Identifying age-modulating compounds using a novel computational framework for evaluating transcriptional age Journal Article

  

Authors:	Zhang, C.; Saurat, N.; Cornacchia, D.; Chung, S. Y.; Sikder, T.; Nemchik, A.; Minotti, A.; Studer, L.; Betel, D.
Article Title:	Identifying age-modulating compounds using a novel computational framework for evaluating transcriptional age
Abstract:	The differentiation of human pluripotent stem cells (hPSCs) provides access to a wide range of cell types and tissues. However, hPSC-derived lineages typically represent a fetal stage of development, and methods to expedite the transition to an aged identity to improve modeling of late-onset disease are limited. In this study, we introduce RNAge, a transcriptome-based computational platform designed to enable the evaluation of an induced aging or a rejuvenated state. We validated this approach across independent datasets spanning different tissues and species, and show that it can be used to evaluate the effectiveness of existing age-retaining or age-modulating interventions. We also used RNAge to perform an in silico compound screen using the LINCS L1000 dataset. This approach led to the identification and experimental confirmation of several novel compounds capable of inducing aging or rejuvenation in primary fibroblasts or hPSC-derived neurons. Additionally, we observed that applying this novel induced aging strategy to an hPSC model of Alzheimer's disease (AD) accelerated neurodegeneration in a genotype-specific manner. Our study offers a robust method for quantifying age-related manipulations and unveils compounds that significantly broaden the toolkit for age-modifying strategies in hPSC-derived lineages. © 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
Keywords:	aging; alzheimer's disease; cortical neurons; disease modeling; human pluripotent stem cells; age score; transcriptional age
Journal Title:	Aging Cell
ISSN:	1474-9718
Publisher:	Anatomical Society
Publication status:	Online ahead of print
Date Published:	2025-04-30
Online Publication Date:	2025-04-30
Start Page:	e70075
Language:	English
DOI:	10.1111/acel.70075
PROVIDER:	scopus
PUBMED:	40307992
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105004183349&doi=10.1111%2facel.70075&partnerID=40&md5=efd98bc89f40cfac5c647b94a2cac361
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Lorenz Studer -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/226364