Effects of 1.3-1.6 ß-glucans on aging in vivo and ex-vivo

The short-lived annual fish Nothobranchius furzeri (Nfu) has an extremely short life span and accelerated expression of age markers. This animal model recapitulates the major features of mammalian brain aging, such as gliosis and lipofuscin. Nfu is a convenient model for investigating the effects of interventions on longevity and age-related pathologies in Vertebrates. In this study, I observed the effects of 1.3-1.6 ß-glucans (BGs) in aging. BGs, natural food ingredients derived from the cell wall of Saccharomyces cerevisiae, have immunomodulatory, antioxidant, anti-inflammatory and antineoplastic actions.In the initial part of my thesis, I have used BGsas a chronic and acute dietary supplement in Nfu. Chronic administration of BGs reduces multiple aging hallmarks in several organs, including the brain. BGsact specifically in mechanism related to autophagy, lysosomal activity, peroxidation of proteins, and inflammation. Even acute as well as chronic diet increases autophagy in brain aging, although it is unable to reduce the accumulation of lipofuscin throughout life. Subsequently, I created an ex-vivo brain culture system for Nfu to investigate whether BGs could influence the brain directly. This system replicates age-dependent reduction of autophagy observed in vivo and confirms the induction of autophagy by BGs. Acute treatment with BGs restores impairment of autophagy, induces biogenesis of mitochondria and lysosomes in aged ex-vivo brains. Proteomic analyzes in ex-vivo adult and old brain confirmed the positive activity of BGs on mitochondrial respiration and autophagy. In detail, BGs act on V-ATPase proteins (i.e. ATP6V1A), involved in mitochondrial respiration and the acidification of autophagosomes. Furthermore, BGs restore the inflammation in the brain by acting on microglia. BGs reduce the inflamed microglia in the ex-vivo Tg(mpeg1.1: EGFP) zebrafish model treated by Bafilomycin A1. Moreover, BGs induce autophagy partially mediated by microglia. In fact, the depletion of microglia in the ex-vivo model treated with Plx5622 involves an increase in autophagy by BGs, although to a lesser extent the volume of autophagosomes. Finally, to investigate the direct effect of BGs on neurons, I cultured human iPSC-derived neurons up to 90 DIV. BGs are able to reduce mortality in neurons where autophagy is blocked for 72 hours by Bafilomycin A1. Also, BGs increase autophagy in neurons where autophagic mechanism has been blocked for 24 hours.Overall, these results indicate that BGs can slow progression some age-related markers. BGs act directly on the brain, normalizing cellular processes that are impaired during the aging even in acute treatments. As BGs are part of our normal diet, our results advocate BGs-fortified diet to promote human longevity.