The induction of cellular reprogramming by forced expression of the transcription factors OCT4, SOX2, KLF4, and C-MYC (OSKM) has been shown to allow the dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. Yet to date, the benefits of in vivo reprogramming are limited by the occurrence of detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous in vivo induction of the reprogramming factors leads to hepatic and intestinal dysfunction resulting in decreased body weight and premature death. By generating a novel transgenic reprogrammable mouse strain, which avoids OSKM expression in both liver and intestine, we drastically reduced the early lethality and adverse effects associated with in vivo reprogramming. This new reprogramming mouse allows safe and long-term continuous induction of OSKM and might enable a better understanding of in vivo reprogramming as well as maximize its potential effects on rejuvenation and regeneration.
The establishment of aging clocks based on DNA methylation highlighted the strong link between epigenetic alterations and aging. However, the connection between DNA methylation changes at clock sites and their effect on cellular function remains unclear. We hypothesize that chromatin accessibility, a readout that integrates many epigenetic mechanisms, may connect epigenetic changes with their downstream effects. Here we generated chromatin accessibility profiles from peripheral blood mononuclear cells of 157 human donors and used them to construct a novel aging clock with a median absolute error on prediction of 5.69 years. Moreover, by comparing our chromatin accessibility data to matched transcriptomic profiles, we show that the genomic sites relevant for chromatin accessibility-based age predictions also undergo transcriptional changes during aging and that chromatin accessibility predicts age better than gene expression. This chromatin accessibility clock could therefore be used to investigate the direct effect of aged epigenetic states on cellular function.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.