Abstract
NAD+ supplementation has significant benefits in compromised settings, acting largely through improved mitochondrial function and DNA repair. Elevating NAD+ to physiological levels has been shown to improve the function of some adult stem cells, with implications that these changes will lead to sustained improvement of the tissue or system. Here, we examined the effect of elevating NAD+ levels in models with reduced hematopoietic stem cell (HSC) potential, ATM-deficient and aged WT mice, and showed that supplementation of nicotinamide riboside (NR), a NAD+ precursor, improved lymphoid lineage potential during supplementation. In aged mice, this improved lymphoid potential was maintained in competitive transplants and was associated with transcriptional repression of myeloid gene signatures in stem and lineage-committed progenitor cells after NR treatment. However, the altered transcriptional priming of the stem cells toward lymphoid lineages was not sustained in the aged mice after NR removal. These data characterize significant alterations to the lineage potential of functionally compromised HSCs after short-term exposure to NR treatment.
Highlights
Nicotinamide adenine dinucleotide is a critical coenzyme with broad physiological functions, including the regulation of metabolism and DNA repair
Examination of hematopoietic progenitor cells in whole bone marrow (WBM) showed that nicotinamide riboside (NR)-treated Atm−/− mice had significantly increased common lymphoid-progenitor (CLP) frequency compared to the nontreated Atm−/− mice (Fig. 1a and Supplementary Fig. 1)
While NR treatment did not drive significant changes in the frequencies of the LSK (Lin−Sca1+cKit+) and hematopoietic stem cell (HSC) compartments of Atm−/− mice, we did see significant aging-like phenotypes in these compartments in the Atm−/− mice compared to WT (Fig. 1b, c)
Summary
Nicotinamide adenine dinucleotide (oxidized form, NAD+) is a critical coenzyme with broad physiological functions, including the regulation of metabolism and DNA repair. Decreased levels of NAD+ are often associated with impaired conditions, such as those found in models of cancer, metabolic disorders, neurodegeneration, as well as physiological and accelerated aging processes[1,2,3,4]. We recently examined the role of NAD+ supplementation in models of ataxia–telangiectasia (A–T), which is a disorder caused by mutations (ATM)[9,10,11]. Murine models of ATM loss show defects in DNA damage repair associated with mitochondrial dysfunction[13] and loss of hematopoietic stem cell (HSC) potential[14]. Supplementation of NR in models of A–T led to significantly improved lifespan and healthspan, mediated by improvement of both DNA damage repair and mitophagy in the tissues examined[1,11,15]
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