Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse

<p>Abstract</p> <p>Background</p> <p>Caloric restriction (CR) counters deleterious effects of aging and, for most mouse genotypes, increases mean and maximum lifespan. Previous analyses of microarray data have identified gene expression responses to CR that are shared among multiple mouse tissues, including the activation of anti-oxidant, tumor suppressor and anti-inflammatory pathways. These analyses have provided useful research directions, but have been restricted to a limited number of tissues, and have focused on individual genes, rather than whole-genome transcriptional networks. Furthermore, CR is thought to oppose age-associated gene expression patterns, but detailed statistical investigations of this hypothesis have not been carried out.</p> <p>Results</p> <p>Systemic effects of CR and aging were identified by examining transcriptional responses to CR in 17 mouse tissue types, as well as responses to aging in 22 tissues. CR broadly induced the expression of genes known to inhibit oxidative stress (e.g., <it>Mt1</it>, <it>Mt2</it>), inflammation (e.g., <it>Nfkbia</it>, <it>Timp3</it>) and tumorigenesis (e.g., <it>Txnip</it>, <it>Zbtb16</it>). Additionally, a network-based investigation revealed that CR regulates a large co-expression module containing genes associated with the metabolism and splicing of mRNA (e.g., <it>Cpsf6</it>, <it>Sfpq</it>, <it>Sfrs18</it>). The effects of aging were, to a considerable degree, similar among groups of co-expressed genes. Age-related gene expression patterns characteristic of most mouse tissues were identified, including up regulation of granulin (<it>Grn</it>) and secreted phosphoprotein 1 (<it>Spp1</it>). The transcriptional association between CR and aging varied at different levels of analysis. With respect to gene subsets associated with certain biological processes (e.g., immunity and inflammation), CR opposed age-associated expression patterns. However, among all genes, global transcriptional effects of CR were only weakly related to those of aging.</p> <p>Conclusion</p> <p>The study of aging, and of interventions thought to combat aging, has much to gain from data-driven and unbiased genomic investigations. Expression patterns identified in this analysis characterize a generalized response of mammalian cells to CR and/or aging. These patterns may be of importance in determining effects of CR on overall lifespan, or as factors that underlie age-related disease. The association between CR and aging warrants further study, but most evidence indicates that CR does not induce a genome-wide "reversal" of age-associated gene expression patterns.</p

Gene expression profiling of long-lived dwarf mice: longevity-associated genes and relationships with diet, gender and aging

<p>Abstract</p> <p>Background</p> <p>Long-lived strains of dwarf mice carry mutations that suppress growth hormone (GH) and insulin-like growth factor I (IGF-I) signaling. The downstream effects of these endocrine abnormalities, however, are not well understood and it is unclear how these processes interact with aging mechanisms. This study presents a comparative analysis of microarray experiments that have measured hepatic gene expression levels in long-lived strains carrying one of four mutations (<it>Prop1</it>^{<it>df</it>/<it>df</it>}, <it>Pit1</it>^{<it>dw</it>/<it>dw</it>}, <it>Ghrhr</it>^{<it>lit</it>/<it>lit</it>}, <it>GHR-KO</it>) and describes how the effects of these mutations relate to one another at the transcriptional level. Points of overlap with the effects of calorie restriction (CR), CR mimetic compounds, low fat diets, gender dimorphism and aging were also examined.</p> <p>Results</p> <p>All dwarf mutations had larger and more consistent effects on IGF-I expression than dietary treatments. In comparison to dwarf mutations, however, the transcriptional effects of CR (and some CR mimetics) overlapped more strongly with those of aging. Surprisingly, the <it>Ghrhr</it>^{<it>lit</it>/<it>lit </it>}mutation had much larger effects on gene expression than the <it>GHR-KO </it>mutation, even though both mutations affect the same endocrine pathway. Several genes potentially regulated or co-regulated with the IGF-I transcript in liver tissue were identified, including a DNA repair gene (Snm1) that is upregulated in proportion to IGF-I inhibition. A total of 13 genes exhibiting parallel differential expression patterns among all four strains of long-lived dwarf mice were identified, in addition to 30 genes with matching differential expression patterns in multiple long-lived dwarf strains and under CR.</p> <p>Conclusion</p> <p>Comparative analysis of microarray datasets can identify patterns and consistencies not discernable from any one dataset individually. This study implements new analytical approaches to provide a detailed comparison among the effects of life-extending mutations, dietary treatments, gender and aging. This comparison provides insight into a broad range of issues relevant to the study of mammalian aging. In this context, 43 longevity-associated genes are identified and individual genes with the highest level of support among all microarray experiments are highlighted. These results provide promising targets for future experimental investigation as well as potential clues for understanding the functional basis of lifespan extension in mammalian systems.</p

Putting a strain on diversity.

Human life expectancy is increasing on a global scale, but healthspan—the period of life free from age‐associated ill health—is not improving at a comparable rate. This disconnect means that a greater proportion of the general population will spend a longer period of their life suffering from one or more debilitating age‐associated diseases, such as cardiovascular disease, Alzheimer's disease, osteoporosis, sarcopenia and various cancers. Understanding the processes underlying ageing and age‐related diseases is therefore a major and pressing research challenge in biomedical research

Transcriptional Profiles of Leukocyte Populations Provide a Tool for Interpreting Gene Expression Patterns Associated with High Fat Diet in Mice

Microarray experiments in mice have shown that high fat diet can lead to elevated expression of genes that are disproportionately associated with immune functions. These effects of high fat (atherogenic) diet may be due to infiltration of tissues by leukocytes in coordination with inflammatory processes.The Novartis strain-diet-sex microarray database (GSE10493) was used to evaluate the hepatic effects of high fat diet (4 weeks) in 12 mouse strains and both genders. We develop and apply an algorithm that identifies "signature transcripts" for many different leukocyte populations (e.g., T cells, B cells, macrophages) and uses this information to derive an in silico "inflammation profile". Inflammation profiles highlighted monocytes, macrophages and dendritic cells as key drivers of gene expression patterns associated with high fat diet in liver. In some strains (e.g., NZB/BINJ, B6), we estimate that 50-60% of transcripts elevated by high fat diet might be due to hepatic infiltration by these cell types. Interestingly, DBA mice appeared to exhibit resistance to localized hepatic inflammation associated with atherogenic diet. A common characteristic of infiltrating cell populations was elevated expression of genes encoding components of the toll-like receptor signaling pathway (e.g., Irf5 and Myd88).High fat diet promotes infiltration of hepatic tissue by leukocytes, leading to elevated expression of immune-associated transcripts. The intensity of this effect is genetically controlled and sensitive to both strain and gender. The algorithm developed in this paper provides a framework for computational analysis of tissue remodeling processes and can be usefully applied to any in vivo setting in which inflammatory processes play a prominent role

Transcriptional profiling of Arabidopsis heat shock proteins and transcription factors reveals extensive overlap between heat and non-heat stress response pathways

<p>Abstract</p> <p>Background</p> <p>The heat shock response of <it>Arabidopsis thaliana </it>is dependent upon a complex regulatory network involving twenty-one known transcription factors and four heat shock protein families. It is known that heat shock proteins (Hsps) and transcription factors (Hsfs) are involved in cellular response to various forms of stress besides heat. However, the role of Hsps and Hsfs under cold and non-thermal stress conditions is not well understood, and it is unclear which types of stress interact least and most strongly with Hsp and Hsf response pathways. To address this issue, we have analyzed transcriptional response profiles of <it>Arabidopsis </it>Hsfs and Hsps to a range of abiotic and biotic stress treatments (heat, cold, osmotic stress, salt, drought, genotoxic stress, ultraviolet light, oxidative stress, wounding, and pathogen infection) in both above and below-ground plant tissues.</p> <p>Results</p> <p>All stress treatments interact with Hsf and Hsp response pathways to varying extents, suggesting considerable cross-talk between heat and non-heat stress regulatory networks. In general, Hsf and Hsp expression was strongly induced by heat, cold, salt, and osmotic stress, while other types of stress exhibited family or tissue-specific response patterns. With respect to the Hsp20 protein family, for instance, large expression responses occurred under all types of stress, with striking similarity among expression response profiles. Several genes belonging to the Hsp20, Hsp70 and Hsp100 families were specifically upregulated twelve hours after wounding in root tissue, and exhibited a parallel expression response pattern during recovery from heat stress. Among all Hsf and Hsp families, large expression responses occurred under ultraviolet-B light stress in aerial tissue (shoots) but not subterranean tissue (roots).</p> <p>Conclusion</p> <p>Our findings show that Hsf and Hsp family member genes represent an interaction point between multiple stress response pathways, and therefore warrant functional analysis under conditions apart from heat shock treatment. In addition, our analysis revealed several family and tissue-specific heat shock gene expression patterns that have not been previously described. These results have implications regarding the molecular basis of cross-tolerance in plant species, and raise new questions to be pursued in future experimental studies of the <it>Arabidopsis </it>heat shock response network.</p