Quantitative Survey of NAD+ Flux in Aged Mice

Abstract

Decline of NAD+ is associated with aging and disease; hence this critical metabolite is proposed as a master regulator of age‐dependent pathology. NAD+ is found in all living cells and is an essential coenzyme that broadly impacts metabolism and protein covalent modification. NAD+ depletion contributes to mitochondrial dysfunction, which is a classic hallmark of aging. Redox state and the rates of synthesis and degradation of the NAD+ chemical backbone govern the cellular concentration of NAD+. NAD+ decline during aging reflects depletion of the total NAD(H) pool, rather a shift in the NADH/NAD+ ratio, suggesting defective NAD+ synthesis and over‐consumption of NAD+ by cleaving enzymes. Concentration measurements are ill‐suited to distinguish these possibilities. Thus, there is a critical need to examine NAD+ metabolic flux, i.e. the rates of production and consumption of the NAD+ chemical backbone. To this end, we used isotope‐labeled NAD+ precursors, mass spectrometry, and quantitative modeling to determine NAD+ fluxes in young and aged mice. Tissue‐specific measurements of NAD+ labeling enabled organ‐specific assessment of NAD+ fluxes. These experiments identified accelerated NAD+ production and consumption in aging, and thus rational targets for intervention. Understanding of NAD+ fluxes will lay the foundation for understanding how NAD+ homeostasis is achieved: What are the primary control mechanisms that determine proper NAD+ concentration and fluxes? How do these go wrong in aging and disease?Support or Funding InformationHHMI Hanna H. Gray Fellows Program Burroughs Wellcome Fund Postdoctoral Enrichment ProgramThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.