02110nas a2200301   4500000000100000000000100001008004100002260001500043653001100058653003500069653001800104653002300122653002800145100001100173700001400184700002600198700001600224700001600240700001400256700002200270700002000292700001800312245012400330856005500454300000900509520127600518022001401794       2026                            d  c2026-03-2510aAgeing10aExperimental models of disease10aLab-on-a-chip10aMetabolic diseases10aStem-cell biotechnology1 aLin Qi1 aYuchen He1 aAlexandra Sviercovich1 aXiaoyue Mei1 aErzhen Chen1 aYihan Xia1 aMichael J. Conboy1 aIrina M. Conboy1 aAndreas Stahl00aHuman microphysiological systems of aging recreate the in vivo process expediting evaluation of anti-geronic strategies  uhttps://www.nature.com/articles/s41551-026-01618-6  a1-183 aThe 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 human induced pluripotent stem cell-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. We also investigate unknown biomarkers and mechanisms of plasticity in human tissue aging and 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 signalling networks in human aging, knock-on effects of aging in fat on liver, sexual polymorphisms of aging and 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 and biomarkers, and testing of anti-geronic approaches.  a2157-846X