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Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects

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Abstract

Understanding molecular mechanisms involved in vascular aging is essential to develop novel interventional strategies for treatment and prevention of age-related vascular pathologies. Recent studies provide critical evidence that vascular aging is characterized by NAD+ depletion. Importantly, in aged mice, restoration of cellular NAD+ levels by treatment with the NAD+ booster nicotinamide mononucleotide (NMN) exerts significant vasoprotective effects, improving endothelium-dependent vasodilation, attenuating oxidative stress, and rescuing age-related changes in gene expression. Strong experimental evidence shows that dysregulation of microRNAs (miRNAs) has a role in vascular aging. The present study was designed to test the hypothesis that age-related NAD+ depletion is causally linked to dysregulation of vascular miRNA expression. A corollary hypothesis is that functional vascular rejuvenation in NMN-treated aged mice is also associated with restoration of a youthful vascular miRNA expression profile. To test these hypotheses, aged (24-month-old) mice were treated with NMN for 2 weeks and miRNA signatures in the aortas were compared to those in aortas obtained from untreated young and aged control mice. We found that protective effects of NMN treatment on vascular function are associated with anti-aging changes in the miRNA expression profile in the aged mouse aorta. The predicted regulatory effects of NMN-induced differentially expressed miRNAs in aged vessels include anti-atherogenic effects and epigenetic rejuvenation. Future studies will uncover the mechanistic role of miRNA gene expression regulatory networks in the anti-aging effects of NAD+ booster treatments and determine the links between miRNAs regulated by NMN and sirtuin activators and miRNAs known to act in the conserved pathways of aging and major aging-related vascular diseases.

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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 Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938, to AY and JW), 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.

Author information

Author notes

  1. Tamas Kiss, Cory B. Giles and Stefano Tarantini contributed equally to this work.

Authors and Affiliations

  1. Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA

    Tamas Kiss, Cory B. Giles, Stefano Tarantini, Andriy Yabluchanskiy, Priya Balasubramanian, Tripti Gautam, Tamas Csipo, Ádám Nyúl-Tóth, Agnes Lipecz, Jonathan D. Wren, Anna Csiszar & Zoltan Ungvari

  2. Department of Medical Physics and Informatics / Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary

    Tamas Kiss, Tamas Csipo, Agnes Lipecz, Eszter Farkas, Anna Csiszar & Zoltan Ungvari

  3. Oklahoma Medical Research Foundation, Genes & Human Disease Research Program, Oklahoma City, OK and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

    Cory B. Giles & Jonathan D. Wren

  4. Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Stefano Tarantini, Andriy Yabluchanskiy, Anna Csiszar & Zoltan Ungvari

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

    Andriy Yabluchanskiy, Anna Csiszar & Zoltan Ungvari

  6. Department of Public Health / Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary

    Tamas Csipo, Agnes Lipecz & Zoltan Ungvari

  7. Institute of Biophysics, Biological Research Centre / Theoretical Medicine Doctoral School, Hungarian Academy of Sciences, Szeged, Hungary

    Ádám Nyúl-Tóth

  8. Chair of Pharmacology, Department of Medicine, University of Fribourg, Fribourg, Switzerland

    Csaba Szabo

  9. Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary

    Anna Csiszar

  10. 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. Cory B. Giles
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  3. Stefano Tarantini
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  4. Andriy Yabluchanskiy
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  5. Priya Balasubramanian
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  6. Tripti Gautam
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  7. Tamas Csipo
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  8. Ádám Nyúl-Tóth
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  9. Agnes Lipecz
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  10. Csaba Szabo
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  11. Eszter Farkas
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  12. Jonathan D. Wren
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  13. Anna Csiszar
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  14. Zoltan Ungvari
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Corresponding author

Correspondence to Zoltan Ungvari.

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Kiss, T., Giles, C.B., Tarantini, S. et al. Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects. GeroScience 41, 419–439 (2019). https://doi.org/10.1007/s11357-019-00095-x

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  • DOI: https://doi.org/10.1007/s11357-019-00095-x

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