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1.  Analysis of long non-coding RNAs highlights tissue-specific expression patterns and epigenetic profiles in normal and psoriatic skin 
Genome Biology  2015;16(1):24.
Background
Although analysis pipelines have been developed to use RNA-seq to identify long non-coding RNAs (lncRNAs), inference of their biological and pathological relevance remains a challenge. As a result, most transcriptome studies of autoimmune disease have only assessed protein-coding transcripts.
Results
We used RNA-seq data from 99 lesional psoriatic, 27 uninvolved psoriatic, and 90 normal skin biopsies, and applied computational approaches to identify and characterize expressed lncRNAs. We detect 2,942 previously annotated and 1,080 novel lncRNAs which are expected to be skin specific. Notably, over 40% of the novel lncRNAs are differentially expressed and the proportions of differentially expressed transcripts among protein-coding mRNAs and previously-annotated lncRNAs are lower in psoriasis lesions versus uninvolved or normal skin. We find that many lncRNAs, in particular those that are differentially expressed, are co-expressed with genes involved in immune related functions, and that novel lncRNAs are enriched for localization in the epidermal differentiation complex. We also identify distinct tissue-specific expression patterns and epigenetic profiles for novel lncRNAs, some of which are shown to be regulated by cytokine treatment in cultured human keratinocytes.
Conclusions
Together, our results implicate many lncRNAs in the immunopathogenesis of psoriasis, and our results provide a resource for lncRNA studies in other autoimmune diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0570-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-014-0570-4
PMCID: PMC4311508
2.  Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms 
To increase our understanding of psoriasis, we utilized RNA-seq to assay the transcriptomes of lesional psoriatic and normal skin. We sequenced polyadenylated RNA-derived cDNAs from 92 psoriatic and 82 normal punch biopsies, generating an average of ~38 million single-end 80-bp reads per sample. Comparison of 42 samples examined by both RNA-seq and microarray revealed marked differences in sensitivity, with transcripts identified only by RNA-seq having much lower expression than those also identified by microarray. RNA-seq identified many more differentially expressed transcripts enriched in immune system processes. Weighted gene co-expression network analysis (WGCNA) revealed multiple modules of coordinately expressed epidermal differentiation genes, overlapping significantly with genes regulated by the long non-coding RNA TINCR, its target gene, staufen-1 (STAU1), the p63 target gene ZNF750, and its target KLF4. Other coordinately expressed modules were enriched for lymphoid and/or myeloid signature transcripts and genes induced by IL-17 in keratinocytes. Dermally-expressed genes were significantly down-regulated in psoriatic biopsies, most likely due to expansion of the epidermal compartment. These results demonstrate the power of WGCNA to elucidate gene regulatory circuits in psoriasis, and emphasize the influence of tissue architecture in both differential expression and co-expression analysis.
doi:10.1038/jid.2014.28
PMCID: PMC4057954  PMID: 24441097
skin; inflammation; immunology; cytokine; dermatology; psoriasis; transcriptome; network analysis
3.  Inter-tissue Control of the Nucleolus via a Myokine-dependent Longevity Pathway 
Cell reports  2014;7(5):1481-1494.
SUMMARY
Recent evidence indicates that skeletal muscle influences systemic aging but little is known on the signaling pathways and muscle-released cytokines (myokines) responsible for this inter-tissue communication. Here, we show that muscle-specific overexpression of the transcription factor Mnt decreases age-related climbing defects and extends lifespan in Drosophila. Mnt overexpression in muscle autonomously decreases the expression of nucleolar components and systemically decreases rRNA levels and the size of the nucleolus in adipocytes. This non-autonomous control of the nucleolus, a regulator of ribosome biogenesis and lifespan, relies on Myoglianin, a myokine induced by Mnt and orthologous to human GDF11 and Myostatin. Myoglianin overexpression in muscle extends lifespan and decreases nucleolar size in adipocytes by activating p38 MAPK, while Myoglianin RNAi in muscle has converse effects. Altogether, these findings highlight a key role for myokine signaling in the integration of signaling events in muscle and distant tissues during aging.
doi:10.1016/j.celrep.2014.05.001
PMCID: PMC4125979  PMID: 24882005
4.  IL-32 is a molecular marker of a host defense network in human tuberculosis 
Science translational medicine  2014;6(250):250ra114.
Tuberculosis is a leading cause of infectious disease–related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ– and IL-15–induced “defense response” genes. IL-32 induced the vitamin D–dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15–induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15–induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.
doi:10.1126/scitranslmed.3009546
PMCID: PMC4175914  PMID: 25143364
5.  Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era 
BMC Medical Genomics  2014;7:27.
Background
Genome-scale studies of psoriasis have been used to identify genes of potential relevance to disease mechanisms. For many identified genes, however, the cell type mediating disease activity is uncertain, which has limited our ability to design gene functional studies based on genomic findings.
Methods
We identified differentially expressed genes (DEGs) with altered expression in psoriasis lesions (n = 216 patients), as well as candidate genes near susceptibility loci from psoriasis GWAS studies. These gene sets were characterized based upon their expression across 10 cell types present in psoriasis lesions. Susceptibility-associated variation at intergenic (non-coding) loci was evaluated to identify sites of allele-specific transcription factor binding.
Results
Half of DEGs showed highest expression in skin cells, although the dominant cell type differed between psoriasis-increased DEGs (keratinocytes, 35%) and psoriasis-decreased DEGs (fibroblasts, 33%). In contrast, psoriasis GWAS candidates tended to have highest expression in immune cells (71%), with a significant fraction showing maximal expression in neutrophils (24%, P < 0.001). By identifying candidate cell types for genes near susceptibility loci, we could identify and prioritize SNPs at which susceptibility variants are predicted to influence transcription factor binding. This led to the identification of potentially causal (non-coding) SNPs for which susceptibility variants influence binding of AP-1, NF-κB, IRF1, STAT3 and STAT4.
Conclusions
These findings underscore the role of innate immunity in psoriasis and highlight neutrophils as a cell type linked with pathogenetic mechanisms. Assignment of candidate cell types to genes emerging from GWAS studies provides a first step towards functional analysis, and we have proposed an approach for generating hypotheses to explain GWAS hits at intergenic loci.
doi:10.1186/1755-8794-7-27
PMCID: PMC4060870  PMID: 24885462
AP-1; Fibroblast; GWAS; Keratinocyte; Microarray; Neutrophil; TNFRSF9; Transcription factor
6.  Susceptibility-associated genetic variation at IL12B enhances Th1 polarization in psoriasis 
Human Molecular Genetics  2013;22(9):1807-1815.
The IL12B gene encodes the common p40 subunit of IL-12 and IL-23, cytokines with key roles in Th1 and Th17 biology, respectively, and genetic variation in this region significantly influences risk of psoriasis. Here, we demonstrate that a psoriasis-associated risk haplotype at the IL12B locus leads to increased expression of IL12B by monocytes and correlated with increased serum levels of IL-12, IFN-γ and the IFN-γ induced chemokine, CXCL10. In contrast, serum IL-23 levels were decreased in risk carriers when compared with non-carriers. We further demonstrate that IL-12 is increased in psoriatic skin and that risk carriers manifest a skewing of the inflammatory network toward stronger IFN-γ responses. Taken together, our data demonstrate that the risk variant in IL12B associates with its increased expression and predisposes to stronger Th1 polarization through deviation of the local inflammatory environment toward increased IL-12/IFN-γ at the expense of IL-23/IL-17 responses.
doi:10.1093/hmg/ddt034
PMCID: PMC3613166  PMID: 23376980
7.  Data Mining Identifies Digit Symbol Substitution Test Score and Serum Cystatin C as Dominant Predictors of Mortality in Older Men and Women 
Rejuvenation Research  2012;15(4):405-413.
Abstract
Background
Characterization of long-term health trajectory in older individuals is important for proactive health management. However, the relative prognostic value of information contained in clinical profiles of nonfrail older adults is often unclear.
Methods
We screened 825 phenotypic and genetic measures evaluated during the Health, Aging, and Body Composition Study (Health ABC) baseline visit (3,067 men and women aged 70–79). Variables that best predicted mortality over 13 years of follow-up were identified using 10-fold cross-validation.
Results
Mortality was most strongly associated with low Digit Symbol Substitution Test (DSST) score (DSST<25; 21.9% of cohort; hazard ratio [HR]=1.87±0.06) and elevated serum cystatin C (≥1.30 mg/mL; 12.1% of cohort; HR=2.25±0.07). These variables predicted mortality better than 823 other measures, including baseline age and a 45-variable health deficit index. Given elevated cystatin C (≥1.30 mg/mL), mortality risk was further increased by high serum creatinine, high abdominal visceral fat density, and smoking history (2.52≤HR ≤3.73). Given a low DSST score (<25) combined with low-to-moderate cystatin C (<1.30 mg/mL), mortality risk was highest among those with elevated plasma resistin and smoking history (1.90≤HR≤2.02).
Conclusions
DSST score and serum cystatin C warrant priority consideration for the evaluation of mortality risk in older individuals. Both variables, taken individually, predict mortality better than chronological age or a health deficit index in well-functioning older adults (ages 70–79). DSST score and serum cystatin C can thus provide evidence-based tools for geriatric assessment.
doi:10.1089/rej.2011.1297
PMCID: PMC3419847  PMID: 22607624
8.  Dietary restriction in rats and mice: A meta-analysis and review of the evidence for genotype-dependent effects on lifespan 
Ageing research reviews  2011;11(2):254-270.
Laboratory survival experiments have shown that dietary restriction (DR) can increase median and maximum lifespan. This paper provides a meta-analysis of laboratory experiments that have evaluated the effects of DR on lifespan in rats and mice (1934 – present). In rats, DR increased median lifespan by 14 – 45% in half of all experiments, but in mice the effects of DR have been much weaker (4 – 27%). The least favorable effects of DR on lifespan have been observed among inbred rather than non-inbred mouse strains. In fact, some inbred mouse strains do not necessarily live longer with DR, including DBA/2 male mice and several strains from the ILSXISS recombinant inbred panel. Shortening of lifespan with DR has also been observed and confirmed for ILSXISS strain 114. Importantly, all rodent studies may be biased by the effects of laboratory breeding, since one study has shown that median lifespan is not improved by DR in wild-derived mice. These findings suggest that the set of genetic backgrounds studied in rodent DR experiments should be diversified. This will broaden the scope of genotypes studied in aging research, but may also be critical for translation of findings from rodents to historically outbred and genetically heterogeneous primate species.
doi:10.1016/j.arr.2011.12.006
PMCID: PMC3299887  PMID: 22210149
aging; calorie restriction; CR; DBA/2; genetic background; inbred long sleep; inbred short sleep; survivorship; wild-derived mice
9.  Modulation of Epidermal Transcription Circuits in Psoriasis: New Links between Inflammation and Hyperproliferation 
PLoS ONE  2013;8(11):e79253.
Background
Whole-genome expression profiling has been used to characterize molecular-level differences between psoriasis lesions and normal skin. Pathway analysis, however, is complicated by the fact that expression profiles have been derived from bulk skin biopsies with RNA derived from multiple cell types.
Results
We analyzed gene expression across a large sample of psoriatic (PP) and uninvolved/normal (PN) skin biopsies (n = 215 patients). We identified 1975 differentially expressed genes, including 8 associated with psoriasis susceptibility loci. To facilitate pathway analysis, PP versus PN differences in gene expression were analyzed with respect to 235 gene modules, each containing genes with a similar expression pattern in keratinocytes and epidermis. We identified 30 differentially expressed modules (DEMs) biased towards PP-increased or PP-decreased expression. These DEMs were associated with regulatory axes involving cytokines (e.g., IFN-γ, IL-17A, TNF-α), transcription factors (e.g., STAT1, NF-κB, E2F, RUNX1) and chromatin modifiers (SETDB1). We identified an interferon-induced DEM with genes encoding anti-viral proteins (designated “STAT1-57”), which was activated in psoriatic epidermis but repressed following biologic therapy. Genes within this DEM shared a motif near the transcription start site resembling the interferon-stimulated response element (ISRE).
Conclusions
We analyzed a large patient cohort and developed a new approach for delineating epidermis-specific pathways and regulatory mechanisms that underlie altered gene expression in psoriasis. Our findings highlight previously unrecognized “transcription circuits” that can provide targets for development of non-systemic therapies.
doi:10.1371/journal.pone.0079253
PMCID: PMC3829857  PMID: 24260178
10.  Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice 
eLife  2013;2:e01098.
We examine the impact of targeted disruption of growth hormone-releasing hormone (GHRH) in mice on longevity and the putative mechanisms of delayed aging. GHRH knockout mice are remarkably long-lived, exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter-insulin effects of growth hormone. While these effects overlap with those of caloric restriction, we show that the effects of caloric restriction (CR) and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity.
DOI: http://dx.doi.org/10.7554/eLife.01098.001
eLife digest
There is increasing evidence that the hormonal systems involved in growth, the metabolism of glucose, and the processes that balance energy intake and expenditure might also be involved in the aging process. In rodents, mutations in genes involved in these hormone-signaling pathways can substantially increase lifespan, as can a diet that is low in calories but which avoids malnutrition. As well as living longer, such mice also show reductions in age-related conditions such as diabetes, memory loss and cancer.
Many of these effects appear to involve the actions of growth hormone. Mice with mutations that disrupt the development of the pituitary gland, which produces growth hormone, show increased longevity, as do mice that lack the receptor for growth hormone. However, these animals also show changes in a number of other hormones, making it difficult to be sure that the reduction in growth hormone signaling is responsible for their increased lifespan.
Now, Sun et al. have studied mutant mice that lack a gene called GHRH, which promotes the release of growth hormone. These mice, which have normal levels of all other pituitary hormones, lived for up to 50% longer than their wild-type littermates. They were more active than normal mice and had more body fat, and showed greatly increased sensitivity to insulin.
Some of the changes in these mutant mice resembled those seen in animals with a restricted calorie intake, suggesting that the same mechanisms may be implicated in both. However, Sun et al. found that caloric restriction further increased the lifespans of their GHRH knockout mice, indicating that at least some of the effects of caloric restriction are independent of disrupted growth hormone signaling.
The results of this study are an important step forward for understanding how growth hormone signaling and caloric restriction regulate aging, both individually and in combination. The GHRH knockout mice are likely to become an important model system for studying these processes and for understanding the complex interactions between diet and hormonal pathways.
DOI: http://dx.doi.org/10.7554/eLife.01098.002
doi:10.7554/eLife.01098
PMCID: PMC3810783  PMID: 24175087
mice; aging; caloric restriction; growth hormone; Mouse
11.  Metallothionein and the Biology of Aging 
Ageing Research Reviews  2010;10(1):132-145.
Metallothionein (MT) is a low molecular weight protein with anti-apoptotic properties that has been demonstrated to scavenge free radicals in vitro. MT has not been extensively investigated within the context of aging biology. The purpose of this review, therefore, is to discuss findings on MT that are relevant to basic aging mechanisms and to draw attention to the possible role of MT in pro-longevity interventions. MT is one of just a handful of proteins that, when overexpressed, has been demonstrated to increase mouse lifespan. MT also protects against development of obesity in mice provided a high fat diet as well as diet-induced oxidative stress damage. Abundance of MT is responsive to caloric restriction (CR) and inhibition of the insulin / insulin-like signaling (IIS) pathway, and elevated MT gene expression has been observed in tissues from fasted and CR-fed mice, long-lived dwarf mice, worms maintained under CR conditions, and long-lived daf-2 mutant worms. The dysregulation of MT in these systems is likely to have tissue-specific effects on aging outcomes. Further investigation will therefore be needed to understand how MT contributes to the response of invertebrates and mice to CR and the endocrine mutations studied by aging researchers.
doi:10.1016/j.arr.2010.09.007
PMCID: PMC3386784  PMID: 20933613
caloric restriction; diet; GH; IGF-1; longevity; MTF-1
12.  ALTERATION OF THE EPHA2/EPHRIN-A SIGNALING AXIS IN PSORIATIC EPIDERMIS 
EphA2 is a receptor tyrosine kinase (RTK) that triggers keratinocyte differentiation upon activation and subsequently down-regulation by ephrin-A1 ligand. The objective for this study was to determine if the EphA2/ephrin-A1 signaling axis was altered in psoriasis, an inflammatory skin condition where keratinocyte differentiation is abnormal. Microarray analysis of skin biopsies from psoriasis patients revealed increased mRNA transcripts for several members of this RTK family in plaques, including the EphA1, EphA2 and EphA4 subtypes prominently expressed by keratinocytes. Of these, EphA2 showed the greatest up-regulation, a finding that was confirmed by quantitative RT-PCR, IHC analysis and ELISA. In contrast, psoriatic lesions exhibited reduced ephrin-A ligand immunoreactivity. Exposure of primary keratinocytes induced to differentiated in high calcium or a 3-dimensiosnal raft culture of human epidermis to a combination of growth factors and cytokines elevated in psoriasis increased EphA2 mRNA and protein expression while inducing S100A7 and disrupting differentiation. Pharmacological delivery of a soluble ephrin-A1 peptidomimetic ligand led to a reduction in EphA2 expression and ameliorated proliferation and differentiation in raft cultures exposed to EGF and IL-1α. These findings suggest that ephrin-A1-mediated down-regulation of EphA2 supports keratinocyte differentiation in the context of cytokine perturbation.
doi:10.1038/jid.2012.391
PMCID: PMC3570705  PMID: 23190894
13.  Dissecting the psoriasis transcriptome: inflammatory- and cytokine-driven gene expression in lesions from 163 patients 
BMC Genomics  2013;14:527.
Background
Psoriasis lesions are characterized by large-scale shifts in gene expression. Mechanisms that underlie differentially expressed genes (DEGs), however, are not completely understood. We analyzed existing datasets to evaluate genome-wide expression in lesions from 163 psoriasis patients. Our aims were to identify mechanisms that drive differential expression and to characterize heterogeneity among lesions in this large sample.
Results
We identified 1233 psoriasis-increased DEGs and 977 psoriasis-decreased DEGs. Increased DEGs were attributed to keratinocyte activity (56%) and infiltration of lesions by T-cells (14%) and macrophages (11%). Decreased DEGs, in contrast, were associated with adipose tissue (63%), epidermis (14%) and dermis (4%). KC/epidermis DEGs were enriched for genes induced by IL-1, IL-17A and IL-20 family cytokines, and were also disproportionately associated with AP-1 binding sites. Among all patients, 50% exhibited a heightened inflammatory signature, with increased expression of genes expressed by T-cells, monocytes and dendritic cells. 66% of patients displayed an IFN-γ-strong signature, with increased expression of genes induced by IFN-γ in addition to several other cytokines (e.g., IL-1, IL-17A and TNF). We show that such differences in gene expression can be used to differentiate between etanercept responders and non-responders.
Conclusions
Psoriasis DEGs are partly explained by shifts in the cellular composition of psoriasis lesions. Epidermal DEGs, however, may be driven by the activity of AP-1 and cellular responses to IL-1, IL-17A and IL-20 family cytokines. Among patients, we uncovered a range of inflammatory- and cytokine-associated gene expression patterns. Such patterns may provide biomarkers for predicting individual responses to biologic therapy.
doi:10.1186/1471-2164-14-527
PMCID: PMC3751090  PMID: 23915137
AP-1; Etanercept; IL-17; IL-20; Inflammation; Keratinocyte; Microarray; TNF; T-cell; Transcription factor
14.  IN VIVO ANALYSIS OF GENE EXPRESSION IN LONG-LIVED MICE LACKING THE PREGNANCY-ASSOCIATED PLASMA PROTEIN A (PAPPA) GENE 
Experimental gerontology  2010;45(5):366-374.
Mice lacking the pregnancy-associated plasma protein A (PappA) gene exhibit diminished localized IGF-1 bioavailability and a 30% increase in mean life span. However, it is uncertain which tissues exhibit reduced IGF-1 signals in the PappA(−/−) mouse, and whether effects of this mutation parallel those of mutations that diminish IGF-1 in serum. Across a panel of 21 tissues, we used RT-PCR to evaluate the effects of the PappA(−/−) mutation on expression of Igfbp5, which served as an in vivo indicator of IGF-1 signaling. Among these tissues, expression of Igfbp5 was significantly reduced by PappA(−/−) only in kidney. A broader survey of IGF-associated genes in six organs identified five other genes responsive to PappA(−/−) in kidney, with stronger effects in this organ relative to other tissues. Renal expression of Irs1 and Mt1 was increased by PappA(−/−) as well as by mutations that reduce IGF-1 in serum (i.e., Ghr(−/−), Pit1(dw/dw) and Prop1(df/df)), and we demonstrate that expression of these genes is regulated by growth hormone-treatment and calorie restriction. These results provide in vivo data on an important new model of mammalian aging, and characterize both similar and contrasting expression patterns between long-lived mice with reduced local IGF-1 availability and diminished IGF-1 in serum.
doi:10.1016/j.exger.2010.02.009
PMCID: PMC2860881  PMID: 20197085
aging; dwarf; growth hormone; insulin-like growth factor; lifespan; longevity
15.  Robust shifts in S100a9 expression with aging: A novel mechanism for chronic inflammation 
Scientific Reports  2013;3:1215.
The S100a8 and S100a9 genes encode a pro-inflammatory protein (calgranulin) that has been implicated in multiple diseases. However, involvement of S100a8/a9 in the basic mechanisms of intrinsic aging has not been established. In this study, we show that shifts in the abundance of S100a8 and S100a9 mRNA are a robust feature of aging in mammalian tissues, involving a range of cell types including the central nervous system. To identify transcription factors that control S100a9 expression, we performed a large-scale transcriptome analysis of 62 mouse and human cell types. We identified cell type-specific trends, as well as robust associations linking S100a9 coexpression to elevated frequency of ETS family motifs, and in particular, to motifs recognized by the transcription factor SPI/PU.1. Sparse occurrence of SATB1 motifs was also a strong predictor of S100a9 coexpression. These findings offer support for a novel mechanism by which a SPI1/PU.1-S100a9 axis sustains chronic inflammation during aging.
doi:10.1038/srep01215
PMCID: PMC3564041  PMID: 23386971
17.  ACCELERATED FAILURE TIME MODELS PROVIDE A USEFUL STATISTICAL FRAMEWORK FOR AGING RESEARCH 
Experimental gerontology  2008;44(3):190-200.
Survivorship experiments play a central role in aging research and are performed to evaluate whether interventions alter the rate of aging and increase lifespan. The accelerated failure time (AFT) model is seldom used to analyze survivorship data, but offers a potentially useful statistical approach that is based upon the survival curve rather than the hazard function. In this study, AFT models were used to analyze data from 16 survivorship experiments that evaluated the effects of one or more genetic manipulations on mouse lifespan. Most genetic manipulations were found to have a multiplicative effect on survivorship that is independent of age and well-characterized by the AFT model “deceleration factor”. AFT model deceleration factors also provided a more intuitive measure of treatment effect than the hazard ratio, and were robust to departures from modeling assumptions. Age-dependent treatment effects, when present, were investigated using quantile regression modeling. These results provide an informative and quantitative summary of survivorship data associated with currently known long-lived mouse models. In addition, from the standpoint of aging research, these statistical approaches have appealing properties and provide valuable tools for the analysis of survivorship data.
doi:10.1016/j.exger.2008.10.005
PMCID: PMC2718836  PMID: 19007875
AFT model; cox; insulin-like growth factor; proportional hazard; survival analysis
18.  HOW LONG WILL MY MOUSE LIVE? MACHINE LEARNING APPROACHES FOR PREDICTION OF MOUSE LIFESPAN 
Prediction of individual lifespan based upon characteristics evaluated at middle-age represents a challenging objective for aging research. In this study, we used machine learning algorithms to construct models that predict lifespan in a stock of genetically heterogeneous mice. Lifespan-prediction accuracy of 22 algorithms was evaluated using a cross-validation approach, in which models were trained and tested with distinct subsets of data. Using a combination of body weight and T-cell subset measures evaluated before two years of age, we show that the lifespan quartile to which an individual mouse belongs can be predicted with an accuracy of 35.3% (± 0.10%). This result provides a new benchmark for the development of lifespan-predictive models, but improvement can be expected through identification of new predictor variables and development of computational approaches. Future work in this direction can provide tools for aging research and will shed light on associations between phenotypic traits and longevity.
PMCID: PMC2693389  PMID: 18840793
aging; classification; longevity; shrunken centroid; T-cell subset; weight
19.  COMPARATIVE ANALYSIS OF MICROARRAY DATA IDENTIFIES COMMON RESPONSES TO CALORIC RESTRICTION AMONG MOUSE TISSUES 
Caloric restriction has been extensively investigated as an intervention that both extends lifespan and delays age-related disease in mammals. In mice, much interest has centered on evaluating gene expression changes induced by caloric restriction (CR) in particular tissue types, but the overall systemic effect of CR among multiple tissues has been examined less extensively. This study presents a comparative analysis of microarray datasets that have collectively examined the effects of CR in ten different tissue types (liver, heart, muscle, hypothalamus, hippocampus, white adipose tissue, colon, kidney, lung, cochlea). Using novel methods for comparative analysis of microarray data, detailed comparisons of the effects of CR among tissues are provided, and 28 genes for which expression response to CR is most shared among tissues are identified. These genes characterize common responses to CR, which consist of both activation and inhibition of stress-response pathways. With respect to liver tissue, transcriptional effects of CR exhibited surprisingly little overlap with those of aging, and a variable degree of overlap with the potential CR-mimetic drug resveratrol. These analyses shed light on the systemic transcriptional activity associated with CR diets, and also illustrate new approaches for comparative analysis of microarray datasets in the context of aging biology.
doi:10.1016/j.mad.2007.11.003
PMCID: PMC2702675  PMID: 18155270
aging; diet restriction; gene expression; longevity; microarray
20.  Heat shock proteins in long-lived worms and mice with insulin/insulin-Like signaling mutations 
Aging  2009;1(6):573-577.
Heat shock proteins (HSPs) have proven to be effective tools for extending invertebrate lifespan, and inC. elegans daf-2 mutants, longevity resulting from loss of insulin / insulin-like signals is at least partly dependent upon elevated HSP expression. In mice, inhibition of the orthologous growth hormone / insulin-like growth factor I (GH / IGF-I) pathway has similar pro-longevity effects. A recent study, however, suggests that loss of GH / IGF-I signals in long-lived mice does not broadly elevate HSP expression, but in fact decreases HSP expression in many tissue types, such as liver and kidney. The contribution of chaperones to the longevity of long-lived mice with altered GH / IGF-I signals may therefore differ from that described in C. elegans daf-2 mutants. This result, in combination with other recent findings, underscores the possibility that systemic overexpression of chaperones will have dissimilar effects on longevity in vertebrate and invertebrate systems.
PMCID: PMC2806032  PMID: 20157538
Aging; chaperone; growth hormone; longevity; Snell; stress
21.  GENES REGULATED BY CALORIC RESTRICTION HAVE UNIQUE ROLES WITHIN TRANSCRIPTIONAL NETWORKS 
Mechanisms of ageing and development  2008;129(10):580-592.
Caloric restriction (CR) has received much interest as an intervention that delays age-related disease and increases lifespan. Whole-genome microarrays have been used to identify specific genes underlying these effects, and in mice, this has led to the identification of genes with expression responses to CR that are shared across multiple tissue types. Such CR-regulated genes represent strong candidates for future investigation, but have been understood only as a list, without regard to their broader role within transcriptional networks. In this study, co-expression and network properties of CR-regulated genes were investigated using data generated by more than 600 Affymetrix microarrays. This analysis identified groups of co-expressed genes and regulatory factors associated with the mammalian CR response, and uncovered surprising network properties of CR-regulated genes. Genes downregulated by CR were highly connected and located in dense network regions. In contrast, CR-upregulated genes were weakly connected and positioned in sparse network regions. Some network properties were mirrored by CR-regulated genes from invertebrate models, suggesting an evolutionary basis for the observed patterns. These findings contribute to a systems-level picture of how CR influences transcription within mammalian cells, and point towards a comprehensive understanding of CR in terms of its influence on biological networks.
doi:10.1016/j.mad.2008.06.001
PMCID: PMC2688445  PMID: 18634819
ageing; connectivity; dietary restriction; lifespan; longevity; microarray
23.  Heterogeneity of Inflammatory and Cytokine Networks in Chronic Plaque Psoriasis 
PLoS ONE  2012;7(3):e34594.
The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients), moderate (39%) and weak inflammatory infiltrates (24%). Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50%) and attenuation of these patterns in a second sub-group (IL-13-weak; 50%). These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2). Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments.
doi:10.1371/journal.pone.0034594
PMCID: PMC3315545  PMID: 22479649
24.  Meta-Profiles of Gene Expression during Aging: Limited Similarities between Mouse and Human and an Unexpectedly Decreased Inflammatory Signature 
PLoS ONE  2012;7(3):e33204.
Background
Skin aging is associated with intrinsic processes that compromise the structure of the extracellular matrix while promoting loss of functional and regenerative capacity. These processes are accompanied by a large-scale shift in gene expression, but underlying mechanisms are not understood and conservation of these mechanisms between humans and mice is uncertain.
Results
We used genome-wide expression profiling to investigate the aging skin transcriptome. In humans, age-related shifts in gene expression were sex-specific. In females, aging increased expression of transcripts associated with T-cells, B-cells and dendritic cells, and decreased expression of genes in regions with elevated Zeb1, AP-2 and YY1 motif density. In males, however, these effects were contrasting or absent. When age-associated gene expression patterns in human skin were compared to those in tail skin from CB6F1 mice, overall human-mouse correspondence was weak. Moreover, inflammatory gene expression patterns were not induced with aging of mouse tail skin, and well-known aging biomarkers were in fact decreased (e.g., Clec7a, Lyz1 and Lyz2). These unexpected patterns and weak human-mouse correspondence may be due to decreased abundance of antigen presenting cells in mouse tail skin with age.
Conclusions
Aging is generally associated with a pro-inflammatory state, but we have identified an exception to this pattern with aging of CB6F1 mouse tail skin. Aging therefore does not uniformly heighten inflammatory status across all mouse tissues. Furthermore, we identified both intercellular and intracellular mechanisms of transcriptome aging, including those that are sex- and species-specific.
doi:10.1371/journal.pone.0033204
PMCID: PMC3296693  PMID: 22413003
25.  SRT1720 improves survival and healthspan of obese mice 
Scientific Reports  2011;1:70.
Sirt1 is an NAD+-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals.
doi:10.1038/srep00070
PMCID: PMC3216557  PMID: 22355589

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