NAD to the Bone

Separating Hype from Science on the ‘Longevity Molecule.’

hen people learn that Dr. Miranda Orr studies strategies to stave off Alzheimer’s disease (AD), they often ask her opinion on supplements that increase the body’s supply of a substance known as nicotinamide adenine dinucleotide or NAD+.

“I’ll be at a casual lunch, and people will bring it up,” said Dr. Orr, who is an associate professor of neurology at the Washington University School of Medicine in St. Louis, Missouri. “If you go on TikTok, it’s one of the most talked about ‘longevity nutraceuticals’ out there.”

A sampling of search results for the term on that social media platform include, “NAD+ has reversed my aging,” an LA plastic surgeon who cites NAD+ supplementation as his #2 “anti-aging” hack, and videos of celebrity/influencers hooked up to IV bags labelled NAD+.

Elsewhere, you might also come across so-called NAD+ precursors on a list of supplements and medications that prominent longevity researcher and author Dr. David Sinclair has stated might extend lifespan.

A growing body of evidence does indeed suggest that bolstering NAD+ levels holds promise for preventing and treating a range of age-related diseases, including AD and other neurodegenerative conditions.

IS THERE SUFFICIENT, SOLID SCIENCE TO SUPPORT ALL OF THE HYPE?

Here’s what several researchers in the field had to say about what NAD+ is, how it might protect brain health, and why it’s too soon to say whether increasing the body’s supply of NAD+ can protect brain health.

WHAT IS NAD+?

NAD+ is a molecule that, “is essential for pretty much every metabolic function in the body,” said Dr. Christopher R. Martens, associate professor of kinesiology and applied physiology and Director of the Delaware Center for Cognitive Aging Research at the University of Delaware in Newark, Delaware.

“It’s so critically involved in energy production that every cell in our body needs NAD+ in order to survive.” (NAD+ is also involved in a number of other functions, such as regulating DNA repair.)

For this reason, the brain depends heavily on NAD+, probably more so than any other part of the body. “The brain demands a lot of energy, and it doesn’t have a place to store energy easily,” explained Dr. Martens.

Unlike say, muscle, which can pack itself with sugar or fat for later use as energy, “the brain is relying on what is flowing through the blood, so it needs a really well-defined metabolism to be able to extract that energy and convert it to something the brain can use.” Consequently, Dr. Martens pointed out, “it makes sense that the brain would be uniquely vulnerable to energetic crisis,” should its NAD+ supply fall too short to meet demands.

LINK TO LONGEVITY GENE

NAD+ started creating a stir in the scientific community in 1999, thanks to the work of a group of researchers at the Massachusetts Institute of Technology. The scientists had been studying how a group of proteins called SIR2 could switch off whole sections of DNA. They had already established that the gene that makes SIR2 was linked to slowed aging in yeast.

In 1999, the research team, led by Dr. Leonard Guarante, discovered that SIR2 was actually a new enzyme, and its ability to turn off genes depended entirely on the level of energy present in the cell, which is actually NAD+ itself. The paper outlining this discovery appeared in Nature in February 2000.

“It turns out that this enzymatic activity is critical to regulate the process of aging and also to determine the lifespan of a whole bunch of organisms, including yeast, fruit flies, mice, and potentially humans,” explained Dr. Shin-ichiro Imai, who co-led the research and is now a distinguished professor of environmental medicine in the Department of Developmental Biology and the Department of Medicine at the Washington University School of Medicine.

THAT SPARKED THE ENTHUSIASM AROUND NAD+ AND ITS REGULATION OF AGING AND DIFFERENT KINDS OF AGE-RELATED DISEASES.

Dr. Imai has been studying NAD+ ever since. In a 2008 paper published in Aging Cell, his research team showed that NAD+ levels in mice declined with age, and that giving the animals nicotinamide mononucleotide (NMN), which the body converts to NAD+, “can rescue impairments in insulin secretion in aged mice,” he explained.

Why feed the mice NMN rather than NAD+? According to Dr. Imai, gut bacteria and the gut itself in both mice and humans consume NAD+, and consequently, it degrades almost immediately into nicotinamide, a form of vitamin B3.

RESEARCH IN AGE-RELATED DISEASES

“In 2011, we published another paper demonstrating for the first time that NAD+ decreases significantly in multiple tissues and organs in Type 2 diabetes-model mice, and during aging in healthy mice,” he said.

“Then when we administered NMN to Type 2 diabetes-model mice, it dramatically ameliorated the symptoms. In the case of female mice, the symptoms were almost gone.” This research was published in Cell Metabolism.

Next, the team tested the effects of two different doses of NMN in healthy, normal mice from five months of age until 17 months (the equivalent of young to old age in humans). “We published a paper in 2016 in Cell Metabolism basically demonstrating that NMN has a remarkable range of anti-aging effects in mice.”

NOW THERE ARE HUNDREDS OF PAPERS FROM LABS ALL OVER THE WORLD DEMONSTRATING THAT NMN HAS ANTI-AGING EFFECTS, AND THERAPEUTIC AND PREVENTIVE EFFECTS FOR SUCH MAJOR AGE-ASSOCIATED DISEASES AS TYPE 2 DIABETES, AD, AND PARKINSON’S DISEASE IN MICE.

On the other hand, of the studies that have been done on supplementation with NAD+ and its precursors to prevent cognitive decline across different diseases, “only about half make positive findings, and when they do, they’re not very strong,” said Dr. Jared Campbell, a researcher in the graduate school of biomedical engineering at the University of New South Wales in Australia, and author of a 2022 literature review published in the journal Nutrients.

Meanwhile, other researchers had been doing similar work using nicotinamide riboside (NR), a form of vitamin B3 and one of the main precursors the body can use to make NAD+.

For example, “there have been really excellent studies in mice showing improvement in neurodegenerative disease pathways with NAD+ precursors,” including NR, noted Dr. Martens, who was involved in a 2014 trial that examined the impact of the latter compound on vascular function in rodents. (This research was published in 2016, in the journal Aging Cell.)

EARLY SAFETY STUDIES

When experimental drugs are first tested in humans, these Phase 1 trials, which enroll small numbers of participants, are mainly focused on establishing whether the substance is safe.

It’s worth noting that sometimes, adverse side effects of medications and supplements don’t become apparent until they’re tested in very large-scale trials, or even later. (Supplements are also subject to much less strict regulation than drugs, which means they don’t have to undergo the same rigorous pre-market approval process.)

Dr. David S. Seres, a professor of medicine and Director of Medical Nutrition at the Columbia University Irving Medical Center in New York, pointed out one classic example of how supplements can sometimes have unanticipated and undesirable side effects. “Based on the observation that men with prostate cancer had low vitamin E and selenium, a ten-year study randomized 30,000 men to get one or the other or both against placebo,” he explained.

An analysis of data from this trial, published in JAMA in 2011, found the rate of prostate cancer was 17% higher among men who took vitamin E alone compared to those in the placebo group.

This is why Dr. Martens and many other researchers in the field are determined to approach NAD+ precursors like NR, “with as much rigour as a pharmaceutical trial,” even though dietary supplements aren’t subject to the same regulations, Dr. Martens explained, “so we can stand by the results we publish and say either this works or it doesn’t.”

“The first study we did was a small pilot in relatively healthy middle-aged and older adults,” Dr. Martens said. It was also the first trial in which people took NR for an extended period – six weeks – versus a single dose. This work was published in Nature Communications in 2018.

WE WERE ABLE TO SHOW A PRETTY ROBUST IMPROVEMENT IN BLOOD NAD+ AND ITS METABOLITES.

And participants tolerated the supplement well and didn’t report any serious side effects.

THE BLOODSTREAM-BRAIN CONNECTION

But this study couldn’t answer a key question: does raising blood NAD+ translate into higher levels in the brain? Dr. Martens used an indirect method to try and arrive at an answer. Using blood samples from the first trial, the research team extracted extracellular vesicles (EVs) tagged with a unique marker suggesting that they oriented in neurons.

These tiny bubble-like structures, “bud off neurons in the brain, and we can detect them in blood. We showed that NAD+ does go up in these EVs, which suggests that NAD+ goes up in the brain when people take NR,” Dr. Martens explained. (The study appeared in Aging Cell in 2023.) Other researchers are now using specialized imaging to find out whether NAD+ levels increase in the brain with supplementation.

Work by Dr. Imai and his colleagues demonstrated that NMN, on the other hand, is taken up in certain areas of the brain. In a 2019 study, published in Nature Metabolism, they identified a protein that specifically transports NMN from the gut into the bloodstream. Subsequently, they showed certain neurons in the hypothalamus express this transporter. This work was published in Cell Reports in 2022.

The hypothalamus, “regulates muscle structure and function,” noted Dr. Imai. “When you reduce the level of this transporter in neurons, mice have sarcopenia, a significant decrease in muscle mass, and increased frailty. But if we restore the expression of this transporter in the hypothalamus, those mice show significant improvement of sarcopenia.”

A 2021 study by Dr. Imai and one of his Washington University Medicine colleagues, Dr. Samuel Klein, found similarly promising results in a small group of postmenopausal, prediabetic women with overweight or obesity. (The research was published in the journal Science.)

AFTER TAKING 250 MG OF NMN DAILY FOR TEN WEEKS, PARTICIPANTS SAW A 25% INCREASE IN SKELETAL MUSCLE INSULIN SENSITIVITY, WHICH IS VITAL FOR BLOOD SUGAR CONTROL.

That improvement, “is comparable to the effect of 10% weight loss, or 12 weeks of treatment” with some diabetes medications, Dr. Imai said. This could have important implications for brain health, since overall stable blood sugars may blunt the increased risk of dementia that’s associated with diabetes.

POSSIBLE PROTECTION FROM TAU

An unexpected discovery made by researchers who study circadian clocks (the body’s internal timekeepers) and sleep points to another way NAD+ could potentially benefit the brain. Dr. Erik Musiek, a professor of neurology and Co-director of the Center on Biological Rhythms and Sleep (COBRAS) Diagnostic Center at the Washington University School of Medicine and his colleagues have been working on finding ways to reset the circadian clocks.

“In people who have Alzheimer’s disease and other degenerative diseases, these clocks seem to be dysregulated, and they have problems sleeping and getting up at the wrong time of night,” Dr. Musiek explained. “We’ve been interested in a particular part of the clock – proteins called Rev-Erb (pronounced ree-verb) that essentially help drive circadian rhythms – because they are potential drug targets.”

In a 2025 Nature Aging paper, the researchers found that when mice were given a drug that inhibits these proteins, or had the proteins genetically knocked out, they were protected against the accumulation of abnormal tau protein tangles in the brain that are one of the hallmarks of AD.

So where does NAD+ come in? “This Rev-Erb protein seems to regulate levels of NAD+ in the brain,” said Dr. Musiek. “When we inhibited Rev-Erb, it increased levels of NAD+ pretty substantially. Then we found that when we increased levels of NAD+ in glial cells, which are sort of like immune cells in the brain, these glial cells can take up tau and degrade it more effectively. There are probably many different mechanisms of this, but that one was new.”

THE FINDINGS SUGGEST THAT DRUGS THAT TARGET REV-ERB OR NAD+ SUPPLEMENTATION, MIGHT BE ABLE TO HELP WITH CLEARANCE OF TAU FROM THE BRAIN.

“We show in the paper, too, that NAD+ goes down in the tauopathy model as well.” While the reasons for this aren’t clear, it could be that NAD+ is being used up in other pathways, or the machinery that makes NAD+ declines over time,
Dr. Musiek added.

New findings also suggest that stabilizing the brain’s NAD+ balance may have the potential to restore, not just protect, neurological function. In late 2025, researchers reported that a compound called P7C3-A20 reversed Alzheimer’s-like damage and restored cognitive performance in mouse models, challenging the long-held belief that the disease is only manageable once it develops.

While the study, published in Cell Reports Medicine, is preliminary and based solely on animal research, it strengthens scientific interest in NAD+ pathways as a therapeutic target and underscores why rigorous human trials are essential before any conclusions can be drawn.

A wave of human pilot studies testing NAD+ in a range of conditions has begun building in size and momentum. Two small randomized controlled trials, one led by Dr. Orr while at UT Health San Antonio and the other by the University of Delaware’s Dr. Martens, have looked at NR supplementation versus placebo in adults with mild cognitive impairment over several weeks. (The former was published in GeroScience in 2023; the initial results from the latter were presented at the 2025 Alzheimer’s Association International Conference, although the full results are still being analyzed.)

Neither trial showed robust improvements in memory or thinking, but the studies were likely too short at ten and 12 weeks respectively for any such benefits to emerge. Several other trials of NAD+ precursors in people with AD, Parkinson’s disease, and other neurodegenerative disorders are now underway, some of which will follow participants for a year or more.

CAUTIONS TO CONSIDER

So, should you consider taking an NAD+ precursor to protect your brain health? “As a physician, I’m always hesitant to recommend anything to people unless there’s real data from trials in humans, which there isn’t,” said Dr. Musiek.

WE STILL NEED A LOT OF RIGOROUS, RANDOMIZED CONTROLLED TRIALS TO KNOW WHAT THE TRUE BENEFIT WILL BE, AND WHAT THE POTENTIAL HARMS MIGHT BE.

Dr. Orr also noted, “One study in an animal model reported increased metastasis of breast cancer to the brain. While that study used higher doses than people typically take and involved immunocompromised mice with aggressive cancer cells, it still makes the research community cautious. People can easily buy these compounds over the counter and take them however they want, without consulting their doctors or understanding how best to use them.”

“I hate the word supplement, because it has the connotation of not having hardcore scientific evidence (behind it),” said Dr. Imai. “NMN and NR have very deep, rich scientific evidence,” at the animal level, he added. While it’s too early to say whether these substances can prevent or treat age-related diseases like AD in humans, “in the next five years, I’m sure we’ll see more results from clinical trials, and I’m optimistic and hopeful to see a more beneficial effect with NMN.”

In the meantime, “I would borrow a line from David (Sinclair),” said Dr. Campbell at the University of New South Wales, “which is, of all the interventions that we’ve found” that protect against negative effects of aging, “good diet and exercise have yet to be beaten.”

Source: Mind Over Matter 22