Melatonin — The Circadian Regulator and Antioxidant
Melatonin is a pineal hormone that regulates circadian rhythms and sleep-wake cycles. Beyond sleep, it is a potent mitochondrial antioxidant, anti-inflammatory, and immunomodulator. Endogenous melatonin production declines sharply after age 40, making it one of the most physiologically relevant supplements for aging.
Mechanism of Action
Melatonin binds MT1 and MT2 receptors in the suprachiasmatic nucleus to synchronise circadian rhythms. It is also a direct free radical scavenger (particularly hydroxyl and peroxynitrite radicals) and upregulates antioxidant enzymes (SOD, GPx, catalase) via Nrf2 activation. It reduces mitochondrial oxidative stress and protects mtDNA.
Human Trial Evidence
Hundreds of RCTs confirm melatonin improves sleep onset latency (meta-analysis: −7 min), sleep quality, and jet lag. A 2022 Antioxidants meta-analysis of 23 trials showed melatonin significantly reduced inflammatory markers (IL-6, TNF-α, CRP). The TRIIM trial included melatonin in its epigenetic age-reversal protocol.
Dosing Protocol
0.5–1 mg for sleep onset (physiological replacement dose). 3–10 mg for jet lag or shift work. Longevity-focused protocols use 0.5–1 mg 30–60 min before bed. Higher doses (>5 mg) do not improve sleep further and may cause morning grogginess. Timed-release formulations may improve sleep maintenance.
Safety & Contraindications
Extremely safe at physiological doses (0.5–3 mg). Higher doses may cause morning drowsiness, vivid dreams, or headache. Theoretical concern about suppressing endogenous production with long-term high-dose use — not confirmed in humans. Caution with anticoagulants (mild interaction). Safe in older adults.