Alpha-lipoic acid (ALA)

Alpha-lipoic acid (ALA) is a sulfur-containing fatty acid serving as an essential cofactor for two mitochondrial enzyme complexes — pyruvate dehydrogenase and α-ketoglutarate dehydrogenase — linking glycolysis to the citric acid cycle. Only the R-enantiomer (R-ALA) is protein-bound and biologically active; commercial supplements contain a racemic R/S mixture, and oral bioavailability of R-ALA is ~40–50% greater than the S form. ALA and its reduced metabolite dihydrolipoic acid (DHLA) are lipid- and water-soluble, enabling free-radical scavenging across cellular compartments and regeneration of oxidized glutathione, vitamin C, and vitamin E — a recycling cascade distinguishing ALA from single-compartment antioxidants. Mitochondrial function and endogenous glutathione decline with aging; ALA partially restored both in rodent models, though direct evidence in humans is limited. The strongest clinical evidence concerns diabetic polyneuropathy: the SYDNEY trial (Ametov et al., 2003, n=120) found intravenous ALA at 600 mg/day over three weeks significantly reduced neuropathic symptom scores versus placebo (p<0.001). The four-year randomized NATHAN 1 trial (Ziegler et al., 2011, n=460) tested oral ALA 600 mg/day; the primary composite endpoint (NIS-Lower Limbs plus seven neurophysiologic tests) did not reach significance (p=0.105), though secondary scores (NIS, NIS-LL) favoured ALA. In healthy aging populations evidence is preliminary and largely confined to animal or small mechanistic studies; long-term longevity benefit in humans has not been established.