Researchers have tested nicotinamide mononucleotide on aged mice to see if it can help reverse age-related cognitive decline by improving blood flow in the brain.

The brain is a hungry organ

Healthy brain function relies on efficient cerebral blood flow (CBF) to wash away harmful waste products for disposal and supply the brain with an adequate supply of oxygen and sufficient nutrients.

The brain is a hungry organ and consumes around 20% of the resting total of oxygen, which is staggering given that it only accounts for about 2% of our total body mass. The demand for oxygen and energy also increases during times of high neuronal activity, which means that the brain needs to quickly adjust the incoming oxygen and glucose levels via CBF.

This rapid response to differing levels of demand by the brain is facilitated by a mechanism known as neurovascular coupling (NVC). NVC refers to the relationship between local neural activity and the subsequent changes in cerebral blood flow (CBF).







One way in which NVC adjusts CBF is via the release of nitric oxide from the cell walls of the microvascular endothelium, the tiny blood vessels that supply brain tissue. Nitric oxide is a vasodilator, meaning that it opens up the blood vessels upon exposure; this allows for a greater flow of blood, leading to more oxygen and nutrients reaching the brain.

As we age, the NVC response appears to decline just as it does in lab mice, and it is thought to contribute to cognitive decline and the ability to coordinate and walk properly.

NAD+ repletion with NMN restores neurovascular coupling

In a new study, a research team including Dr. David Sinclair tested the hypothesis that nicotinamide mononucleotide (NMN) supplementation could rescue NVC responses in aged mice by reducing mitochondrial oxidative stress in the microvascular endothelial cells of the brain [1].

The team’s previous studies had shown that NVC response could be restored in aged mice using mitochondrial antioxidant peptides and SIRT1-activating drugs. This laid the groundwork for suggesting that targeting the cellular mechanisms that contribute to age-related NVC dysfunction could be a potential way to treat cognitive decline in older people.







NAD+ plays a key role in mitochondrial function in all of our cells, which includes the endothelial cells in the brain. As we age, our available levels of NAD+ begin to fall, and with that comes reduced cellular function and critically poorer DNA repair, which NAD+ facilitates.

Some researchers suggest that the decline of NAD+ is one reason we age and that increasing NAD+ to more youthful levels may mitigate some of the negative effects of aging. Certainly, a number of studies support this, and NAD+ repletion therapies have increased healthspan in progeric mouse strains that are engineered to experience a form of accelerated aging.

In the case of NMN, there is good evidence that NAD+ repletion using this compound is able to reverse some aspects of aging in a number of organs, including the eyes, skeletal muscle, and arteries. One of the primary reasons NMN appears effective is due to its reversal of age-related mitochondrial dysfunction [2]. Given that NMN might improve mitochondrial function and have a protective effect on the brain, improving NVC response, the research team set out to test this hypothesis.

The mice were given NMN injections for a two-week period at a dosage of 500 mg NMN/kg body weight per day. The team used aged C57BL/6 mice, a popular strain of lab mouse that is not engineered to experience accelerated aging; this was important for the purposes of this study, as it would mean that any beneficial results would be affecting real aging and not an artificial form of aging, as is the case when using progeric mouse strains.

During the period of treatment, the mice were given cognition and motor coordination tests, both of which are linked to the NVC responses in the brain. They also tested NVC response and how well endothelial cells were performing in the brain’s microvascular system. During this time, the research team also measured biomarkers for oxidative stress, gene expression relating to NVC responses, antioxidant responses in cells, and mitochondrial function.







The researchers found that NMN treatment was able to improve the NVC response of aged mice via improving nitric oxide-mediated vasodilation of the microvasculature in the brain. The increased level of CBF significantly improved cognition and walking ability in aged mice. The researchers conclude that the age-related fall of NAD+ levels facilitates dysfunction in the microvasculature of the brain, leading to a poor NVC response and contributing to age-related cognitive decline.

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).

Conclusion

NMN therapy appears to have a protective effect on brain microvasculature and improves the production of nitric oxide, which improves blood flow in the brains of aged mice. This opens the door for testing NMN therapy in humans as a potential treatment for age-related cognitive decline.







Literature

[1] Tarantini, S., Valcarcel-Ares, M. N., Toth, P., Yabluchanskiy, A., Tucsek, Z., Kiss, T., … & Farkas, E. (2019). Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biology, 101192.

[2] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Yoshino, J. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795-806.