In summary, our results reinforce the link between exposure to GAS antigen, dysfunction of central dopaminergic pathways and motor and behavioral alterations, and suggest that some of these deleterious effects can be attenuated by antibiotic treatment, independently of the latter’s direct impact on GAS. With the growing population and extended lifespan, brain aging becomes a worldwide problem due to its substantial associated disability. For example, one of the strongest risk factors for the Alzheimer’s disease is brain aging. The brain is particularly vulnerable to oxidative stress because of its high oxygen metabolic rate and its relative deficiency in both free-radical scavenging enzymes and antioxidant molecules compared with other organs. During aging, the accumulation of free radicals progressively damages the brain structure and function. Hippocampus is closely related to learning and memory abilities, and as an area where NSCs/NPCs exist in the adult brain, it is of a particular interest in the age-associated neurodegeneration. Panax ginseng has been used as a tonic drug in traditional Chinese medicine for over 2000 years. Ginsenoside Rg1 is one of the most active ingredients of Panax ginseng, and has been proven to have various pharmacological actions in anti-oxidation, anti-aging and particularly in memory deterioration. Our previous work has showed a protective anti-aging function of Ginsenoside Rg1 in the neuron system that delays senescence of NSCs/NPCs in vitro. To elucidate the function and the underlying mechanism of Ginsenoside Rg1 in age-associated neurodegeneration, we employed the D-gal induced aging rat model. Chronic systemic exposure of rodents to D-gal induces accelerated aging including deterioration of cognitive and motor skills that are similar to symptoms in natural aging. Therefore, it is regarded and widely used as an ideal model to study the mechanisms and screen drugs for brain aging. We investigated the effect of Rg1 on spatial memory and hippocampal histopathological damages in the D-gal induced aging rat model. Senescence-associated biomarker, neurogenesis, oxidative stress biomarkers, neuroinflammation biomarkers, telomere shortenting and senescence associated genes expression in the hippocampus were examined. We propose that ginsenoside Rg1 is able to improve cognitive ability, protect NSCs/NPCs and promote neurogenesis by its antioxidative and anti-inflammation capacity. The intermediate filament protein, Nestin, is expressed predominantly in stem cells of the adult brain and is PR-171 required for the proper self-renewal of NSCs. We further detected the expression of SOX2 and Nestin to investigate the effect of Rg1 on NSCs/NPCs survival in aged hippocampus. In accordance with our expectation, the protein expression of SOX2 in the D-gal-administration group was significantly lower than that of the control group. During natural aging, the brain undergoes progressive morphologic and functional changes resulting in the observed behavioral retrogression, such as declines in motor and cognitive performance. It will be of a great value to find out drugs against neurodegeneration to delay brain senescence.