biostudies-literatureLee JNational Research Foundation of Korea (NRF)NCATS NIH HHSNIDDK NIH HHSNIA NIH HHSU.S. Department of Health &amp; Human Services | NIH | National Institute on AgingNCI NIH HHSNINDS NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)U.S. Department of Health & Human Services | National Institutes of Health (NIH)National Research Foundation of KoreaU.S. Department of Health &amp; Human Services | National Institutes of Health2070-2085https://www.ebi.ac.uk/biostudies/studies/S-EPMC12532575biostudies-literatureUnknown5(10)Nicotinamide adenine dinucleotide (NAD⁺) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD⁺ levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD⁺ regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD⁺ via control of the NAD⁺-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD⁺ levels through a distinct pathway involving NFIL3-dependent suppression of the NAD⁺-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD<sup>+</Nature agingREV-ERBα regulates brain NAD&lt;sup&gt;+&lt;/sup&gt; levels and tauopathy via an NFIL3-CD38 axis.PMC12532575RF1AG061776RF1 AG062077R01AG063743RF1 AG062171UL1 TR002345P01 NS084974RF1AG062077P30 DK020579R35NS097273RF1AG062171R35 NS097273R01 DK045586P30 CA091842P01NS084974-01R01DK45586R21 AG089851R01 AG063743RS-2019-NR040055RF1 AG061776Voorhees JRKang RBurris TPLee JWoodie LNPark SLazar MALananna BVMusiek ESGan LGoo YAZhao GSaliu IOSon MDimitry JMQuillin EIfalseREV-ERBα regulates brain NAD&lt;sup&gt;+&lt;/sup&gt; levels and tauopathy via an NFIL3-CD38 axis.Nicotinamide adenine dinucleotide (NAD⁺) is a critical metabolic co-enzyme implicated in brain aging, and augmenting NAD⁺ levels in the aging brain is an attractive therapeutic strategy for neurodegeneration. However, the molecular mechanisms of brain NAD⁺ regulation are incompletely understood. In cardiac tissue, the circadian nuclear receptor REV-ERBα has been shown to regulate NAD⁺ via control of the NAD⁺-producing enzyme NAMPT. Here we show that REV-ERBα controls brain NAD⁺ levels through a distinct pathway involving NFIL3-dependent suppression of the NAD⁺-consuming enzyme CD38, particularly in astrocytes. REV-ERBα deletion does not affect NAMPT expression in the brain and has an opposite effect on NAD<sup>+</2025-01-01T00:00:00Z2025 Oct2026-06-04T14:31:55.589Z2026-05-10T03:11:05.403ZS-EPMC125325754089033810.1038/s43587-025-00950-x