TY - JOUR
T1 - Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages
AU - Covarrubias, Anthony J.
AU - Kale, Abhijit
AU - Perrone, Rosalba
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
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/11
Y1 - 2020/11
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85096043878&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096043878&partnerID=8YFLogxK
U2 - 10.1038/s42255-020-00305-3
DO - 10.1038/s42255-020-00305-3
M3 - Article
C2 - 33199924
AN - SCOPUS:85096043878
SN - 2522-5812
VL - 2
SP - 1265
EP - 1283
JO - Nature Metabolism
JF - Nature Metabolism
IS - 11
ER -
