Withania somnifera (WS), also known as ashwagandha, is a popular botanical supplement used to treat various conditions including memory loss, anxiety and depression. Previous studies from our group showed an aqueous extract of WS root (WSAq) enhances cognition and alleviates markers for depression in Drosophila. Here, we sought to confirm these effects in the 5xFAD mouse model of β-amyloid (Aβ) accumulation. Six- to seven-month-old male and female 5xFAD mice were treated with WSAq in their drinking water at 0 mg/mL, 0.5 mg/mL or 2.5 mg/mL for four weeks. In the fourth week of treatment, spatial memory, anxiety and depressive-like symptoms were evaluated. At the conclusion of behavioral testing, brain tissue was harvested, immunohistochemistry was performed, and the cortical expression of antioxidant response genes was evaluated. Both concentrations of WSAq improved spatial memory and reduced depressive and anxiety-related behavior. These improvements were accompanied by a reduction in Aβ plaque burden in the hippocampus and cortex and an attenuation of activation of microglia and astrocytes. Antioxidant response genes were upregulated in the cortex of WSAq-treated mice. Oral WSAq treatment could be beneficial as a therapeutic option in AD for improving disease pathology and behavioral symptoms. Future studies focused on dose optimization of WSAq administration and further assessment of the mechanisms by which WSAq elicits its beneficial effects will help inform the clinical potential of this promising botanical therapy.

Withania somnifera (WS), also known as ashwagandha, is a popular botanical supplement used to treat various conditions including memory loss, anxiety and depression. Previous studies from our group showed an aqueous extract of WS root (WSAq) enhances cognition and alleviates markers for depression in Drosophila. Here, we sought to confirm these effects in the 5xFAD mouse model of β-amyloid (Aβ) accumulation. Six- to seven-month-old male and female 5xFAD mice were treated with WSAq in their drinking water at 0 mg/mL, 0.5 mg/mL or 2.5 mg/mL for four weeks. In the fourth week of treatment, spatial memory, anxiety and depressive-like symptoms were evaluated. At the conclusion of behavioral testing, brain tissue was harvested, immunohistochemistry was performed, and the cortical expression of antioxidant response genes was evaluated. Both concentrations of WSAq improved spatial memory and reduced depressive and anxiety-related behavior. These improvements were accompanied by a reduction in Aβ plaque burden in the hippocampus and cortex and an attenuation of neuroinflammatory markers. Antioxidant response genes were upregulated in the cortex of WSAq treated mice. Oral WSAq treatment could be beneficial as a therapeutic option in AD for improving disease pathology and behavioral symptoms. Future studies focused on dose optimization of WSAq administration and further assessment of the mechanisms by which WSAq elicits its beneficial effects will help inform the clinical potential of this promising botanical therapy.

Alterations in epigenetic modifications, like DNA methylation, in peripheral blood could serve as a useful, minimally invasive biomarker of the effects of anti-aging interventions. This study explores this potential with a water extract of the botanical Centella asiatica (CAW). Eighteen-month-old mice were treated with CAW in their drinking water for 5 weeks alongside vehicle-treated eighteen-month-old C57BL6 mice. Reduced representation bisulfite sequencing (RRBS) was used to identify genome-wide differential methylation in the blood of CAW-treated aged mice compared to vehicle-treated aged mice. Our results showed a distinct enrichment of differentially methylated regions (DMRs) nearby genes involved in biological processes relevant to aging (i.e., antioxidant response, metabolic regulation, cellular metabolism). A distinct difference was observed between males and females in both the number of methylation sites and the state of methylation. Moreover, genes nearby or overlapping DMRs were found to be enriched for biological processes related to previously described cellular effects of CAW in the mouse brain (i.e., antioxidant response, metabolic regulation, calcium regulation, and circadian rhythm). Together, our data suggest that the peripheral blood methylation signature of CAW in the blood could be a useful, and readily accessible, biomarker of CAW’s effects in aging.