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

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice is a mouse study which investigated the effects of NMN supplementation on neurovascular coupling and endothelial functioning in aged mice. The three experimental groups were young mice, aged control mice, and aged mice treated for 14 days with 500mg/kg of NMN injected intra-peritoneally. The authors found that although in aging control mice, brain endothelial NAD⁺ was decreased to about 70% of young mice, treatment with NMN was associated in a statistically significant increase in NAD⁺ to about the level of healthy young mice (p < 0.05). The authors further reported that NMN supplementation was associated with improved cerebral blood flow in response to stimulus, demonstrating that the associated increase in young mice and NMN treated mice was approximately 20% compared to 10% in aged control mice (p < 0.05). Additional confirmatory studies conducted by the authors affirmed that the improvement in endothelial function was mitochondrially mediated and were associated with improved functioning of the mitochondria rather than simply increased numbers of mitochondria. With respect to behavior tests which assessed cognitive function, the authors found that NMN supplementation improved learning latency in aging mice, mirroring the results of the young cohort. In addition, NMN supplementation improved novel object recognition testing in the aging cohort as well.

Article 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).

Implications

Overall, this study adds to the growing body of literature that NMN supplementation appears to result in tangible improvements in mitochondrial functioning on an in vitro basis. This study takes these results further by showing the physiologic results of these improvements via the improvement of neurovascular coupling and cerebral blood flow in NMN-treated aged mice. Additional behavior studies in these mice highlighted the potential cognitive benefits of these previously established in vitro improvements.

Additional research to be conducted

The authors report in their manuscript that future planned directions of study will investigate previously reported relationships between hydrogen sulfide and aging. Specifically, the authors note that since previous studies have highlighted the potentially beneficial role of hydrogen sulfide in reversing vascular aging, they would recommend investigating the interaction between hydrogen sulfide and known NAD⁺ metabolic pathways.

In addition to this topic, which was highlighted within the manuscript, future directions for this research could involve non-invasively measuring the blood flow effects that oral NMN supplementation has in humans. Recent work has highlighted the safety and efficacy of oral NMN supplementation in humans already, and investigations into the potential effects of this supplementation should follow.

Institution

Dr. Zoltan Ungvari has published extensively on topics ranging including aging and mitochondrial health and effects that aging has on the vasculature from his lab at the University of Oklahoma. Prior to this article they had published numerous articles investigating the effects of NMN and resveratrol on mitochondrial functioning and endothelial health.

Funding

This study was funded by grants from the American Heart Association, the National Institute on Aging, and the National Institute of Neurologic Disorders and Stroke, among others. The authors report no industry sources of funding and note the funding sources had no input into study design, review, or publication.

Authors/ Researchers

• Stefano Tarantini – Department of Geriatric Medicine, University of Oklahoma
• Marta Valcarcel-Ares - Department of Geriatric Medicine, University of Oklahoma
• Peter Toth - Department of Geriatric Medicine, University of Oklahoma
• Andriy Yabluchanskiy - Department of Geriatric Medicine, University of Oklahoma
• Zsuzsanna Tucsek - Department of Geriatric Medicine, University of Oklahoma
• Tamas Kiss - Department of Geriatric Medicine, University of Oklahoma
• Peter Hertelendy - Department of Geriatric Medicine, University of Oklahoma
• Michael Kinter – Aging and Metabolism Research Program, Oklahoma Medical Research Foundation
• Praveen Ballabh – Department of Pediatrics, Albert Einstein College of Medicine
• Zoltan Sule – Department of Anatomy, University of Szeged
• Eszter Farkas – Department of Medical Physics, University of Szeged
• Joseph A. Baur – Department of Physiology, University of Pennsylvannia
• David A. Sinclair – Department of Genetics, Harvard Medical School
• Anna Csiszar – Department of Public Health, Semmelweis University
• Zoltan Ungvari - Departments of Geriatric Medicine, Health Promotion Sciences, University of Oklahoma; Department of Medical Physics, University of Szeged; Department of Public Health, Semmelweis University