Trehalose — The Autophagy-Inducing Disaccharide

Trehalose is a naturally occurring disaccharide that acts as an mTOR-independent inducer of autophagy. It promotes the clearance of misfolded proteins and damaged organelles by activating transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. In the vasculature, trehalose reduces oxidative stress and inflammation, thereby increasing nitric oxide (NO) bioavailability and preserving endothelial function. It also functions as a chemical chaperone, directly stabilizing proteins and protecting cellular membranes against environmental stressors.

A 12-week randomized, double-blind trial in healthy middle-aged and older adults demonstrated that 100 g/day of oral trehalose improved resistance artery endothelial function and smooth muscle sensitivity to nitric oxide, provided body weight was maintained (Aging, 2016). Other small human trials suggest low-dose oral trehalose (3.3–10 g/day) may help maintain glucose homeostasis. Intravenous trehalose is currently in clinical trials for neurodegenerative conditions like ALS and Machado-Joseph disease.

100 g/day dissolved in water is the most studied dose for improving vascular function in older adults. Lower doses (3.3–10 g/day) have been used in trials targeting glucose homeostasis. Intravenous administration (15–30 g/week) is being investigated for neurodegenerative diseases. Oral doses are typically consumed throughout the day to minimize gastrointestinal discomfort.

Oral trehalose is generally recognized as safe (GRAS) and well-tolerated. The most common adverse effects are dose-dependent, transient gastrointestinal discomfort, including bloating, flatulence, and loose stools, typical of high disaccharide consumption. High oral doses (e.g., 100 g/day) carry a significant caloric burden (~400 kcal) that may lead to weight gain if not accounted for in the diet. Individuals with trehalase deficiency should avoid trehalose due to severe gastrointestinal intolerance.

Key Papers