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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280361 | GEO | 2025/12/08

REPOSITORIES: GEO

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

Project description: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.

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Systemic factors from young human serum rejuvenate human skin in vitro using a microphysiological system featuring BM-derived blood cells

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Characterizing expression changes in noncoding RNAs during aging and heterochronic parabiosis across mouse tissues

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Project description:Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains following parabiosis. For each cell type, we catalogued alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions, and senescence status. Our analyses identified gene signatures demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest novel strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.

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Project description:The notion that germline does not age goes back to the 19th century ideas of August Weismann. However, being in a metabolically active state, germline accumulates damage and other age-related changes over time, i.e., they age. For new life to begin in the same young state, they must be rejuvenated in the offspring. Here, we developed a new multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e. rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (the ground zero) marks the beginning of organismal aging.

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