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Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects

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Abstract

Aging-induced structural and functional alterations of the neurovascular unit lead to impairment of neurovascular coupling responses, dysregulation of cerebral blood flow, and increased neuroinflammation, all of which contribute importantly to the pathogenesis of age-related vascular cognitive impairment (VCI). There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in age-related neurovascular and cerebromicrovascular dysfunction. Our recent studies demonstrate that restoring cellular NAD+ levels in aged mice rescues neurovascular function, increases cerebral blood flow, and improves performance on cognitive tasks. To determine the effects of restoring cellular NAD+ levels on neurovascular gene expression profiles, 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. Transcriptome analysis of preparations enriched for cells of the neurovascular unit was performed by RNA-seq. Neurovascular gene expression signatures in NMN-treated aged mice were compared with those in untreated young and aged control mice. We identified 590 genes differentially expressed in the aged neurovascular unit, 204 of which are restored toward youthful expression levels by NMN treatment. The transcriptional footprint of NMN treatment indicates that increased NAD+ levels promote SIRT1 activation in the neurovascular unit, as demonstrated by analysis of upstream regulators of differentially expressed genes as well as analysis of the expression of known SIRT1-dependent genes. Pathway analysis predicts that neurovascular protective effects of NMN are mediated by the induction of genes involved in mitochondrial rejuvenation, anti-inflammatory, and anti-apoptotic pathways. In conclusion, the recently demonstrated protective effects of NMN treatment on neurovascular function can be attributed to multifaceted sirtuin-mediated anti-aging changes in the neurovascular transcriptome. Our present findings taken together with the results of recent studies using mitochondria-targeted interventions suggest that mitochondrial rejuvenation is a critical mechanism to restore neurovascular health and improve cerebral blood flow in aging.

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Funding

This work was supported by grants from the American Heart Association (ST), the Oklahoma Center for the Advancement of Science and Technology (to AC, AY, ZU), the National Institute on Aging (R01-AG047879; R01-AG038747; R01-AG055395), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to AC, R01-NS100782 to ZU), the National Institute of General Medical Sciences Oklahoma Shared Clinical and Translational Resources (OSCTR) (GM104938, to AY and JW) and Molecular Mechanisms and Genetics of Autoimmunity COBRE (P30-GM110766, to LG), the Presbyterian Health Foundation (to ZU, AC, AY), the NIA-supported Geroscience Training Program in Oklahoma (T32AG052363), the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (1P20GM125528, sub#5337). The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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Author notes

  1. Tamas Kiss, Ádám Nyúl-Tóth, Priya Balasubramanian and Stefano Tarantini contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA

    Tamas Kiss, Ádám Nyúl-Tóth, Priya Balasubramanian, Stefano Tarantini, Chetan Ahire, Andriy Yabluchanskiy, Tamas Csipo, Jonathan D. Wren & Zoltan Ungvari

  2. International Training Program in Geroscience, Theoretical Medicine Doctoral School/Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary

    Tamas Kiss, Eszter Farkas, Anna Csiszar & Zoltan Ungvari

  3. Institute of Biophysics, Biological Research Centre, Szeged, Hungary

    Ádám Nyúl-Tóth

  4. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

    Stefano Tarantini, Tamas Csipo, Anna Csiszar & Zoltan Ungvari

  5. International Training Program in Geroscience, Department of Cardiology, Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Tamas Csipo

  6. Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    Jonathan D. Wren & Lori Garman

  7. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Anna Csiszar & Zoltan Ungvari

  8. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Zoltan Ungvari

Authors
  1. Tamas Kiss
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  2. Ádám Nyúl-Tóth
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  3. Priya Balasubramanian
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  5. Chetan Ahire
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  6. Andriy Yabluchanskiy
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  7. Tamas Csipo
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  9. Jonathan D. Wren
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  10. Lori Garman
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  11. Anna Csiszar
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  12. Zoltan Ungvari
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Corresponding author

Correspondence to Zoltan Ungvari.

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All procedures were approved by the Institutional Animal Use and Care Committees of the University of Oklahoma Health Sciences Center. All animal experiments complied with the ARRIVE guidelines and were carried out in accordance with the National Institutes of Health guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978).

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Kiss, T., Nyúl-Tóth, Á., Balasubramanian, P. et al. Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. GeroScience 42, 527–546 (2020). https://doi.org/10.1007/s11357-020-00165-5

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