Age-dependent Changes In Gene Expression Research Articles

Tau polarizes an aging transcriptional signature to excitatory neurons and glia.

Aging is a major risk factor for Alzheimer's disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell-type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.

Targeted RNAi screen identifies transcriptional mechanisms that prevent premature degeneration of adult photoreceptors.

Aging is associated with a decline in visual function and increased prevalence of ocular disease, correlating with changes in the transcriptome and epigenome of cells in the eye. Here, we sought to identify the transcriptional mechanisms that are necessary to maintain photoreceptor viability and function during aging. To do this, we performed a targeted photoreceptor-specific RNAi screen in Drosophila to identify transcriptional regulators whose knockdown results in premature, age-dependent retinal degeneration. From an initial set of 155 RNAi lines each targeting a unique gene and spanning a diverse set of transcription factors, chromatin remodelers, and histone modifiers, we identified 18 high-confidence target genes whose decreased expression in adult photoreceptors leads to premature and progressive retinal degeneration. These 18 target genes were enriched for factors involved in the regulation of transcription initiation, pausing, and elongation, suggesting that these processes are essential for maintaining the health of aging photoreceptors. To identify the genes regulated by these factors, we profiled the photoreceptor transcriptome in a subset of lines. Strikingly, two of the 18 target genes, Spt5 and domino, show similar changes in gene expression to those observed in photoreceptors with advanced age. Together, our data suggest that dysregulation of factors involved in transcription initiation and elongation plays a key role in shaping the transcriptome of aging photoreceptors. Further, our findings indicate that the age-dependent changes in gene expression not only correlate but might also contribute to an increased risk of retinal degeneration.

Nicotine Patch Improved Autosomal Dominant Sleep-Related Hypermotor Epilepsy

Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is a genetic focal epilepsy associated with mutations in the nicotinic acetylcholine receptor. Mutations in two major nicotinic acetylcholine receptor subunit genes, CHRNA4 and CHRNB2, are commonly associated with ADSHE.1Saberi B. Tehrani B.S. Pore-forming M2 domains of CHRNA4 and CHRNB2 mutations in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) phenotype.Am J Biomed Sci Res. 2019; 1: 222-223Crossref Google Scholar In up to one-third of patients with ADSHE, seizures are refractory to antiseizure medications. Here, we report complete seizure freedom with transdermal nicotine in two pediatric patients from the same family with medically refractory ADSHE. Both patients, who are siblings, presented with exclusively nocturnal focal seizures in childhood, at ages seven years (Patient 1) and 4.5 years (Patient 2). Elelctroencephalographies (EEGs) demonstrated focal electroclinical seizures with hypermotor features and interictal epileptiform discharges in sleep (Fig A and B). Genetic testing revealed a heterozygous missense mutation in CHRNA4 (c.851C>T P.Ser284Leu), which has been described as a common pathogenic gain-of-function mutation in ADSHE. Patient 2 was also diagnosed with an autism spectrum disorder. Both patients had a high nightly seizure burden with minimal improvement on numerous antiseizure medications. A trial of low-dose (7 mg/24 hour) nicotine patch was initiated at ages 16 years (Patient 1) and 14 years (Patient 2). Clinical seizures stopped in both the first night the patch was applied. Follow-up overnight EEGs confirmed seizure freedom and showed normalization or near-normalization of their interictal EEGs (Fig C). Both patients have experienced sustained seizure freedom for over 18 months with nicotine patch 7 mg/24 hour in addition to oxcarbazepine. Transdermal nicotine has been reported to provide marked seizure improvement in a subset of patients with ADSHE.2Fox J. Thodeson D.M. Dolce A.M. Nicotine: a targeted therapy for epilepsy due to nAChR gene variants.J Child Neurol. 2020; 36: 371-377Crossref PubMed Scopus (3) Google Scholar,3Lossius K. de Saint Martin A. Myren-Svelstad S. et al.Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy.Epilepsy Behav. 2020; 105: 106944Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar The siblings reported here have the same CHRNA4 mutation as a 19-year-old patient who had considerable seizure improvement, although not complete resolution, with transdermal nicotine at a higher dose of 14 mg/24 hour.2Fox J. Thodeson D.M. Dolce A.M. Nicotine: a targeted therapy for epilepsy due to nAChR gene variants.J Child Neurol. 2020; 36: 371-377Crossref PubMed Scopus (3) Google Scholar Lossius et al. described striking improvement in seizures and neuropsychological test performance in three six- to 10-year-old children with a different CHRNA4 mutation (c.839C>T P.Ser280Phe) who were treated with 3.5 to 7 mg/24 hour nicotine.3Lossius K. de Saint Martin A. Myren-Svelstad S. et al.Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy.Epilepsy Behav. 2020; 105: 106944Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar With different patient characteristics, age as well as specific mutation might contribute to the efficacy of nicotine patches in controlling seizure activity. Christensen et al. discussed how nicotine increases neuronal firing of cholinergic cells in younger animals, which in turn affects the action potential shape and afterhyperpolarization.4Christensen M.H. Ishibashi M. Nielsen M.L. Leonard C.S. Kohlmeier K.A. Age-related changes in nicotine response of cholinergic and non-cholinergic laterodorsal tegmental neurons: implications for the heightened adolescent susceptibility to nicotine addiction.Neuropharmacology. 2014; 85: 263-283Crossref PubMed Scopus (15) Google Scholar Nicotine has been found to cause age-dependent changes in gene expression in adolescent female rat brains.5Polesskaya O.O. Fryxell K.J. Merchant A.D. et al.Nicotine causes age-dependent changes in gene expression in the adolescent female rat brain.Neurotoxicol Teratol. 2007; 29: 126-140Crossref PubMed Scopus (33) Google Scholar In adolescence, GABAergic signaling in the prefrontal cortex, an important brain region associated with ADSHE, is still developing.6Caballero A. Tseng K.Y. GABAergic function as a limiting factor for prefrontal maturation during adolescence.Trends Neurosci. 2016; 39: 441-448Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Therefore, age might be an important factor when determining whether nicotine patch treatment may be beneficial for patients with ADSHE, with regard to both seizure improvement and neuropsychologic outcomes. A limitation of our report is that our patients are from the same family and therefore may possess unique characteristics that influenced their dramatic response to transdermal nicotine. This possibility might prevent generalization of our results to all patients with same mutation in CHRNA4. Nevertheless, the two siblings reported here add to the small number of pediatric reports documenting the successful use of nicotine patches in ADSHE. Future research is needed to establish whether the nicotine patch could become an adjunct or first-line treatment in a subset of pediatric patients with ADSHE. The authors wish to thank all the patients, family members, and staff members who participated in the study.

Validation of reference genes for whole blood gene expression analysis in cord blood of preterm and full-term neonates and peripheral blood of healthy adults

BackgroundPreterm birth is the leading cause of neonatal morbidity and mortality, but research efforts in neonatology are complicated due to the unavailability of large volume blood samples. Whole blood assays can be used to overcome this problem by performing both functional and gene expression studies using small amounts of blood. Gene expression studies using RT-qPCR estimate mRNA-levels of target genes normalized to reference genes. The goal of this study was to identify and validate stable reference genes applicable to cord blood samples obtained from developing neonates of different gestational age groups as well as to adult peripheral blood samples. Eight reference gene candidates (ACTB, B2M, GAPDH, GUSB, HPRT, PPIB, RPLP0, RPL13) were analyzed using the three published software algorithms Bestkeeper, GeNorm and NormFinder.ResultsA normalization factor consisting of ACTB and PPIB allows for comparative expression analyses of neonatal samples from different gestational age groups. Normalization factors consisting of GAPDH and PPIB or ACTB and GAPDH are suitable when samples from preterm and full-term neonates and adults are compared. However, all candidate reference genes except RPLP0 exhibited significant intergroup gene expression variance and a higher gene expression towards an older age which resulted in a small but statistically significant systematic bias. Systematic analysis of RNA-seq data revealed new reference gene candidates with potentially superior stability.ConclusionsThe current study identified suitable normalization factors and proposed the use of the additional single gene RPLP0 to avoid systematic bias. This combination will enable comparative analyses not only between neonates of different gestational ages, but also between neonates and adults, as it facilitates more detailed investigations of developmental gene expression changes. The use of software algorithms did not prevent unintended systematic bias. This generally highlights the need for careful validation of such results to prevent false interpretation of potential age-dependent changes in gene expression. To identify the most stable reference genes in the future, RNA-seq based global approaches are recommended.

Pharmacogenomics for Drug Dosing in Children: Current Use, Knowledge, and Gaps.

Pharmacogenomics research ranges from the discovery of genetic factors to explain interpatient variability in drug exposure and response to clinical implementation of this knowledge to improve pharmacotherapy. Medications with actionable pharmacogenomic associations are frequently used in children, and therefore pharmacogenomics-guided precision medicine is readily applicable to the pediatric population. Although heritable genetics are considered immutable, the impact of genetic variation in pharmacogenes is modified by other factors such as age-dependent changes in gene expression. Early evidence has emerged indicating that the interaction between ontogeny and pharmacogenomics determines whether or how genetics-based dosing algorithms should be adjusted in children versus adults. However, there is still a paucity of data describing pharmacogenomic associations in patient populations across the life span. Future research is much needed to evaluate the impact of pharmacogenomics on drug dosing specific to the pediatric population, along with consideration of other developmental and physiological factors uniquely related to drug disposition in this population.

Purkinje Neurons with Loss of STIM1 Exhibit Age-Dependent Changes in Gene Expression and Synaptic Components.

The stromal interaction molecule 1 (STIM1) is an ER-Ca2+ sensor and an essential component of ER-Ca2+ store operated Ca2+ entry. Loss of STIM1 affects metabotropic glutamate receptor 1 (mGluR1)-mediated synaptic transmission, neuronal Ca2+ homeostasis, and intrinsic plasticity in Purkinje neurons (PNs). Long-term changes of intracellular Ca2+ signaling in PNs led to neurodegenerative conditions, as evident in individuals with mutations of the ER-Ca2+ channel, the inositol 1,4,5-triphosphate receptor. Here, we asked whether changes in such intrinsic neuronal properties, because of loss of STIM1, have an age-dependent impact on PNs. Consequently, we analyzed mRNA expression profiles and cerebellar morphology in PN-specific STIM1 KO mice (STIM1PKO ) of both sexes across ages. Our study identified a requirement for STIM1-mediated Ca2+ signaling in maintaining the expression of genes belonging to key biological networks of synaptic function and neurite development among others. Gene expression changes correlated with altered patterns of dendritic morphology and greater innervation of PN dendrites by climbing fibers, in aging STIM1PKO mice. Together, our data identify STIM1 as an important regulator of Ca2+ homeostasis and neuronal excitability in turn required for maintaining the optimal transcriptional profile of PNs with age. Our findings are significant in the context of understanding how dysregulated calcium signals impact cellular mechanisms in multiple neurodegenerative disorders.SIGNIFICANCE STATEMENT In Purkinje neurons (PNs), the stromal interaction molecule 1 (STIM1) is required for mGluR1-dependent synaptic transmission, refilling of ER Ca2+ stores, regulation of spike frequency, and cerebellar memory consolidation. Here, we provide evidence for a novel role of STIM1 in maintaining the gene expression profile and optimal synaptic connectivity of PNs. Expression of genes related to neurite development and synaptic organization networks is altered in PNs with persistent loss of STIM1. In agreement with these findings the dendritic morphology of PNs and climbing fiber innervations on PNs also undergo significant changes with age. These findings identify a new role for dysregulated intracellular calcium signaling in neurodegenerative disorders and provide novel therapeutic insights.

Abstract A10: Taz regulates aging of hematopoietic stem cells

Abstract During aging, several tissues display a progressive functional decline potentially leading to malfunction of whole organ systems. This phenomenon can also be observed in the hematopoietic system since aged hematopoietic stem cells (HSCs) display several cell-intrinsic defects, e.g., a strongly reduced self-renewal capacity as well as a skewing towards myeloid differentiation. To investigate a potential involvement of the Hippo pathway in the aging of HSCs, we performed RNA-sequencing in several stem and progenitor populations of young and aged mice, respectively. Here, we identified Taz as one of the most strongly upregulated genes, specifically in long-term hemtatopoietic stem cells (LT-HSCs), those cells that are at the apex of the hematopoietic system. Further analyses revealed that Taz actively contributes to the aging-specific gene expression changes in LT-HSCs and that Tazhigh cells accumulate over time in the LT-HSC compartment. Furthermore, we identified a novel surface marker as a Taz target gene, which allows us to trace Taz activity in the aging mouse and separate Tazhigh from Tazlow cells. Strikingly, our functional characterization revealed that Tazlow cells closely resemble young LT-HSCs whereas Tazhigh cells display a gene expression program that is found in aged LT-HSCs. Consistent with these observations, Tazhigh cells are functionally impaired, e.g., during cell cycle re-entry. Our observations demonstrate that Taz is potently induced during aging of the blood system and most prominently in the LT-HSC compartment where it contributes to age-dependent gene expression changes and functional decline of hematopoietic stem cells. Citation Format: Anna Mura-Meszaros, Florian Heidel, Bjoern von Eyss. Taz regulates aging of hematopoietic stem cells [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A10.

Age-related cognitive decline in baboons: modeling the prodromal phase of Alzheimer's disease and related dementias.

The aging of brain cells and synaptic loss are the major underlying pathophysiological processes contributing to the progressive decline in cognitive functions and Alzheimer’s disease. The difference in cognitive performances observed between adult and aged subjects across species highlights the decline of brain systems with age. The inflection point in age-related cognitive decline is important for our understanding of the pathophysiology of neurodegenerative diseases and for timing therapeutic interventions. Humans and nonhuman primates share many similarities including age-dependent changes in gene expression and decline in neural and immune functions. Given these evolutionary conserved organ systems, complex human-like behavioral and age-dependent changes may be modeled and monitored longitudinally in nonhuman primates. We integrated three clinically relevant outcome measures to investigate the effect of age on cognition, motor function and diurnal activity in aged baboons. We provide evidence of a naturally-occurring age-dependent precipitous decline in movement planning, in learning novel tasks, in simple discrimination and in motivation. These results suggest that baboons aged ~20 years (equivalent to ~60 year old humans) may offer a relevant model for the prodromal phase of Alzheimer’s disease and related dementias to investigate mechanisms involved in the precipitous decline in cognitive functions and to develop early therapeutic interventions

UNIQUE TRANSCRIPTOME OF AGE-ASSOCIATED VISCERAL FAT-RESIDENT GAMMA DELTA T CELLS

Gamma delta T cells (Tγδ) are a unique group of immune cells that perform both adaptive and innate functions. We recently identified a population of Tγδ cells which show an age-dependent expansion in the visceral fat of both mice and humans. However, little is known regarding the role of these cells in the fat. The purpose of this study was to begin delineating their role by: (1) comparing the gene expression profile of visceral fat-resident Tγδ to conventional T cells (Tconv) and to circulating Tγδ, and (2) identifying age-dependent changes in gene expression within the visceral fat-resident Tγδ population. Tγδ and Tconv were magnetically purified from blood and visceral fat of young and aged mice. Using NanoString technology, we found that overall transcriptomes of Tγδ in fat and blood were strikingly different. Transcriptomes of Tγδ and Tconv within the fat were more similar, but distinct with the former having high representation of pathways related to inflammation, cytokine and chemokine signaling, and macrophage function and the latter having high representation of pathways related to T- and B-cell function and TNF superfamily. Within the Tγδ population we identified significant (>1.8-fold change, p<0.01) age-associated differences in expression for 8 upregulated genes (C6, Cxcl13, Prg2, Il5ra, Ctla4, Marco, Ccl8, Il10) and 10 downregulated genes (Col4a1, Xcl1, Col1a1, Cfd, Col3a1, Lbp, Thbs1, Klrd1, Il6st, Ccl17). These genes will guide further research aimed at understanding the role of these cells and how their age-associated changes contribute to chronic inflammation, an underlying component of multiple age-related diseases.

Age-related regulation and region-specific distribution of ion channel subunits promoting atrial fibrillation in human left and right atria.

Age-induced changes and electrical remodelling are important components of the atrial fibrillation (AF) substrate. To study regional distribution and age-dependent changes in gene expression that may promote AF in human atria. Human left atrial (LA) and right atrial (RA) tissue samples were obtained from donor hearts unsuitable for transplantation and from patients undergoing mitral valve repair. Atrial fibrillation was mimicked in vitro by tachypacing of human atrial tissue slices. Ionic currents were studied by the whole-cell patch-clamp technique; gene expression was analysed by real-time qPCR and immunoblotting. Both healthy RA and RA from older patients showed greater CACNA1c mRNA and CaV1.2 protein expression than LA. No age-dependent changes of Kir2.1 expression in both atria were seen. Remodelling occurred in a qualitatively similar manner in RA and LA. IK1 and Kir2.1 protein expression increased with AF. MiR-1, miR-26a, and miR-26b were down-regulated with AF in both atria. ICa,L was decreased. CACNA1c and CACNA2b expression decreased and miR-328 increased in RA and LA during AF. Ex vivo tachypacing of human atrial slices replicated these findings. There were age-dependent increases in miR-1 and miR-328, while miR-26a decreased with age in atrial tissues from healthy human donor hearts. Features of electrical remodelling in man occur in a qualitatively similar manner in both human atria. Age-related miR-328 dysregulation and reduced ICa,L may contribute to increased AF susceptibility with age.

Deletion of p16 expressing senescent cells improves muscle mass and age‐dependent outcomes in multiple organ systems

BackgroundCellular senescence is defined as permanent cell cycle arrest due to upregulation of cyclin dependent kinases such as p16. Senescent cells accumulate with age and can contribute to aging related pathologies. Recently, deletion of p16 expressing senescent cells in vivo has been shown to increase healthspan and lifespan, and ameliorate some tissue specific pathologies in mice. However, it is unknown whether cellular senescence plays a role in age associated declines in skeletal muscle function. We hypothesized that deletion of p16 expressing senescent cells will preserve age‐induced declines in muscle function and mass.MethodsTo eliminate senescent cells in vivo, we utilized p16‐3MR transgenic mice in which administration of the drug ganciclovir will induce cell death in p16 expressing cells. Mice were treated with 25 mg/kg ganciclovir or saline (control) intraperitoneally for 5 days at monthly intervals from 20–26 months of age. Animals were sacrificed at 26 months of age, muscles were weighed, and gastrocnemius muscles were tested for force production in vivo, while extensor digitorum longus and soleus muscles were tested in vitro. Muscle fiber cross sectional areas and fiber type were determined by immunohistochemistry. Additional organs were snap frozen for downstream protein, cytokine, and RNA analyses. mRNA expression was measured using qPCR.ResultsMice that were treated with ganciclovir lived longer and had a lower incidence of cancer than control mice. Muscle masses of the soleus, tibialis anterior and gastrocnemius were greater in ganciclovir‐treated mice compared with controls. The higher muscle mass in treated mice was not associated with any shift in fiber type distribution, increase in fiber cross‐sectional area, or any expansion of the volume of extracellular matrix, suggesting the higher muscle mass was due to preservation of fiber number. There was no effect of p16 deletion on muscle force production. However, upon examining muscle, spinal cord, serum and lung tissue, p16 deletion impacted age‐dependent changes in gene expression and cytokines.ConclusionsDifferential effects of senescent cell deletion on skeletal muscle mass and function suggests the role of senescent cells in skeletal muscle aging may be context specific. Further studies are needed to more thoroughly determine tissue‐specific benefits, but our work suggests that deletion of senescent cells even late in life may provide protection against global aging processes.Support or Funding InformationAG051442K12GM111725This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Rat Prefrontal-Cortex Transcriptome: Effects of Aging and Sporadic Alzheimer's Disease-Like Pathology.

Alzheimer's disease (AD) is the most widespread late-life dementia and involves the prefrontal cortex, a vulnerable brain region implicated in memory, emotion, cognition, and decision-making behavior. To understand the molecular differences between the effects of aging and AD on the prefrontal cortex, this study characterized the age-dependent changes in gene expression in Wistar rats (control) and OXYS rats (rodents that simulate key characteristics of sporadic AD) using RNA sequencing. We found that major altered biological processes during aging in Wistar rats were associated with immune processes. Gene expression changes during development of AD-like pathology as well as at the preclinical stage were related to neuronal plasticity, catalytic activity, lipid and immune processes, and mitochondria. A comparison of genes between data sets "OXYS rats" and "human AD" revealed similarity in expression alterations of genes related primarily to mitochondrial function; immune, endocrine, and circulatory systems; signal transduction; neuronal and synaptic processes; hypoxia; and apoptosis. Expression changes in mitochondrial processes identified in OXYS rats by RNA sequencing were confirmed by ultrastructural neuronal organelle alterations and low activity of respiratory chain complexes I, IV, and V in cortical mitochondria, suggesting that mitochondrial dysfunction appears to mediate or possibly even initiate the development of AD.

Transcriptomic profiling of the human brain reveals that altered synaptic gene expression is associated with chronological aging

Aging is a biologically universal event, and yet the key events that drive aging are still poorly understood. One approach to generate new hypotheses about aging is to use unbiased methods to look at change across lifespan. Here, we have examined gene expression in the human dorsolateral frontal cortex using RNA- Seq to populate a whole gene co-expression network analysis. We show that modules of co-expressed genes enriched for those encoding synaptic proteins are liable to change with age. We extensively validate these age-dependent changes in gene expression across several datasets including the publically available GTEx resource which demonstrated that gene expression associations with aging vary between brain regions. We also estimated the extent to which changes in cellular composition account for age associations and find that there are independent signals for cellularity and aging. Overall, these results demonstrate that there are robust age-related alterations in gene expression in the human brain and that genes encoding for neuronal synaptic function may be particularly sensitive to the aging process.

Gene expression changes in male accessory glands during ageing are accompanied by reproductive decline in Drosophila melanogaster.

Senescence is accompanied by loss of reproductive functions. Here, we studied reproductive ageing in Drosophila melanogaster males and asked whether the expected decline in male reproductive success is due to diminished functionality of the male accessory gland (AG). The male AG produces the majority of seminal fluid proteins (SFPs) transferred to the female at mating. SFPs induce female postmating changes and are key to male reproductive success. We measured age-dependent gene expression changes for five representative SFP genes in males from four different age groups ranging from 1 to 6weeks after eclosion. Simultaneously, we also measured male reproductive success in postmating traits mediated by transfer of these five SFPs. We found a decreased in male SFP gene expression with advancing age and an accompanying decline in male postmating success. Hence, male reproductive senescence is associated with a decline in functionality of the male AG. While overall individual SFP genes decreased in expression, our results point towards the idea that the composition of an ejaculate might change with male age as the rate of change was variable for those five genes.

Age-Dependent Pancreatic Gene Regulation Reveals Mechanisms Governing Human β Cell Function

Intensive efforts are focused on identifying regulators of human pancreatic islet cell growth and maturation to accelerate development of therapies for diabetes. After birth, islet cell growth and function are dynamically regulated; however, establishing these age-dependent changes in humans has been challenging. Here, we describe a multimodal strategy for isolating pancreatic endocrine and exocrine cells from children and adults to identify age-dependent gene expression and chromatin changes on a genomic scale. These profiles revealed distinct proliferative and functional states of islet α cells or βcells and histone modifications underlying age-dependent gene expression changes. Expression of SIX2 and SIX3, transcription factors without prior known functions in the pancreas and linked to fasting hyperglycemia risk, increased with age specifically in human islet β cells. SIX2 and SIX3 were sufficient toenhance insulin content or secretion in immature β cells. Our work provides a unique resource to study human-specific regulators of islet cell maturation and function.

Age-related changes in tissue macrophages precede cardiac functional impairment.

Cardiac tissue macrophages (cTMs) are abundant in the murine heart but the extent to which the cTM phenotype changes with age is unknown. This study characterizes aging-dependent phenotypic changes in cTM subsets. Using theCx3cr1(GFP/+) mouse reporter line where GFP marks cTMs, and the tissue macrophage marker Mrc1, we show that two major cardiac tissue macrophage subsets, Mrc1-GFP(hi) and Mrc1+GFP(hi) cTMs, are present in the young (<10 week old) mouse heart, and a third subset, Mrc1+GFP(lo), comprises ~50% of total Mrc1+ cTMs from 30 weeks of age. Immunostaining and functional assays show that Mrc1+ cTMs are the principal myeloid sentinels in the mouse heart and that they retain proliferative capacity throughout life. Gene expression profiles of the two Mrc1+ subsets also reveal that Mrc1+GFP(lo) cTMs have a decreased number of immune response genes (Cx3cr1, Lpar6, CD9, Cxcr4, Itga6 and Tgfβr1), and an increased number of fibrogenic genes (Ltc4s, Retnla, Fgfr1, Mmp9 and Ccl24), consistent with a potential role for cTMs in cardiac fibrosis. These findings identify early age-dependent gene expression changes in cTMs, with significant implications for cardiac tissue injury responses and aging-associated cardiac fibrosis.

Type 1 diabetes in mice and men: gene expression profiling to investigate disease pathogenesis

Type 1 diabetes (T1D) is a complex polygenic disease that is triggered by various environmental factors in genetically susceptible individuals. The emphasis placed on genome-wide association studies to explain the genetics of T1D has failed to advance our understanding of T1D pathogenesis or identify biomarkers of disease progression or therapeutic targets. Using the nonobese diabetic (NOD) mouse model of T1D and the non-disease prone congenic NOD.B10 mice, our laboratory demonstrated striking tissue-specific and age-dependent changes in gene expression during disease progression. We established a "roadmap" of differential gene expression and used this to identify candidate genes in mice (and human orthologs) that play a role in disease pathology. Here, we describe two genes, Deformed epidermal autoregulatory factor 1 (Deaf1) and Adenosine A1 receptor (Adora1), that are differentially expressed and alternatively spliced in the pancreatic lymph nodes or islets of NOD mice and T1D patients to form dominant-negative non-functional isoforms. Loss of Deaf1 function leads to reduced peripheral tissue antigen expression in lymph node stromal cells and may contribute to a breakdown in peripheral tolerance, while reduced Adora1 function results in an early intrinsic alpha cell defect that may explain the hyperglucagonemia and resulting beta cell stress observed prior to the onset of diabetes. Remarkably, both genes were also alternatively spliced in the same tissues of auto-antibody positive prediabetic patients, and these splicing events resulted in similar downstream effects as those seen in NOD mice. These findings demonstrate the value of gene expression profiling in studying disease pathogenesis in T1D.

Molecular aging of the brain, neuroplasticity, and vulnerability to depression and other brain-related disorders

The increased risk for neurodegenerative and neuropsychiatric disorders associated with extended lifespan has long suggested mechanistic links between chronological age and brain-related disorders, including depression, Recent characterizations of age-dependent gene expression changes now show that aging of the human brain engages a specific set of biological pathways along a continuous lifelong trajectory, and that the same genes that are associated with normal brain aging are also frequently and similarly implicated in depression and other brain-related disorders. These correlative observations suggest a model of age-by-disease molecular interactions, in which brain aging promotes biological changes associated with diseases, and additional environmental factors and genetic variability contribute to defining disease risk or resiliency trajectories. Here we review the characteristic features of brain aging in terms of changes in gene function over time, and then focus on evidence supporting accelerated molecular aging in depression. This proposed age-by-disease biological interaction model addresses the current gap in research between "normal" brain aging and its connection to late-life diseases. The implications of this model are profound, as it provides an investigational framework for identifying critical moderating factors, outlines opportunities for early interventions or preventions, and may form the basis for a dimensional definition of diseases that goes beyond the current categorical system.

The role of the nervous system in aging and longevity

The role of the nervous system in aging and longevity

Gestational Age-Dependent Changes in Gene Expression of Metabolic Enzymes and Transporters in Pregnant Mice

Pregnancy-induced changes in drug pharmacokinetics can be explained by changes in expression of drug-metabolizing enzymes and transporters and/or normal physiology. In this study, we determined gestational age-dependent expression profiles for all metabolic enzyme and transporter genes in the maternal liver, kidney, small intestine, and placenta of pregnant mice by microarray analysis. We specifically examined the expression of genes important for xenobiotic, bile acid, and steroid hormone metabolism and disposition, namely, cytochrome P450s (Cyp), UDP-glucuronosyltranserases (Ugt), sulfotransferases (Sult), and ATP-binding cassette (Abc), solute carrier (Slc), and solute carrier organic anion (Slco) transporters. Few Ugt and Sult genes were affected by pregnancy. Cyp17a1 expression in the maternal liver increased 3- to 10-fold during pregnancy, which was the largest observed change in the maternal tissues. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 expression in the liver decreased on gestation days (gd) 15 and 19 compared with nonpregnant controls (gd 0). In contrast, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. In the placenta, Cyp expression on gd 10 and 15 was upregulated compared with gd 19. Notable changes were also observed in Abc and Slc transporters. Abcc3 expression in the liver and Abcb1a, Abcc4, and Slco4c1 expression in the kidney were downregulated on gd 15 and 19. In the placenta, Slc22a3 (Oct3) expression on gd 10 was 90% lower than that on gd 15 and 19. This study demonstrates important gestational age-dependent expression of metabolic enzyme and transporter genes, which may have mechanistic relevance to drug disposition in human pregnancy.