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

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).

Accelerated decline in cognition in a mouse model of increased oxidative stress

“…Increasing oxidative stress by genetic deletion of Nrf2, the master transcription factor that regulates anti-oxidant genes, has been shown to increase cerebrovascular inflammation, affect neurovascular coupling responses, promote senescence and results in cognitive dysfunction (Tarantini et al 2018a;Fulop et al 2018). Furthermore, interventions that attenuate vascular oxidative stress has been shown to restore microvascular function and cognition (Tarantini et al 2018b(Tarantini et al , 2019.…”

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury

“…Catalase in the mitochondrial matrix can also convert H 2 O 2 into water and molecular oxygen [86,87]. Glutathione biosynthesis is catalyzed by glutathione reductase using the oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) into NADP and is crucial in antioxidant activities in the mitochondria [88,89] Another important source of ROS in the re-perfused heart are the two isoforms of monoamine oxidases (MAO), MAO-A and MAO-B, which are located on the outer mitochondrial membrane [92]. It has been demonstrated that MAO-A activity is enhanced by I/R injury and is responsible for the precipitation of hydrogen peroxide and the progression towards left ventricle hypertrophy and cardiac remodeling [93].…”

Accelerated cerebral vascular injury in diabetes is associated with vascular smooth muscle cell dysfunction

“…Although MLCK210 mainly expressed in the endothelium and deletion of MLCK210 had no effects on the constriction of aortic rings in response to vasoconstrictor and vasodilator agonists (Ohlmann et al 2005), it remains to be determined whether the MLCK210 plays a role in the constriction of CVSMCs. Administration of nicotinamide mononucleotide, an important NAD + intermediate, improved mitochondrial membrane potential, enhanced ATP and NO production, and reduced mitochondrial ROS in cerebral microvascular endothelial cells in aged mice (Tarantini et al 2019a). NAD + , an oxidized form of nicotinamide adenine dinucleotide (NAD), is a substrate of poly (ADP-ribose) polymerase that regulates DNA damage and repair, and is a rate-limiting cosubstrate for silent information regulator-2-like enzymes that mediate mitochondrial biogenesis, energetics, and mitochondrial antioxidant defenses (Csiszar et al 2019;Kiss et al 2020;Pehar et al 2018;Tarantini et al 2019b).…”