NAD + metabolism governs the proinflammatory senescence-associated secretome

Timothy Nacarelli, Lena Lau, Takeshi Fukumoto, Joseph Zundell, Nail Fatkhutdinov, Shuai Wu, Katherine 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 journalArticle

3 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)397-407
Number of pages11
JournalNature Cell Biology
Volume21
Issue number3
DOIs
StatePublished - Mar 1 2019

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NAD
Phenotype
Nicotinamide Phosphoribosyltransferase
High Mobility Group Proteins
Neoplasms
Cell Aging
p38 Mitogen-Activated Protein Kinases
Glycolysis
Growth
Respiration
Up-Regulation
Cytokines
Enzymes

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., ... 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
Nacarelli, Timothy ; Lau, Lena ; Fukumoto, Takeshi ; Zundell, Joseph ; Fatkhutdinov, Nail ; Wu, Shuai ; Aird, Katherine ; Iwasaki, Osamu ; Kossenkov, Andrew V. ; Schultz, David ; Noma, Ken ichi ; Baur, Joseph A. ; Schug, Zachary ; Tang, Hsin Yao ; Speicher, David W. ; David, Gregory ; Zhang, Rugang. / NAD + metabolism governs the proinflammatory senescence-associated secretome In: Nature Cell Biology. 2019 ; Vol. 21, No. 3. pp. 397-407.
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Nacarelli, T, Lau, L, Fukumoto, T, Zundell, J, Fatkhutdinov, N, Wu, S, Aird, K, 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

NAD + metabolism governs the proinflammatory senescence-associated secretome . / Nacarelli, Timothy; Lau, Lena; Fukumoto, Takeshi; Zundell, Joseph; Fatkhutdinov, Nail; Wu, Shuai; Aird, Katherine; Iwasaki, Osamu; Kossenkov, Andrew V.; Schultz, David; Noma, Ken ichi; Baur, Joseph A.; Schug, Zachary; Tang, Hsin Yao; Speicher, David W.; David, Gregory; Zhang, Rugang.

In: Nature Cell Biology, Vol. 21, No. 3, 01.03.2019, p. 397-407.

Research output: Contribution to journalArticle

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AU - Nacarelli, Timothy

AU - Lau, Lena

AU - Fukumoto, Takeshi

AU - Zundell, Joseph

AU - Fatkhutdinov, Nail

AU - Wu, Shuai

AU - Aird, Katherine

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

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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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Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S et al. NAD + metabolism governs the proinflammatory senescence-associated secretome Nature Cell Biology. 2019 Mar 1;21(3):397-407. https://doi.org/10.1038/s41556-019-0287-4