Research Paper|Volume 6, Issue 2|pp 98—117

MDL-1, a growth- and tumor-suppressor, slows aging and prevents germline hyperplasia and hypertrophy in C. elegans

Michèle Riesen¹, Inna Feyst¹, Nattaphong Rattanavirotkul¹, Marina Ezcurra¹, Jennifer M.A. Tullet¹, Irene Papatheodorou², Matthias Ziehm², Catherine Au¹, Ann F. Gilliat¹, Josephine Hellberg¹, Janet M. Thornton², David Gems¹

¹Institute of Healthy Ageing, and Research Department of Genetics, Evolution and Environment, University College London, London, United Kingdom
²European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom

Received: December 22, 2013Accepted: February 14, 2014Published: February 16, 2014

https://doi.org/10.18632/aging.100638

Copyright: © 2014 Riesen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

In C. elegans, increased lifespan in daf-2 insulin/IGF-1 receptor mutants is accompanied by up-regulation of the MDL-1 Mad basic helix-loop-helix leucine zipper transcription factor. Here we describe the role of mdl-1 in C. elegans germline proliferation and aging. The deletion allele mdl-1(tm311) shortened lifespan, and did so significantly more so in long-lived daf-2 mutants implying that mdl-1(+) contributes to effects of daf-2 on lifespan. mdl-1 mutant hermaphrodites also lay increased numbers of unfertilized oocytes. During aging, unfertilized oocytes in the uterus develop into tumors, whose development was accelerated by mdl-1(tm311). Opposite phenotypes were seen in daf-2 mutants, i.e. mdl-1 and daf-2 mutant germlines are hyperplastic and hypoplastic, respectively. Thus, MDL-1, like its mammalian orthologs, is an inhibitor of cell proliferation and growth that slows progression of an age-related pathology in C. elegans (uterine tumors). In addition, intestine-limited rescue of mdl-1 increased lifespan but not to wild type levels. Thus, mdl-1 likely acts both in the intestine and the germline to influence age-related mortality.