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Carrière, Audrey (2)
Hekimi, Siegfried (2)
Argyriou, Catherine (1)
Herault, Yann (1)
Liu, Xingxing (1)
Malo, Danielle (1)
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Wang, Ying (1)
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An Enhanced Immune Response of Mclk1+/− Mutant Mice Is Associated with Partial Protection from Fibrosis, Cancer and the Development of Biomarkers of Aging
The immune response is essential for survival by destroying microorganisms and pre-cancerous cells. However, inflammation, one aspect of this response, can result in short- and long-term deleterious side-effects. Mclk1+/− mutant mice can be long-lived despite displaying a hair-trigger inflammatory response and chronically activated macrophages as a result of high mitochondrial ROS generation. Here we ask whether this phenotype is beneficial or simply tolerated. We used models of infection by Salmonella serovars and found that Mclk1+/− mutants mount a stronger immune response, control bacterial proliferation better, and are resistant to cell and tissue damage resulting from the response, including fibrosis and types of oxidative damage that are considered to be biomarkers of aging. Moreover, these same types of tissue damage were found to be low in untreated 23 months-old mutants. We also examined the initiation of tumour growth after transplantation of mouse LLC1 carcinoma cells into Mclk1+/− mutants, as well as during spontaneous tumorigenesis in Mclk1+/− Trp53+/− double mutants. Tumour latency was increased by the Mclk1+/− genotype in both models. Furthermore, we used the transplantation model to show that splenic CD8+ T lymphocytes from Mclk1+/− graft recipients show enhanced cytotoxicity against LLC1 cells in vitro. Mclk1+/− mutants thus display an association of an enhanced immune response with partial protection from age-dependent processes and from pathologies similar to those that are found with increased frequency during the aging process. This suggests that the immune phenotype of these mutants might contribute to their longevity. We discuss how these findings suggest a broader view of how the immune response might impact the aging process.
The age of heterozygosity
Two mutant mouse models of longevity in which the loss of only one copy of the gene leads to a significantly increased lifespan have recently been described: Igf1r+/- and mclk1+/-. Igf1r encodes a transmembrane receptor kinase for the insulin-like growth factor-1, and mclk1 encodes a hydroxylase that is necessary for the biosynthesis of ubiquinone. Interestingly, the motivation for testing the longevity of both of these mutants came from observations in the nematode Caenorhabditis elegans. IGF-1R protein is homologous to DAF-2 and mCLK1 is the mouse orthologue of the C. elegans enzyme CLK-1. In worms, the homozygous inactivation of both of these longevity genes is viable and no dominant mutations are known. In addition to aging slowly, old mclk1+/- mice were found to undergo loss-of-heterozygosity at the mclk1 locus, which results in clones of mclk1-/- cells in the liver, presumably because mclk1-/- cells can outcompete mclk1+/- cells under certain conditions. We will discuss how these observations suggest novel directions of research, but also call for some caution in the interpretation of past and future results.
aging; evolutionary conservation; loss-of-heterozygosity; mclk1; mouse models of longevity; ubiquinone
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