Posted by reCellorCircadian AM+PM
on November 13, 2025
Reading time: 8~10 minutes
Last Updated November 13, 2025
Introduction
Circadian rhythm is a regulatory system in organisms with an approximate 24-hour cycle, encompassing gene expression, metabolic activities, behavioral-sleep cycles, and more. Its core mechanism involves the activation of CLOCK/BMAL1 in the transcription-translation feedback loop (TTFL) and the subsequent inhibition by PER2/CRY1, among other components. Circadian rhythm disruption is closely associated with metabolic diseases, aging, sleep disorders, and other conditions.
In recent years, growing attention has been paid to the interaction between NAD⁺—a key intracellular metabolic coenzyme, redox carrier, and essential cofactor for sirtuin family deacetylases (e.g., SIRT1, SIRT3)—and circadian rhythms. Meanwhile, NMN, as a direct precursor of NAD⁺, has also been proposed for elevating NAD⁺ levels. However, based on current literature, directly increasing NAD⁺ itself appears to have certain mechanistic advantages for the specific goal of "improving or synchronizing circadian rhythms." The following explains this from three aspects.
Mechanistic Advantages: The Core Role of NAD⁺ in Circadian Rhythm Regulation
1.Circadian Oscillation of NAD⁺ Levels and Rhythm Control
Multiple studies have shown that NAD⁺ exhibits diurnal oscillation characteristics in cells and tissues. For example, fluctuations in total NAD⁺ and mitochondrial NAD⁺ in mouse livers have been observed to synchronize with PER2 oscillations (PMC).
This mechanism can also be described as follows: CLOCK/BMAL1 promotes the expression of NAMPT (nicotinamide phosphoribosyltransferase), thereby driving the NAD⁺ regeneration pathway; elevated NAD⁺ levels activate SIRT1, which then deacetylates BMAL1/CLOCK or their target genes, providing feedback regulation of rhythm components (Wiley Online Library).
Thus, NAD⁺ is not only a metabolic coenzyme but also a "clock-metabolism" interface node in the circadian rhythm system.
2.Direct Action of NAD⁺ vs. Delayed Precursor Conversion
Although NMN is a precursor of NAD⁺, it must be taken up by cells and undergo a series of enzymatic reactions to generate NAD⁺. Therefore, NMN supplementation is limited by conversion efficiency, tissue distribution, cellular uptake, localization (cytoplasm/mitochondria), and other factors. In contrast, directly increasing NAD⁺ (or rapidly raising bioavailable NAD⁺ levels in the body) allows for faster and more direct participation in sirtuin activation, regulation of the CLOCK/BMAL1 cycle, and restoration of circadian rhythm disruption.
3."Timing" Sensitivity for Rhythm Alignment and Synchronization
Literature also indicates that the effects of NAD⁺ elevation are time-of-day dependent: in a mouse model of obesity induced by a high-fat diet, administering NAD⁺ supplementation during the active phase (e.g., the active period of nocturnal animal models) significantly improved metabolic indicators and synchronized the hepatic clock; however, administration during the resting phase yielded limited effects and even reversed the hepatic clock phase (Nature).
It is evident that directly manipulating NAD⁺ levels is more conducive to "chronotherapy" for circadian rhythms, rather than merely passively increasing NAD⁺ precursors.
Experimental Support: Evidence That NAD⁺ Supplementation Outperforms NMN Alone in Rhythm Parameters
The following summarizes currently available relevant experimental data to corroborate the aforementioned mechanistic advantages.
1.NAD⁺ Supplementation and Rhythm Synchronization
In a study on Mus musculus, Escalante-Covarrubias et al. found that NAD⁺ oscillation in the liver was attenuated in obese models. By administering NAD⁺ (rather than just precursors) via daily injections during the active phase, they observed improved synchronization of the hepatic molecular clock and enhanced metabolic markers (e.g., body weight, insulin resistance). Conversely, administration at the wrong time reversed the rhythm (Nature).
This study clearly demonstrates that supplementing NAD⁺ itself + matching the appropriate timing = significant effects.
2.Rhythm-Related Effects of NMN Supplementation: Limited and Conditional
While studies have reported positive effects of NMN on metabolic improvement, evidence of its direct improvement on circadian rhythms and clock gene expression is weaker compared to NAD⁺. For example, Kwon et al. found in a study on hepatic ER stress that short-term NMN administration alleviated ER stress induced by a high-fat diet and was associated with phase changes in clock gene expression (Electronic NRP).
However, the study also noted that total NAD⁺ levels or the NAD⁺/NADH ratio measured in the liver did not change significantly under short-term NMN administration. In other words, although NMN can enhance NAD⁺ pathway activity, it may not significantly restore NAD⁺ oscillation amplitude or synchronization (Electronic NRP).
Additionally, multiple reviews have pointed out that while NMN is a NAD⁺ precursor, direct data on its role in rhythm intervention remain scarce (ScienceDirect).
3.Comparative Summary
-
NAD⁺: Direct experimental data show that supplementation at the appropriate time can synchronize peripheral clocks and improve rhythm-related metabolic indicators.
-
NMN: While it has the potential to enhance the NAD⁺ pathway, data supporting its efficacy for the specific goal of "circadian rhythm synchronization" are insufficient; its effects still depend on its conversion to NAD⁺ and the actual restoration of oscillation.
Thus, based on current evidence, if the goal is to "regulate or synchronize circadian rhythms," directly increasing NAD⁺ may be more effective than supplementing NMN alone.
Summary of Potential Advantages
In summary, directly increasing NAD⁺ may offer the following advantages in regulating circadian rhythms:
-
More direct access to the rhythm-metabolism node: NAD⁺ itself is essential for sirtuin activity and has a feedback relationship with the CLOCK/BMAL1 system.
-
Faster/more reliable effects: Avoids delays and uncertainties associated with precursor conversion (e.g., carrier dependence, tissue uptake limitations, enzymatic activity constraints).
-
Precise timing (chronotherapy): Literature shows that the effects of NAD⁺ supplementation are time-dependent; direct elevation facilitates alignment with rhythm peaks to enhance synchronization.
-
Broad cross-tissue effects: As NAD⁺ participates in multiple metabolic and repair pathways, its synchronization effects may cover multiple tissues (liver, muscle, brain) rather than being limited to metabolic endpoints.
References
-
Peek CB, Levine DC, et al. “Circadian Clock NAD⁺ Cycle Drives Mitochondrial Oxidative Function.” Science, 2013. (PMC)
-
Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P. “The Circadian NAD⁺ Metabolism: Impact on Chromatin Remodeling and Aging.” Biomed Res Int., 2016;2016:3208429. (Wiley Online Library)
-
Escalante-Covarrubias Q, Mendoza-Viveros L, González-Suárez M, et al. “Time-of-day defines NAD⁺ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice.” Nature Communications, 2023;14:1685. (Nature)
-
Kwon SY, et al. “Nicotinamide mononucleotide attenuates hepatic ER stress response linked to circadian regulation in high-fat diet mice.” Nutrition Research and Practice, 2024;19:e54. (Electronic NRP)
-
Levine DC, et al. “Review: Circadian NAD(P)(H) cycles in cell metabolism.” Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, 2022. (ScienceDirect)
-
Liao G, et al. “Advancements in NMN biotherapy and research updates in ageing-related diseases.” Journal of Translational Medicine, 2024. (BioMed Central)
These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
