Melatonin: More Than a Sleep Aid

Unlocking its power in immune regulation, mitochondrial health, and Alzheimer’s prevention

Melatonin plays a multifaceted and increasingly recognized role in preventing aberrant phase separation—a process implicated in protein aggregation pathways that drive Alzheimer’s disease (AD).

1. 🧪 What Is Aberrant Phase Separation?

• Liquid–liquid phase separation (LLPS) enables biomolecules to form dynamic, membraneless droplets (condensates) that organize cellular functions.

• When dysregulated—due to insufficient hydration, oxidative damage, aging-related ATP, decline—LLPS can transition into irreversible protein aggregates such as amyloid‑β or tau fibrils common in AD.

• viral and bacterial infections can profoundly disrupt normal phase separation, contributing to the misfolding, aggregation, and dysfunction of key proteins involved in cellular homeostasis. This disruption is increasingly linked to neurodegenerative diseases, including Alzheimer’s, and even long-Covid, through mechanisms like inflammation, oxidative stress, and direct hijacking of condensate biology

• Limited hydration within condensates, increased interfacial viscosity, and disrupted lipid rafts raise the risk of insoluble aggregate formation

2. How Melatonin Regulates Phase Separation

a) Membrane & Lipid Raft Stabilization

• Melatonin helps maintain membrane fluidity, stabilizes lipid raft domains, and reduces line tension—all key to healthy condensate formation and dissolution.

• These effects support proper trafficking, signaling, and protein management within the cell.

b) Antioxidant & Viscosity Reduction

• It acts as a mitochondria-targeted antioxidant, neutralizing reactive oxygen species and preventing lipid peroxidation that increases matrix viscosity.

• By lowering interfacial viscosity, melatonin enhances ATP synthase efficiency, increasing ATP output, and supporting hydration needed to prevent condensate collapse into aggregates.

c) Hydration & ATP Synergy

• Melatonin increases availability of free water molecules around proteins, enabling better hydration and reducing the tendency for hydrophobic collapse and aggregation

• It forms favorable interactions with ATP’s adenosine moiety, reinforcing ATP’s hydrotropic solubilizing power over amyloidogenic proteins.

3. Relevance to Alzheimer's Disease Prevention

• AD progression involves protein aggregation (amyloid‑β, tau) driven by aberrant phase transitions. Melatonin targets these early biophysical mechanisms.

• During deep (slow-wave) sleep, melatonin peaks and ATP levels are elevated—critical for glymphatic clearance of amyloid aggregates. Age-related declines in melatonin impair that clearance, accelerating plaque accumulation

• Postmortem studies show CSF melatonin levels are 3–7× lower in AD patients than in age-matched controls, signaling a deep link between melatonin deficits and pathology Exploration Publishing.

• Melatonin has also been shown to suppress tau hyperphosphorylation, a hallmark of AD, via miRNA-mediated pathways and enzyme regulation in cell and animal models BioMed Central.

🧠 Bottom Line

Melatonin isn’t just a sleep hormone—it’s a powerful modulator of protein phase behavior. By preserving hydration, enabling ATP-driven solubilization, and protecting lipid membranes, it helps prevent the early biophysical cascades of amyloid and tau aggregation in AD. Maintaining healthy melatonin rhythms and considering exogenous support, especially in aging or sleep-impaired individuals, could be a strategic component of Alzheimer’s prevention.

My personal use of melatonin:
I purchase melatonin as a bulk powder and cycle a high dose regularly.

Supporting Studies:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10054283/
https://www.sciencedirect.com/science/article/pii/S2590279224000075
https://www.phytomelatonin.org/viral-defense-and-phase-separation