Highlights

  • NAD+ is an essential molecule for cellular energy production, DNA repair, and cellular stress response signaling, processes that can become dysregulated in the aging brain.
  • In animal models, strategies that restore NAD+ levels can improve the functioning of the cell’s powerhouses (mitochondria), reduce inflammation, and enhance neuronal resilience, highlighting their possible relevance to cognitive aging.
  • Although NAD+ precursors, such as NMN and NR, can raise NAD+ levels in some human tissues, clinical evidence that they improve cognition or alter neurodegenerative disease progression remains preliminary.

Nicotinamide adenine dinucleotide (NAD+) is a molecule essential for neurons’ and other brain cells’ growth, maturation, and survival. Accordingly, NAD+ plays key roles in the generation of cellular energy, DNA repair, quality control of mitochondria, and the orchestration of the sleep-wake cycle (circadian rhythm), among other roles. Moreover, researchers have proposed that declining NAD+ levels with age lead to mitochondrial dysfunction, inflammation, and ultimately, neurodegeneration. With that in mind, the following will explore the potential of NAD+-boosting strategies to prevent or slow age-related neurodegeneration and cognitive decline.

What Human Data Says About Declining NAD+ in the Brain

Past research suggests NAD+ levels fall with age, but this phenomenon is tissue-specific and much clearer in animal models than in humans. Breaking down some of the human data on NAD+ levels in the brain may offer some insight as to whether an age-related decline in NAD+ occurs in this organ and whether certain supplements counter it.

In the human nervous system, one study provides preliminary evidence of an age-related decline in NAD+ in cerebrospinal fluid (a clear, watery fluid that circulates through spaces inside the brain and around the brain and spinal cord). However, since this study did not directly measure NAD+ levels in neurons, it only offers a clue that NAD+ levels may decline with age in the brain.

Because direct measurements of NAD+ levels in the brain remain challenging, blood NAD+ has been used as a proxy for systemic NAD+ levels and, indirectly, NAD+ levels in the brain. Complicating this, a recent study found that blood NAD+ levels remain stable with age. This finding suggests the need to identify whether different organs may show notable age-related changes in NAD+ levels and which may be most sensitive to NAD+-boosting strategies.

Direct evidence for brain NAD+ dysregulation comes from a rare disorder associated with accelerated aging called ataxia-telangiectasia (a genetic disorder with a progressive neurodegenerative component). As such, in a human study of ataxia-telangiectasia, replenishing NAD+ modulated brain networks correlated with neurological improvement. NAD+ depletion was also observed in animal models of this disorder. These findings suggest that NAD+ deficiency can drive neurodegeneration, as seen in this disorder, and that augmenting NAD+ may improve neuronal function.

In common age-related neurodegenerative diseases, a similar story emerges. In both Alzheimer’s disease and Parkinson’s disease, defective mitochondrial recycling, DNA damage, and failure to generate cellular energy share a common biological source: faltering NAD+ levels. Collectively, the data suggest that falling NAD+ with age, to some degree, facilitates neurodegeneration.

Early Promise Supporting NAD+ Therapy for Neurodegeneration and the Path to Definitive Evidence

The therapeutic potential of NAD+ augmentation in human age-related neurological diseases is somewhat encouraging. For example, a 2-year clinical trial in ataxia-telangiectasia, one of the longest-duration human trials on NAD+ interventions to date, reported clinically meaningful improvements in coordination and eye movements with NR supplementation. This finding provides evidence that NAD+ augmentation can provide measurable neurological benefits.

Similarly, a human trial in newly diagnosed Parkinson’s disease patients showed that oral NR supplementation increased NAD+ metabolite levels in the brain (suggesting increased NAD+ levels). This result has provided the biological rationale for the ongoing Norway Parkinson’s trial with 400 participants, evaluating high-dose NR in early-stage Parkinson’s disease.

Also, a human trial in patients with subjective cognitive decline has reported promising data. The data include reductions in blood markers of neurodegeneration with NR supplementation. This finding hints that augmenting NAD+ may alleviate neurodegeneration in patients experiencing cognitive decline.

Most active ongoing human trials related to NAD+ augmentation’s effects on neurodegeneration focus on Alzheimer’s disease and Parkinson’s disease. They place a growing emphasis on the prevention of neurodegeneration in cognitively healthy older adults.

The Path Forward: Confirming Whether NAD+ Therapies Work Against Brain Aging and Neurodegeneration

Longer-duration trials in major neurodegenerative conditions, like Alzheimer’s and Parkinson’s, have yet to be completed. Definitive conclusions on whether NAD+-boosting therapies work against these highly prevalent age-related diseases will thus require longer and more rigorously designed studies that directly monitor things like brain NAD+ levels and disease progression. Ultimately, determining whether NAD+ augmentation can mitigate brain aging and neurodegeneration will be determined, hopefully decisively, by these trials still to come.