Sleep regulation: circadian timing and sleep pressure

Sleep is regulated by interacting biological processes. Circadian timing helps organise patterns of sleep and wakefulness across the approximately 24-hour day, while sleep homeostasis describes the pressure to sleep that generally increases during wakefulness and decreases during sleep. These systems interact with environmental and behavioural signals, including light exposure, activity and the timing of food intake.

At the molecular level, circadian timing is generated by networks of clock-related proteins and genes. CLOCK and BMAL1 promote the expression of period (PER) and cryptochrome (CRY) genes. PER and CRY proteins subsequently participate in feedback processes that help produce rhythmic changes in gene expression. This molecular clock is linked with metabolic pathways throughout the body.

The NAD+-sirtuin axis in circadian biology

Nicotinamide adenine dinucleotide (NAD+) is an intracellular coenzyme involved in cellular redox reactions and energy metabolism. It also acts as a required substrate for sirtuin enzymes, including SIRT1 and SIRT3. Because cellular NAD+ availability and sirtuin activity can vary with metabolic state, researchers have investigated how these pathways interact with circadian regulation.

Reviews by Abbas and colleagues (2024) and Roh and Kim (2020) describe links between NAD+-dependent sirtuin activity and molecular clock components. Experimental research indicates that SIRT1 can interact with CLOCK-BMAL1 complexes and influence PER2 and BMAL1-related signalling. NAD+ synthesis and SIRT1 activity also show circadian variation in several experimental systems. These findings support a relationship between cellular metabolism and circadian timing.

Most of the mechanistic evidence discussed in these reviews comes from cell-based research, animal models or studies of endogenous cellular pathways. It should therefore be distinguished from evidence about consuming an NAD+ precursor or administering NAD+ as an intervention.

Sleep, mitochondria and redox metabolism

Mitochondria generate energy through oxidative phosphorylation, a process that is also associated with the production of reactive oxygen species. Redox signalling is part of normal cellular function, but excessive or poorly regulated oxidative stress may disrupt cellular processes. Sleep and redox metabolism appear to influence one another in a bidirectional manner.

Mir, Lark and Nehs (2025) review evidence connecting sleep, mitochondrial function, reactive oxygen species and ageing. Their review describes changes in mitochondrial and redox biology during sleep disruption and notes that altered NAD+/NADH ratios and reduced sirtuin activity have been observed in relevant experimental contexts.

Melatonin and metabolic context

Melatonin is an endogenous hormone involved in signalling biological night and coordinating sleep-wake timing. Its synthesis from serotonin involves enzymes including arylalkylamine N-acetyltransferase (AANAT). Melatonin biology is connected with mitochondrial function, redox signalling and inflammatory pathways, although these relationships are complex and context dependent.

The reviews by Anderson (2019), Hardeland (2019), Kołodziejska and colleagues (2025), and Ribeiro and colleagues (2025) examine aspects of melatonin, oxidative stress, inflammation and neurobiology. These papers provide useful background on melatonin-related systems.

Sirtuins, inflammation and sleep-related biology

Inflammatory signalling and sleep are also interconnected. Chen and colleagues (2023) review the SIRT1-NLRP3 pathway and describe how it participates in the regulation of inflammatory responses. Research discussed in that review includes molecular, cellular and disease-model evidence concerning SIRT1, the NLRP3 inflammasome and inflammatory mediators.

This mechanistic literature is relevant to understanding relationships between metabolism and inflammation. Those outcomes would require appropriately designed human clinical studies using defined interventions and validated sleep measurements.

Conclusion

NAD+ is an important component of cellular metabolism and a necessary substrate for sirtuin enzymes. Research has identified biologically plausible links between the NAD+-sirtuin axis and circadian-clock mechanisms. Current research therefore contributes to a broader systems-level understanding of sleep, metabolism and ageing. Further well-controlled human studies are needed before conclusions can be drawn about whether any NAD+-related intervention meaningfully changes sleep outcomes.

Reference list

1. Abbas, K., Sharf, R., Alam, M., Sharf, Y. and Usmani, N. (2024). Chronotherapeutic and epigenetic regulation of circadian rhythms: nicotinamide adenine dinucleotide-sirtuin axis. Journal of Sleep Medicine, 21(3), 127-133. https://doi.org/10.13078/jsm.240015

2. Anderson, G. (2019). Mitochondria and the gut as crucial hubs for the interactions of melatonin with sirtuins, inflammation, butyrate, tryptophan metabolites, and alpha-7 nicotinic receptors. Melatonin Research, 2(4), 145-166. http://www.melatonin-research.net/index.php/MR/article/view/30

3. Chen, H., Deng, J., Gao, H., Song, Y., Zhang, Y., Sun, J. et al. (2023). Involvement of the SIRT1-NLRP3 pathway in the inflammatory response. Cell Communication and Signaling, 21, 185. https://doi.org/10.1186/s12964-023-01177-2

4. Hardeland, R. (2019). Aging, melatonin, and the pro- and anti-inflammatory networks. International Journal of Molecular Sciences, 20(5), 1223. https://doi.org/10.3390/ijms20051223

5. Kolodziejska, R., Wozniak, A., Bilski, R., Wesolowski, R. et al. (2025). Melatonin - a powerful antioxidant in neurodegenerative diseases. Antioxidants, 14(7), 819. https://doi.org/10.3390/antiox14070819

6. Mir, F.A., Lark, A.R.S. and Nehs, C.J. (2025). Unraveling the interplay between sleep, redox metabolism, and aging: implications for brain health and longevity. Frontiers in Aging, 6, 1605070. https://doi.org/10.3389/fragi.2025.1605070

7. Ribeiro, R.F.N., Santos, M.R., Aquino, M., Pereira de Almeida, L., Cavadas, C. and Silva, M.M.C. (2025). The therapeutic potential of melatonin and its novel synthetic analogs in circadian rhythm sleep disorders, inflammation-associated pathologies, and neurodegenerative diseases. Medicinal Research Reviews, 45(5), 1515-1539. https://doi.org/10.1002/med.22117

8. Roh, E. and Kim, M.S. (2020). Hypothalamic NAD+-sirtuin axis: function and regulation. Biomolecules, 10(3), 396. https://doi.org/10.3390/biom10030396

Editorial note