CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels

Claudia C.S. Chini; Thais R. Peclat; Gina M. Warner; Sonu Kashyap; Jair Machado Espindola-Netto; Guilherme C. de Oliveira; Lilian S. Gomez; Kelly A. Hogan; Mariana G. Tarragó; Amrutesh S. Puranik; Guillermo Agorrody; Katie L. Thompson; Kevin Dang; Starlynn Clarke; Bennett G. Childs; Karina S. Kanamori; Micaela A. Witte; Paola Vidal; Anna L. Kirkland; Marco De Cecco; Karthikeyani Chellappa; Melanie R. McReynolds; Connor Jankowski; Tamara Tchkonia; James L. Kirkland; John M. Sedivy; Jan M. van Deursen; Darren J. Baker; Wim van Schooten; Joshua D. Rabinowitz; Joseph A. Baur; Eduardo N. Chini

doi:10.1038/s42255-020-00298-z

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD⁺ and NMN levels

Claudia C.S. Chini, Thais R. Peclat, Gina M. Warner, Sonu Kashyap, Jair Machado Espindola-Netto, Guilherme C. de Oliveira, Lilian S. Gomez, Kelly A. Hogan, Mariana G. Tarragó, Amrutesh S. Puranik, Guillermo Agorrody, Katie L. Thompson, Kevin Dang, Starlynn Clarke, Bennett G. Childs, Karina S. Kanamori, Micaela A. Witte, Paola Vidal, Anna L. Kirkland, Marco De CeccoKarthikeyani Chellappa, Melanie R. McReynolds, Connor Jankowski, Tamara Tchkonia, James L. Kirkland, John M. Sedivy, Jan M. van Deursen, Darren J. Baker, Wim van Schooten, Joshua D. Rabinowitz, Joseph A. Baur, Eduardo N. Chini

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

178 Scopus citations

Abstract

Decreased NAD⁺ levels have been shown to contribute to metabolic dysfunction during aging. NAD⁺ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD⁺ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38⁺ immune cells. Inflammation increases CD38 and decreases NAD⁺. In addition, senescent cells and their secreted signals promote accumulation of CD38⁺ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD⁺ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD⁺ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD⁺.

Original language	English (US)
Pages (from-to)	1284-1304
Number of pages	21
Journal	Nature Metabolism
Volume	2
Issue number	11
DOIs	https://doi.org/10.1038/s42255-020-00298-z
State	Published - Nov 2020

All Science Journal Classification (ASJC) codes

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

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Chini, C. C. S., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., Gomez, L. S., Hogan, K. A., Tarragó, M. G., Puranik, A. S., Agorrody, G., Thompson, K. L., Dang, K., Clarke, S., Childs, B. G., Kanamori, K. S., Witte, M. A., Vidal, P., Kirkland, A. L., ... Chini, E. N. (2020). CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD⁺ and NMN levels. Nature Metabolism, 2(11), 1284-1304. https://doi.org/10.1038/s42255-020-00298-z

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title = "CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels",

abstract = "Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.",

author = "Chini, {Claudia C.S.} and Peclat, {Thais R.} and Warner, {Gina M.} and Sonu Kashyap and Espindola-Netto, {Jair Machado} and {de Oliveira}, {Guilherme C.} and Gomez, {Lilian S.} and Hogan, {Kelly A.} and Tarrag{\'o}, {Mariana G.} and Puranik, {Amrutesh S.} and Guillermo Agorrody and Thompson, {Katie L.} and Kevin Dang and Starlynn Clarke and Childs, {Bennett G.} and Kanamori, {Karina S.} and Witte, {Micaela A.} and Paola Vidal and Kirkland, {Anna L.} and {De Cecco}, Marco and Karthikeyani Chellappa and McReynolds, {Melanie R.} and Connor Jankowski and Tamara Tchkonia and Kirkland, {James L.} and Sedivy, {John M.} and {van Deursen}, {Jan M.} and Baker, {Darren J.} and {van Schooten}, Wim and Rabinowitz, {Joshua D.} and Baur, {Joseph A.} and Chini, {Eduardo N.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = nov,

doi = "10.1038/s42255-020-00298-z",

language = "English (US)",

volume = "2",

pages = "1284--1304",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Springer Berlin",

number = "11",

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Chini, CCS, Peclat, TR, Warner, GM, Kashyap, S, Espindola-Netto, JM, de Oliveira, GC, Gomez, LS, Hogan, KA, Tarragó, MG, Puranik, AS, Agorrody, G, Thompson, KL, Dang, K, Clarke, S, Childs, BG, Kanamori, KS, Witte, MA, Vidal, P, Kirkland, AL, De Cecco, M, Chellappa, K, McReynolds, MR, Jankowski, C, Tchkonia, T, Kirkland, JL, Sedivy, JM, van Deursen, JM, Baker, DJ, van Schooten, W, Rabinowitz, JD, Baur, JA & Chini, EN 2020, 'CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD⁺ and NMN levels', Nature Metabolism, vol. 2, no. 11, pp. 1284-1304. https://doi.org/10.1038/s42255-020-00298-z

TY - JOUR

T1 - CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels

AU - Chini, Claudia C.S.

AU - Peclat, Thais R.

AU - Warner, Gina M.

AU - Kashyap, Sonu

AU - Espindola-Netto, Jair Machado

AU - de Oliveira, Guilherme C.

AU - Gomez, Lilian S.

AU - Hogan, Kelly A.

AU - Tarragó, Mariana G.

AU - Puranik, Amrutesh S.

AU - Agorrody, Guillermo

AU - Thompson, Katie L.

AU - Dang, Kevin

AU - Clarke, Starlynn

AU - Childs, Bennett G.

AU - Kanamori, Karina S.

AU - Witte, Micaela A.

AU - Vidal, Paola

AU - Kirkland, Anna L.

AU - De Cecco, Marco

AU - Chellappa, Karthikeyani

AU - McReynolds, Melanie R.

AU - Jankowski, Connor

AU - Tchkonia, Tamara

AU - Kirkland, James L.

AU - Sedivy, John M.

AU - van Deursen, Jan M.

AU - Baker, Darren J.

AU - van Schooten, Wim

AU - Rabinowitz, Joshua D.

AU - Baur, Joseph A.

AU - Chini, Eduardo N.

PY - 2020/11

Y1 - 2020/11

N2 - Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.

AB - Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.

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U2 - 10.1038/s42255-020-00298-z

DO - 10.1038/s42255-020-00298-z

M3 - Article

C2 - 33199925

AN - SCOPUS:85096057845

SN - 2522-5812

VL - 2

SP - 1284

EP - 1304

JO - Nature Metabolism

JF - Nature Metabolism

IS - 11

ER -

CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD⁺ and NMN levels

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