NAD+ and Mitochondria: How Your Cells Make Energy

Your cells cannot spend a meal directly. They have to convert it. Much of that work happens in mitochondria, the small energy makers inside a cell. NAD+ is the helper that keeps the handoff moving. This page is a plain map of that idea, plus what age related studies and human NMN trials actually show.

The shorter picture is on the Science pathway. NMN can enter the cell and be turned into NAD+. Mitochondria are one branch of the work NAD+ supports.

Food has to become energy a cell can spend

Food is broken into smaller pieces. Those pieces hand a tiny load to NAD+. Once NAD+ is carrying the load, scientists call it NADH. After the delivery, NAD+ is empty again and can go back for more.

Think of a shuttle. NADH ferries the load toward the energy makers. NAD+ makes the return trip. Cells need both forms. Rajman and colleagues call NAD the cell's hydrogen carrier. A hydrogen carrier is simply a molecule that moves that load. Covarrubias and colleagues call NAD+ a redox coenzyme at the center of energy metabolism. Redox means the load, made of electrons, is passed from one molecule to another. Cantó, Menzies, and Auwerx describe this as a balance between the energy makers and the rest of the cell, not a single switch.

Inside the energy makers, the load takes a short trip

Inside mitochondria, the load moves along a short relay. That relay is what lets the cell finish the job and make ATP. ATP is the form of energy a cell can actually spend.

The relay has a lab name, the electron transport chain. Finishing it as ATP is called oxidative phosphorylation. Nolfi-Donegan, Braganza, and Shiva review that sequence.

The first stop is called Complex I. In plain terms, it takes the load off NADH, passes it onward, and helps build the push that makes ATP. That push is called the proton motive force, a buildup of charged particles across the inner wall of the energy maker. Hirst reviews the mechanism, including the longer name NADH:ubiquinone oxidoreductase. The picture below keeps the everyday version. The load arrives, the first stop takes it, ATP is made, and NAD+ is free again.

The energy makers also need their own supply of NAD+ inside them. Luongo and colleagues identified a transporter called SLC25A51 that can bring NAD+ in. In cell experiments, losing it left the energy makers short and slowed their work. That is a lab finding about supply, not a supplement result.

Some tissues have less of this helper at older ages

A major review says NAD+ in tissues tends to be lower with age in animals and in people. The same review says a lot is still unknown about raising it in humans, and about whether that helps.

Human data are real and specific. In pelvic skin from surgical patients, Massudi and colleagues found that NAD+ was negatively correlated with age in both males and females. That is one tissue, not a whole body percentage.

In healthy volunteers, Zhu and colleagues used magnetic resonance to estimate NAD+ and NADH in the living brain. They reported lower NAD+, lower total NAD, a lower NAD+ to NADH redox state, and higher NADH at older ages. One organ, one method. The fair reading is directional. It is not a diagnosis.

Mouse work should stay labeled as mouse work. Gomes and colleagues found that lower nuclear NAD+ during aging tracked with changes in mitochondrial energy proteins. Raising NAD+ in old mice restored mitochondrial function in a way that depended on SIRT1. That is a clue from mice. It does not describe what happens in people.

NMN is a building block, not the finished helper

NMN is not NAD+. It is a building block cells can turn into NAD+. The helper that does that conversion is an enzyme called NMNAT. An enzyme is a protein that does a specific job. Yoshino, Baur, and Imai review NMN and nicotinamide riboside as NAD+ intermediates, and they note that handling still depends on the tissue. An intermediate is a step on the way to the finished molecule.

The 2018 Rajman review gathered animal studies in which restoring NAD+ changed metabolism and health measures in old or diseased animals. It describes careful human research as the next step. It does not establish a disease treatment.

Four human studies, and they do not all agree

These are the four studies already on the Science page. They are small, they are short, and they did not all use the same NMN.

Huang, 2022, in Frontiers in Aging, enrolled 66 healthy adults aged 40 to 65. They took 300 mg of Uthever NMN or a placebo daily for 60 days. Serum NAD+/NADH rose in the Uthever group, and the difference versus placebo was not statistically significant. Walking, a general health score, and an insulin resistance score were not statistically different between groups either. The dose was reported as well tolerated.

Yi and colleagues, 2023, in GeroScience, randomized 80 healthy middle aged adults to a placebo or to 300 mg, 600 mg, or 900 mg of NMN daily for 60 days. Serum NAD+ plus NADH was statistically higher than placebo at day 30 and day 60. Six minute walk distance also increased more than placebo. An insulin resistance score did not differ significantly from placebo at day 60. Doses were reported as well tolerated. The NMN was AbinoNutra, not Uthever. One walk result is not a claim about any other bottle.

Igarashi and colleagues, 2022, in npj Aging, gave healthy men aged 65 and older 250 mg of Mitsubishi NMN or a placebo. Whole blood NAD+ was higher with NMN, and it was well tolerated. A supplier mix up at six weeks meant 22 people were excluded from the 12 week visit. Gait speed and left grip showed nominal improvements the authors say need larger studies. Body composition did not change significantly.

Okabe and colleagues, 2022, in Frontiers in Nutrition, studied 30 healthy adults on 250 mg of Mitsubishi NMN or a placebo for 12 weeks. Whole blood NAD+ rose, with no obvious adverse effects reported. A blood change is not itself a report of more energy in daily life.

Together, the honest summary is narrow. Oral NMN can raise blood NAD related measures in some trials. It did not separate from placebo on NAD+/NADH in the Uthever trial. Physical results are mixed, early, and tied to the product and the people in each paper.

A fair way to read this

NAD+ supports energy metabolism because it takes part in the chemistry that lets the energy makers produce ATP. That is cell biology. It is not a promise about how your day will feel.

In Canada, Anera's marketed NMN products are licensed for the antioxidant use on the label: a source of antioxidants that helps protect cells against free radicals. The NPN note in NAD+ and aging explains the limit. Sleep, food, movement, and medical care remain the base.

Sirtuins use NAD+ for cellular maintenance, and they consume it rather than simply recycling it. That companion explainer is Sirtuins and NAD+: The Cell Maintenance Connection.

FAQ

References

1. Covarrubias et al., 2021. NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology. NAD+ is a redox coenzyme central to energy metabolism, and the review states that tissue NAD+ declines with age in several organisms, including humans, while much about restoring it in people is still unknown.
2. Rajman et al., 2018. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metabolism. NAD is the hydrogen carrier for redox enzymes. The review gathers mostly animal evidence and treats human benefit as a question for trials, not a finished result.
3. Nolfi-Donegan et al., 2020. Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biology. The electron transport chain uses electron transfer to make ATP through oxidative phosphorylation.
4. Hirst, 2013. Mitochondrial complex I. Annual Review of Biochemistry. Complex I oxidizes NADH from the tricarboxylic acid cycle and from fat breakdown, reduces ubiquinone, and moves protons, which contributes to the proton motive force.
5. Luongo et al., 2020. SLC25A51 is a mammalian mitochondrial NAD+ transporter. Nature. Mitochondria need NAD+ for respiration. In cell experiments, SLC25A51 can import NAD+, and losing it lowered mitochondrial NAD+ and impaired respiration.
6. Cantó et al., 2015. NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metabolism. NAD+ metabolism connects energy status in mitochondria with the rest of the cell.
7. Massudi et al., 2012. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLOS ONE. In human pelvic skin from a surgical cohort, NAD+ was negatively correlated with age in both males and females. That is one tissue, not a whole body percentage.
8. Zhu et al., 2015. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proceedings of the National Academy of Sciences. In healthy volunteers, brain NAD+, total NAD, and the NAD+ to NADH redox state were lower at older ages, and NADH was higher. One organ and one imaging method.
9. Gomes et al., 2013. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. In mice, lower nuclear NAD+ tracked with changes in mitochondrial energy proteins. Raising NAD+ in old mice restored mitochondrial function in a SIRT1 dependent way. This is animal research.
10. Yoshino et al., 2018. NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metabolism. NMN is an NAD+ intermediate. Cells can use it in NAD+ biosynthesis. How it is handled still depends on the tissue.
11. Huang, 2022. Uthever NMN trial in middle aged and older adults. Frontiers in Aging. Healthy adults aged 40 to 65 took 300 mg of Uthever NMN or placebo daily for 60 days. Serum NAD+/NADH rose in the Uthever group, and the between group difference was not statistically significant. Walking, the SF-36 score, and HOMA-IR were also not statistically different from placebo. The dose was reported as well tolerated.
12. Yi et al., 2023. The efficacy and safety of β-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults. GeroScience. Eighty healthy middle aged adults took placebo or 300, 600, or 900 mg of AbinoNutra NMN daily for 60 days. Serum NAD+ plus NADH was higher than placebo at day 30 and day 60. Six minute walk distance increased more than placebo. HOMA-IR did not differ significantly from placebo at day 60. Doses were reported as well tolerated. This was not Uthever.
13. Igarashi et al., 2022. Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men. npj Aging. Healthy men 65 and older took 250 mg of Mitsubishi NMN or placebo. Whole blood NAD+ was higher with NMN, and it was well tolerated. A mix up at six weeks excluded 22 people from the 12 week visit. Gait speed and left grip showed nominal improvements the authors say need larger studies. Body composition did not change significantly.
14. Okabe et al., 2022. Oral Administration of Nicotinamide Mononucleotide Is Safe and Efficiently Increases Blood Nicotinamide Adenine Dinucleotide Levels in Healthy Subjects. Frontiers in Nutrition. Thirty healthy adults took 250 mg of Mitsubishi NMN or placebo daily for 12 weeks. Whole blood NAD+ rose after NMN. The authors report no obvious adverse effects. A blood change is not itself a change in how someone feels.

Back to the Science pathway

Educational content from Anera Life Inc. Not medical advice. Natural health products should be used according to their labels. Consult a qualified practitioner for personal guidance.