Rejuvenating the Aging Brain With NMN, One Blood Vessel at a Time

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Rejuvenating the Aging Brain With NMN, One Blood Vessel at a Time

Responsible for every thought, emotion, movement, and memory that we have, our brains are undeniably the most complex and powerful organ in the body. However, despite this sophistication, the brain has one (sometimes) fatal flaw — it has no way to store the large amounts of energy required to keep your body and mind functioning. Rather than relying on a storage system, the brain constantly receives nutrients and oxygen through its network of blood vessels called the neurovascular system. It’s well known that after just a few minutes, a complete blockage of blood flow to the brain — commonly known as a stroke — can cause irreparable brain damage or death. 

However, a less immediate and more subtle injury to the brain occurs when there’s a slight mismatch between the brain’s energy needs and its cerebral blood flow functioning. If the brain’s vascular system becomes less regulated, dysfunctional, or damaged, cognitive impairment or dementia can begin to develop from this lack of proper blood flow. And, with age, a dysregulated neurovascular system becomes more and more likely.

Although we don’t know for sure how to prevent or reverse this age-related vascular dysfunction in the brain, many researchers have recently been focusing on the decline in NAD+ (nicotinamide adenine dinucleotide) levels that commonly occur with advancing age. NAD+ is a crucial coenzyme needed by every one of our cells to function properly; its declining levels are implicated in many, if not all, age-related chronic diseases — including cognitive decline and neurovascular disorders.

In a recent study published in GeroScience, researchers primarily based out of the University of Oklahoma aimed to combat both the low NAD+ levels and the neurovascular dysfunction commonly seen with age, using one of NAD+’s precursors — NMN (nicotinamide mononucleotide). With this research, Kiss and colleagues uncover how this NAD+ booster improves the health and integrity of both the cerebral blood flow system and the brain as a whole, leading to neurovascular rejuvenation in a group of aged mice.

Going With the Flow: How the Brain Relies on Its Blood Vessels

It was once thought that the brain and its blood vessels were two completely separate systems, with many early neuroscientists believing that the brain didn’t have much control or regulatory capacity over the nutrient- and oxygen-rich blood flowing into it. Now, the interdependence between brain cells and cerebral blood vessels is embraced, with this complex network being coined the neurovascular unit (NVU). As the health of the NVU underlies the health of the entire brain, damage or dysfunction to this system increases the risk of neurodegenerative diseases in aging adults.

One vital aspect of a functional NVU is its ability to maintain a tight “coupling” between brain activity and cerebral blood flow. Known as neurovascular coupling, this process ensures that the regions of the brain that require more energy receive it when they need it, while less energy-intensive areas get matched with a slightly lower quantity of blood flow. On the flip side, neurovascular uncoupling occurs when brain cell activity and blood vessel function and flow are impaired or mismatched, leading to cognitive impairment.

neurovascular uncoupling occurs when brain cell activity and blood vessel function and flow are impaired or mismatched, leading to cognitive impairment.

Boosting NAD+ Bolsters Brain Function

In this study, Kiss and colleagues treated 24-month-old mice (translating to about 60 in human years) with injections of the NAD+ precursor, NMN, for two weeks. At 500 mg/kg/day, this dose was the human equivalent of almost 3 grams of NMN per day in an average-sized American of 176 pounds. From there, they looked at the activity of genes involved with the NVU and how they changed with NMN supplementation.

In aged mice who didn’t receive NMN treatment, almost 600 genes related to the NVU were differentially activated than young mice’s genes. Aging was associated with increases in genes related to inflammation, apoptosis (programmed cell death), dysfunction of our cells’ energy powerhouses (the mitochondria), and oxidative stress — the buildup of inflammatory compounds called reactive oxygen species — all of which can damage the NVU. After receiving NMN treatment, over half of these altered genes exhibited a reversal to youthful levels. 

NMN also boosted the activity of several genes related to the integrity of the blood-brain barrier (BBB) — the semi-permeable yet highly selective border of cells that act as an internal security system for the brain, protecting it from toxins or other foreign substances while allowing in vital nutrients and oxygen. This barrier is made up of tiny cells called brain microvascular endothelial cells, making the BBB an essential component of the NVU.

As the BBB starts to break down in the face of increased neuroinflammation and oxidative stress, supplemental NMN could be a simple way to preserve BBB integrity and reduce the risk of neurovascular disorders with age. As stated by the authors, “On the basis of our findings that NMN upregulates factors controlling barrier integrity, it will be also of great interest to determine whether NMN treatment can also protect against age-related disruption of the blood-brain barrier.”

The Supporting Role of Sirtuins

One key aspect of NMN’s beneficial effects on neurovascular health is the activity of SIRT1, a protein in the sirtuin family that helps to regulate various cellular processes, including mitochondrial function, resistance to oxidative stress and inflammation, and aging. As SIRT1 is dependent on NAD+ to function properly, low levels of NAD+ would subsequently dampen SIRT1 activity. These age-related declines in SIRT1 activity were verified in this study — the aged mice had significantly reduced activity of genes that are tightly regulated by SIRT1, which was reversed upon NMN treatment. 

The research team also wondered if SIRT1 was necessary for NMN to provide its neurovascular-rejuvenating effects — and, turns out, it was. In a previously published study by the same team, deleting SIRT1 in mice prevented NMN’s beneficial effects from taking hold in the neurovascular system of aged mice, indicating that SIRT1 plays an essential role in protecting the NVU. 

Kiss and colleagues are also curious about how a combination supplement of NMN with compounds that activate SIRT1, like resveratrol, would benefit vascular and cognitive health with age. The authors propose, “Potentially, NAD+ booster treatments (e.g., in combination with STACs [SIRT1-activating compounds] ) could be harnessed for the development of new pharmacological approaches for neurovascular protection for the prevention and treatment of VCI [vascular cognitive impairment] and neurodegenerative diseases in older adults.”

boosting NAD+ levels (with its subsequent increases in SIRT1 activity) may be a novel way to combat these diseases and support brain health with age.

NMN is the VIP for the NVU

With one in 10 Americans over age 65 and almost one-third of those over age 85 afflicted by some form of dementia or cognitive impairment, it’s imperative we find ways to prevent, treat, or reverse this brain-related decline. As NVU dysfunction has only recently been found to play an essential role in neurodegenerative disease development, boosting NAD+ levels (with its subsequent increases in SIRT1 activity) may be a novel way to combat these diseases and support brain health with age. As summarized by Kiss and colleagues, “We hope that our findings will facilitate future endeavors to uncover the mechanistic role of neurovascular NAD+ depletion in brain aging and the pathogenesis of VCI.”

Show references
 

Kiss T, Nyúl-Tóth Á, Balasubramanian P, et al. Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. Geroscience. 2020;42(2):527-546. doi:10.1007/s11357-020-00165-5

Tarantini S, Valcarcel-Ares MN, Toth P, et al. Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol. 2019;24:101192. doi:10.1016/j.redox.2019.101192

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