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

Tamas Kiss^{1

2}, Cory B Giles^{1

3}, Stefano Tarantini^{1

4}, Andriy Yabluchanskiy^{1

4

5}, Priya Balasubramanian¹, Tripti Gautam¹, Tamas Csipo^{1

2

6}, Ádám Nyúl-Tóth^{1

7}, Agnes Lipecz^{1

2

6}, Csaba Szabo⁸, Eszter Farkas², Jonathan D Wren^{1

3}, Anna Csiszar^{1

2

4

5

9}, Zoltan Ungvari^{10

11

12

13

14

15}

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.
² Department of Medical Physics and Informatics / Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary.
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.
⁴ Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵ The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
⁶ Department of Public Health / Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary.
⁷ Institute of Biophysics, Biological Research Centre / Theoretical Medicine Doctoral School, Hungarian Academy of Sciences, Szeged, Hungary.
⁸ Chair of Pharmacology, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
⁹ Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
¹⁰ 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. zoltan-ungvari@www.qiuluzeuv.cn.
¹¹ Department of Medical Physics and Informatics / Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary. zoltan-ungvari@www.qiuluzeuv.cn.
¹² Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. zoltan-ungvari@www.qiuluzeuv.cn.
¹³ The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. zoltan-ungvari@www.qiuluzeuv.cn.
¹⁴ Department of Public Health / Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary. zoltan-ungvari@www.qiuluzeuv.cn.
¹⁵ Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. zoltan-ungvari@www.qiuluzeuv.cn.

PMID: 31463647
PMCID: PMC6815288
DOI: 10.1007/s11357-019-00095-x

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

Tamas Kiss et al. Geroscience. 2019 Aug.

. 2019 Aug;41(4):419-439.

doi: 10.1007/s11357-019-00095-x. Epub 2019 Aug 28.

Authors

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.
² Department of Medical Physics and Informatics / Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary.
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.
⁴ Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
⁵ The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
⁶ Department of Public Health / Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary.
⁷ Institute of Biophysics, Biological Research Centre / Theoretical Medicine Doctoral School, Hungarian Academy of Sciences, Szeged, Hungary.
⁸ Chair of Pharmacology, Department of Medicine, University of Fribourg, Fribourg, Switzerland.
⁹ Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Budapest, Hungary.
¹⁰ 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. zoltan-ungvari@www.qiuluzeuv.cn.
¹¹ Department of Medical Physics and Informatics / Theoretical Medicine Doctoral School, University of Szeged, Szeged, Hungary. zoltan-ungvari@www.qiuluzeuv.cn.
¹² Translational Geroscience Laboratory, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. zoltan-ungvari@www.qiuluzeuv.cn.
¹³ The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. zoltan-ungvari@www.qiuluzeuv.cn.
¹⁴ Department of Public Health / Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary. zoltan-ungvari@www.qiuluzeuv.cn.
¹⁵ Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. zoltan-ungvari@www.qiuluzeuv.cn.

PMID: 31463647
PMCID: PMC6815288
DOI: 10.1007/s11357-019-00095-x

VSports - 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 VSports手机版. 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. .

Keywords: Atherosclerosis; Endothelial dysfunction; Epigenetics; Oxidative stress; Senescence; Vascular aging; Vascular cognitive impairment. V体育安卓版.

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Figures

**Fig. 1**
NMN treatment reverses age-related changes in miRNA expression profile in the mouse aorta. a The heat map is a graphic representation of normalized miRNA expression values in aortas derived from young (3-month-old), aged (24-month-old), and NMN-treated aged mice. Hierarchical clustering analysis revealed the similarities on miRNA expression profiles of aortas from young and NMN-treated aged mice. b Principal component analysis (PCA) plot of miRNA expression profiles from aortas derived from young, aged control, and NMN-treated aged mice. The profiles from aged mice (red dots) cluster separately to clusters representative of young mice (blue circles) and NMN-treated aged mice (green triangles). PC1 and PC2: Principal components 1 and 2, respectively. c Venn diagrams showing the differentially expressed miRNAs in each group, which are significantly up- or down-regulated in aortas from aged mice compared to those from young mice or aged NMN-treated mice

**Fig. 2**
Effects of aging and NMN treatment on miRNA expression in the mouse aorta. a, b qPCR data showing miRNA expression in aortas isolated from young (3-month-old), aged (24-month-old), and NMN-treated aged mice. Data are mean ± S.E.M. (n = 3–4 for each data point). *P < 0.05 vs. young; #P < 0.05 vs. aged

**Fig. 3**
Proposed scheme for the mechanisms by which restoration of NAD+ levels in the aged vasculature by NMN supplementation promotes anti-aging miRNA expression profile, rescues endothelial function, and prevents atherogenesis. The model, based on our present and previous findings and earlier data from the literature (Tarantini et al. ; Csiszar et al. 2019), predicts that increased NAD+ activates sirtuin-mediated pathways, restores cellular energetics and attenuates mitochondrial ROS (mtROS) production, which lead to epigenetic changes promoting youthful gene/miRNA expression, restore Dicer1-mediated miRNA processing, increase NO bioavailability, decrease inflammation, and improve protein homeostasis. All of these effects are predicted to act to decrease large artery stiffness, inhibit atherogenesis, improve vasodilation, and promote angiogenesis at the level of the microcirculation

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References

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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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"VSports" 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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