1,3-1,6 β-glucans reduce aging hallmarks in multiple organs and rapidly induce mitochondrial biogenesis and autophagy via direct effect on the killifish brain and human neurons

ABSTRACT The short-lived annual fish Nothobranchius furzeri ( Nfu ) is a powerful vertebrate model for aging research due to its rapid lifespan and accelerated development of age-associated phenotypes, including gliosis and lipofuscin accumulation. Here, we investigated the effects of dietary 1,3-1,6 β-glucans (BGs), natural polysaccharides derived from Saccharomyces cerevisiae , on aging-related processes across multiple tissues, with particular focus on the brain. Chronic treatment with BG-fortified food reduced several telomere(definition) attrition, cellular senescence(definition))." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">hallmarks of aging(definition) in multiple organs. Mechanistically, BG treatment modulated pathways associated with autophagy(definition), lysosomal function, protein oxidation, and inflammation. Both acute and chronic BG administration increased autophagic activity in the aging brain, although lipofuscin accumulation was not affected. To assess whether BGs act directly on neural tissue, we established an ex-vivo Nfu brain culture system that recapitulates the age-dependent decline in autophagy observed in vivo. In this model, acute BG treatment restored impaired autophagy and promoted mitochondrial and lysosomal biogenesis in aged brains. Proteomic analyses revealed increased mitochondrial respiration and modulation of V-ATPase components involved in autophagosome acidification. Depletion of microglia reduced but not eliminated this effect, suggesting direct action of BGs on neurons. To verify the validity of these findings in humans, we performed BG treatment in human iPSC-derived neurons under conditions of impaired autophagy and found an increase in survival. Together, these findings identify β-glucans as modulators of autophagy, mitochondrial function, and inflammation, highlighting their potential to promote healthy aging.