Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial

Kristoffer L. Norheim; Michael Ben Ezra; Indra Heckenbach; Louise Munkholm Andreasson; Lise Lotte Eriksen; Nanna Dyhre-Petersen; Mads Vargas Damgaard; Magnus Berglind; Luca Pricolo; Dayle Sampson; Ryan W. Dellinger; Asger Sverrild; Jonas T. Treebak; Sisse Bolm Ditlev; Celeste Porsbjerg; Morten Scheibye-Knudsen

doi:10.1038/s43587-024-00758-1

Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial

Kristoffer L. Norheim, Michael Ben Ezra, Indra Heckenbach, Louise Munkholm Andreasson, Lise Lotte Eriksen, Nanna Dyhre-Petersen, Mads Vargas Damgaard, Magnus Berglind, Luca Pricolo, Dayle Sampson, Ryan W. Dellinger, Asger Sverrild, Jonas T. Treebak, Sisse Bolm Ditlev, Celeste Porsbjerg, Morten Scheibye-Knudsen^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift › Letter › Forskning › peer review

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive, incurable disease associated with smoking and advanced age, ranking as the third leading cause of death worldwide. DNA damage and loss of the central metabolite nicotinamide adenine dinucleotide (NAD⁺) may contribute to both aging and COPD, presenting a potential avenue for interventions. In this randomized, double-blind, placebo-controlled clinical trial, we treated patients with stable COPD (n = 40) with the NAD⁺ precursor nicotinamide riboside (NR) for 6 weeks and followed-up 12 weeks later. The primary outcome was change in sputum interleukin-8 (IL-8) from baseline to week 6. The estimated treatment difference between NR and placebo in IL-8 after 6 weeks was −52.6% (95% confidence interval (CI): −75.7% to −7.6%; P = 0.030). This effect persisted until the follow-up 12 weeks after the end of treatment (−63.7%: 95% CI −85.7% to −7.8%; P = 0.034). For secondary outcomes, NR treatment increased NAD⁺ levels by more than twofold in whole blood, whereas IL-6 levels in plasma remained unchanged. In exploratory analyses, treatment with NR showed indications of upregulated gene pathways related to genomic integrity in the airways and reduced epigenetic aging, possibly through a reduction in cellular senescence. These exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov identifier: NCT04990869.

Originalsprog	Engelsk
Tidsskrift	Nature Aging
Vol/bind	4
Udgave nummer	12
Sider (fra-til)	1772–1781
Antal sider	10
ISSN	2662-8465
DOI	https://doi.org/10.1038/s43587-024-00758-1
Status	Udgivet - 2024

Bibliografisk note

Funding Information:
M.S.-K. is supported by the Novo Nordisk Foundation Challenge Programme (NNF17OC0027812), the Nordea Foundation (02-2017-1749), the Neye Foundation, the Lundbeck Foundation (R324-2019-1492), the Ministry of Higher Education and Science (0238-00003B), VitaDAO and Insilico Medicine. K.L.N. is supported by the Carl og Ellen Hertz\u02BC legat til Dansk L\u00E6ge- og Naturvidenskab (5.21.1). J.T.T. and M.V.D. were supported by the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR). The CBMR is an independent research center at the University of Copenhagen and is partially funded by an unrestricted donation (NNF18CC0034900) from the Novo Nordisk Foundation. M.V.D. was also supported by a PhD scholarship from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation (NNF17SA0031406). Elysium Health (New York) provided the NR and placebo capsules and funded and carried out the DNA methylation analyses. The funders had no role in study design, data collection, decision to publish or preparation of the manuscript.

Publisher Copyright:
© The Author(s) 2024.

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10.1038/s43587-024-00758-1Licens: CC BY-NC-ND

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Citationsformater

Norheim, K. L., Ben Ezra, M., Heckenbach, I., Andreasson, L. M., Eriksen, L. L., Dyhre-Petersen, N., Damgaard, M. V., Berglind, M., Pricolo, L., Sampson, D., Dellinger, R. W., Sverrild, A., Treebak, J. T., Ditlev, S. B., Porsbjerg, C., & Scheibye-Knudsen, M. (2024). Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial. Nature Aging, 4(12), 1772–1781. https://doi.org/10.1038/s43587-024-00758-1

Effect of nicotinamide riboside on airway inflammation in COPD : a randomized, placebo-controlled trial. / Norheim, Kristoffer L.; Ben Ezra, Michael ; Heckenbach, Indra; Andreasson, Louise Munkholm; Eriksen, Lise Lotte; Dyhre-Petersen, Nanna; Damgaard, Mads Vargas; Berglind, Magnus; Pricolo, Luca; Sampson, Dayle; Dellinger, Ryan W.; Sverrild, Asger ; Treebak, Jonas T.; Ditlev, Sisse Bolm; Porsbjerg, Celeste ; Scheibye-Knudsen, Morten.

I: Nature Aging, Bind 4, Nr. 12, 2024, s. 1772–1781.

Publikation: Bidrag til tidsskrift › Letter › Forskning › peer review

Norheim, KL, Ben Ezra, M , Heckenbach, I, Andreasson, LM, Eriksen, LL, Dyhre-Petersen, N, Damgaard, MV, Berglind, M, Pricolo, L, Sampson, D, Dellinger, RW, Sverrild, A , Treebak, JT, Ditlev, SB, Porsbjerg, C & Scheibye-Knudsen, M 2024, 'Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial', Nature Aging, bind 4, nr. 12, s. 1772–1781. https://doi.org/10.1038/s43587-024-00758-1

Norheim, Kristoffer L. ; Ben Ezra, Michael ; Heckenbach, Indra ; Andreasson, Louise Munkholm ; Eriksen, Lise Lotte ; Dyhre-Petersen, Nanna ; Damgaard, Mads Vargas ; Berglind, Magnus ; Pricolo, Luca ; Sampson, Dayle ; Dellinger, Ryan W. ; Sverrild, Asger ; Treebak, Jonas T. ; Ditlev, Sisse Bolm ; Porsbjerg, Celeste ; Scheibye-Knudsen, Morten. / Effect of nicotinamide riboside on airway inflammation in COPD : a randomized, placebo-controlled trial. I: Nature Aging. 2024 ; Bind 4, Nr. 12. s. 1772–1781.

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abstract = "Chronic obstructive pulmonary disease (COPD) is a progressive, incurable disease associated with smoking and advanced age, ranking as the third leading cause of death worldwide. DNA damage and loss of the central metabolite nicotinamide adenine dinucleotide (NAD+) may contribute to both aging and COPD, presenting a potential avenue for interventions. In this randomized, double-blind, placebo-controlled clinical trial, we treated patients with stable COPD (n = 40) with the NAD+ precursor nicotinamide riboside (NR) for 6 weeks and followed-up 12 weeks later. The primary outcome was change in sputum interleukin-8 (IL-8) from baseline to week 6. The estimated treatment difference between NR and placebo in IL-8 after 6 weeks was −52.6% (95% confidence interval (CI): −75.7% to −7.6%; P = 0.030). This effect persisted until the follow-up 12 weeks after the end of treatment (−63.7%: 95% CI −85.7% to −7.8%; P = 0.034). For secondary outcomes, NR treatment increased NAD+ levels by more than twofold in whole blood, whereas IL-6 levels in plasma remained unchanged. In exploratory analyses, treatment with NR showed indications of upregulated gene pathways related to genomic integrity in the airways and reduced epigenetic aging, possibly through a reduction in cellular senescence. These exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov identifier: NCT04990869.",

author = "Norheim, {Kristoffer L.} and {Ben Ezra}, Michael and Indra Heckenbach and Andreasson, {Louise Munkholm} and Eriksen, {Lise Lotte} and Nanna Dyhre-Petersen and Damgaard, {Mads Vargas} and Magnus Berglind and Luca Pricolo and Dayle Sampson and Dellinger, {Ryan W.} and Asger Sverrild and Treebak, {Jonas T.} and Ditlev, {Sisse Bolm} and Celeste Porsbjerg and Morten Scheibye-Knudsen",

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T1 - Effect of nicotinamide riboside on airway inflammation in COPD

T2 - a randomized, placebo-controlled trial

AU - Norheim, Kristoffer L.

AU - Ben Ezra, Michael

AU - Heckenbach, Indra

AU - Andreasson, Louise Munkholm

AU - Eriksen, Lise Lotte

AU - Dyhre-Petersen, Nanna

AU - Damgaard, Mads Vargas

AU - Berglind, Magnus

AU - Pricolo, Luca

AU - Sampson, Dayle

AU - Dellinger, Ryan W.

AU - Sverrild, Asger

AU - Treebak, Jonas T.

AU - Ditlev, Sisse Bolm

AU - Porsbjerg, Celeste

AU - Scheibye-Knudsen, Morten

PY - 2024

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N2 - Chronic obstructive pulmonary disease (COPD) is a progressive, incurable disease associated with smoking and advanced age, ranking as the third leading cause of death worldwide. DNA damage and loss of the central metabolite nicotinamide adenine dinucleotide (NAD+) may contribute to both aging and COPD, presenting a potential avenue for interventions. In this randomized, double-blind, placebo-controlled clinical trial, we treated patients with stable COPD (n = 40) with the NAD+ precursor nicotinamide riboside (NR) for 6 weeks and followed-up 12 weeks later. The primary outcome was change in sputum interleukin-8 (IL-8) from baseline to week 6. The estimated treatment difference between NR and placebo in IL-8 after 6 weeks was −52.6% (95% confidence interval (CI): −75.7% to −7.6%; P = 0.030). This effect persisted until the follow-up 12 weeks after the end of treatment (−63.7%: 95% CI −85.7% to −7.8%; P = 0.034). For secondary outcomes, NR treatment increased NAD+ levels by more than twofold in whole blood, whereas IL-6 levels in plasma remained unchanged. In exploratory analyses, treatment with NR showed indications of upregulated gene pathways related to genomic integrity in the airways and reduced epigenetic aging, possibly through a reduction in cellular senescence. These exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov identifier: NCT04990869.

AB - Chronic obstructive pulmonary disease (COPD) is a progressive, incurable disease associated with smoking and advanced age, ranking as the third leading cause of death worldwide. DNA damage and loss of the central metabolite nicotinamide adenine dinucleotide (NAD+) may contribute to both aging and COPD, presenting a potential avenue for interventions. In this randomized, double-blind, placebo-controlled clinical trial, we treated patients with stable COPD (n = 40) with the NAD+ precursor nicotinamide riboside (NR) for 6 weeks and followed-up 12 weeks later. The primary outcome was change in sputum interleukin-8 (IL-8) from baseline to week 6. The estimated treatment difference between NR and placebo in IL-8 after 6 weeks was −52.6% (95% confidence interval (CI): −75.7% to −7.6%; P = 0.030). This effect persisted until the follow-up 12 weeks after the end of treatment (−63.7%: 95% CI −85.7% to −7.8%; P = 0.034). For secondary outcomes, NR treatment increased NAD+ levels by more than twofold in whole blood, whereas IL-6 levels in plasma remained unchanged. In exploratory analyses, treatment with NR showed indications of upregulated gene pathways related to genomic integrity in the airways and reduced epigenetic aging, possibly through a reduction in cellular senescence. These exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov identifier: NCT04990869.

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