A researcher at the University of Delaware College of Health Sciences, working with a team at the National Institute on Aging, a division of the National Institutes of Health, has discovered for the first time that the naturally occurring dietary supplement nicotinamide riboside (NR) can enter the brain.
The finding is significant because it supports the notion that NR, once in the brain, can alter the metabolism of relevant biological pathways involved in neurodegenerative diseases such as Alzheimer’s. Dr. Dimitrios Kapogiannis, a senior investigator at the National Institute on Aging, and Christopher Martens, assistant professor of kinesiology and applied physiology and director of the Delaware Center for Cognitive Aging Research, made the discovery.
When consumed, nicotinamide riboside is quickly converted into nicotinamide adenine dinucleotide (NAD+), essential for cellular repair and repairing damaged DNA.
NAD+ Deficiency
NAD+ is gradually depleted as we age or develop chronic diseases. Obesity and other negative lifestyle habits, such as smoking, are linked to NAD+ deficiency.
“Because more NAD+ is needed to counteract those negative consequences, it’s more likely to be depleted in the face of negative lifestyle habits,”
Martens said.
Martens has researched the compound since his postdoctoral fellowship days at the University of Colorado Boulder. In an initial study published in Nature, he discovered that consuming NR increased NAD+ levels in the blood, but whether it could reach other tissues in the body was unclear.
“We had some preliminary signs of efficacy, including lower blood pressure in people who had high blood pressure to begin with. But until now, it was unknown whether NR reached targeted organs like the brain to have a real therapeutic effect,”
he said.
A Liquid Biopsy of Neurons
Measuring NAD+ levels in the human brain is difficult. There are emerging MRI techniques, but they only provide an indirect measure and are costly and difficult to perform.
Martens and colleagues instead measured NAD+ directly in extracellular vesicles, which originate in neurons and end up in the blood. These extracellular vesicles can provide cutting-edge blood-based biomarkers for brain disorders and act as a “liquid biopsy” of neurons, giving researchers a rare look inside them.
“Each vesicle has a unique molecular signature on its surface, including proteins that give you clues about its origin. In our case, we selected vesicles that carry markers that are characteristic of neurons, and so we have confidence that the NAD+ we measured in them reflects what happens in the neurons, and by extension the brain,”
Martens said.
Neurodegenerative Biomarker Association
Using samples from their first clinical trial, the researchers discovered that NAD+ levels increased in these vesicles after six weeks.
When NAD+ levels rose in the vesicles, the researchers noticed a link to some neurodegenerative disease biomarkers.
“Particularly, in people where we saw an increase in NAD+, we also saw changes in biomarkers like amyloid beta and tau, which are both related to Alzheimer’s disease,”
Martens said.
Martens and Kapogiannis discovered a link between these neurodegenerative biomarkers and changes in NAD+ levels.
“If NAD+ went up a lot, there was typically a larger change in some of the disease biomarkers,”
Martens said.
This indicates that NAD+ is not only entering the brain, but it is also likely influencing its metabolism and multiple interconnected pathways.
Nicotinamide Riboside and Cognitive Impairment
Some of these blood-based biomarkers could be used to determine whether NAD+ deficiency is a cause of Alzheimer’s and other neurodegenerative diseases in the future. It is even possible that these types of tests will become more widely available to the general public for routine testing.
Martens is in charge of a 12-week NR study in older adults with mild cognitive impairment. The study is actively recruiting new participants. Martens’ study aims to determine whether increased nicotinamide riboside consumption has an even greater effect in people with cognitive impairment.
“They’re coming in with cognitive deficits, and as a result, are more likely to have an accumulation of some of these biomarkers in their brain, so there’s a chance we’ll see bigger reductions in these biomarkers because they have more of them in their cells,”
Martens said.
Underlying Alzheimer’s Disease Process
Almost all drugs on the market for Alzheimer’s patients have only a minor effect on symptoms and do not significantly slow the disease’s progression.
“In our ongoing trial, we’re measuring markers of cognitive function and other things related to functional independence and quality of life, but we’re also hoping to gain some insight on the underlying disease process,” Martens said. “We’re hoping that the people who take the NR might have preserved function.”
After proving its efficacy, Martens and Kapogiannis will test whether increased use of nicotinamide riboside improves cognition, and, ultimately, whether it can be used to slow neurodegenerative disease progression.
“We were among the first to do a chronic dosing study in humans, and as a result, we’ve been at the forefront of this field for a few years,”
Martens said.
They have reached a tipping point where they can begin to determine whether NAD+ increases in other tissues as well, which is likely to be the more important signal in terms of disease resolution.
References:
- Vreones, M., Mustapic, M., Moaddel, R., Pucha, K. A., Lovett, J., Seals, D. R., Kapogiannis, D., & Martens, C. R. (2023). Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin. Aging Cell, 22, e13754.
- Martens, C. R., Denman, B. A., Mazzo, M. R., Armstrong, M. L., Reisdorph, N., McQueen, M. B., Chonchol, M., & Seals, D. R. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications,9(1), 1– 11.
Last Updated on November 11, 2023