Historically, most aging research has been conducted in a small number of cell and animal models. This ap- proach has led to a growing understanding of the cellular and organismal phenotypes associated with aging and has identified potential therapies for aging and age-related disease in humans. However, no single model system fully recapitulates aging in humans, and every model organism has inherent limitations. Thus, mechanisms of, and therapies for, aging found in a single animal model have frequently failed to translate to humans, leading to wasted time and resources. There is a growing realization that the mechanisms and therapies most likely to be relevant in people will be those that are conserved across a range of models. Such a comparative biology ap- proach requires a breadth of model systems, each with unique characteristics to address a diversity of questions, and each with a robust experimental toolkit. In keeping with the NIA?s goal of increasing the diversity of model systems relevant to human aging, this project will advance the development of the monogonont rotifer, Brachi- nonus manjavacas, as a modern model for aging. Rotifers are microscopic, aquatic, invertebrate animals with many advantages as a model for aging, including a century of aging-related research; a two-week lifespan ena- bling high replication and rapid experimentation; asexual (clonal) and sexual propagation; easy delivery of phar- maceuticals in liquid culture; conservation of human homologs not present in established invertebrate model systems, and genetic resources including draft genomes, transcriptomes, and RNAi. Despite the appeal of roti- fers as a model system, current methods to study aging in rotifers are low throughput, labor intensive, and prone to operator variability; this limits replication and rigor, slows testing of gene targets and interventions, increases expense, and prevents other researchers from adopting rotifers as a model. There is thus a critical need for high-throughput and automated techniques to increase experimental capacity and rigor in the rotifer system. To address this need, we will design, construct, and test microfluidic chambers for high-throughput analysis of lifespan and healthspan in rotifers (Aim 1); develop an automated image acquisition and image analysis pipeline to quantify rotifer lifespan and health in microfluidic chambers (Aim 2); and demonstrate the utility of the rotifer microfluidic systems and image analysis pipeline in a screen of FDA-approved drugs for potential new uses as aging therapies (Aim 3). The resulting system will be open access, inexpensive, and easy to use, allowing new laboratories to adopt the rotifer model system. This research will increase experimental throughput by 10 ? 100 times, improve scientific rigor in the rotifer model system, and identify new uses for approved drugs to delay aging and extend lifespan. The technology and data generated in this project will pave the way for future research using rotifers for large-scale, rapid screening of pharmaceuticals for novel uses in aging and age-related disease, and for investigation of age-related neurodegeneration.
/RELEVANCE TO PUBLIC HEALTH This project will contribute to the development of a novel invertebrate animal model system for studies relevant to human aging. The proposed work is innovative and significant in its creation of microfluidic chambers and automated image analysis pipelines for studying lifespan, healthspan, and interventions to aging and age-related disease. The project will increase experimental throughput, improve scientific rigor, and and has the potential to identify new uses for approved drugs to delay aging and extend lifespan.
