Trends in genetics – Volume 36, Issue 2, February 2020

Christof Niehrs (Institute of Molecular Biology), Cornelis F. Calkhoven (European Research Institute for the Biology of Ageing)

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.

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