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.
Christine Müller1,2†, Laura M Zidek2†, Tobias Ackermann1, Tristan de Jong1, Peng Liu3, Verena Kliche2, Mohamad Amr Zaini1, Gertrud Kortman1, Liesbeth Harkema4, Dineke S Verbeek5, Jan P Tuckermann3, Julia von Maltzahn2, Alain de Bruin4,5, Victor Guryev1, Zhao-Qi Wang2, Cornelis F Calkhoven1,2*
1European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands; 2Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany; 3Institute for Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany; 4Dutch Molecular Pathology Centre, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands; 5Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.