ERCC1 mice, unlike other premature aging models, display accelerated epigenetic age

Abstract

Over the last decades, several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (ERCC1, LAKI, POLG and XPG). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in ERCC1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. In line with these results, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight ERCC1 as a particularly attractive mouse model for to study aging in mammals and suggest a strong connection between DNA damage and epigenetic dysregulation during aging.

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging

“…Recent evidence from our lab indicates that D/KO FBs display accelerated aging based on the DNA methylation clock and are therefore a good in vitro model to investigate aging mechanisms and interventions ( Perez et al, 2022 ). Furthermore, cellular reprogramming has been observed to reverse epigenetic age in mouse and human cell types but the effects on an accelerated aging model with a DNA repair defect are unknown ( Horvath, 2013 ; Olova et al, 2019 ).…”

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging

“…The DNA methylation clock is restored in Ercc1 ∆/− following short term reprogramming Recent evidence from our lab indicates that D/KO FBs display accelerated aging based on the DNA methylation clock and are therefore a good in vitro model to investigate aging mechanisms and interventions 59 . Furthermore, cellular reprogramming has been observed to reverse epigenetic age in mouse and human cell types but the effects on an accelerated aging model with a DNA repair defect are unknown 60,61 .…”