Posted by reCellorCircadian AM+PM
on November 13, 2025
Reading time: 10~12 minutes
Last Updated November 13, 2025
--A Comparative Analysis Based on Nearly Two Decades of Molecular and Human Studies
I. Introduction: The Central Pacemaker of Circadian Rhythms and Health
Nearly all cells in the human body follow rhythmic activities of approximately 24 hours—from gene transcription and energy metabolism to hormone secretion and immune responses, all tightly regulated by the circadian clock. The "master clock" located in the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates the molecular clocks of peripheral tissues throughout the body, ensuring metabolism synchronizes with external photoperiods. Circadian rhythm disruption (such as shift work, jet lag, and nighttime blue light exposure) is closely associated with metabolic syndrome, obesity, depression, inflammation, and premature aging.
Among all rhythm regulation strategies, the melatonin pathway and the NAD⁺ metabolic axis are the two most concerned. Melatonin "tells the body it is night" through hormonal signals, while NAD⁺ "resets" cell-level rhythms by regulating cellular metabolism and gene acetylation status. Studies over the past two decades have shown: if melatonin is the "signal of night," then NAD⁺ is more like the "fuel of rhythms"—it supports the molecular operation of the entire circadian clock.
II. Melatonin: The "Downstream Output Signal" of Rhythms
Melatonin is secreted by the pineal gland in dark environments. Its rhythmic secretion pattern is directly regulated by light, making it the most classic "timekeeping hormone." A large number of human randomized controlled trials (RCTs) have confirmed that taking melatonin at the appropriate time can achieve a physiological phase advance or delay of approximately 0.5–2 hours (Burke et al., Sci Transl Med, 2015). Therefore, it has sufficient clinical evidence in the treatment of jet lag and shift work sleep disorders.
However, melatonin only acts on regulating downstream signaling pathways (MT1/MT2 receptors) and does not change the "driving mechanism" of the endogenous molecular clock. Most studies indicate that melatonin-induced phase adjustment requires synchronous environmental cues with exogenous administration to maintain; its rhythmic recovery is usually short-term and highly dependent. In other words, it is "output correction" rather than "core spring resetting."
III. NAD⁺—SIRT1 Axis: The Metabolic Engine Driving Circadian Rhythms
In 2008, Cell published two landmark papers (Nakahata et al.; Asher et al.), first revealing the bidirectional regulatory mechanism between NAD⁺ and core clock genes. Studies have shown:
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NAD⁺ levels fluctuate circadianly in cells;
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This fluctuation is driven by the NAMPT gene activated by CLOCK:BMAL1 (the rate-limiting enzyme of the NAD⁺ salvage pathway);
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NAD⁺ in turn regulates the acetylation and stability of key clock proteins such as BMAL1 and PER2 by activating the SIRT1 deacetylase, thereby forming a closed-loop feedback.
This discovery established the molecular rhythmic cycle of "metabolite (NAD⁺)—deacetylase (SIRT1)—clock complex." Subsequently, Chang et al. (Cell, 2013) further demonstrated that knocking out or reducing SIRT1 in the mouse SCN significantly disrupts behavioral rhythms and gene oscillations; conversely, enhancing SIRT1 expression can restore rhythm stability.
IV. Human Evidence: NAD⁺ Supplementation Indeed Alters the Basis of Metabolic Rhythms
Although direct evidence of NAD⁺ in human circadian behavioral endpoints is still limited, a series of high-quality human studies have shown that it can significantly change the supply of "rhythm fuel" at the biochemical level:
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Martens et al. (Nat Commun, 2018): Elderly individuals who took nicotinamide riboside (NR) orally daily for 6 weeks showed a significant increase in plasma and muscle NAD⁺ levels (+60%~90%), accompanied by upregulated metabolic activity.
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Metabolomic studies have shown that NAD⁺ derivatives (NADH, NMN, NAM) all exhibit circadian oscillation patterns, suggesting that their changes can reshape intracellular clock rhythms.
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Animal experiments further found that NR/NMN supplementation can restore the declined clock gene amplitude and mitochondrial rhythmic metabolism in aging models, showing anti-aging and metabolic remodeling effects.
In contrast, although melatonin can quickly adjust the external phase, it cannot continuously change the metabolic oscillation of NAD⁺–SIRT1, nor can it directly repair the molecular rhythms of aging tissues.
V. Mechanism Comparison: Upstream Driving vs. Downstream Output
| Characteristics | Melatonin | NAD⁺–SIRT1 Axis |
| Main Action Level | Neuro-hormonal output (SCN → Pineal Gland → Periphery) | Cellular metabolic core (metabolism–epigenetic regulation) |
| Regulatory Target | Phase signal (time cue) | Rhythm mechanism itself (time generation) |
| Human Evidence | Phase adjustment (short-term) | NAD⁺ elevation, biochemical rhythm remodeling (mechanism-level) |
| Persistence | Short-acting, dependent on exogenous administration | Long-term oscillation maintainable through metabolic feedback |
| Potential for Aging and Metabolic Diseases | Beneficial for sleep regulation | Associated with anti-aging, metabolic remodeling, and circadian coupling repair |
At the mechanism level, NAD⁺ is located in the upstream metabolic core of the circadian rhythm system: it not only affects key enzymes such as SIRT1, PARP, and CLOCK but also directly couples with energy status (ATP/AMP ratio) and redox balance. Therefore, supplementing NAD⁺ precursors can "reset" the molecular clock from the cellular energy and epigenetic levels; while melatonin only sends a signal to the periphery that "it's time to sleep now."
VI. Comprehensive Conclusion: From "Signal Supplementation" to "Metabolic Resetting"
In summary, as a timekeeping hormone, melatonin remains the gold standard intervention for short-term sleep-wake phase adjustment; however, its role is limited to the neurohormonal signal level. In contrast, by directly regulating the clock molecular mechanism, NAD⁺ provides a more fundamental metabolic fulcrum for reshaping systemic rhythmic homeostasis.
In the future, if further verification of the comprehensive effects of NAD⁺ precursors on clock gene expression, metabolic rhythms, and behavioral rhythms can be obtained in humans, NAD⁺ supplementation strategies may become a "circadian resynchronization nutrition" approach starting from the energy metabolism level.
References
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Nakahata, Y., et al. (2008). Cell, 134(2), 329–340. “The NAD⁺-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control.”
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Asher, G., et al. (2008). Cell, 134(3), 317–328. “SIRT1 regulates circadian clock gene expression through PER2 deacetylation.”
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Chang, H. C., et al. (2013). Cell, 153(7), 1448–1460. “SIRT1 is essential for circadian control in the suprachiasmatic nucleus.”
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Martens, C. R., et al. (2018). Nature Communications, 9, 1286. “Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD⁺ in healthy middle-aged and older adults.”
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Baur, J. A., et al. (2006). Nature, 444(7117), 337–342. “Resveratrol improves health and survival of mice on a high-calorie diet.”
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Burke, T. M., et al. (2015). Science Translational Medicine, 7(305), 305ra146. “Caffeine delays human circadian phase.”
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Ramsey, K. M., et al. (2009). Science, 324(5927), 651–654. “Circadian clock feedback cycle through NAD⁺ biosynthesis.”
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Reiter, R. J., et al. (2021). Nature Reviews Endocrinology, 17(7), 439–458. “Melatonin: clinical perspectives in circadian rhythm disorders and beyond.”
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Okabe, K., et al. (2019). Cell Metabolism, 29(6), 1290–1302. “NAD⁺ homeostasis regulates circadian clock through SIRT1–BMAL1 axis.”
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