Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice
Stefano Tarantini,
Marta Noa Valcarcel-Ares,
Peter Toth,
Andriy Yabluchanskiy,
Zsuzsanna Tucsek,
Tamas Kiss,
Peter Hertelendy,
Michael Kinter,
Praveen Ballabh,
Zoltán Süle,
Eszter Farkas,
Joseph A. Baur,
David A. Sinclair,
Anna Csiszar,
Zoltan Ungvari
Affiliations
Stefano Tarantini
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
Marta Noa Valcarcel-Ares
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
Peter Toth
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
Andriy Yabluchanskiy
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
Zsuzsanna Tucsek
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
Tamas Kiss
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
Peter Hertelendy
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
Michael Kinter
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
Praveen Ballabh
Division of Neonatology, Department of Pediatrics, Albert Einstein College of Medicine, USA
Zoltán Süle
Department of Anatomy, University of Szeged, Szeged, Hungary
Eszter Farkas
Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary
Joseph A. Baur
Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
David A. Sinclair
Department of Genetics, Harvard Medical School, Boston, USA
Anna Csiszar
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
Zoltan Ungvari
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; Corresponding author. 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.
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: Oxidative stress, ROS, Endothelial dysfunction, Functional hyperemia, Microcirculation