Dataset Information

Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice.

ABSTRACT: Inhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age-associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate-specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.

SUBMITTER: Baar EL

PROVIDER: S-EPMC4717274 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice.

Baar Emma L EL Carbajal Kathryn A KA Ong Irene M IM Lamming Dudley W DW

Aging cell 20151124 1

Inhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age-associated changes ...[more]

PMID: 26695882

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Project description:Aim: Aging is thought to coincide with gradual and progressive changes in brain function and behavior over the lifetime. Our previous meta-analytic study reported age-related behavioral changes from young to middle age in male C57BL/6J mice. However, the previous study had some limitations that could affect the generalizability of the findings because of the potential influence of genetic and environmental factors on behavior, in addition to a lack of information regarding the behaviors of old-aged mice. Here, to investigate age-related behavioral changes from young to old age in mice, we analyzed the behaviors of male C57BL/6J mice from four different age groups (8, 47, 73, and 99 weeks of age at the beginning of the experiment) from a colony that had been maintained in a genetically controlled condition based on The Jackson Laboratory's Genetic Stability Program in an environmentally controlled animal facility.Methods: We used a battery of behavioral tests, including the light/dark transition, open field, elevated plus maze, hot plate, social interaction, rotarod, three-chamber social approach, prepulse inhibition, Porsolt forced swim, T-maze, Barnes maze, tail suspension, and fear-conditioning tests.Results: Some behavioral changes occurred between young and middle age, and further changes in various behaviors were observed in old age. Decreased locomotor activity and increased anxiety-like behavior were found in old-aged mice compared to those in young and middle-aged mice in the light/dark transition test. Similarly, an age-dependent decrease in locomotor activity was observed in the open field test and the elevated plus maze test, while there was an age-dependent increase in the time spent in the center area in the open field test and there were no significant differences among age groups in behavioral measures of anxiety in the elevated plus maze test. Decreases in motor performance and the auditory startle response were found in middle-aged mice compared to those in young mice. Similar behavioral changes and increased pain sensitivity, decreased social novelty preference, reduced working and spatial memory, and impaired cued fear memory were observed in old-aged mice compared to those in young mice. Prepulse inhibition was higher in middle-aged mice than in young and old-aged mice. Age-related changes in depression-related behavior were dependent on the type of test and the test time period.Conclusions: This study generally confirmed our previous report regarding age-related behavioral changes from young to middle age and expanded the previous observations by examining the behaviors of old-aged mice. Our results show age-related changes in a wide range of behaviors in mice from young to old age. Most behaviors showed gradual changes with advancing age, but some types of behaviors, such as vertical activity, prepulse inhibition, and depression-related behavior, did not show unidirectional changes with age. These findings provide basic information about the behavioral characteristics of young, middle-aged, and aged male C57BL/6J mice.

Project description:Prenatal alcohol exposure can result in fetal alcohol spectrum disorders (FASD). Not all women who consume alcohol during pregnancy have children with FASD and studies have shown that genetic factors can play a role in ethanol teratogenesis. We examined gene expression in embryos and placentae from C57BL/6J (B6) and DBA/2J (D2) mice following prenatal alcohol exposure. B6 fetuses are susceptible to morphological malformations following prenatal alcohol exposure while D2 are relatively resistant.Male and female B6 and D2 mice were mated for 2 hours in the morning, producing 4 embryonic genotypes: true-bred B6B6 and D2D2, and reciprocal B6D2 and D2B6. On gestational day 9, dams were intubated with 5.8 g/kg ethanol, an isocaloric amount of maltose dextrin, or nothing. Four hours later, dams were sacrificed and embryos and placentae were harvested. RNA was extracted, labeled and hybridized to Affymetrix Mouse Genome 430 v2 microarray chips. Data were normalized, subjected to analysis of variance and tested for enrichment of gene ontology molecular function and biological process using the Database for Annotation, Visualization and Integrated Discovery (DAVID).Several gene classes were differentially expressed in B6 and D2 regardless of treatment, including genes involved in polysaccharide binding and mitosis. Prenatal alcohol exposure altered expression of a subset of genes, including genes involved in methylation, chromatin remodeling, protein synthesis, and mRNA splicing. Very few genes were differentially expressed between maltose-exposed tissues and tissues that received nothing, so we combined these groups for comparisons with ethanol. While we observed many expression changes specific to B6 following prenatal alcohol exposure, none were specific for D2. Gene classes up- or down-regulated in B6 following prenatal alcohol exposure included genes involved in mRNA splicing, transcription, and translation.Our study identified several classes of genes with altered expression following prenatal alcohol exposure, including many specific for B6, a strain susceptible to ethanol teratogenesis. Lack of strain specific effects in D2 suggests there are few gene expression changes that confer resistance. Future studies will begin to analyze functional significance of the expression changes.

Dataset Information

Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice.

Publications

Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice.

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