Format

Send to

Choose Destination
Redox Biol. 2019 Jun;24:101192. doi: 10.1016/j.redox.2019.101192. Epub 2019 Apr 10.

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice.

Author information

1
Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
2
Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Neurosurgery, Medical School, University of Pecs, Hungary.
3
Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
4
Division of Neonatology, Department of Pediatrics, Albert Einstein College of Medicine, USA.
5
Department of Anatomy, University of Szeged, Szeged, Hungary.
6
Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.
7
Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Department of Genetics, Harvard Medical School, Boston, USA.
9
Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary.
10
Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary; Department of Public Health, Semmelweis University, Budapest, Hungary; Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Electronic address: zoltan-ungvari@ouhsc.edu.

Abstract

Adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling (NVC) has an essential role in maintenance of healthy cognitive function. In aging increased oxidative stress and cerebromicrovascular endothelial dysfunction impair NVC, contributing to cognitive decline. There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in a range of age-related cellular impairments but its role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that restoring NAD+ concentration may exert beneficial effects on NVC responses in aging. To test this hypothesis 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2 weeks. NVC was assessed by measuring CBF responses (laser Doppler flowmetry) evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. NMN supplementation rescued NVC responses by increasing endothelial NO-mediated vasodilation, which was associated with significantly improved spatial working memory and gait coordination. These findings are paralleled by the sirtuin-dependent protective effects of NMN on mitochondrial production of reactive oxygen species and mitochondrial bioenergetics in cultured cerebromicrovascular endothelial cells derived from aged animals. Thus, a decrease in NAD+ availability contributes to age-related cerebromicrovascular dysfunction, exacerbating cognitive decline. The cerebromicrovascular protective effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective interventions in patients at risk for vascular cognitive impairment (VCI).

KEYWORDS:

Endothelial dysfunction; Functional hyperemia; Microcirculation; Oxidative stress; ROS

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center