NAD+ precursors and exercise in Friedreich's ataxia -- what a landmark RCT means for everyday functional medicine

A randomised controlled trial published in early 2025 tested whether individualised exercise, an NAD+ precursor supplement, or their combination was safe and effective for people with Friedreich's ataxia -- a rare inherited neurological disease that quietly dismantles the body's ability to produce cellular energy (https://pubmed.ncbi.nlm.nih.gov/42009009/). The trial is specific to a rare condition, but the questions it asks -- can we restore NAD+ levels in people whose cells are running low, and does exercise amplify or blunt that effect -- sit at the centre of a much larger conversation in functional medicine.

At NoMi Beach Health, we field questions about NAD+ therapy almost every week. Some people arrive having read that it "reverses aging." Others arrive more sceptical, wondering whether it is another expensive supplement with a good story. The honest answer, which this trial helps sharpen, is somewhere in between. Here is what we actually know, what this research adds, and how we think about NAD+ at a clinical level.

What Friedreich's ataxia has to do with cellular energy

Friedreich's ataxia is caused by a mutation in the FXN gene, which reduces production of a protein called frataxin. Frataxin lives inside mitochondria -- the structures inside every cell that convert food into usable energy. When frataxin is low, mitochondria malfunction, oxidative stress accumulates, and the body's NAD+ pool shrinks (https://pubmed.ncbi.nlm.nih.gov/35276348/).

NAD+ -- nicotinamide adenine dinucleotide -- is not a vitamin you swallow. It is a coenzyme that every cell uses to carry electrons during energy production. When NAD+ levels fall, cells struggle to generate ATP, which is the currency of all biological work: muscle contraction, nerve signalling, DNA repair, everything. The hallmarks of aging research has documented declining NAD+ as one of the core features of cellular ageing, separate from any single disease (https://pubmed.ncbi.nlm.nih.gov/36599349/).

Friedreich's ataxia accelerates this decline dramatically and early in life. That is why researchers have turned to NAD+ precursors -- compounds the body can convert into NAD+ -- as a potential therapeutic tool. And it is why this disease serves as a kind of stress test for ideas that also appear in healthy aging and functional medicine.

What the 2025 RCT actually found

The trial used what is called a 2x2 factorial design. That means participants were randomly assigned to one of four groups: exercise alone, NAD+ precursor alone, both together, or neither. The NAD+ precursor used was nicotinamide riboside (NR), which has a well-established record of raising blood NAD+ levels in human trials (https://pubmed.ncbi.nlm.nih.gov/29599478/). The exercise component was individualised -- meaning it was prescribed to each person's actual capacity, not a generic programme dropped on top of a disease that affects coordination and heart muscle.

The primary finding was one that matters before any efficacy question: both interventions were safe and well-tolerated in this population. That is not a trivial result. People with Friedreich's ataxia often have significant cardiac involvement, so demonstrating that structured exercise and NR supplementation do not worsen cardiac or neurological status is a meaningful clinical signal.

On efficacy measures -- function, biomarkers, quality of life -- the trial was designed to detect signals rather than declare winners. What the authors found was consistent with what the broader NAD+ literature suggests: raising NAD+ precursor intake does change the biochemical environment, and exercise amplifies mitochondrial signalling in ways that may interact with that change. Whether the combination outperforms each alone in a statistically meaningful way requires a larger, longer trial (https://pubmed.ncbi.nlm.nih.gov/42009009/).

That is an honest finding. We are honest about that here, too.

What the NAD+ evidence looks like outside rare disease

Most people asking about NAD+ at NBH do not have Friedreich's ataxia. They are 40 to 65, they feel like their energy and recovery have slipped, and they have heard that NAD+ might help. The evidence base for this group is real but more modest than the marketing suggests.

A 2018 study in Nature Communications showed that chronic NR supplementation was safe and consistently raised blood NAD+ levels in healthy middle-aged and older adults -- but the clinical translation of that biochemical change was not dramatic in a short trial (https://pubmed.ncbi.nlm.nih.gov/29599478/). A 2021 Science paper found that NMN (nicotinamide mononucleotide, a related precursor) improved muscle insulin sensitivity in prediabetic women -- a more concrete clinical outcome, but in a specific population (https://pubmed.ncbi.nlm.nih.gov/33888596/). A 2020 trial in mitochondrial myopathy -- another disease of energy production -- found that high-dose niacin, also an NAD+ precursor, produced meaningful improvements in muscle function and NAD+ repletion in a diseased population (https://pubmed.ncbi.nlm.nih.gov/32386566/).

The pattern across these trials is consistent: NAD+ precursors raise NAD+ levels, the effect is clearest when the baseline is depleted, and clinical outcomes are most convincing in populations with documented mitochondrial or metabolic dysfunction. In healthy people with already-adequate NAD+, the marginal benefit is harder to measure -- not necessarily absent, but harder to pin down with current tools.

We tell people that directly. We also point out, as we do in our post on IV vitamin therapy, that delivery route matters -- IV NAD+ and oral precursors are not interchangeable, and the evidence base for each is slightly different.

Why exercise is not a footnote in this research

The 2025 trial treated individualised exercise as an equal arm, not a background variable. That framing is worth noticing. Exercise is the single best-studied intervention for mitochondrial biogenesis -- the process by which cells build new, functional mitochondria (https://pubmed.ncbi.nlm.nih.gov/25567906/). It does this partly by activating sirtuins, a class of proteins that depend on NAD+ to function. In other words, exercise and NAD+ are not parallel tracks. They share molecular machinery.

The practical implication is that NAD+ supplementation taken without any change in physical activity is working with one hand tied. The signal from the Friedreich's ataxia trial -- that individualised exercise was safe, tolerable, and produced its own functional benefits -- reinforces what the exercise physiology literature has shown for decades: structured movement, dosed to a person's actual capacity, is one of the most powerful tools in medicine.

"Individualised" is the word we want you to hold onto. A person with Friedreich's ataxia cannot follow a generic fitness influencer programme. Neither can someone with a significant cardiac history, a recent injury, deconditioning from long illness, or a connective tissue disorder. The principle of matching the exercise prescription to the person is not a rare-disease concept -- it is a clinical concept that applies broadly. Our functional medicine approach starts there.

How we actually think about NAD+ in clinical practice

When someone comes to us asking about NAD+ therapy, the first conversation is not about dose or delivery route. It is about what is driving the question. Fatigue? We look at sleep quality, thyroid function, iron, ferritin, cortisol patterns, and metabolic markers before we recommend anything. Low energy that turns out to be sleep apnea does not improve with NR. Low energy from iron deficiency anaemia does not improve with IV NAD+. Getting the diagnosis right matters more than getting the supplement right.

If the workup points to genuine mitochondrial strain -- poor metabolic health, significant age-related decline, or a condition with documented NAD+ depletion -- then NAD+ precursor supplementation enters the conversation as one tool among several. We are transparent about what the evidence supports and where the gaps are. We do not sell the idea that NAD+ is a shortcut around the basics.

The basics, in our view, are: quality sleep, structured resistance exercise, adequate protein, and metabolic health. These are the levers with the deepest evidence base. We explore this in more detail in our post on functional wellness without the woo, which covers how we separate signal from noise in this space.

For people who are good candidates -- and some are -- we discuss NR and NMN as oral options, and IV NAD+ for cases where we want to raise levels more rapidly or where absorption is a concern. We set expectations clearly: you are likely to feel a change in energy within a few weeks if NAD+ repletion is relevant to your biology. If you do not, that is information, not a failure.

What this research means for the field going forward

The Friedreich's ataxia trial matters beyond its specific population because it is one of the few rigorous randomised controlled trials to test both an NAD+ precursor and structured exercise in the same design. Most NAD+ research to date has been either preclinical (mice) or short observational studies in humans. A factorial RCT -- even in a rare disease -- raises the quality bar for future work and gives researchers a template for testing these combinations in other conditions.

The geroscience field is moving toward exactly this kind of thinking: that ageing-related decline is not one disease but a set of overlapping biological processes, and that interventions need to be tested in combination, not in isolation (https://pubmed.ncbi.nlm.nih.gov/41957871/). NAD+ metabolism is one of those processes. Exercise biology is another. The 2025 trial is a step toward understanding how they interact in a human body under genuine stress.

We follow this literature closely at NBH because our patients deserve answers grounded in current evidence, not in what was exciting five years ago or what a supplement company funded last quarter.

What to do if you are curious about NAD+ and your own health

If you have been wondering whether NAD+ supplementation makes sense for you -- whether you have a specific condition driving the question or simply feel like your energy and recovery are not what they were -- the right starting point is a full clinical picture, not a supplement order.

Dr. Jezwah Harris (NP, JD, MBA, FNP-BC, MEP-C) reviews labs, symptoms, and health history together, then builds a plan that is honest about what the evidence supports for your specific situation. That may include NAD+ therapy. It will definitely include a conversation about sleep, movement, and metabolic health -- because those are where the deepest evidence lives.

If this sounds like the kind of conversation you have been looking for, visit our functional medicine services page to learn what a new-patient visit looks like, or call us at (786) 744-5152. We will look at the whole picture and tell you what we actually think.