Urolithin A and nicotinamide riboside differentially regulate innate immune defenses and metabolism in human microglial cells

Helena Borland Madsen; Claudia Navarro; Emilie Gasparini; Jae-Hyeon Park; Zhiquan Li; Deborah L Croteau; Vilhelm A Bohr

doi:10.3389/fnagi.2024.1503336

Urolithin A and nicotinamide riboside differentially regulate innate immune defenses and metabolism in human microglial cells

Front Aging Neurosci. 2024 Nov 27:16:1503336. doi: 10.3389/fnagi.2024.1503336. eCollection 2024.

Authors

Helena Borland Madsen¹, Claudia Navarro¹, Emilie Gasparini¹, Jae-Hyeon Park², Zhiquan Li¹, Deborah L Croteau^{2

3}, Vilhelm A Bohr^{1

2}

Affiliations

¹ Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
² Section on DNA Repair, National Institute on Aging, Baltimore, MD, United States.
³ Computational Biology and Genomics Core, Laboratory of Genetics and Genomics, National Institute on Aging, Baltimore, MD, United States.

Abstract

Introduction: During aging, many cellular processes, such as autophagic clearance, DNA repair, mitochondrial health, metabolism, nicotinamide adenine dinucleotide (NAD+) levels, and immunological responses, become compromised. Urolithin A (UA) and Nicotinamide Riboside (NR) are two naturally occurring compounds known for their anti-inflammatory and mitochondrial protective properties, yet the effects of these natural substances on microglia cells have not been thoroughly investigated. As both UA and NR are considered safe dietary supplements, it is equally important to understand their function in normal cells and in disease states.

Methods: This study investigates the effects of UA and NR on immune signaling, mitochondrial function, and microglial activity in a human microglial cell line (HMC3).

Results: Both UA and NR were shown to reduce DNA damage-induced cellular senescence. However, they differentially regulated gene expression related to neuroinflammation, with UA enhancing cGAS-STING pathway activation and NR displaying broader anti-inflammatory effects. Furthermore, UA and NR differently influenced mitochondrial dynamics, with both compounds improving mitochondrial respiration but exhibiting distinct effects on production of reactive oxygen species and glycolytic function.

Discussion: These findings underscore the potential of UA and NR as therapeutic agents in managing neuroinflammation and mitochondrial dysfunction in neurodegenerative diseases.

Keywords: aging; innate immune signaling; microglia; mitochondrial health; nicotinamide riboside; urolithin A.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported, in part, by the Intramural Program of the National Institute on Aging, NIH, by a FAPESP fellowship to CN and by the Novo Nordisk Foundation (NNF17OC0027812).