Many botanical agents, including Centella asiatica (CA; “gotu kola”) and Withania somnifera (WS; “ashwagandha”), are purported to improve resilience to aging-related changes, yet few have been evaluated in well-designed clinical trials. An ideal clinical trial would use a product optimized for its active constituents and investigate the botanical for appropriate measures of efficacy in a relevant target population. Sound preclinical research is therefore needed to identify the functional effects of a botanical, mechanisms underlying these effects, and the phytochemical constituents modulating these processes. Studies should also identify interactions between different constituents of the botanical, in vivo biomarkers of target engagement by the botanical, distribution of the compounds in the body, and variability of response in different populations (e.g., age or gender groups).
The BENFRA Center will establish a pipeline of experimental approaches and techniques required to deliver answers to these critical issues, with a focus on “Botanicals enhancing neurological and functional resilience in aging.” This research platform will be used to consolidate and expand our extensive preliminary studies on Centella asiatica in preparation for a clinical trial in aging participants. A second botanical, Withania somnifera, with compelling reports of similar biological effects to CA, will be examined in earlier stages of the research pipeline. Research will be conducted through two main research projects. These projects will receive complementary input for test material integrity and chemical characterization, as well as metabolomics and transcriptomics from the Botanical Research Core and support for statistical analysis and data management through the Administrative Core. Learn more about our cores.
This project will focus on the resilience-promoting effects of the plant Centella asiatica (L.) Urban. This herb is used in Ayurvedic and traditional Chinese medicine as a nerve tonic and to improve cognitive function. Our lab and others have shown that low doses of a water extract of Centella asiatica (CAW) can improve cognitive function in rodent models of aging and Alzheimer’s disease. Anxiolytic effects and improvement in insomnia as a result of administering the extract have also been reported. However, few clinical trials have attempted to validate these effects, and each has suffered from severe methodological flaws such as lack of controls, being underpowered or evaluating poorly characterized products. Very little attention has been paid to assessing appropriate biomarkers of target engagement, which may provide an early indication of possible efficacy in longer trials of clinical outcome.
In this study, we will address critical knowledge gaps hindering the clinical development of CAW including proper dosage, optimal product formulation and identification of translational biomarkers. Using aged mice, we will explore the effects of a range of CAW doses on cognitive impairment, sleep and resilience to sleep deprivation, and anxiety and depression. Brain imaging, sleep phenotype, as well as circulating hormone levels and blood DNA methylation patterns will all be evaluated as biomarkers for target engagement. We will also determine the effects of constituent triterpene and caffeoylquinic acid compounds from the CAW extract on the same behavioral endpoints in order to inform product formulation to be used in a clinical trial.
These experiments will determine the efficacy of CAW as a therapeutic agent to promote functional resilience to age-related challenges and thereby facilitate its translation to a clinical trial in older adults. Additionally, this study will establish a methodological platform that can be used in future studies with any promising botanical to provide the necessary in vivo testing to move towards clinical testing.
This project will use several preclinical models including mouse primary neurons, mouse brain slices, and Drosophila melanogaster (fruit flies) to explore mechanisms and active compounds of Centella asiatica (CA; “gotu kola”) and Withania somnifera (WS; “ashwagandha”). These two herbs have considerable evidence to suggest that they can improve cognition, sleep and mood, all of which may be compromised in normal aging. Learn more about these botanicals. The chosen assays are related to functional effects or specific mechanisms and neurotransmitters that may influence cognition, sleep or mood.
Drosophila models will be used to determine the effects of CA and WS on age-related decline in locomotion and reactivity. We will also test effects on a described depression-like state in Drosophila, using courtship as an assay, and we will measure serotonin levels in neuronal subpopulations identified as mediating this depression-like state. Furthermore, Drosophila will be used to determine effects on sleep patterns, which are also altered by age in flies and mammals. The cellular and molecular pathways regulating sleep are well-known in Drosophila and we can therefore also investigate whether CA and/or WS extracts promote healthy sleep patterns by altering neuronal activity and neurotransmitter signaling in the neuronal populations that promote or suppress sleep. Besides serotonin and acetylcholine, this also includes GABA. To expand these studies to the mouse model, we will measure neuronal activity in mouse brain slices and address whether treatment with CA and/or WS affects GABA signaling (using GABA inhibitors). In parallel experiments, mouse primary neurons will be used to explore the influence of CA and WS extracts on neuronal health by improving antioxidant response, mitochondrial activity and dendritic arborization. The hypothesized ability of CA to improve brain vascular health will be explored using mouse brain slices.
For each bioassay, the CA and WS extracts tested will be chemically characterized by the Botanical Research Core, and bio-chemometric correlations will be applied to identify active compounds for the activities examined. Together, these studies will identify the mechanisms of action and active compounds in CA and WS relevant to their potential ability to improve resilience to age related declines in cognition, sleep and/or mood. Future studies can then confirm these effects in in vivo mouse models and eventually provide the basis for testing CA or WS products containing the active compounds in humans.