**If regular movement helps preserve muscle function with age, could part of that pattern be associated with higher muscle NAD+ levels?**

**TL;DR**

In a human muscle study, older adults had lower muscle NAD+ than younger adults, but exercise-trained older adults looked much closer to the young group than physically impaired peers.

**Quick Takeaways**

• This study looked at how skeletal muscle metabolism changes with aging, with a special focus on NAD+, a central molecule in cellular energy metabolism.  
• Researchers analyzed muscle biopsies from young adults and three groups of older adults: trained, normally active, and physically impaired.  
• The main finding was associative rather than causal: lower muscle NAD+ tracked with poorer muscle and mitochondrial health, while exercise-trained older adults had NAD+ levels much closer to those of younger adults.

**Context**

Aging muscle does not just get smaller or weaker. It also changes metabolically. Mitochondria tend to function less efficiently, insulin sensitivity often declines, and older muscle becomes less adaptable under stress. That matters because skeletal muscle is one of the major tissues supporting mobility, glucose handling, metabolic health, and resilience later in life.

One molecule that repeatedly appears in aging research is NAD+ (nicotinamide adenine dinucleotide). NAD+ helps shuttle electrons for energy production and also serves enzymes involved in DNA repair, stress responses, and mitochondrial regulation. In animal studies, NAD+ often declines with age, and raising it can improve some aspects of physiology. Human evidence has been less consistent. This paper tried to narrow that gap by asking a simple but important question: does NAD+ actually fall in aging human muscle, and if so, is that linked to muscle health in real people? The study suggests yes, with a major caveat: this was a cross-sectional design, so it supports association more than causation.

**What the researchers actually did**

The study included 52 people total: 12 young adults aged 20–30, plus 40 older adults aged 65–80. The older participants were divided into three groups: 17 exercise-trained older adults, 17 older adults with normal activity levels, and 6 physically impaired older adults. The trained group had performed at least three structured exercise sessions per week for at least one year. The impaired group was defined by a Short Physical Performance Battery score of 9 or below.

This design is more informative than a simple young-versus-old comparison because it allows the researchers to ask whether metabolic differences track not only with age, but also with healthier versus less healthy aging muscle states. That matters, because two older adults of the same age can have very different muscle biology depending on training, function, and physical capacity.

Participants wore activity monitors for 5 days. Young adults and the “normal” older adults both averaged about 10,000 steps per day, which helps reduce the chance that every age effect is merely a fitness effect. The trained older adults averaged roughly 13,000 steps per day and spent more time in high-intensity activity, whereas the impaired group averaged closer to 6,000 steps per day. Researchers then took vastus lateralis muscle biopsies and used mass spectrometry-based metabolomics to profile 137 annotated metabolites. They also assessed mitochondrial respiration, mitochondrial protein abundance, muscle strength, muscle volume, exercise efficiency, and in vivo mitochondrial function.

That combination is one of the strengths of the paper. It was not just a single-metabolite observation; it connected metabolite abundance to actual physiological and functional parameters.

**NAD+ stood out**

Among the 137 muscle metabolites measured, NAD+ was one of the most clearly depleted in older adults compared with young adults. More importantly, it followed a graded pattern across the groups. The physically impaired older adults had the lowest NAD+ levels. The normally active older adults were also lower than the young group. But the exercise-trained older adults had NAD+ levels much closer to those of young adults. This pattern is visible in Figure 2 on page 3, where NAD+ also shows the strongest association with the study’s “healthy aging” trend.

So the finding was not simply that older age was associated with less NAD+, but that healthier muscle aging profiles were associated with more preserved NAD+.

The paper also found the opposite pattern for oxidative stress-related signals. Ophthalmic acid, a marker associated with oxidative stress, was higher in older adults and highest in the impaired group, while being less elevated in the trained group. Oxiglutathione showed a similar trend. In plain language, lower NAD+ tended to appear in the same biological setting as more oxidative stress and poorer muscle status. That does not prove oxidative stress is causing NAD+ loss, or vice versa, but it does support the idea that they are part of the same aging muscle phenotype.

**Why this matters for muscle function**

The more useful question is whether this biochemical pattern relates to how muscle actually performs. Here, the answer was yes, at least associationally.

Across the older adults, higher muscle NAD+ was positively associated with mitochondrial respiration. In Figure 4 on page 5, the reported correlation between NAD+ abundance and maximal ADP-stimulated mitochondrial respiration was R = 0.57, P = 0.00014. NAD+ was also positively associated with average daily step count, with R = 0.45, P = 0.0043. In other words, older adults whose muscles contained more NAD+ also tended to have better mitochondrial function and move more in daily life.

The study also identified potentially less favorable signals in the kynurenine pathway. Kynurenic acid was negatively associated with muscle strength, and kynurenine was negatively associated with exercise efficiency in the older adults. That broadens the picture: aging muscle is not just “low NAD+,” but a network shift involving energy metabolism, redox balance, and amino-acid-derived signaling molecules. Still, NAD+ emerged as one of the clearest metabolic markers associated with healthier muscle aging in this dataset.

**What this does, and does not, say about boosting NAD+**

This is where it is easy to overread the paper. The study supports the idea that muscle NAD+ is relevant to human muscle aging. It does not prove that taking an NAD+ precursor will recreate the physiology seen in the trained older adults.

The authors are careful on this point. They note that changing the NAD+ metabolome in humans does not automatically translate into the full physiological pattern seen with long-term exercise training, which suggests that NAD+ is likely one part of a broader muscle-health picture rather than the whole story. That means NAD+ may be important, but it may not be a single magic lever. Exercise changes blood flow, fiber recruitment, mitochondrial turnover, insulin signaling, inflammation, and many other pathways at once. Preserved NAD+ may be one component of that broader package rather than the whole story.

There are also real limitations. The study was cross-sectional, so reverse causation remains possible: people with healthier muscle biology may maintain higher NAD+, which then helps them stay active, rather than activity itself preserving NAD+. The impaired group was especially small, with only 6 participants, which limits confidence in finer subgroup differences. And muscle biopsies are heterogeneous, meaning the findings could reflect shifts in muscle fiber type or subcellular NAD+ pools rather than a uniform fall in NAD+ everywhere. The authors explicitly raise these issues in the discussion.

So the headline should stay measured: aging human muscle shows lower NAD+, and lower muscle NAD+ is associated with poorer muscle and mitochondrial health. That is a meaningful result, but not yet proof of a supplementation strategy.

**Conclusion / Discussion Prompt**

What I like about this paper is that it brings NAD+ down from the level of supplement discourse and back into actual human physiology. The most interesting signal here is not that NAD+ is “anti-aging.” It is that exercise-trained older adults seemed to preserve a more youthful-looking muscle metabolic profile, and NAD+ was one of the clearest markers associated with that pattern.

**Informational only.** 

**Reference:** [**https://www.nature.com/articles/s43587-022-00174-3**](https://www.nature.com/articles/s43587-022-00174-3)

NAD+ is lower in aging muscle, and exercise-trained older adults seem to preserve more of it