Ergothioneine as a potential geroprotector: Targeting molecular hallmarks of ageing and age-related diseases

Hypothesized to be a diet-derived 'longevity vitamin', Ergothioneine (ET) is increasingly recognized for its potential to modulate cellular homeostasis and support healthy ageing in preclinical models. This systematic review, encompassing evidence from 2005 to 2025, investigates ET's unique pharmacokinetics mediated by the OCTN1 (SLC22A4) transporter, which ensures its selective accumulation in tissues susceptible to age-related oxidative decline. Beyond its role as a secondary antioxidant buffer, we critically evaluate ET's ability to target molecular hallmarks of ageing, specifically focusing on telomere maintenance, mitochondrial integrity, and the NRF2-mediated cytoprotective response. Utilizing network pharmacology, this review deciphers the multi-target regulatory landscape of ET in mitigating neurodegeneration, cardiovascular remodeling, and metabolic dysfunction. Furthermore, we address clinical gaps by discussing ET's potential utility as a candidate biomarker of biological aging and emphasizing the necessity of precision nutrition strategies incorporating SLC22A4/SLC22A15 genetic stratification. By synthesizing mechanistic insights and longitudinal human data, we highlight ET as an emerging candidate with geroprotective potential that warrants rigorous clinical evaluation for extending healthspan.