High-content study to analyze the nutritional value of natural products for healthy aging

As lifespans increase and the population of older adults grows, there is a mounting need for ways to stay healthy during aging. Neuromuscular health is an important aspect as it allows people to participate in regular daily activities and lowers the risk of fall injuries. Currently, there is a lack of safe and effective drugs to treat muscle health decline (sarcopenia), which has a complex set of mechanisms and etiology. However, consuming natural products can benefit muscle health and promote healthy aging. While the natural product market is growing globally, there is still a lack of unified knowledge about their safety and efficacy, partly due to a lack of cost- effective and rapid screening capabilities. Standard testing methods, such as rodent models are time-consuming, expensive, and increasingly restricted by legislation due to ethical issues. New Approach Methodologies (NAMs) such as in silico analysis, microphysiological systems, and alternative model organisms such as zebrafish and C. elegans are gradually replacing these methods. Among these model organisms, C. elegans is particularly well suited to study aging due to its short life cycle (~5 days from hatching), simple and inexpensive culture, high genetic homology (~70%), and conserved muscle structure and physiology with humans, targeted CRISPR modifications, and amenability to microfluidics and high throughput screens. Current methods for studying C. elegans during aging have limited scalability and higher costs as they can only support a few populations and animals or require constant imaging and feeding on expensive microfluidic imaging systems. We have developed the first high-throughput scalable phenotypic screening platform for conducting efficacy and toxicology studies with C. elegans using our patented vivoChip platform. This automated imaging platform can collect multi-color, high-resolution, timelapse images of ~1,000 animals over 24 individually treated populations in ~30 min. This proposal aims to develop assays to assess the effects of natural products, including whole plant extracts and their individual compounds on slowing the decline in muscle health in aging worms. In Aim 1, we will develop imaging-based assays to characterize muscle mass, mitochondria volume, and protein homeostasis in aging worms using reporter strains We will also develop fully automated image-analysis pipelines for these health assessments to allow high-throughput screens. In Aim 2, we will assess the developmental toxicity of 10 natural products using N2 strains using our established developmental toxicity assays using body volume as an endpoint and look at cellular stress using autofluorescence. Once our new assays are established and we have found the toxicity points of departure for the 10 products, we will study their health benefits with the new assays using the vivoChip-24x device. The outcome of this work will be a dataset describing the relative health benefits of these products over any potential toxicity. The robust protocol and analysis pipeline will allow us to test a large set of natural products and lay down the foundations for our customers to use C. elegans- based NAMs for in vivo testing to bring safe and effective products to market and minimize health risks.