@article{4a389b5599fa495e85a248d84610e2c4,
title = "NAD+ flux is maintained in aged mice despite lower tissue concentrations",
abstract = "NAD+ is an essential coenzyme for all living cells. NAD+ concentrations decline with age, but whether this reflects impaired production or accelerated consumption remains unclear. We employed isotope tracing and mass spectrometry to probe age-related changes in NAD+ metabolism across tissues. In aged mice, we observed modest tissue NAD+ depletion (median decrease ∼30%). Circulating NAD+ precursors were not significantly changed, and isotope tracing showed the unimpaired synthesis of nicotinamide from tryptophan. In most tissues of aged mice, turnover of the smaller tissue NAD+ pool was modestly faster such that absolute NAD+ biosynthetic flux was maintained, consistent with more active NAD+-consuming enzymes. Calorie restriction partially mitigated age-associated NAD+ decline by decreasing consumption. Acute inflammatory stress induced by LPS decreased NAD+ by impairing synthesis in both young and aged mice. Thus, the decline in NAD+ with normal aging is relatively subtle and occurs despite maintained NAD+ production, likely due to increased consumption.",
keywords = "CD38, NAD, NADH, PARP, PARP1, SIRT1, aging, flux, mononucleotide, niacin, nicotinamide, redox, riboside, sirtuins",
author = "McReynolds, {Melanie R.} and Karthikeyani Chellappa and Eric Chiles and Connor Jankowski and Yihui Shen and Li Chen and Descamps, {H{\'e}l{\`e}ne C.} and Sarmistha Mukherjee and Bhat, {Yashaswini R.} and Lingala, {Siddharth R.} and Qingwei Chu and Paul Botolin and Faisal Hayat and Tomohito Doke and Katalin Susztak and Thaiss, {Christoph A.} and Wenyun Lu and Migaud, {Marie E.} and Xiaoyang Su and Rabinowitz, {Joshua D.} and Baur, {Joseph A.}",
note = "Funding Information: This work was funded and supported by both the Howard Hughes Medical Institute and Burroughs Wellcome Fund via the PDEP and Hanna H. Gray Fellow Programs awarded to M.R.M.; Crohn{\textquoteright}s and Colitis Career Development Award to K.C.; and NIH grants CA211437 to W.L., DP1DK113643 to J.D.R., and R01DK098656 and R01AG043483 to J.A.B. We thank Ophir Shalem (CHOP) for support with cell sorting. Furthermore, we acknowledge support from the Regional Metabolomics and Fluxomics Core and the Rodent Metabolic Phenotyping Core of the Penn Diabetes Research Center P30-DK19525 , the CINJ Cancer Center Support Grant, and the Rutgers Cancer Institute of New Jersey Metabolomics Shared Resource, supported, in part, with funding from NCI -CCSG P30CA072720-5923 . Funding Information: This work was funded and supported by both the Howard Hughes Medical Institute and Burroughs Wellcome Fund via the PDEP and Hanna H. Gray Fellow Programs awarded to M.R.M.; Crohn's and Colitis Career Development Award to K.C.; and NIH grants CA211437 to W.L. DP1DK113643 to J.D.R. and R01DK098656 and R01AG043483 to J.A.B. We thank Ophir Shalem (CHOP) for support with cell sorting. Furthermore, we acknowledge support from the Regional Metabolomics and Fluxomics Core and the Rodent Metabolic Phenotyping Core of the Penn Diabetes Research Center P30-DK19525, the CINJ Cancer Center Support Grant, and the Rutgers Cancer Institute of New Jersey Metabolomics Shared Resource, supported, in part, with funding from NCI-CCSG P30CA072720-5923. M.R.M. K.C. J.D.R. and J.A.B. conceived the project. M.R.M. and K.C. conceived all experiments. M.R.M. and K.C. performed and analyzed most experiments. M.R.M. and X.S. conducted the flux analysis. M.R.M. K.C. W.L. E.C. C.J. Y.S. L.C. H.C.D. S.M. Y.R.B. Q.C. X.J. F.S. and P.B. performed specific in vivo experiments and analyses. M.R.M. and J.A.B. wrote the manuscript with input from all authors. J.D.R. and J.A.B. are consultants to Pfizer. J.D.R. is an advisor and stock owner in Colorado Research Partners, L.E.A.F. Pharmaceuticals, Rafael Pharmaceuticals, Raze Therapeutics, Kadmon Pharmaceuticals, and Agios pharmaceuticals. J.D.R. is a co-inventor of SHIN2 and related SHMT inhibitors, which have been patented by Princeton University, and is a co-founder of Toran Therapeutics. G.X. M.F.C. and G.J.T. are current or former employees of Pfizer who may hold Pfizer stock and/or stock options. J.A.B. and S.M. are inventors on a patent for using NAD+ precursors in liver injury and have received research funding and materials from Elysium Health and Metro International Biotech, both of which have an interest in NAD+ precursors. The remaining authors have nothing to declare. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = dec,
day = "15",
doi = "10.1016/j.cels.2021.09.001",
language = "English (US)",
volume = "12",
pages = "1160--1172.e4",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "12",
}