New Human Data Is Reshaping What We Know About NAD⁺

The “Age-Related NAD⁺ Decline” Model Is Being Revisited

Early human studies helped build the case for age-related NAD⁺ decline.

• Lower NAD⁺ levels in older adults were found using blood metabolomics. (Chaleckis et al., 2016)

• Declines in plasma NAD⁺ and related metabolites were reported in older populations. (Clement et al., 2019)

These findings aligned with strong biological reasoning. Aging is associated with increased NAD⁺ consumption and reduced NAD⁺ production, which would be expected to lower overall levels.

However, more recent, larger, and better-controlled studies are challenging the idea of a universal decline, at least when NAD⁺ is measured in blood.

For example, a recent study measured NAD⁺ levels in blood across different groups of people using precise, well-controlled methods. They found:

• No consistent change in whole-blood NAD⁺ with age.

• No clear effect of lifestyle interventions on blood NAD⁺.

This has led researchers to rethink whether blood NAD⁺ is a reliable marker of aging.

Importantly, this does not negate the role of NAD⁺ in aging or the decades of research behind it. Instead, it refines the picture: NAD⁺ biology remains central to aging, but how we measure it, and where we measure it, matters.

Blood NAD⁺ Doesn’t Tell the Whole Story

Blood is easy to collect, which makes it practical for human studies. But it does not necessarily reflect what’s happening inside tissues, where many aging processes occur.

Observations in tissues:

• Skin: NAD⁺ levels show a strong negative correlation with age in human skin tissue. (Massudi et al., 2012)

• Muscle: Muscle NAD⁺ was among the most prominently reduced metabolites in older adults, and even lower in those with physical impairment. (Janssens et al., 2022)

• Brain and Central Nervous System: Lower NAD(H) was detected in cerebrospinal fluid after midlife. (Guest et al., 2014) Brain NAD⁺ was lower in older individuals in two additional studies. (Zhu et al., 2014, Bagga et al., 2020)

The muscle findings deserve particular attention.

• In older adults who are physically active, muscle NAD⁺ levels are often comparable to those seen in younger individuals. Higher NAD⁺ in muscle is also associated with better mitochondrial function, greater daily activity (like step count), and improved muscle performance. (Janssens et al., 2022)

• While NAMPT levels decline with age in sedentary muscle, they can increase substantially with exercise. (Sun et al., 2023)

However, an impact of exercise on blood NAD+ levels is not always observed. (Trętowicz et al., 2026).

The takeaway:

⇨ Blood NAD⁺ is useful, but it’s only part of the picture. To understand how NAD⁺ relates to aging, it’s important to look at what’s happening inside specific tissues.

NAD⁺ and Biological Dysfunction

Lower NAD⁺ levels have also been observed across a range of age-related conditions:

• Neurodegenerative diseases (Guest et al., 2014)

• High blood pressure (Katayoshi et al., 2023)

• Age-related muscle loss (sarcopenia) (Migliavacca et al., 2019)

This pattern suggests that NAD⁺ may reflect biological dysfunction and disease burden more closely than chronological age itself.

In other words, two 65-year-olds with very different health and fitness profiles may have meaningfully different NAD⁺ levels in their tissues, not because of their age per se, but because of the biological state that age has produced in each of them.

NAD⁺ Is Dynamic and Modifiable

Even if blood NAD⁺ isn’t a perfect aging marker, it is still biologically meaningful and responsive to interventions.

Clinical trials show that increasing NAD⁺ availability can lead to measurable physiological changes:

• NR increased NAD⁺ and improved cardiovascular health markers in healthy middle-aged and older adults. (Martens et al., 2018)

• NR augmented skeletal muscle NAD⁺ metabolism and reduced inflammatory signaling molecules in older men. (Elhassan et al., 2019)

• In prediabetic women, NMN improved how effectively muscle tissue responds to insulin, which is important for blood sugar control. (Yoshino et al., 2021)

• In older men, NMN increased NAD⁺ levels and showed measurable effects on muscle function. (Igarashi et al., 2022)

At the same time, responses are not uniform across individuals.

Not everyone experiences the same increase in NAD⁺ from the same supplement and dose. In a human NMN study, some participants showed large increases in NAD⁺, while others had minimal changes. This variability appears to be driven by underlying biology:

• “Responders” tended to have higher expression of enzymes involved in NAD⁺ production

• “Non-responders” showed higher activity of NAD⁺-consuming enzymes (Wang et al., 2023)

Same supplement. Same dose. Different biology.

Key point:

⇨ Blood NAD⁺ may not consistently track aging, but it does track response to interventions.

Olivia Harrier

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Olivia is a biochemist and longevity researcher focused the molecular architecture of aging. Her work centers on metabolic health and the systems-level mechanisms that shape how we age. She translates dense research into clear frameworks for improving energy, resilience, and long-term health, grounded in physiology and evidence-driven frameworks that help people align daily habits with cellular performance. If you understand how the system works, you can work with it, and aging becomes something to navigate rather than just endure.