Reduced expression of C/EBPβ-LIP extends health and lifespan in mice

Christine Müller,Gertrud Kortman,Dineke S Verbeek,Liesbeth Harkema,Alain De Bruin,Victor Guryev,Cornelis F Calkhoven,Peng Liu,Verena Kliche,Tobias Ackermann,Tristan De Jong,Julia Von Maltzahn,Zhao-Qi Wang,Mohamad Amr Zaini,Laura M Zidek,Jan P Tuckermann

doi:10.7554/elife.34985

Abstract

Ageing is associated with physical decline and the development of age-related diseases such as metabolic disorders and cancer. Few conditions are known that attenuate the adverse effects of ageing, including calorie restriction (CR) and reduced signalling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Synthesis of the metabolic transcription factor C/EBPβ-LIP is stimulated by mTORC1, which critically depends on a short upstream open reading frame (uORF) in the Cebpb-mRNA. Here, we describe that reduced C/EBPβ-LIP expression due to genetic ablation of the uORF delays the development of age-associated phenotypes in mice. Moreover, female C/EBPβΔuORF mice display an extended lifespan. Since LIP levels increase upon aging in wild type mice, our data reveal an important role for C/EBPβ in the aging process and suggest that restriction of LIP expression sustains health and fitness. Thus, therapeutic strategies targeting C/EBPβ-LIP may offer new possibilities to treat age-related diseases and to prolong healthspan.

Highlights

Delaying the occurrence of age related-diseases and frailty and prolonging healthspan, would substantially increase the quality of life of the ageing population and could help to reduce healthcare costs
Here we show that loss-of-function mutation of a single cis-regulatory element - the upstream open reading frame (uORF) - in the Cebpb-mRNA, which prevents the translation into the transcription factor C/EBPb-liver-enriched inhibitory protein (LIP), results in a remarkable juvenile phenotype in aged mice including lower cancer incidence, lower body weight and body fat, better glucose tolerance, lower memory/naıve T cell ratios, and better maintenance of motor coordination
A significant lifespan extension was only observed for the female C/EBPbDuORF mice

Summary

Introduction

Delaying the occurrence of age related-diseases and frailty (disabilities) and prolonging healthspan, would substantially increase the quality of life of the ageing population and could help to reduce healthcare costs. The results presented by Muller, Zidek et al suggest that targeting the activity of the LIP gene could help to slow the ageing process. It is not yet clear whether shutting off LIP has similar beneficial effects in humans. Pharmacological or CRinduced inhibition of mTORC1 in mice selectively reduces LIP-protein synthesis and thereby increases the LAP/LIP ratio in different tissues (Zidek et al, 2015). B type improved metabolic profile, including enhanced fatty acid oxidation and reduction of steatosis, improved insulin sensitivity and glucose tolerance, and higher adiponectin levels These metabolic improvements are achieved without reducing calorie intake (Albert and Hall, 2015; Zidek et al, 2015). We show an improvement in a broad spectrum of age-associated phenotypes to varying degrees in males and females

Results

Discussion

Materials and methods

Funding Funder Deutsche Forschungsgemeinschaft