NIH grant: Human Stem Cell Based Microphysiological Systems for Aging Research (1R01AG096197-01A1)

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NIH grant 1R01AG096197-01A1: Human Stem Cell Based Microphysiological Systems for Aging Research
Institute: {'code': 'AG', 'abbreviation': 'NIA', 'name': 'National Institute on Aging', 'admin_org_id': '12500002', 'admin_funding_url': ''}. PI: Andreas  Stahl. Award: $648930.
Start: 2026-08-15T00:00:00.
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.

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