Why Balance May Define the Next Phase of Longevity Science

As NAD+, also known as nicotinamide adenine dinucleotide, continues to dominate conversations in healthy aging and longevity science, new questions are emerging around how best to translate biochemical gains into meaningful physiological outcomes.

Mathias Ziegler, MD, PhD, a leading researcher in NAD+ biology at the University of Bergen, Norway—where he also teaches biomedicine—discusses why simply increasing NAD+ levels may not be sufficient. Instead, he points to a more nuanced understanding of NAD+ balance, encompassing production, consumption, and cellular distribution, as critical to advancing next-generation interventions.

From the role of CD38 enzymes to mitochondrial transport mechanisms and clinical trial design, Ziegler outlines where the science stands today and what challenges remain for the field.

Nicholas Saraceno: There continues to be significant debate around NAD+ despite its popularity in longevity science. What do you see as the most critical unanswered questions that researchers still need to resolve?

Mathias Ziegler: If we had no NAD+ in our bodies, we would die in literally 30 seconds. What’s fascinating is that NAD+ levels tend to decline as we age, and that decline appears to influence many of the biological processes associated with aging. That’s why NAD+ has become such a major focus in longevity research. But the story is more complicated than simply trying to raise NAD+ levels. The real question is how NAD+ is produced, used, and maintained in the body over time.

We are starting to see evidence that increasing NAD+ production alone may not sustain NAD+ if the enzymes that use up NAD+ are not also addressed.

Imagine that NAD+ in the body is a bit like water in a sink. You have a faucet adding more water—that’s NAD+ production. But you also have a drain—enzymes like CD38 that consume NAD+ and research shows its activity tends to increase as we age. If the drain gets larger over time, simply turning the faucet on higher may not fully restore the level in the sink.

That’s why researchers today are increasingly interested not just in boosting NAD+ production, but in understanding the whole balance of how NAD+ is produced, consumed, and maintained in the body as we age.

Besides my work as a professor and researcher at the University of Bergen in Norway where I have conducted many studies into NAD+ mechanics, I am chair of the medical advisory board for Blue Helix Health. The company has developed a natural, plant-based NAD+ booster that also targets the CD38 enzymes which break down NAD+. That means NAD+ levels can stay elevated for longer. A study published in December 2025 validates this concept.¹ So we are starting to see other researchers dig into this issue around CD38 enzymes as they relate to NAD+ levels.

Saraceno: Your work highlights the role of mitochondria in maintaining NAD balance. What evidence currently supports this connection, and where does the science remain uncertain?

Ziegler: Mitochondria contain a high concentration of NAD+ and therefore were suspected to represent a cellular storage of the molecule. The discovery—about five years ago—of a mitochondrial NAD+ transporter in human cells marked a turning point in our understanding of how cells handle their NAD+.

Our work indicated that, in concert with a mitochondrial enzyme called NMNAT3, the transporter can provide the molecule from this storage to NAD+-dependent processes (such as DNA repair or epigenetic modifications) throughout the cell when the demand increases.

Interestingly, liver regeneration depends on the functional activity of the transporter and a healthy mitochondrial NAD+ pool, as recently demonstrated by a study² from the Baur group, to which we also contributed.

While we now know how NAD+ is transported across the mitochondrial membrane, this is an open question for other organelles such as peroxisomes and the endoplasmic reticulum, membrane-bounded structures with important functions in oxidative defense and protein homeostasis.

Saraceno: Many NAD+ interventions show increases in circulating levels, but not always clear functional outcomes. How should researchers interpret this gap between biochemical markers and real-world physiological effects?

Ziegler: I’d like to discuss that December 2025 study¹ on BluNADBooster because its end points went beyond circulating blood levels of NAD+.

The study evaluated 140 healthy aging adults who received either a placebo, 500 mg nicotinamide riboside (NR), 1,000 mg BluNADBooster alone, or a 500 mg BluNADBooster + 500 mg NR combination. Results show that BluNADBooster—with its dual mechanism of enhancing NAD⁺ metabolism and moderating CD38 activity—consistently outperformed placebo across biochemical, physical, and cognitive measures.

In the published study, BluNADBooster delivered superior NAD+ support and mitochondrial function, increasing blood NAD+ levels by 26.48% and outperforming NR, which achieved a 22.69% increase. These gains reflect meaningful improvements in cellular energy and mitochondrial efficiency. The combination of BluNADBooster with NR produced the largest rise—31.76%—highlighting synergistic effects characteristic of advanced anti-aging nutraceutical strategies.

The study also demonstrated clinically validated CD38 modulation. Age-related elevation in CD38 is a major driver of NAD+ depletion, and BluNADBooster acted as a natural CD38 inhibitor, reducing enzymatic activity by 17.98%. This preservation of intracellular NAD+ pools supports healthier energy balance, more efficient metabolic signaling, and broader longevity pathways.

The study design also looked at key biomarkers associated with systemic inflammation, including TNF-α, IL-6, and GDF-15. By combining synergistic polyphenols from pomegranate and marigold, the formulation functions as a targeted polyphenol supplement that promotes healthier inflammatory balance and reinforces overall cellular resilience.

Here’s where it got really interesting, and addresses your question directly.

In addition to metabolic and inflammatory benefits, BluNADBooster delivered notable cognitive support and healthy aging outcomes. Participants experienced significant improvements in cognitive performance, as measured by the MMSE-2, The Mini-Mental State Examination, Second Edition, which is a screening tool that assesses memory, orientation, and language. This reinforces the supplement’s potential as a cognitive-support nutraceutical for adults seeking better brain function, stress resilience, and long-term healthy longevity.

Then, BluNADBooster also contributed to improved physical endurance and energy, with the combination group showing a 9.94% increase in six-minute walk test distance. This improvement reflects meaningful gains in mobility, endurance, and functional vitality—key outcomes for consumers prioritizing active, healthy aging, and overall quality of life.

Finally, health-related quality of life scores were significantly greater in all groups after 60 days, with the combination therapy of BluNADBooster and NR having the greatest improvements in energy and fatigue, daily living, bodily pain, emotional well-being, social functioning, and general health.

Saraceno: Given the limitations that have been observed in first-generation NAD precursor technologies, what biological or mechanistic barriers must be overcome to achieve more consistent and meaningful clinical results?

Ziegler: Additional studies need to figure out how to evaluate the effect of enhanced blood NAD+ levels in other tissues. A different question researchers still need to resolve is that we are still missing human trials with a high number of participants to document and quantify benefits for healthy individuals and to establish an optimal dose.

References

1. Bandi VK, Chundru VK, Yarasani A, Gajula R, Pulipaka VK, Syed T. Comparative efficacy of a standardized herbal composition LN22199, nicotinamide riboside, and their combination on NAD+ metabolism in healthy aging adults. J Funct Foods. 2025;135:107115. doi:10.1016/j.jff.2025.107115.

2. Mukherjee S, Velázquez Aponte, RA, Perry CE, et al. Hepatocyte mitochondrial NAD⁺ content is limiting for liver regeneration. Nat Metab 7, 2424–2437 (2025). doi:10.1038/s42255-025-01408-5