Sirtuins and NAD+: The Cell Maintenance Connection

NAD+ has two famous jobs. One is energy: it helps move a load from food to the cell's energy makers. The other is upkeep. Sirtuins are the helpers that use NAD+ while they tidy proteins. This page explains that connection without turning it into a promise.

On the Science pathway, sirtuins sit beside mitochondria and PARPs. The energy half is in NAD+ and Mitochondria: How Your Cells Make Energy. PARPs are another family that uses NAD+, this time while the cell signals for DNA repair. That third box links to the NMN and NAD article.

A helper that uses NAD+ while it tidies proteins

A sirtuin is a helper protein. It takes a small chemical tag off other proteins, and it needs NAD+ in order to do that. When the tag comes off, the protein can behave differently. That is the whole everyday idea.

The story starts with a yeast protein called Sir2. In 2000, Imai, Armstrong, Kaeberlein, and Guarente showed that yeast Sir2, and the related mouse protein, are NAD dependent histone deacetylases. A histone is a protein that packages DNA, so the tags on it affect how genes are read. Deacetylase is the lab name for an enzyme that takes those tags off. This family uses NAD+ inside the reaction.

Mammals have seven sirtuins, SIRT1 through SIRT7. Feldman, Dittenhafer-Reed, and Denu describe them as NAD+ dependent deacylases that help regulate transcription, metabolism, and stress responses. Deacylase is the broader name for taking a small tag off a protein. Transcription means how genes are read. Houtkooper, Pirinen, and Auwerx map the locations. Some act in the nucleus, the cell's library, some in the cytoplasm, the fluid around it, and some in mitochondria, the energy makers. That is how they can influence fat and glucose metabolism when the cell's energy status changes.

Imai and Guarente name the feature that matters here. NAD+ breakdown is coupled to protein deacylation. In plain words, the helper does not borrow NAD+ and hand the same molecule straight back. It uses some of it up. Nicotinamide is the fragment left from spent NAD+. Follow the arrows: NAD+ in, a protein with its tag in, the protein leaving with the tag removed, and nicotinamide out.

The tidy-up happens in more than one place

Some of this work happens near the cell's instructions. Some of it happens inside the energy makers. Both jobs draw on the same NAD+ supply.

In the nucleus, sirtuins such as SIRT1 change how genes are read by removing tags from histones and from other proteins. Imai and Guarente, in 2014, also place sirtuins next to PARPs and CD38, two other enzymes that use up NAD+. The pool is shared. Covarrubias and colleagues make the same split: NAD+ is both a redox coenzyme, the energy carrier, and a cofactor for sirtuins, CD38, and PARPs. A cofactor is a helper molecule the enzyme has to have.

In mitochondria, SIRT3 is the clearest example. Hirschey and colleagues showed, in mice, that SIRT3 sits in the mitochondrial matrix, the inner space of the energy makers, and takes acetyl tags off metabolic enzymes. During fasting, livers from mice lacking SIRT3 handled fat burning less readily than livers from ordinary mice. That is a mouse study of how metabolism adapts. It is not a human supplement result.

If NAD+ runs low, the tidy-up can slow

Each job spends a little NAD+. If the cell replaces it as fast as it is used, the helpers keep working. If use runs ahead of replacement, the tidy-up can slow down.

Imai and Guarente describe that link in the models they review, including lower NAD+ with age and less sirtuin activity in those models. A cofactor the cell is short of is a cofactor the enzyme cannot use.

Human tissue is narrower. In pelvic skin, Massudi and colleagues found that NAD+ was negatively correlated with age in both males and females. SIRT1 activity was negatively correlated with age in males in that cohort, and the pattern was not clear in females. Same study, two patterns. It does not mark a birthday when sirtuins stop.

One often quoted mouse paper should stay a mouse paper. Gomes and colleagues reported that raising NAD+ in old mice restored mitochondrial function, and that this depended on SIRT1. In that experiment the maintenance enzyme was part of the response. The animals were still mice.

NMN can feed the NAD+ supply

NMN is a building block, not NAD+ itself. Cells can turn it toward NAD+, the helper sirtuins require. Yoshino, Baur, and Imai review that biology. Rajman, Chwalek, and Sinclair review animal studies of molecules that raise NAD+. In 2018 that evidence was largely from animals. Whether the same patterns hold in people was still an open question.

A careful sentence is enough. NMN can support the body's own NAD+ supply. Supporting the supply is not the same as proving that a specific sirtuin changed, and it is not a disease treatment.

What the human studies actually measured

The four studies below are the ones the Science page already cites. They compared NMN with a placebo, a lookalike with no NMN. None of them measured sirtuin activity.

Huang, 2022 gave healthy adults aged 40 to 65 a daily 300 mg of Uthever NMN or a placebo for 60 days. Serum NAD+/NADH rose in the Uthever group, and the difference versus placebo was not statistically significant. The paper does not report sirtuin activity. The dose was described as well tolerated.

Yi and colleagues, 2023 did see a clear blood NAD change. Eighty healthy middle aged adults took a placebo or 300 mg, 600 mg, or 900 mg of AbinoNutra NMN for 60 days. Serum NAD+ plus NADH was higher than placebo at day 30 and day 60, and the doses were reported as well tolerated. Walk distance also increased more than placebo. Sirtuins were not an endpoint. The ingredient was not Uthever.

Igarashi and colleagues, 2022 studied healthy men 65 and older on 250 mg of Mitsubishi NMN. Whole blood NAD+ rose, and tolerability was reported as good. A supplier mix up at six weeks removed 22 people from the 12 week analysis. Nominal changes in gait and left grip need larger studies, by the authors' own account. There was no sirtuin assay.

Okabe and colleagues, 2022 gave 30 healthy adults 250 mg of Mitsubishi NMN or a placebo for 12 weeks. Whole blood NAD+ increased, with no obvious adverse effects reported. The introduction notes that NAD+ is a substrate for sirtuins and PARPs. The trial result is the blood measurement, not a change in sirtuin activity.

The human record here supports a modest claim. Oral NMN sometimes raises NAD related measures in blood, and sometimes that rise is not statistically separate from placebo. These papers do not show that sirtuin activity in human tissues was measured and confirmed. Early and mixed is the accurate summary.

What this does and does not say

On the Science page, sirtuins are the box for cell upkeep. They are helpers that need NAD+ while they tidy proteins. That is biology. It is not a product claim.

Anera's marketed NMN products are licensed in Canada for the antioxidant use on the label. The NPN note in NAD+ and aging explains why a licence is not permission for extra claims. You can also return to the Science pathway.

FAQ

References

1. Imai et al., 2000. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. Yeast and mouse Sir2 proteins are NAD dependent histone deacetylases. This is the founding evidence that this enzyme family requires NAD+.
2. Feldman et al., 2012. Sirtuin catalysis and regulation. Journal of Biological Chemistry. Sirtuins are a family of NAD+ dependent protein deacylases. They participate in transcription, metabolism, and cellular stress responses.
3. Imai and Guarente, 2016. It takes two to tango: NAD+ and sirtuins in aging/longevity control. npj Aging and Mechanisms of Disease. The coupling of NAD+ breakdown and protein deacylation is a defining feature of sirtuins. The review describes lower NAD+ availability with age as a way sirtuin activity can fall in the models discussed.
4. Imai and Guarente, 2014. NAD+ and sirtuins in aging and disease. Trends in Cell Biology. NAD+ is consumed by sirtuins, PARPs, and CD38. The review links NAD+ decline during aging with stress on nuclear and mitochondrial functions in the experimental systems it covers.
5. Houtkooper et al., 2012. Sirtuins as regulators of metabolism and healthspan. Nature Reviews Molecular Cell Biology. SIRT1 through SIRT7 act in the nucleus, the cytoplasm, and mitochondria. They help regulate fat and glucose metabolism as energy status changes.
6. Hirschey et al., 2010. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. In mice, SIRT3 sits in the mitochondrial matrix and removes acetyl tags from metabolic enzymes, including an enzyme of fat oxidation during fasting. This is animal research.
7. Covarrubias et al., 2021. NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology. NAD+ is required by non redox enzymes that include sirtuins, CD38, and PARPs, in addition to its role in energy metabolism.
8. Massudi et al., 2012. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLOS ONE. In human pelvic skin, SIRT1 activity was negatively correlated with age in males in that cohort, and not clearly in females. NAD+ itself was lower with age in both sexes. One tissue, not a universal rule.
9. Gomes et al., 2013. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. In mice, restoring NAD+ related mitochondrial function in old animals depended on SIRT1. A mouse result is not a human maintenance claim.
10. Rajman et al., 2018. Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence. Cell Metabolism. NAD+ influences NAD sensing enzymes, including pathways tied to energy metabolism. The in vivo evidence reviewed in 2018 was mostly from animals.
11. Yoshino et al., 2018. NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metabolism. NMN is a precursor cells can convert toward NAD+, which is the cofactor sirtuins require.
12. Huang, 2022. Uthever NMN trial in middle aged and older adults. Frontiers in Aging. A 60 day trial of 300 mg Uthever NMN in healthy adults aged 40 to 65. The serum NAD+/NADH difference versus placebo was not statistically significant. The paper does not report a sirtuin activity result.
13. Yi et al., 2023. NMN supplementation in healthy middle aged adults. GeroScience. AbinoNutra NMN at 300, 600, or 900 mg raised serum NAD+ plus NADH versus placebo over 60 days and was reported as well tolerated. Sirtuin activity was not a reported endpoint. This was not Uthever.
14. Igarashi et al., 2022. NMN supplementation in healthy older men. npj Aging. Mitsubishi NMN at 250 mg raised whole blood NAD+ in healthy men 65 and older and was well tolerated. A dosing mix up limited the 12 week sample. Sirtuin activity was not reported.
15. Okabe et al., 2022. Oral NMN in healthy adults. Frontiers in Nutrition. Mitsubishi NMN at 250 mg for 12 weeks raised whole blood NAD+ in 30 healthy adults, with no obvious adverse effects reported. The paper's background names sirtuins as NAD+ consuming enzymes. The trial result is the blood NAD+ change, not a sirtuin measurement.

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