A recent study published in Nature Metabolism generated headlines after researchers reported that whole-blood NAD+ levels may not significantly decline with age in humans. Predictably, many articles quickly suggested that the entire NAD and longevity movement may have been overstated.
In my opinion, that conclusion misses the real science.
At The Hormone Zone and The Longevity Protocol, we believe this study does not disprove the importance of NAD+ in aging. Instead, it highlights one of the biggest limitations in modern longevity research: measuring the wrong compartment of the body and then making broad conclusions about aging itself.
The study primarily measured NAD+ in whole blood.
Not inside mitochondria.
Not inside skeletal muscle.
Not inside neurons.
Not inside stem cells.
Not inside the tissues that actually determine vitality, recovery, cognition, and metabolic health.
That distinction matters enormously.
Aging does not happen in circulating blood. Aging happens inside cells.
It happens inside mitochondria where ATP is generated. It happens inside skeletal muscle where metabolic flexibility is lost. It happens inside the brain where cognitive decline develops. It happens inside immune cells where chronic inflammation accelerates disease.
Whole blood is simply not the same thing as intracellular metabolic health.
One major limitation is that red blood cells — which make up much of whole blood — do not even contain mitochondria. They rely primarily on glycolysis and have very different metabolic demands compared to tissues like brain, heart, liver, and skeletal muscle.
So if aging-related dysfunction is occurring primarily at the mitochondrial or tissue level — and decades of research strongly support that it is — then measuring whole-blood NAD+ may tell us very little about true cellular aging.
The recent headlines essentially implied:
“If blood NAD+ does not decline dramatically with age, then NAD may not matter in longevity.”
That is an oversimplification.
NAD biology is highly compartmentalized. Different NAD pools exist inside mitochondria, nuclei, immune cells, muscle tissue, liver tissue, and the brain. Those pools respond differently to inflammation, oxidative stress, insulin resistance, poor sleep, toxins, and aging itself.
Aging also appears to involve much more than simply “running out” of NAD. It likely involves impaired NAD recycling, excessive NAD consumption, mitochondrial inefficiency, chronic inflammation, and disrupted cellular energy signaling.
So the better question is not:
“Is blood NAD+ lower?”
The better question is:
“Are cells producing and utilizing energy efficiently enough to maintain youthful function?”
Even this same study still demonstrated that NAD precursor therapies such as NR and NMN reliably increase circulating NAD metabolites. Other human studies continue to show improvements in mitochondrial signaling, muscle energetics, insulin sensitivity, vascular function, and metabolic flexibility.
Clinically, this is where things become more meaningful.
At The Hormone Zone and The Longevity Protocol, we do not evaluate longevity through the lens of a single blood biomarker. We evaluate:
- mitochondrial efficiency,
- cardiovascular fitness,
- hormonal optimization,
- body composition,
- inflammation,
- metabolic flexibility,
- recovery capacity,
- and overall human performance.
This is why longevity medicine is increasingly shifting toward functional mitochondrial assessment.
One promising tool is indirect calorimetry systems such as PNOĒ. While these technologies do not directly measure mitochondria under a microscope, they evaluate the physiologic output of mitochondrial metabolism in real time.
Systems like PNOĒ measure:
- VO₂ max,
- oxygen utilization,
- respiratory exchange ratio,
- fat versus carbohydrate burning,
- resting metabolic rate,
- and ventilatory efficiency.
In practical terms, this helps us see how efficiently the body is actually producing and utilizing energy.
Patients with mitochondrial dysfunction often demonstrate:
- poor fat oxidation,
- early carbohydrate dependence,
- impaired aerobic efficiency,
- poor recovery,
- and accelerated metabolic aging.
Those are real-world expressions of impaired mitochondrial health.
The truth is that mitochondrial aging remains one of the strongest theories in longevity science. Loss of mitochondrial efficiency has been linked to sarcopenia, insulin resistance, cardiovascular disease, neurodegeneration, chronic fatigue, frailty, and many degenerative conditions associated with aging.
NAD+ remains central to that conversation.
That does not mean NAD therapy is a miracle cure, nor does it mean every anti-aging trend is evidence-based. But it also does not mean the field is invalid simply because whole-blood NAD+ levels may remain stable in some individuals.
At The Hormone Zone and The Longevity Protocol, we believe longevity is not about chasing headlines or obsessing over one laboratory marker.
Longevity is about preserving cellular energy, metabolic resilience, cognitive vitality, strength, recovery, and the ability to fully engage in life for decades to come.
And from everything modern physiology continues to show us, mitochondrial health — and the NAD pathways that support it — remain deeply connected to that mission.
