Supplementation of aged garlic extract attenuates age-associated memory impairment and cognitive decline: Involvement of molecular pathways in the cortex and hippocampus

The aging of the human population is associated with increases in comorbidities, including functional impairment and cognitive decline. With decreasing numbers of neurons and declining synaptic plasticity, the aging brain exhibits less perfusion, and thus, is more susceptible to attack by reactive oxygen species (ROS). These changes are associated with increased risks of neurodegenerative diseases, which impact the quality of life. Consequently, there is an urgent need to develop nutraceuticals and holistic approaches that may impede the aging process. Aged garlic extract (AGE) is a nutraceutical that has been shown to display neuroprotective properties; in particular, it has the ability to reduce inflammation, apoptosis and ROS. Given these insights, it is reasonable to hypothesize that AGE improves neurological function and cognition by altering neural molecular processes. To test this hypothesis, a battery of behavior tests, including measurements of various cognitive functions, were performed on 82-week-old mice, which were fed a diet supplemented with AGE for 40 weeks. This was followed by label-free global proteomics and machine learning-driven bioinformatics analyses of mouse cortical and hippocampal proteomes for the identification of membrane and cytoskeletal protein targets of the mechanism of action of AGE. Mice in the AGE supplementation group exhibited improvements in learning, memory, exploratory behavior and anxiety (P<0.05), but no obvious changes in other functional domains. Analysis of global proteomes revealed the ability of AGE supplementation to induce expression changes, which were most pronounced in the hippocampus. Further comparative bioinformatics analysis also revealed that AGE supplementation increased synaptogenesis signaling in both brain regions and reduced 14-3-3 signaling related to neuronal apoptosis exclusively in the hippocampus. The predicted upstream global proteome modulators influenced by AGE supplementation included microtubule-associated protein tau, amyloid precursor protein, brain-derived neurotrophic factor, TP53, presenilin 1 and superoxide dismutase 1. Taken together, these findings demonstrated the neuroprotective effects of AGE on cognition and protein expression in aging mice, further suggesting its potential use as a nutraceutical to prevent aging-associated neurological comorbidities.