Long-Term Post-Mitotic Culture of Human Fibroblasts Recapitulates and Accelerates Features of In Vivo Aging and Enables Dynamic Testing of Anti-Aging Compounds.
7 affiliations
- 1Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
- 2Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, USA.
- 3Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California, USA.
- 4Institute for Molecular Biology, University of Innsbruck, Innsbruck, Austria.
- 5Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
- 6Department of Biochemistry and Genetics of Aging, Research Institute for Biomedical Aging Research, University of Innsbruck, Innsbruck, Tyrol, Austria.
- 7Division of Psychiatry I, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
Abstract
Biological aging drives cellular dysfunction and human disease, yet studying human aging dynamics remains challenging due to limited experimental platforms. Here we show that long-term post-mitotic culture of human fibroblasts recapitulates and accelerates features of in vivo aging. Longitudinal paired transcriptomic and epigenetic analyses of four female fibroblast lines revealed that in vitro aging reflects key signatures of in vivo primary fibroblast aging. Direct neuronal conversion of in vitro-aged fibroblasts preserved biological age, enabling pseudo-longitudinal modeling of neuronal aging through direct reprogramming. Single-cell transcriptomics of in vitro-aging fibroblasts revealed a time-dependent increase in age-heterogeneity, consistent with the previously reported age-associated heterogeneity driven by the variable loss of transcriptional programs in vivo. Using this accelerated aging platform, we evaluated anti-aging compounds: Metformin broadly attenuated transcriptomic and epigenetic aging, while Rapamycin showed limited efficacy. These findings align with pre-clinical evidence, providing a platform to evaluate and predict therapeutic anti-aging compound efficacy at molecular resolution. This system advances our understanding of aging mechanisms and facilitates the development of interventions against age-related diseases.
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BibTeX
@article{traxler2026longterm,
title = {{Long-Term Post-Mitotic Culture of Human Fibroblasts Recapitulates and Accelerates Features of In Vivo Aging and Enables Dynamic Testing of Anti-Aging Compounds.}},
author = {Larissa Traxler and Lukas Karbacher and Oliver Borgogno and Taylor Ozbun and Kylie Champion and Anna Smaling and Lucia Zhou-Yang and Joseph R Herdy and Lena Böhnke and Barbara C Böckle and Fred H Gage and Hildegard I D Mack and Michaela Defrancesco and Jerome Mertens},
journal = {Aging cell},
year = {2026},
month = nov,
doi = {10.1111/acel.70796},
url = {https://europepmc.org/article/MED/42967595},
note = {CC BY},
}
RIS
TY - JOUR
TI - Long-Term Post-Mitotic Culture of Human Fibroblasts Recapitulates and Accelerates Features of In Vivo Aging and Enables Dynamic Testing of Anti-Aging Compounds.
AU - Larissa Traxler
AU - Lukas Karbacher
AU - Oliver Borgogno
AU - Taylor Ozbun
AU - Kylie Champion
AU - Anna Smaling
AU - Lucia Zhou-Yang
AU - Joseph R Herdy
AU - Lena Böhnke
AU - Barbara C Böckle
AU - Fred H Gage
AU - Hildegard I D Mack
AU - Michaela Defrancesco
AU - Jerome Mertens
PY - 2026
DA - 2026/11/01
JO - Aging cell
DO - 10.1111/acel.70796
UR - https://europepmc.org/article/MED/42967595
AB - Biological aging drives cellular dysfunction and human disease, yet studying human aging dynamics remains challenging due to limited experimental platforms. Here we show that long-term post-mitotic culture of human fibroblasts recapitulates and accelerates features of in vivo aging. Longitudinal paired transcriptomic and epigenetic analyses of four female fibroblast lines revealed that in vitro aging reflects key signatures of in vivo primary fibroblast aging. Direct neuronal conversion of in vitro-aged fibroblasts preserved biological age, enabling pseudo-longitudinal modeling of neuronal aging through direct reprogramming. Single-cell transcriptomics of in vitro-aging fibroblasts revealed a time-dependent increase in age-heterogeneity, consistent with the previously reported age-associated heterogeneity driven by the variable loss of transcriptional programs in vivo. Using this accelerated aging platform, we evaluated anti-aging compounds: Metformin broadly attenuated transcriptomic and epigenetic aging, while Rapamycin showed limited efficacy. These findings align with pre-clinical evidence, providing a platform to evaluate and predict therapeutic anti-aging compound efficacy at molecular resolution. This system advances our understanding of aging mechanisms and facilitates the development of interventions against age-related diseases.
SN - 1474-9718
SN - 1474-9726
ER -