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; Cory B. Giles; Stefano Tarantini; Andriy Yabluchanskiy; Priya Balasubramanian; Tripti Gautam; Tamas Csipo; Ádám Nyúl-Tóth; Agnes Lipecz; Csaba Szabo; Eszter Farkas; Jonathan D. Wren; Anna Csiszar; Zoltan Ungvari

doi:10.1007/s11357-019-00095-x

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

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English (US)
Pages (from-to)	419-439
Number of pages	21
Journal	GeroScience
Volume	41
Issue number	4
DOIs	https://doi.org/10.1007/s11357-019-00095-x
State	Published - Aug 1 2019

Keywords

Atherosclerosis
Endothelial dysfunction
Epigenetics
Oxidative stress
Senescence
Vascular aging
Vascular cognitive impairment

ASJC Scopus subject areas

Aging
veterinary (miscalleneous)
Complementary and alternative medicine
Geriatrics and Gerontology
Cardiology and Cardiovascular Medicine

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10.1007/s11357-019-00095-x

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Kiss, T., Giles, C. B., Tarantini, S., Yabluchanskiy, A., Balasubramanian, P., Gautam, T., Csipo, T., Nyúl-Tóth, Á., Lipecz, A., Szabo, C., Farkas, E., Wren, J. D., Csiszar, A., & Ungvari, Z. (2019). 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(4), 419-439. https://doi.org/10.1007/s11357-019-00095-x

Kiss, T, Giles, CB, Tarantini, S, Yabluchanskiy, A, Balasubramanian, P, Gautam, T, Csipo, T, Nyúl-Tóth, Á, Lipecz, A, Szabo, C, Farkas, E, Wren, JD, Csiszar, A & Ungvari, Z 2019, 'Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects', GeroScience, vol. 41, no. 4, pp. 419-439. https://doi.org/10.1007/s11357-019-00095-x

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

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.",

keywords = "Atherosclerosis, Endothelial dysfunction, Epigenetics, Oxidative stress, Senescence, Vascular aging, Vascular cognitive impairment",

author = "Tamas Kiss and Giles, {Cory B.} and Stefano Tarantini and Andriy Yabluchanskiy and Priya Balasubramanian and Tripti Gautam and Tamas Csipo and {\'A}d{\'a}m Ny{\'u}l-T{\'o}th and Agnes Lipecz and Csaba Szabo and Eszter Farkas and Wren, {Jonathan D.} and Anna Csiszar and Zoltan Ungvari",

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AU - Kiss, Tamas

AU - Giles, Cory B.

AU - Tarantini, Stefano

AU - Yabluchanskiy, Andriy

AU - Balasubramanian, Priya

AU - Gautam, Tripti

AU - Csipo, Tamas

AU - Nyúl-Tóth, Ádám

AU - Lipecz, Agnes

AU - Szabo, Csaba

AU - Farkas, Eszter

AU - Wren, Jonathan D.

AU - Csiszar, Anna

AU - Ungvari, Zoltan

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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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KW - Endothelial dysfunction

KW - Epigenetics

KW - Oxidative stress

KW - Senescence

KW - Vascular aging

KW - Vascular cognitive impairment

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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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