# An accelerated human in-vitro aging model mimicsin-vivo aging and facilitates dynamic testing of anti-aging compounds

## TL;DR

This study introduces a lab-based model that accelerates human aging in cells, allowing researchers to test anti-aging treatments effectively.

## Contribution

The model authentically replicates in-vivo aging and enables dynamic evaluation of anti-aging compounds with molecular resolution.

## Key findings

- In-vitro aging of human fibroblasts mirrors in-vivo aging signatures and accelerates epigenetic clock patterns.
- Metformin broadly halts aging at both transcriptomic and epigenetic levels, while Rapamycin shows limited efficacy.
- The model reveals time-dependent age-heterogeneity driven by loss of transcriptional programs.

## Abstract

Biological aging drives cellular dysfunction and human disease, yet studying human-specific aging dynamics remains challenging due to limited experimental platforms. Here we show that long-term post-mitotic culture of human fibroblasts authentically recapitulates and accelerates in-vivo aging signatures. Longitudinal paired transcriptomic-epigenetic analyses revealed that in-vitro aging mirrors in-vivo primary fibroblasts aging, with concordant transcriptional aging pathways and accelerated epigenetic clock aging patterns. Direct neuronal conversion of pre-aged fibroblasts preserved biological age, enabling pseudo-longitudinal modeling of neuronal aging. Single-cell transcriptomics revealed a time-dependent increase in age-heterogeneity, reflecting in-vivo observations and revealing heterogeneity driven by the variable loss of transcriptional programs. Using this accelerated aging platform, we evaluated anti-aging compounds: Metformin broadly halted transcriptomic and epigenetic aging, while Rapamycin showed limited efficacy. These findings align with clinical evidence, demonstrating our platform’s capacity to predict therapeutic anti-aging efficacy with molecular resolution. This system advances our understanding of aging mechanisms and facilitates the development of interventions against age-related diseases.