|KUEHNEMANN, CHISAKA - Buck Institute For Age Research
|HU, KANG-QUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
|BUTERA, KAYLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
|PATEL, SANDIP - Buck Institute For Age Research
|BONS, JOANNA - Buck Institute For Age Research
|SCHILLING, BIRGIT - Buck Institute For Age Research
|AGUAYO-MAZZUCATO, CRISTINA - Harvard University
|WILEY, CHRISTOPHER - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
Submitted to: Frontiers in Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/15/2022
Publication Date: 7/14/2022
Citation: Kuehnemann, C., Hu, K., Butera, K., Patel, S.K., Bons, J., Schilling, B., Aguayo-Mazzucato, C., Wiley, C. 2022. Extracellular nicotinamide phosphoribosyltransferase is a component of the senescence-associated secretory phenotype. Frontiers in Endocrinology. 13:Article 935106. https://doi.org/10.3389/fendo.2022.935106.
Interpretive Summary: Cellular senescence is a type of cellular aging where a cell stops dividing and instead releases a collection of factors that can drive aging, diabetes, and other forms of degenerative disease. Aging is also accompanied by a loss of nicotinamide adenine dinucleotide (NAD), a major product of niacin. Methods that either restore NAD levels or kill senescent cells prevent diabetes and other aspects of aging in animal models, but it is unclear how these two mechanisms are inter-related. We have demonstrated in mice that a key enzyme required to maintain NAD levels is elevated in senescent cells, even without an increase in NAD. Instead, senescent cells release this enzyme into the blood where it might drive disease, such as diabetes. When we kill the senescent cells, there is less of the enzyme released into the blood. Together, our results using a mouse model identify a new way in which old cells might cause aging and diabetes.
Technical Abstract: 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 diseases of age. We find that nicotinamide phosphoribosyltransferase (NAMPT), which catalyzes the rate-limiting step in nicotinamide adenine dinucleotide (NAD) biosynthesis, is elevated in senescent cells, but without a commensurate increase in NAD levels. This elevation is distinct from the DNA damage response, in which NAD is lost, and recovery of NAD by NAMPT elevation is 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 free fraction 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.