Stimulation of autophagy and synaptic maintenance are commonalities induced by an exercise‐mimetic and diet supplement to avoid initiators of age‐related cognitive decline

Abstract

Brain aging causes synaptic and cellular vulnerabilities, leading to cognitive impairment and an increased risk for dementia. Removal of old and damaged proteins becomes less efficient with age, causing protein accumulation stress and corresponding synaptopathy as protein clearance systems fail. Interestingly, physical exercise and a healthy diet are well known to promote cognitive health, perhaps by delaying or reducing age‐related changes that cause synaptic compromise. It is vital to understand the mechanism by which exercise and diet positively influence brain health since they are the only avenues implicated in reducing dementia risk. Accordingly, we tested if an exercise‐mimetic and a dietary supplement have a common influence on the protein clearing autophagy‐lysosomal pathway, and if such a mechanistic link promotes synaptic maintenance and resilience. Our study used long‐term brain explants that exhibit multi‐neural cell types and subfields, as well as native neuronal circuitries and synaptic density as compared to the intact adult brain. The exercise‐mimetic compound β‐guanidinopropionic acid (β‐GPA), a creatine analog, and a specific extract of American ginseng (P. quinquefolius; USANA Health Sci), were applied daily to the matured, 3‐dimensional cultures of hippocampal tissue for 3‐6 days. The gently harvested explants were then assessed by immunoblot for several markers including the cathepsin B (CatB) component of the autophagy‐lysosomal pathway, a protease found to improve clearance of pathogenic proteins and preserve synaptic and cognitive measures in models of AD, α‐synucleinopathy, and mild cognitive impairment (Mueller‐Steiner et al. 2006 ‐ Neuron 51:703; Butler et al. 2011 ‐ PLoS ONE 6:e20501; Hwang et al. 2019 ‐ Inter J Mol Sci 20:4432). Both β‐GPA and the American ginseng extract improved the levels of the active CatB isoform and increased autophagic flux. In addition, they both had a positive influence on synaptic markers. Next, β‐GPA and American ginseng were tested in groups of explant cultures that were exposed to a lysosomal inhibitor (chloroquine) as a model for the age‐related compromise of lysosomal protein clearance capacity. Again, both β‐GPA‐ and American ginseng‐treated hippocampal explants displayed protection of pre‐ and postsynaptic proteins, similar to the protected levels produced through pharmacological enhancement of CatB using small‐molecule modulators with drug‐like properties (Viswanathan et al. 2012 – ACS Med Chem Lett 3:920). The significant results from the chloroquine model indicate that preventing age‐related lysosomal stress can slow or delay the associated synaptopathy by different strategies that may be additive. Together, the different experiments support the idea that exercise, exercise‐mimetics, and certain natural products help to limit age‐related synaptic deterioration that is known to be the best correlate of cognitive failure during aging and dementia. The common protective influences mediated by the exercise‐mimetic and the dietary supplement point to protein clearance as having a mechanistic role for healthy cognitive aging.