Extracellular Nicotinamide Phosphoribosyltransferase Is a Component of the Senescence-Associated Secretory Phenotype

Cellular senescence is a stress or damage response by which a cell adopts of state of essentially permanent proliferative arrest, coupled to the secretion of a number of biologically active molecules. This senescence-associated secretory phenotype (SASP) underlies many of the degenerative and regene...

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Published in:Frontiers in endocrinology (Lausanne) Vol. 13; p. 935106
Main Authors: Kuehnemann, Chisaka, Hu, Kang-Quan, Butera, Kayla, Patel, Sandip K., Bons, Joanna, Schilling, Birgit, Aguayo-Mazzucato, Cristina, Wiley, Christopher D.
Format: Journal Article
Language:English
Published: Switzerland Frontiers Media S.A 14.07.2022
Subjects:
AMP-Activated Protein Kinases - metabolism
Animals
cellular senescence
Cytokines - genetics
Cytokines - metabolism
Diabetes Mellitus, Experimental - metabolism
eNAMPT
Endocrinology
Mice
NAD
NAD - metabolism
NAMPT
Nicotinamide Phosphoribosyltransferase - genetics
Nicotinamide Phosphoribosyltransferase - metabolism
SASP
senescence
Senescence-Associated Secretory Phenotype - genetics
Senescence-Associated Secretory Phenotype - physiology
NAD
senescence
cellular senescence
NAMPT
eNAMPT
aging
SASP
diabetes
ISSN:1664-2392, 1664-2392
Online Access:Get full text
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Summary:Cellular senescence is a stress or damage response by which a cell adopts of state of essentially permanent proliferative arrest, coupled to the secretion of a number of biologically active molecules. This senescence-associated secretory phenotype (SASP) underlies many of the degenerative and regenerative aspects of cellular senescence - including promoting wound healing and development, but also driving diabetes and multiple age-associated diseases. We find that nicotinamide phosphoribosyltransferase (NAMPT), which catalyzes the rate-limiting step in nicotinamide adenine dinucleotide (NAD) biosynthesis, is elevated in senescent cells without a commensurate increase in NAD levels. This elevation is distinct from the acute DNA damage response, in which NAD is depleted, and recovery of NAD by NAMPT elevation is AMPK-activated protein kinase (AMPK)-dependent. Instead, we find that senescent cells release extracellular NAMPT (eNAMPT) as part of the SASP. eNAMPT has been reported to be released as a catalytically active extracellular vesicle-contained dimer that promotes NAD increases in other cells and extends lifespan, and also as free monomer that acts as a damage-associated molecular pattern and promotes conditions such as diabetes and fibrosis. Senescent cells released eNAMPT as dimer, but surprisingly eNAMPT appeared in the soluble secretome while being depleted from exosomes. Finally, diabetic mice showed elevated levels of eNAMPT, and this was lowered by treatment with the senolytic drug, ABT-263. Together, these data reveal a new SASP factor with implications for NAD metabolism.
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Edited by: Luigi Ferrucci, National Institute on Aging (NIH), United States
Reviewed by: Brenna Osborne, University of Copenhagen, Denmark; Bela Ozsvari, University of Salford, United Kingdom
This article was submitted to Endocrinology of Aging, a section of the journal Frontiers in Endocrinology
ISSN:1664-2392
1664-2392
DOI:10.3389/fendo.2022.935106