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B E H I N D P A Y W A L L S O U R C E : Cell - Trends in Genetics
Highlights
Ageing is closely associated with and influenced by energy metabolism, and C/EBPβ is emerging as a key regulator of energy metabolism and longevity.
DNA hypermethylation in GADD45α/ING1 mutant mice is associated with progeria due to a failure of TET-dioxygenase mediated demethylation of C/EBPβ binding sites.
Accordingly, GADD45α/ING1 mutant mice phenocopy major symptoms of C/EBPβ mutant mice, indicating that a GADD45α–ING1–C/EBPβ axis regulates energy metabolism and ageing.
mTORC1 controls the translation of Cebpb-mRNA into two isoforms, the transcriptional activator liver-enriched activating protein (LAP), and inhibitor liver-enriched inhibitory protein (LIP). C/EBPβ super-mice, in which the inhibitory LIP is inactivated display healthier ageing and prolonged life span.
The results indicate a causal nexus between C/EBPβ, energy metabolism, and DNA demethylation in organismal ageing.
Changes in epigenetic DNA methylation are the most promising predictor of biological age and lifespan in humans, but whether methylation changes affect ageing is unresolved. Here, we discuss converging data, which indicate that one mode by which aberrant DNA methylation can affect ageing is via CCAAT/enhancer binding protein beta (C/EBPβ). This basic leucine-zipper (bZIP) transcription factor is controlled by the lifespan regulator mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and plays an important role in energy homeostasis and adipose tissue differentiation. Emerging evidence indicates that access of C/EBPβ proteins to cognate binding sites is regulated by DNA demethylation via ten-eleven translocation (TET) methylcytosine dioxygenases and their adaptor proteins growth arrest and DNA damage-inducible protein 45 alpha (GADD45 α) and inhibitor of growth 1 (ING1). We discuss the emerging causal nexus between C/EBPβ, energy metabolism, and DNA demethylation in organismal ageing.
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