Human Stem Cell Based Microphysiological Systems for Aging Research

About This Grant

We are proposing to create a novel human aging-on-a-chip (microphysiological system, MPS) of fat and liver that will offer a complimentary approach to current models to study mechanisms, heterogeneity, and interorgan communication in aging and will serve as a testbed for discovery and testing of rejuvenation strategies. Important understanding of aging was yielded by animal models and human peripheral blood samples, yet these methods are not well suited for studying aging of critical human internal organs, are not real-time and rarely cover the influences of genetic and functional diversity on the paradigm of human aging. Here we propose to innovate human models of systemic aging and rejuvenation, using hiPSC-derived MPS of fat and liver and microfluidics with serum from young vs. old human (both male and female) donors. In Aim 1, we will define which hallmarks of aging can be generated and will determine the biological age of the on-chip tissues in the presence of heterochronic microfluidics. In Aim2, we will correlate sex specific expression signatures of human aging in vitro and in vivo based on developing a sex specific transcriptome-based age-predictor machine learning model for human WAT and liver and leverage it to identifying biomarkers of human aging. Under Aim 3, we will use our multi-tissue iAH-MPS platform to first establish age-related dysfunctions and subsequently test the ability of serum from young humans as well as multiple pharmacological approaches that worked in mice for their ability to rejuvenate the system. Moreover, we will identify drivers of biological diversity in the rejuvenation response with respect to cell types, sex, and genetics of hiPSC lines, and, importantly, sex, diversity, and geographic origin of serum donors. The outcomes of this work will create a tool to empower the aging field to investigate human age-associated functional, tissue, cellular and molecular declines in real-time, to study inter-organ communication in aging and to rapidly screen longevity drug targets and therapeutic candidates, using organ-on-a-chip systems.