A small number of naturally occurring and engineered mutations in mice result in extension of lifespan. Functional growth hormone (GH) deficiency has been associated with increased longevity in at least four strains of mice, two of which, the Ames (Prop1df/df) and Little (Ghrhrlit/lit) mice, we have studied intensively. Global gene expression analysis of the liver in GH deficient, long-lived mice, as well as calorically restricted (and thus long-lived) mice, shows a correlation between increased lifespan and elevation of genes which belong to the category of xenobiotic or detoxification metabolism. Detoxification of endogenous metabolic intermediates is a major function of the liver. This pathway is comprised of transporters, cytochromes, transferases, and exporters which become transcriptionally regulated by nuclear hormone receptors (NHRs) upon activation of the NHRs by several endogenous compounds including bile acids, steroids, vitamins, and lipids. Long-lived mutants of C. elegans show similar elevations of NHRs, cytochromes, and transferases (23, 24) In this proposal, we will test the hypothesis that chronic activation of xenobiotic metabolism as seen in the GH deficient, long-lived mice, is beneficial to longevity.
Specific Aim 1 will use a mutant mouse line (a knockout of cytochrome 7b1) that mimics the changes in detoxification pathways that are found in the long-lived mice. This knockout mouse model has patterns of elevation of xenobiotic metabolism genes similar to the GH deficient mice. The Cyp 7b1 null mice will be examined for longevity extension.
Specific Aim 2 is designed to elucidate the molecular mechanisms that control the activation of the detoxification response genes by examining the requirement for NHRs in double and triple KO mice and by knockdown of specific NHRs and candidate transcription factors in the liver. Finally, the consequences of reduction of Stat Sab signaling in the liver will be assessed by gene expression arrays to determine whether or not a reduction in Stat Sab in the liver accounts for the majority of gene expression changes seen in the GH deficient Ames and Little mice, and to identify potential co-regulators.
These aims will directly test whether or not chronic activation of xenobiotic metabolism impacts lifespan and will elucidate molecular targets that may be useful points of intervention in the aging process.
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|Reddy, Anilkumar K; Hartley, Craig J; Pham, Thuy T et al. (2014) Young little mice express a premature cardiovascular aging phenotype. J Gerontol A Biol Sci Med Sci 69:152-9|
|Hong, Il-Hwa; Lewis, Kyle; Iakova, Polina et al. (2014) Age-associated change of C/EBP family proteins causes severe liver injury and acceleration of liver proliferation after CCl4 treatments. J Biol Chem 289:1106-18|
|Sun, Deqiang; Luo, Min; Jeong, Mira et al. (2014) Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14:673-88|
|Jin, Jingling; Iakova, Polina; Jiang, Yanjun et al. (2013) Transcriptional and translational regulation of C/EBP?-HDAC1 protein complexes controls different levels of p53, SIRT1, and PGC1? proteins at the early and late stages of liver cancer. J Biol Chem 288:14451-62|
|Jiang, Yanjun; Jin, Jingling; Iakova, Polina et al. (2013) Farnesoid X receptor directly regulates xenobiotic detoxification genes in the long-lived Little mice. Mech Ageing Dev 134:407-15|
|Jiang, Yanjun; Iakova, Polina; Jin, Jingling et al. (2013) Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer. Hepatology 57:1098-106|
|Jin, Jingling; Iakova, Polina; Breaux, Meghan et al. (2013) Increased expression of enzymes of triglyceride synthesis is essential for the development of hepatic steatosis. Cell Rep 3:831-43|
|Jones, Karlie; Timchenko, Lubov; Timchenko, Nikolai A (2012) The role of CUGBP1 in age-dependent changes of liver functions. Ageing Res Rev 11:442-9|
|Jones, Karlie; Wei, Christina; Iakova, Polina et al. (2012) GSK3? mediates muscle pathology in myotonic dystrophy. J Clin Invest 122:4461-72|
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