language	English (US)
Pages (from-to)	397-407
Number of pages	11
Journal	Nature Cell Biology
Volume	21
Issue number	3
DOIs	https://doi.org/10.1038/s41556-019-0287-4
State	Published - Mar 1 2019

All Science Journal Classification (ASJC) codes

Cell Biology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41556-019-0287-4

Cite this

Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., Aird, K. M., Iwasaki, O., Kossenkov, A. V., Schultz, D., Noma, K. I., Baur, J. A., Schug, Z., Tang, H. Y., Speicher, D. W., David, G., & Zhang, R. (2019). NAD ⁺ metabolism governs the proinflammatory senescence-associated secretome Nature Cell Biology, 21(3), 397-407. https://doi.org/10.1038/s41556-019-0287-4

@article{c2efa8c17c1e4712b2a50195bd03fec1,

title = " NAD + metabolism governs the proinflammatory senescence-associated secretome ",

abstract = " Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD + metabolism influences both tissue ageing and cancer. However, the role of NAD + metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD + salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA–NAMPT–NAD + signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD + -mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD + metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD + augmentation should be administered with precision.",

author = "Timothy Nacarelli and Lena Lau and Takeshi Fukumoto and Joseph Zundell and Nail Fatkhutdinov and Shuai Wu and Aird, {Katherine M.} and Osamu Iwasaki and Kossenkov, {Andrew V.} and David Schultz and Noma, {Ken ichi} and Baur, {Joseph A.} and Zachary Schug and Tang, {Hsin Yao} and Speicher, {David W.} and Gregory David and Rugang Zhang",

note = "Funding Information: The authors thank the Wistar Institute Proteomics and Metabolomics Facility for technical assistance. This work was supported by grants from the following organizations: the US National Institutes of Health (R01CA160331, R01CA163377, R01CA202919 and P50CA228991 to R.Z.; P01AG031862 to R.Z., K.N. and D.S.; R01CA148639 and R21CA155736 to G.D.; F31CA206387 to L.L.; R00CA194309 to K.M.A.; R01DK098656 to J.A.B.; R01CA131582 to D.W.S.; R50CA211199 to A.V.K.; R50CA221838 to H.-Y.T.; and T32CA009191 to T.N.); the US Department of Defense (OC140632P1 and OC150446 to R.Z.); The Honorable Tina Brozman Foundation for Ovarian Cancer Research (to R.Z.); and the Ovarian Cancer Research Alliance (Collaborative Research Development Grant to R.Z. and D.W.S., and Ann and Sol Schreiber Mentored Investigator Award to S.W.). Support of Core Facilities was provided by Cancer Centre Support Grant CA010815 to The Wistar Institute. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2019",

month = mar,

day = "1",

doi = "10.1038/s41556-019-0287-4",

language = "English (US)",

volume = "21",

pages = "397--407",

journal = "Nature Cell Biology",

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Nacarelli, T, Lau, L, Fukumoto, T, Zundell, J, Fatkhutdinov, N, Wu, S, Aird, KM, Iwasaki, O, Kossenkov, AV, Schultz, D, Noma, KI, Baur, JA, Schug, Z, Tang, HY, Speicher, DW, David, G & Zhang, R 2019, ' NAD ⁺ metabolism governs the proinflammatory senescence-associated secretome ', Nature Cell Biology, vol. 21, no. 3, pp. 397-407. https://doi.org/10.1038/s41556-019-0287-4

TY - JOUR

T1 - NAD + metabolism governs the proinflammatory senescence-associated secretome

AU - Nacarelli, Timothy

AU - Lau, Lena

AU - Fukumoto, Takeshi

AU - Zundell, Joseph

AU - Fatkhutdinov, Nail

AU - Wu, Shuai

AU - Aird, Katherine M.

AU - Iwasaki, Osamu

AU - Kossenkov, Andrew V.

AU - Schultz, David

AU - Noma, Ken ichi

AU - Baur, Joseph A.

AU - Schug, Zachary

AU - Tang, Hsin Yao

AU - Speicher, David W.

AU - David, Gregory

AU - Zhang, Rugang

N1 - Funding Information: The authors thank the Wistar Institute Proteomics and Metabolomics Facility for technical assistance. This work was supported by grants from the following organizations: the US National Institutes of Health (R01CA160331, R01CA163377, R01CA202919 and P50CA228991 to R.Z.; P01AG031862 to R.Z., K.N. and D.S.; R01CA148639 and R21CA155736 to G.D.; F31CA206387 to L.L.; R00CA194309 to K.M.A.; R01DK098656 to J.A.B.; R01CA131582 to D.W.S.; R50CA211199 to A.V.K.; R50CA221838 to H.-Y.T.; and T32CA009191 to T.N.); the US Department of Defense (OC140632P1 and OC150446 to R.Z.); The Honorable Tina Brozman Foundation for Ovarian Cancer Research (to R.Z.); and the Ovarian Cancer Research Alliance (Collaborative Research Development Grant to R.Z. and D.W.S., and Ann and Sol Schreiber Mentored Investigator Award to S.W.). Support of Core Facilities was provided by Cancer Centre Support Grant CA010815 to The Wistar Institute. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD + metabolism influences both tissue ageing and cancer. However, the role of NAD + metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD + salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA–NAMPT–NAD + signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD + -mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD + metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD + augmentation should be administered with precision.

AB - Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD + metabolism influences both tissue ageing and cancer. However, the role of NAD + metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD + salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA–NAMPT–NAD + signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD + -mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD + metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD + augmentation should be administered with precision.

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U2 - 10.1038/s41556-019-0287-4

DO - 10.1038/s41556-019-0287-4

M3 - Article

C2 - 30778219

AN - SCOPUS:85061731316

SN - 1465-7392

VL - 21

SP - 397

EP - 407

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 3

ER -