Supplementation with NAD+ and Its Precursors Support Healthy Brain Aging

The process of brain aging is intricate. This phenomenon is frequently rooted in metabolic dysregulation and is intimately related to deteriorating cognitive health.

The relationship between brain aging and decreased levels of the crucial chemical nicotinamide adenine dinucleotide (NAD+), which is required to carry out important metabolic activities, has attracted increasing attention. It has been hypothesized that metabolic disturbance may play a role in inefficient brain aging, given the high metabolic demand of brain cells (neurons) and the age-related reduction in NAD+.

Here, we summarize the findings of a recent review that dove into what we currently know about NAD+, its precursors, and brain aging.

Animal Studies of NAD+ Precursors and Brain Aging

There have been dozens of studies on NAD+, its derivatives, and brain aging in rodent models. One recent review identified eleven studies published on the subject up through December 2020. The synthesis of their findings supports the conclusion that treatment with NAD+ precursors did restore its levels in the brain, supporting learning and memory.

A study of old compared to young mice showed that the NAD+ precursor nicotinamide mononucleotide (NMN) could improve higher brain function. These findings were supported by a 2019 study showing that injecting aged (2 years) rats with NMN (100 mg/kg every other day for 28 days) alleviated age-related cognitive impairment, including working, recognition, and reference memories, as well as cognitive flexibility. Additionally, a 2018 study where researchers orally administered 20-month-old mice with NMN (300 mg/kg/day for three weeks) found that it ameliorated the cognitive hypersensitivity observed in older mice.

The age-related effects on the cognitive health of other NAD+ precursors have also been the subject of research. For instance, a nicotinamide riboside (NR) enriched diet increased short-term spatial memory in mid-aged mice (14 months old) for three months. Other studies' findings that NR can promote brain function in rats on high-fat diets or with insulin regulation imbalances are consistent with this. In one study, mice fed a high-fat diet demonstrated enhanced locomotor activity and spatial recognition recall after receiving NR (400 mg/kg/day) orally for six weeks. In a different study, scientists found that administering NMN (500 mg/kg) to rats in a model of inefficient insulin regulation increased neuronal survival and lessened cognitive impairment six weeks after the damage.

More promising, however, are the collective findings made in a series of related papers on the impact of NMN on the cognitive health of aged mice. The authors found that NMN significantly improved higher brain function in older mice (2 years) compared to the decreases that were observed relative to young mice (2 months). These studies also found that NMN  significantly supported the health of the brain’s blood vessels, which is critical to brain health.

Current NAD+ and Brain Aging Human Studies

While the findings are mostly positive, they have been made primarily in animal models, with some reports of null or adverse effects. A large body of preclinical research supports the potential effectiveness of NAD+ precursor supplementation for preserving cognitive health across various contexts. Overall, preclinical research suggests that NAD+ precursors can support different forms of brain aging. However, findings have not been unanimous, and some investigations have reported adverse effects.

A review of the clinical trials register, clinicaltrials.gov, indicates that several trials that will investigate NAD+ and its precursors for cognitive protection have been initiated or have begun recruiting. These include:

• A double-blind placebo-controlled study investigating nicotinamide riboside called “NAD Therapy for Improving Memory and Brain Blood Flow in Older Adults With Mild Cognitive Impairment.”
• A single-group, open-label study called “Effects of Nicotinamide Riboside on Bioenergetics and Oxidative Stress in Mild Cognitive Impairment.”
• A placebo-controlled crossover trial for NR: “Crossover Trial for Nicotinamide Riboside in Subjective Cognitive Decline and Mild Cognitive Impairment.”
• A double-blind, randomized study on NR: “NAD Therapy for Improving Memory and Brain Blood Flow in Older Adults With Mild Cognitive Impairment.”

There was only one completed study on NAD+ precursors and brain aging, called "The Effects of Nicotinamide Adenine Dinucleotide (NAD) on Brain Function and Cognition (NAD)." While associated findings are yet to be published, according to a conference presentation related to this trial, NR was well tolerated, raised NAD+, and enhanced brain blood flow as well as physical function; however, the researchers could not identify a significant change in cognition. Since access to NAD+ precursors is generally unrestricted all around the world, the general public has become more interested in understanding the potential of supplementing with these molecules. To give conclusive information on its safety and efficacy when used in humans, further controlled clinical trials are required.  

The Future of NAD+ in Brain Aging Research

Given these factors' increasing popularity and availability as nutritional supplements, further, adequately controlled clinical research is needed to provide definitive answers regarding this strategy’s likely impact on human cognitive health when used to address different drivers of brain aging. That’s why clinical studies have sprung up in which researchers posit that supporting NAD+ levels through supplementation with NAD+ precursors could support brain health.

However, head-to-head comparisons of the available NAD+ precursors still need to be improved, which could help inform the optimal factor for translation. Furthermore, work is required to investigate the safety and effectiveness of prophylactic supplementation with NAD+ precursors to prevent the onset of age-related cognitive decline — regardless of the driving cause — in healthy people, before aging begins.