Human microphysiological systems of aging recreate the in vivo process expediting evaluation of anti-gerontic strategies

The search for biological mechanisms of human aging is stalled by a lack of suitable models and it remains unknown whether, and to what degree, rejuvenation reported in rodents translates to people. Here we report a hiPSC-derived microphysiological system modelling the white adipose tissue-liver axis in the presence of heterochronic human serum to study aging and rejuvenation in humans. We reveal changes in functional and molecular hallmarks of aging and rejuvenation, and we investigate unknown biomarkers and mechanisms of plasticity in human tissue aging as well as potential rejuvenation strategies. The microphysiological chip recapitulates, in 4 days, aging-associated hallmarks that occur after decades of aging in people, including gerontic shifts in gene expression and oxidative DNA damage. We uncover unknown signaling networks in human aging, knock-on effects of aging in fat on liver, sexual polymorphisms of aging, tissue memory of age, and develop a custom machine learning model for biological age. Combining heterochronic human serum with the microphysiological system allows for rapidly establishing human tissue aging, discovering clinically relevant mechanisms, biomarkers, and testing of anti-gerontic approaches. Overall design: To investigate the effect of human serum from old and young donors on WAT-MPS, we performed RNA-seq using RNA extracted from WAT-MPS perfused with old circulatory milieu (OCM) and young circulatory milieu (YCM). Then, inspired by heterochronic parabiosis, we examined whether switching from OCM to YCM can reverse experimental on-chip aging for WAT-MPS. RNA extracted from OY (old-to-young) and YO (young-to-old) serum treated WAT-MPS, as well as the OO and YY controls, were sequenced.