HM568, NAD+ biosynthesis, and what new Parkinson's research means for mitochondrial health

A paper published in 2025 caught our attention in a way that most preclinical studies do not. Researchers studying Parkinson's disease models tested a compound called HM568 and found that it appeared to boost NAD+ biosynthesis, reduce PARP1 overactivation, and protect neurons from the kind of mitochondrial failure that drives neurodegeneration (https://pubmed.ncbi.nlm.nih.gov/42247013/). The compound is nowhere close to a human therapy yet. But the biology it targets -- NAD+ depletion, energy failure in mitochondria, and runaway DNA-damage signaling -- is not unique to Parkinson's disease. It is basic cell biology, and it gets more relevant with every year you age.

This post is not about Parkinson's disease management. We are not going to tell you that HM568 is something you can take or that NAD+ infusions prevent neurodegeneration. What we will do is explain what the study actually found, why the mechanisms matter beyond a single disease model, and what the current human evidence says about supporting NAD+ levels in practice.

What HM568 actually did in the study

In the 2025 study, researchers used both cell-based and animal models of Parkinson's disease -- models that replicate the dopamine neuron damage and mitochondrial dysfunction characteristic of the condition. HM568 was tested as a small molecule capable of upregulating the NAD+ biosynthesis pathway, specifically through the NAMPT enzyme, which is the rate-limiting step in the main NAD+ recycling route in human cells (https://pubmed.ncbi.nlm.nih.gov/42247013/).

The findings showed that HM568 increased intracellular NAD+ levels, which in turn reduced the overactivation of PARP1 -- an enzyme that consumes NAD+ rapidly when it detects DNA strand breaks. In conditions of high oxidative stress, PARP1 can go into overdrive, burning through the cell's NAD+ supply and creating an energy crisis that pushes the neuron toward cell death. By restoring NAD+, HM568 appeared to interrupt that spiral.

The outcome in the models was meaningful: less mitochondrial dysfunction, less neurotoxicity, and better neuronal survival compared to controls. The researchers described the PARP1 connection as a "putative link" -- their language, and honest language. It means the mechanism is plausible and supported by the data, but not yet proven as the only or primary explanation.

To be clear: this is preclinical data. Cell models and animal models are important, but they fail to translate to humans at a rate that should make anyone cautious about jumping ahead of the evidence.

Why NAD+ depletion matters beyond Parkinson's disease

NAD+ is not a Parkinson's-specific molecule. It is a coenzyme present in every cell in your body, and it does two essential jobs: it helps mitochondria convert food into usable energy (ATP), and it acts as a substrate for enzymes that manage DNA repair and gene expression regulation (https://pubmed.ncbi.nlm.nih.gov/29514063/).

The problem is that NAD+ levels decline with age -- measurably and significantly. Research published in Cell Metabolism identified CD38, an NAD+-consuming enzyme, as a major driver of age-related NAD+ decline, and linked that decline to mitochondrial dysfunction through a SIRT3-dependent mechanism (https://pubmed.ncbi.nlm.nih.gov/27304511/). That finding was not in a Parkinson's model. It was in normal aging biology.

When NAD+ falls, several things happen. Mitochondria become less efficient, producing more oxidative byproducts and less ATP. Sirtuins -- the proteins that regulate cellular stress responses, metabolism, and longevity pathways -- lose their substrate and slow down. PARP1 and other NAD+-consuming enzymes compete for a shrinking pool, sometimes at the expense of each other's function (https://pubmed.ncbi.nlm.nih.gov/22560221/).

This is why the HM568 research is worth paying attention to even if you have no family history of Parkinson's disease. The mechanisms it targets are the same mechanisms that underlie garden-variety mitochondrial aging. Whether a compound like HM568 will ever prove useful in humans -- in any condition -- depends on clinical trials that have not happened yet. But the biology it is working with is not speculative.

What human trials on NAD+ precursors actually show

Because HM568 is not available for human use, the relevant question for anyone sitting across from us in a consult is: what do we actually know about raising NAD+ in people?

The short answer is: precursor supplementation works to raise blood NAD+ levels, and the clinical outcomes evidence is developing but still limited.

Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are the two most-studied oral precursors. A 2016 Nature Communications study confirmed that NR is orally bioavailable in healthy humans and measurably raises whole-blood NAD+ (https://pubmed.ncbi.nlm.nih.gov/27721479/). That is the easy part -- raising the number on a lab panel.

The harder part is demonstrating that raising NAD+ in the bloodstream produces meaningful clinical outcomes. The evidence here is more mixed. A review in Nutrients summarized the human NR literature and found improvements in some metabolic and cardiovascular markers in specific populations, but called the overall clinical evidence "still limited" (https://pubmed.ncbi.nlm.nih.gov/32455705/).

Perhaps most directly relevant to the HM568 study: the NADPARK trial, published in Cell Metabolism in 2022, tested nicotinamide riboside supplementation in patients with Parkinson's disease (https://pubmed.ncbi.nlm.nih.gov/35235774/). Participants who received NR showed increased NAD+ levels in the brain and blood, and the treatment was safe and well-tolerated. The trial was a Phase I study -- designed primarily to test safety and dosing, not to prove clinical benefit. It did not establish that NR slows Parkinson's progression. But it did confirm that the brain's NAD+ level is movable with an oral supplement, and it opened the door to larger efficacy trials.

We cover the broader NAD+ therapy evidence in more depth in our post on NAD therapy and cellular rejuvenation, and we discuss functional medicine's approach to longevity biology in our post on functional wellness without the woo.

The PARP1 angle -- and why it matters for treatment design

One of the more interesting aspects of the HM568 paper is the PARP1 connection, because it points toward a design challenge that matters for any NAD+-related therapy.

PARP1 is activated by DNA damage. When your cells are under oxidative stress -- from environmental toxins, poor sleep, metabolic dysfunction, or the normal wear of aging -- DNA strand breaks increase, PARP1 activates, and NAD+ gets consumed in the repair process. If you simply add more NAD+ without addressing the upstream source of DNA damage, you may just be feeding an overactive PARP1 system.

This is not an argument against NAD+ support. It is an argument for addressing the total picture. In a functional medicine context, that means looking at what is driving oxidative stress in the first place -- blood sugar regulation, sleep quality, toxin exposure, mitochondrial stressors -- rather than treating NAD+ as a standalone input (https://pubmed.ncbi.nlm.nih.gov/28364380/).

HM568's apparent ability to modulate PARP1 activity while boosting NAD+ is what makes it mechanistically interesting compared to a simple precursor supplement. If that mechanism holds up in further research and eventually in human trials, it could represent a more targeted approach. But that is a significant conditional, and we are years away from knowing.

What we do -- and what we are honest about

At NoMi Beach Health, Dr. Jezwah Harris (NP, JD, MBA, FNP-BC, MEP-C) works with patients who want to take their mitochondrial health seriously -- whether that means reviewing lab markers of metabolic function, discussing oral NAD+ precursor protocols, or exploring IV NAD+ infusions for people who have specific indications and realistic expectations.

We offer IV NAD+ infusions and we are honest about what the human evidence does and does not support. Raising NAD+ levels is achievable. Whether doing so produces the specific clinical outcomes a given person is hoping for -- better energy, sharper cognition, slower biological aging -- is harder to guarantee, because the human trials are still catching up to the cell biology (https://pubmed.ncbi.nlm.nih.gov/35041996/).

What we do not do is tell you that IV NAD+ reverses neurodegeneration, that any supplement replicates what HM568 did in a Parkinson's model, or that preclinical results translate automatically to your bloodstream. That is the kind of overclaiming that makes patients distrust functional medicine, and it is not how we practice.

If you are interested in what mitochondrial health means for you specifically -- your labs, your energy, your cognitive function, your biological age markers -- that is a conversation worth having with a clinician who can look at the full picture.

The honest bottom line on HM568 and NAD+ research

The 2025 HM568 study adds a useful data point to a growing body of research showing that NAD+ biosynthesis is a legitimate therapeutic target in neurodegenerative disease -- and probably in aging biology more broadly. The compound itself is experimental, the human evidence does not yet exist, and no one should be sourcing it outside a clinical trial.

What the study does well is clarify the mechanism: restoring NAD+ in neurons appears to reduce PARP1-driven energy depletion and protect mitochondrial function under stress conditions. That mechanism is consistent with what we see in the broader NAD+ literature, and it reinforces why this area of research deserves continued serious attention.

For you, right now, the practical takeaway is simpler. If you are interested in supporting mitochondrial function and NAD+ levels, there are evidence-based options available -- oral precursors, IV infusions, and lifestyle inputs that reduce the oxidative stress burning through your NAD+ in the first place. None of them replicate what HM568 did in a lab model. Some of them have genuine human evidence behind them.

If you want to explore what that looks like for your specific situation, we are here for that conversation.

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Book a functional medicine consultation with us at nomibeach.health/services/functional-medicine or call us at (786) 744-5152. We will look at your labs, your history, and your goals -- and build a protocol grounded in what the evidence actually supports.