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. 2024 Dec;23(12):e14326.
doi: 10.1111/acel.14326. Epub 2024 Oct 1.

Dysregulated nicotinamide adenine dinucleotide metabolome in patients hospitalized with COVID-19

Rodrigo J Valderrábano  1 , Benjamin Wipper  1 , Karol Mateusz Pencina  1 , Marie Migaud  2 , Yili Valentine Shang  1 , Nancy K Latham  1 , Monty Montano  1 , James M Cunningham  3 , Lauren Wilson  1 , Liming Peng  1 , Yusnie Memish-Beleva  1 , Avantika Bhargava  1 , Pamela M Swain  4 , Phoebe Lehman  4 , Siva Lavu  4 , David J Livingston  4 , Shalender Bhasin  1
Affiliations

Dysregulated nicotinamide adenine dinucleotide metabolome in patients hospitalized with COVID-19

Rodrigo J Valderrábano et al. Aging Cell. 2024 Dec.

Abstract

Nicotinamide adenine dinucleotide (NAD+) depletion has been postulated as a contributor to the severity of COVID-19; however, no study has prospectively characterized NAD+ and its metabolites in relation to disease severity in patients with COVID-19. We measured NAD+ and its metabolites in 56 hospitalized patients with COVID-19 and in two control groups without COVID-19: (1) 31 age- and sex-matched adults with comorbidities, and (2) 30 adults without comorbidities. Blood NAD+ concentrations in COVID-19 group were only slightly lower than in the control groups (p < 0.05); however, plasma 1-methylnicotinamide concentrations were significantly higher in patients with COVID-19 (439.7 ng/mL, 95% CI: 234.0, 645.4 ng/mL) than in age- and sex-matched controls (44.5 ng/mL, 95% CI: 15.6, 73.4) and in healthy controls (18.1 ng/mL, 95% CI 15.4, 20.8; p < 0.001 for each comparison). Plasma nicotinamide concentrations were also higher in COVID-19 group and in controls with comorbidities than in healthy control group. Plasma concentrations of 2-methyl-2-pyridone-5-carboxamide (2-PY), but not NAD+, were significantly associated with increased risk of death (HR = 3.65; 95% CI 1.09, 12.2; p = 0.036) and escalation in level of care (HR = 2.90, 95% CI 1.01, 8.38, p = 0.049). RNAseq and RTqPCR analyses of PBMC mRNA found upregulation of multiple genes involved in NAD+ synthesis as well as degradation, and dysregulation of NAD+-dependent processes including immune response, DNA repair, metabolism, apoptosis/autophagy, redox reactions, and mitochondrial function. Blood NAD+ concentrations are modestly reduced in COVID-19; however, NAD+ turnover is substantially increased with upregulation of genes involved in both NAD+ biosynthesis and degradation, supporting the rationale for NAD+ augmentation to attenuate disease severity.

Keywords: 1‐methylnicotinamide; 2PY; NAD+ augmentation in COVID‐19; NAD+ metabolites; NAD+ turnover; SARS‐CoV‐2 infection; nicotinamide.

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Conflict of interest statement

Dr. Bhasin's institution has received grants from NIA, NICHD‐NCMRR, DoD, AbbVie, Besins, FPT, and Metro International Biotech, on which Dr. Bhasin serves as the principal investigator, and consulting fees from Besins, Novartis, and Varsenis. These conflicts are overseen by the Office of Industry Interaction of Mass General Brigham in accordance with institutional rules and regulations. DJL, PS, PL, and SL are employed by Metro International Biotech. MMnt receives support from the Merck Investigators Studies Program and the Claude D. Pepper OAIC. MMnt is also the Editor‐in‐Chief of Aging Cell and was blinded to the review of this manuscript. RV, BW, KP, YS, NL, MMig, JC, LW, LP, YM, and AB have no conflicts of interest to declare.

Figures

FIGURE 1
FIGURE 1
NAD+ levels in whole blood (Panel a) and PBMCs in the 3 groups: Three study groups patients hospitalized with COVID‐19; a control group of prospectively enrolled age‐ and sex‐matched adults with co‐morbidities; and a second control group of healthy middle‐aged and older adults. The first two groups—patients hospitalized with COVID‐19 and a control group of prospectively enrolled age‐ and sex‐matched adults with co‐morbidities were enrolled concurrently prospectively as a part of this study. The data on NAD+ levels in whole blood (Panel a) and PBMCs from a second control group of healthy middle‐aged and older adults were derived from a previously published study and were included as a reference for comparison (Pencina et al., 2023). The horizontal line in the box represents mean, the upper and lower margins of the box represent the 25th and 75th percentile values, and the whiskers represent the 95th percentile values.
FIGURE 2
FIGURE 2
Circulating levels of NAD+ metabolites in COVID and in patients hospitalized with COVID‐19 and a control group of prospectively enrolled age‐ and sex‐matched adults with co‐morbidities. The horizontal line in the box represents mean, the upper and lower margins of the box represent the 25th and 75th percentile values, and the whiskers represent the 95th percentile values.
FIGURE 3
FIGURE 3
Circulating levels of inflammatory markers: CRP (left panel), IL‐6 (middle panel), and TNF‐alpha (right panel) in COVID‐19 group (a), age‐ and sex‐matched Non‐COVID‐19 group (b), and healthy controls (c).
FIGURE 4
FIGURE 4
Volcano plot showing differentially expressed genes in the COVID‐19 group (n = 11) as compared to the matched control group (n = 8). Differentially expressed genes (DEGs) were defined as genes with an absolute log2 fold change >1 and an adjusted p‐value of <0.05. Down‐regulated DEGs are shown in blue and up‐regulated DEGs are in red, with select labeled genes in violet. Expression data from select genes is shown in overlying tables; genes meeting DEG criteria are listed in bold.
FIGURE 5
FIGURE 5
Quantitative reverse transcription polymerase chain reaction (RT‐qPCR) analysis comparing RNA levels of target genes in the COVID‐19 (n = 6) and matched control (n = 6) groups. Target genes were CD38 (a), and the nicotinamide mononucleotide adenylyl transferases (b). The hypoxanthine phosphoribosyl transferase 1 (HPRT) gene was used for normalization. Median values for each group are shown (represented by horizontal lines).
See this image and copyright information in PMC

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