Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages

Anthony J. Covarrubias; Abhijit Kale; Rosalba Perrone; Jose Alberto Lopez-Dominguez; Angela Oliveira Pisco; Herbert G. Kasler; Mark S. Schmidt; Indra Heckenbach; Ryan Kwok; Christopher D. Wiley; Hoi Shan Wong; Eddy Gibbs; Shankar S. Iyer; Nathan Basisty; Qiuxia Wu; Ik Jung Kim; Elena Silva; Kaitlyn Vitangcol; Kyong Oh Shin; Yong Moon Lee; Rebeccah Riley; Issam Ben-Sahra; Melanie Ott; Birgit Schilling; Morten Scheibye-Knudsen; Katsuhiko Ishihara; Stephen R. Quake; John Newman; Charles Brenner; Judith Campisi; Eric Verdin

doi:10.1038/s42255-020-00305-3

Senescent cells promote tissue NAD⁺ decline during ageing via the activation of CD38⁺ macrophages

Anthony J. Covarrubias, Abhijit Kale, Rosalba Perrone, Jose Alberto Lopez-Dominguez, Angela Oliveira Pisco, Herbert G. Kasler, Mark S. Schmidt, Indra Heckenbach, Ryan Kwok, Christopher D. Wiley, Hoi Shan Wong, Eddy Gibbs, Shankar S. Iyer, Nathan Basisty, Qiuxia Wu, Ik Jung Kim, Elena Silva, Kaitlyn Vitangcol, Kyong Oh Shin, Yong Moon LeeRebeccah Riley, Issam Ben-Sahra, Melanie Ott, Birgit Schilling, Morten Scheibye-Knudsen, Katsuhiko Ishihara, Stephen R. Quake, John Newman, Charles Brenner, Judith Campisi, Eric Verdin^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

248 Scopus citations

Abstract

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

Original language	English (US)
Pages (from-to)	1265-1283
Number of pages	19
Journal	Nature Metabolism
Volume	2
Issue number	11
DOIs	https://doi.org/10.1038/s42255-020-00305-3
State	Published - Nov 2020

Funding

All authors have reviewed and approved the manuscript. C.B. is the inventor of intellectual property on the nutritional and therapeutic uses of NR, serves as chief scientific advisor of and holds stock in ChromaDex. E.V. is a scientific cofounder of NAPA Therapeutics. A.J.C., R.P., Q.W., E.S. and K.V. received partial salary support from NAPA Therapeutics. J.C. is a scientific cofounder of Unity Biotechnology. The other authors declare no competing interests. This project was supported by NIH grant R24DK085610 (E.V.), Gladstone Institute intramural funds (E.V.) and Buck Institute intramural funds (E.V. and J.C.). A.J.C. is a recipient of the UC President’s Postdoctoral Fellowship at UCSF and was supported by NIH training grant T32AG000266 (Buck Institute). A.K. was supported by the SENS Research Foundation and NIH grant R01AG051729 (J.C.). B.S. and N.B. were supported by NIH grant U01AG060906 (B.S., principal investigator) and NIH Shared Instrumentation Grant 1S10OD016281 (Buck Institute). M.S.S. and C.B. were supported by NIH grant R01HL147545 and the Roy J. Carver Trust to C.B. We thank M. Walter for help with imaging cells, and P. Dighe for help optimizing Seahorse assay conditions. We thank R. Camarda, V. Byles and D. Powell for reviewing the manuscript and helpful discussions.

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Physiology (medical)
Cell Biology

UN SDGs

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

Access to Document

10.1038/s42255-020-00305-3

Cite this

Covarrubias, A. J., Kale, A., Perrone, R., Lopez-Dominguez, J. A., Pisco, A. O., Kasler, H. G., Schmidt, M. S., Heckenbach, I., Kwok, R., Wiley, C. D., Wong, H. S., Gibbs, E., Iyer, S. S., Basisty, N., Wu, Q., Kim, I. J., Silva, E., Vitangcol, K., Shin, K. O., ... Verdin, E. (2020). Senescent cells promote tissue NAD⁺ decline during ageing via the activation of CD38⁺ macrophages. Nature Metabolism, 2(11), 1265-1283. https://doi.org/10.1038/s42255-020-00305-3

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title = "Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages",

abstract = "Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.",

author = "Covarrubias, {Anthony J.} and Abhijit Kale and Rosalba Perrone and Lopez-Dominguez, {Jose Alberto} and Pisco, {Angela Oliveira} and Kasler, {Herbert G.} and Schmidt, {Mark S.} and Indra Heckenbach and Ryan Kwok and Wiley, {Christopher D.} and Wong, {Hoi Shan} and Eddy Gibbs and Iyer, {Shankar S.} and Nathan Basisty and Qiuxia Wu and Kim, {Ik Jung} and Elena Silva and Kaitlyn Vitangcol and Shin, {Kyong Oh} and Lee, {Yong Moon} and Rebeccah Riley and Issam Ben-Sahra and Melanie Ott and Birgit Schilling and Morten Scheibye-Knudsen and Katsuhiko Ishihara and Quake, {Stephen R.} and John Newman and Charles Brenner and Judith Campisi and Eric Verdin",

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Covarrubias, AJ, Kale, A, Perrone, R, Lopez-Dominguez, JA, Pisco, AO, Kasler, HG, Schmidt, MS, Heckenbach, I, Kwok, R, Wiley, CD, Wong, HS, Gibbs, E, Iyer, SS, Basisty, N, Wu, Q, Kim, IJ, Silva, E, Vitangcol, K, Shin, KO, Lee, YM, Riley, R, Ben-Sahra, I, Ott, M, Schilling, B, Scheibye-Knudsen, M, Ishihara, K, Quake, SR, Newman, J, Brenner, C, Campisi, J & Verdin, E 2020, 'Senescent cells promote tissue NAD⁺ decline during ageing via the activation of CD38⁺ macrophages', Nature Metabolism, vol. 2, no. 11, pp. 1265-1283. https://doi.org/10.1038/s42255-020-00305-3

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AU - Lopez-Dominguez, Jose Alberto

AU - Pisco, Angela Oliveira

AU - Kasler, Herbert G.

AU - Schmidt, Mark S.

AU - Heckenbach, Indra

AU - Kwok, Ryan

AU - Wiley, Christopher D.

AU - Wong, Hoi Shan

AU - Gibbs, Eddy

AU - Iyer, Shankar S.

AU - Basisty, Nathan

AU - Wu, Qiuxia

AU - Kim, Ik Jung

AU - Silva, Elena

AU - Vitangcol, Kaitlyn

AU - Shin, Kyong Oh

AU - Lee, Yong Moon

AU - Riley, Rebeccah

AU - Ben-Sahra, Issam

AU - Ott, Melanie

AU - Schilling, Birgit

AU - Scheibye-Knudsen, Morten

AU - Ishihara, Katsuhiko

AU - Quake, Stephen R.

AU - Newman, John

AU - Brenner, Charles

AU - Campisi, Judith

AU - Verdin, Eric

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N2 - Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

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