Every cell in your body runs on a molecular currency you've probably never heard of. NAD+—nicotinamide adenine dinucleotide—is as essential to your cellular economy as ATP, yet it receives far less attention. This coenzyme sits at the crossroads of energy production, DNA repair, and the activation of longevity-promoting proteins.

Here's the troubling reality: NAD+ levels decline substantially as we age. By middle age, many tissues contain only half the NAD+ they held in youth. This isn't merely a biomarker of aging—emerging research suggests it may be a driver of the aging process itself, creating a progressive energy crisis that impairs nearly every cellular function.

Understanding why NAD+ declines—and whether we can do anything about it—has become one of the most active frontiers in longevity research. The science is still evolving, but what we know already challenges how we think about cellular aging and offers potential strategies for intervention.

NAD+ functions as a critical coenzyme in over 500 enzymatic reactions. Its most fundamental role involves redox reactions—shuttling electrons between molecules to enable the chemical transformations that power cellular life. Without adequate NAD+, your mitochondria cannot efficiently convert food into usable energy.

But NAD+'s importance extends far beyond energy production. It serves as the essential substrate for sirtuins—a family of proteins that regulate everything from DNA repair to inflammation to metabolic efficiency. When sirtuins work, they consume NAD+ directly. The same is true for PARPs (poly-ADP-ribose polymerases), enzymes that repair DNA damage by using NAD+ as their raw material.

This creates an elegant but fragile system. DNA damage increases with age, demanding more PARP activity. Cellular stress rises, requiring more sirtuin function. Yet both processes consume NAD+, potentially depleting the very resource needed to maintain cellular health. It's a molecular tug-of-war where the rope itself gets shorter over time.

Research in animal models has demonstrated that declining NAD+ correlates with reduced mitochondrial function, impaired DNA repair, and metabolic dysfunction. Restoring NAD+ levels in aged mice has shown remarkable effects—improved muscle function, better cognitive performance, and enhanced metabolic health. Whether these findings translate fully to humans remains an active area of investigation.

Takeaway

Think of NAD+ not as a supplement target but as a metabolic crossroads—its depletion creates cascading failures across energy production, DNA repair, and cellular stress responses simultaneously.

The age-related decline in NAD+ stems from a simple but devastating imbalance: consumption increasingly outpaces production. One major culprit is CD38, an enzyme whose expression increases dramatically with age and chronic inflammation. CD38 degrades NAD+ directly, and research suggests it may account for much of the age-related decline in tissue NAD+ levels.

Simultaneously, the pathways that synthesize NAD+ become less efficient. The enzymes involved in converting precursors into NAD+ show reduced activity with age. NAMPT, the rate-limiting enzyme in the NAD+ salvage pathway, declines in expression across multiple tissues. Your cellular factories produce less while consumption rises.

Chronic inflammation—often called "inflammaging"—worsens this dynamic. Inflammatory signaling increases CD38 expression while also generating oxidative stress that damages DNA, which triggers PARP activity that further depletes NAD+. It becomes a self-reinforcing cycle where inflammation drives depletion, and depletion impairs the cellular repair mechanisms that might otherwise resolve inflammation.

The tissue-specific nature of NAD+ decline adds complexity. Some organs—particularly metabolically active tissues like liver, muscle, and brain—show more pronounced depletion. This may explain why aging manifests differently across organ systems, with metabolic dysfunction and cognitive decline often appearing before other symptoms.

Takeaway

NAD+ decline isn't passive wear—it's an active process driven primarily by CD38 enzyme overexpression and chronic inflammation, suggesting that targeting these mechanisms may matter as much as simply adding precursors.

If NAD+ declines with age, can we simply supplement our way back to youthful levels? This question has driven intense research into NAD+ precursors—molecules that cells can convert into NAD+. The two leading candidates are NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside).

Animal studies have shown promising results. Mice supplemented with NMN or NR demonstrate increased tissue NAD+ levels and improvements in various age-related parameters—from insulin sensitivity to exercise capacity to cognitive function. These findings generated enormous excitement and a booming supplement industry.

Human data, however, remains more limited and mixed. Several trials have confirmed that oral NMN and NR can indeed raise blood NAD+ levels in humans. But whether this translates to the functional benefits seen in mice is less clear. Some trials show modest improvements in specific biomarkers; others show no significant effects. Dosing, duration, individual variation, and measurement techniques all complicate interpretation.

What the science does support: these precursors appear safe at commonly used doses and can elevate measurable NAD+ levels. What remains unproven: whether supplementation meaningfully impacts human aging or healthspan. Researchers emphasize that lifestyle factors—exercise, fasting, and avoiding chronic inflammation—also influence NAD+ dynamics and may be equally or more important than supplementation.

Takeaway

Current evidence supports that NAD+ precursors can raise measurable levels in humans, but functional benefits remain unproven—consider them experimental tools rather than established longevity interventions while awaiting longer-term human trial data.

The NAD+ story illustrates a central truth about aging biology: decline often stems from disrupted balance rather than simple deficiency. Consumption rises while production falls, creating a progressive energy crisis that cascades across cellular systems.

Current research offers both hope and humility. We understand the mechanisms increasingly well, and precursor supplementation represents a plausible intervention strategy. Yet the gap between mouse models and human outcomes reminds us that aging remains complex, and simple solutions may prove insufficient.

The most evidence-based approach combines multiple strategies: reducing chronic inflammation, maintaining metabolic health through exercise and appropriate nutrition, and—perhaps—supporting NAD+ levels through precursors while awaiting more definitive human data. The currency crisis is real; the optimal response remains under investigation.