Why Does NAD+ Decline With Age? The Barrier Connection

What Does the Evidence Say?

Short answer: NAD+ declines with age because cells both produce less of this coenzyme and consume it faster through enzymes like CD38 — and this mismatch between production and consumption grows progressively with age. Looking more closely, research in mouse models showed that CD38 enzyme activity in tissue and plasma increases with age and is a major driver of NAD+ decline; researchers also found that CD38 breaks down the NAD+ precursor NMN.^{Camacho-Pereira et al., 2016} This finding matters because it shows that NAD+ decline isn't just a matter of "less production" — it's also a matter of actively increased "consumption." Practical takeaway: as you age, your cells are essentially trying to hold NAD+ in an increasingly "leaky bucket" — as the leak (CD38 activity) grows, it becomes harder to maintain the level no matter how much water (NAD+ precursor) you add.

Factors That Accelerate NAD+ Consumption

CD38: The "NAD+ Consumer" Enzyme That Increases With Age

CD38 is an enzyme found on the cell surface that breaks down NAD+. The age-related increase in CD38 activity in tissue and immune cells has also been linked to chronic low-grade inflammation ("inflammaging").^{Camacho-Pereira et al., 2016} This mirrors the broader pattern seen in skin barrier changes observed in your 40s: both collagen production and cellular energy metabolism tend to follow a similar "production drops, consumption/damage rises" pattern with age.

PARP1: Consumption Accelerated by UV Damage

The second major NAD+ consumer is PARP1, the enzyme responsible for DNA repair. When UV radiation causes DNA damage in keratinocytes, PARP1 activates to repair it, and in the process can rapidly deplete the cellular NAD+ pool.^{Surjana et al., 2013} Sun exposure accumulated over the years can therefore place a burden not just on visible photoaging, but also on cells' long-term NAD+ balance. The clinical significance of this relationship has been shown even more clearly in immunosuppressed organ transplant recipients: in this high-risk group, oral nicotinamide (an NAD+ precursor) supplementation significantly reduced new skin cancer cases.^{Allen et al., 2023}

How Does the Barrier Connection Work?

A Lower-Energy Cell Has a Harder Time Repairing Its Barrier

The skin barrier — the lipid structure and tight junctions of the stratum corneum — is a dynamic system in constant renewal, and that renewal requires energy. Given that NAD+-dependent sirtuins (SIRT1, SIRT3) regulate mitochondrial function, it has been suggested that declining NAD+ levels may indirectly affect cellular energy production and, in turn, the speed of barrier repair.^{Imai & Guarente, 2014} This overlaps with the picture we describe in our article on how TEWL (transepidermal water loss) changes with age: aging skin prevents water loss less efficiently, and one of the underlying reasons may be an overall decline in cellular energy and repair capacity. It would be a mistake to simplify this into "the barrier deteriorates because NAD+ declines" — the relationship is indirect and multifactorial — but it's clear the two processes move in the same direction.

What Do These Signs Mean for You?

While NAD+ decline can't be directly measured, researchers link certain age-related skin changes to this mechanism. Here's a summary of the most common signs and their possible connection:

Conclusion

"The age-related decline in NAD+ levels is the result of both reduced production and increased consumption through enzymes like CD38 and PARP1. This decline doesn't directly 'damage' the skin barrier, but by limiting cells' energy and repair capacity, it may indirectly affect the barrier's overall resilience."

CIRÈLL is committed to addressing age-related changes in the skin barrier within a multifactorial, evidence-based framework, rather than reducing them to a single molecule.

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