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Disease epidemiology during ageing shows a transition from cancer to degenerative chronic disorders as dominant contributors to mortality in the old. Nevertheless, it has remained unclear to what extent molecular signatures of ageing reflect this phenomenon. Here we report on the identification of a conserved transcriptomic signature of ageing based on gene expression data from four vertebrate species across four tissues. We find that ageing-associated transcriptomic changes follow trajectories similar to the transcriptional alterations observed in degenerative ageing diseases but are in opposite direction to the transcriptomic alterations observed in cancer. We confirm the existence of a similar antagonism on the genomic level, where a majority of shared risk alleles which increase the risk of cancer decrease the risk of chronic degenerative disorders and vice versa. These results reveal a fundamental trade-off between cancer and degenerative ageing diseases that sheds light on the pronounced shift in their epidemiology during ageing., Nature Communications, 9, ISSN:2041-1723

Summary The brains of teleost fish show extensive adult neurogenesis and neuronal regeneration. The patterns of gene regulation during fish brain aging are unknown. The short-lived teleost fish Nothobranchius furzeri shows markers of brain aging including reduced learning performances, gliosis, and reduced adult neurogenesis. We used RNA-seq to quantify genome-wide transcript regulation and sampled five different time points to characterize whole-genome transcript regulation during brain aging of N. furzeri. Comparison with human datasets revealed conserved up-regulation of ribosome, lysosome, and complement activation and conserved down-regulation of synapse, mitochondrion, proteasome, and spliceosome. Down-regulated genes differ in their temporal profiles: neurogenesis and extracellular matrix genes showed rapid decay, synaptic and axonal genes a progressive decay. A substantial proportion of differentially expressed genes (~40%) showed inversion of their temporal profiles in the last time point: spliceosome and proteasome showed initial down-regulation and stress-response genes initial up-regulation. Extensive regulation was detected for chromatin remodelers of the DNMT and CBX families as well as members of the polycomb complex and was mirrored by an up-regulation of the H3K27me3 epigenetic mark. Network analysis showed extensive coregulation of cell cycle/DNA synthesis genes with the uncharacterized zinc-finger protein ZNF367 as central hub. In situ hybridization showed that ZNF367 is expressed in neuronal stem cell niches of both embryonic zebrafish and adult N. furzeri. Other genes down-regulated with age, not previously associated with adult neurogenesis and with similar patterns of expression are AGR2, DNMT3A, KRCP, MEX3A, SCML4, and CBX1. CBX7, on the other hand, was up-regulated with age.

The original version of this Article contained an error in the spelling of the author Jule Müller, which was incorrectly given as Julia Müller. Additionally, in Fig. 4a, the blue-red colour scale for fold change in ageing/disease regulation included a blue stripe in place of a red stripe at the right-hand end of the scale. These errors have been corrected in both the PDF and HTML versions of the Article.

Dietary restriction (DR) extends lifespan and promotes metabolic health in evolutionary distinct species. DR is widely believed to promote longevity by causing an energy deficit leading to increased mitochondrial respiration. We here show that inhibitors of mitochondrial complex I promote physical activity, stress resistance as well as lifespan of Caenorhabditis elegans despite normal food uptake, i.e. in the absence of DR. However, complex I inhibition does not further extend lifespan in dietarily restricted nematodes, indicating that impaired complex I activity mimics DR. Promotion of longevity due to complex I inhibition occurs independently of known energy sensors, including DAF-16/FoxO, as well as AAK-2/AMPK and SIR-2.1/sirtuins, or both. Consistent with the concept of mitohormesis, complex I inhibition transiently increases mitochondrial formation of reactive oxygen species (ROS) that activate PMK-1/p38 MAP kinase and SKN-1/NRF-2. Interference with this retrograde redox signal as well as ablation of two redox-sensitive neurons in the head of the worm similarly prevents extension of lifespan. These findings unexpectedly indicate that DR extends organismal lifespan through transient neuronal ROS signaling rather than sensing of energy depletion, providing unexpected pharmacological options to promote exercise capacity and healthspan despite unaltered eating habits., Molecular Metabolism, 2 (2)

The brain plays a central role in organismal aging but is itself most sensitive to aging-related functional impairments and pathologies. Insights into processes underlying brain aging are the basis to positively impact brain health. Using high-throughput RNA sequencing and quantitative polymerase chain reaction (PCR), we monitored cerebral gene expression in mice throughout their whole lifespan (2, 9, 15, 24, and 30 months). Differentially expressed genes were clustered in 6 characteristic temporal expression profiles, 3 of which revealed a distinct change between 24 and 30 months, the period when most mice die. Functional annotation of these genes indicated a participation in protection against cancer and oxidative stress. Specifically, the most enriched pathways for the differentially expressed genes with higher expression at 30 versus 24 months were found to be glutathione metabolism and chemokine signaling pathway, whereas those lower expressed were enriched in focal adhesion and pathways in cancer. We therefore conclude that brains of very old mice are protected from certain aspects of aging, in particular cancer, which might have an impact on organismal health and lifespan.

FungiFun assigns functional annotations to fungal genes or proteins and performs gene set enrichment analysis. Based on three different classification methods (FunCat, GO and KEGG), FungiFun categorizes genes and proteins for several fungal species on different levels of annotation detail. It is web-based and accessible to users without any programming skills. FungiFun is the first tool offering gene set enrichment analysis including the FunCat categorization. Two biological datasets for Aspergillus fumigatus and Candida albicans were analyzed using FungiFun, providing an overview of the usage and functions of the tool. FungiFun is freely accessible at https://www.omnifung.hki-jena.de/FungiFun/.

Scope: Carnitine improves protein accretion, muscle mass, and protein:fat accretion in piglets. The underlying mechanisms, however, are largely unknown. Methods and results: To gain insight into mechanisms through which carnitine exerts these effects, we fed piglets either a control or a carnitine-supplemented diet, and analyzed the transcriptome in skeletal muscle. Carnitine concentrations in plasma and muscle were about four-fold higher in the carnitine group when compared to the control group. Transcript profiling revealed 211 genes to be differentially expressed in muscle by carnitine supplementation. The identified genes were mainly involved in molecular processes such as cytoskeletal protein binding, insulin-like growth factor (IGF) binding, transcription factor activity, and insulin receptor binding. Identified genes with the molecular function transcription factor activity encoded primarily transcription factors, most of which were down-regulated by carnitine, including pro-apoptotic transcription factors such as proto-oncogene c-fos, proto-oncogene c-jun and activating transcription factor 3. Furthermore, atrophy-related genes such as atrogin-1, MuRF1, and DRE1 were significantly down-regulated by carnitine. IGF signalling and insulin signalling were identified as significantly up-regulated regulatory pathways in the carnitine group. Conclusion: Carnitine may have beneficial effects on skeletal muscle mass through stimulating the anabolic IGF-1 pathway and suppressing pro-apoptotic and atrophy-related genes, which are involved in apoptosis of muscle fibers and proteolysis of muscle proteins, respectively.

Background Rotenone inhibits the electron transfer from complex I to ubiquinone, in this way interfering with the electron transport chain in mitochondria. This chain of events induces increased levels of intracellular reactive oxygen species, which in turn can contribute to acceleration of telomere shortening and induction of DNA damage, ultimately resulting in aging. In this study, we investigated the effect of rotenone treatment in human fibroblast strains. Results For the first time we here describe that rotenone treatment induced a hormetic effect in human fibroblast strains. We identified a number of genes which were commonly differentially regulated due to low dose rotenone treatment in fibroblasts independent of their cell origin. However, these genes were not among the most strongly differentially regulated genes in the fibroblast strains on treatment with rotenone. Thus, if there is a common hormesis regulation, it is superimposed by cell strain specific individual responses. We found the rotenone induced differential regulation of pathways common between the two fibroblast strains, being weaker than the pathways individually regulated in the single fibroblast cell strains. Furthermore, within the common pathways different genes were responsible for this different regulation. Thus, rotenone induced hormesis was related to a weak pathway signal, superimposed by a stronger individual cellular response, a situation as found for the differentially expressed genes. Conclusion We found that the concept of hormesis also applies to in vitro aging of primary human fibroblasts. However, in depth analysis of the genes as well as the pathways differentially regulated due to rotenone treatment revealed cellular hormesis being related to weak signals which are superimposed by stronger individual cell-internal responses. This would explain that in general hormesis is a small effect. Our data indicate that the observed hormetic phenotype does not result from a specific strong well-defined gene or pathway regulation but from weak common cellular processes induced by low levels of reactive oxygen species. This conclusion also holds when comparing our results with those obtained for C. elegans in which the same low dose rotenone level induced a life span extending, thus hormetic effect. Electronic supplementary material The online version of this article (doi:10.1186/s12979-015-0038-8) contains supplementary material, which is available to authorized users.

Summary The killifish Nothobranchius furzeri is the shortest-lived vertebrate that can be bred in the laboratory. Its rapid growth, early sexual maturation, fast aging, and arrested embryonic development (diapause) make it an attractive model organism in biomedical research. Here, we report a draft sequence of its genome that allowed us to uncover an intra-species Y chromosome polymorphism representing—in real time—different stages of sex chromosome formation that display features of early mammalian XY evolution "in action." Our data suggest that gdf6Y , encoding a TGF-β family growth factor, is the master sex-determining gene in N. furzeri . Moreover, we observed genomic clustering of aging-related genes, identified genes under positive selection, and revealed significant similarities of gene expression profiles between diapause and aging, particularly for genes controlling cell cycle and translation. The annotated genome sequence is provided as an online resource (http://www.nothobranchius.info/NFINgb).

Replicative senescence is of fundamental importance for the process of cellular aging, since it is a property of most of our somatic cells. Here, we elucidated this process by comparing gene expression changes, measured by RNA-seq, in fibroblasts originating from two different tissues, embryonic lung (MRC-5) and foreskin (HFF), at five different time points during their transition into senescence. Although the expression patterns of both fibroblast cell lines can be clearly distinguished, the similar differential expression of an ensemble of genes was found to correlate well with their transition into senescence, with only a minority of genes being cell line specific. Clustering-based approaches further revealed common signatures between the cell lines. Investigation of the mRNA expression levels at various time points during the lifespan of either of the fibroblasts resulted in a number of monotonically up- and downregulated genes which clearly showed a novel strong link to aging and senescence related processes which might be functional. In terms of expression profiles of differentially expressed genes with age, common genes identified here have the potential to rule the transition into senescence of embryonic lung and foreskin fibroblasts irrespective of their different cellular origin.

Ageing has been defined as a global decline in physiological function depending on both environmental and genetic factors. Here we identify gene transcripts that are similarly regulated during physiological ageing in nematodes, zebrafish and mice. We observe the strongest extension of lifespan when impairing expression of the branched-chain amino acid transferase-1 (bcat-1) gene in C. elegans, which leads to excessive levels of branched-chain amino acids (BCAAs). We further show that BCAAs reduce a LET-363/mTOR-dependent neuro-endocrine signal, which we identify as DAF-7/TGFβ, and that impacts lifespan depending on its related receptors, DAF-1 and DAF-4, as well as ultimately on DAF-16/FoxO and HSF-1 in a cell-non-autonomous manner. The transcription factor HLH-15 controls and epistatically synergizes with BCAT-1 to modulate physiological ageing. Lastly and consistent with previous findings in rodents, nutritional supplementation of BCAAs extends nematodal lifespan. Taken together, BCAAs act as periphery-derived metabokines that induce a central neuro-endocrine response, culminating in extended healthspan., Nature Communications, 6, ISSN:2041-1723

D-Glucosamine (GlcN) is a freely available and commonly used dietary supplement potentially promoting cartilage health in humans, which also acts as an inhibitor of glycolysis. Here we show that GlcN, independent of the hexosamine pathway, extends Caenorhabditis elegans life span by impairing glucose metabolism that activates AMP-activated protein kinase (AMPK/AAK-2) and increases mitochondrial biogenesis. Consistent with the concept of mitohormesis, GlcN promotes increased formation of mitochondrial reactive oxygen species (ROS) culminating in increased expression of the nematodal amino acid-transporter 1 (aat-1) gene. Ameliorating mitochondrial ROS formation or impairment of aat-1-expression abolishes GlcN-mediated life span extension in an NRF2/SKN-1-dependent fashion. Unlike other calorie restriction mimetics, such as 2-deoxyglucose, GlcN extends life span of ageing C57BL/6 mice, which show an induction of mitochondrial biogenesis, lowered blood glucose levels, enhanced expression of several murine amino-acid transporters, as well as increased amino-acid catabolism. Taken together, we provide evidence that GlcN extends life span in evolutionary distinct species by mimicking a low-carbohydrate diet., D-Glucosamine is a dietary supplement widely used for the treatment of osteoarthritis. Here Weimer et al. show that D-glucosamine extends the life span of Caenorhabditis elegans and of mice by mimicking the molecular effects of a diet low in carbohydrates.

Cellular senescence is described to be a consequence of telomere erosion during the replicative life span of primary human cells. Quiescence should therefore not contribute to cellular aging but rather extend lifespan. Here we tested this hypothesis and demonstrate that cultured long-term quiescent human fibroblasts transit into senescence due to similar cellular mechanisms with similar dynamics and with a similar maximum life span as proliferating controls, even under physiological oxygen conditions. Both, long-term quiescent and senescent fibroblasts almost completely fail to undergo apoptosis. The transition of long-term quiescent fibroblasts into senescence is also independent of HES1 which protects short-term quiescent cells from becoming senescent. Most significantly, DNA damage accumulates during senescence as well as during long-term quiescence at physiological oxygen levels. We suggest that telomere-independent, potentially maintenance driven gradual induction of cellular senescence during quiescence is a counterbalance to tumor development.

Glucose restriction mimicked by feeding the roundworm Caenorhabditis elegans with 2-deoxy-D-glucose (DOG) - a glucose molecule that lacks the ability to undergo glycolysis - has been found to increase the life span of the nematodes considerably. To facilitate understanding of the molecular mechanisms behind this life extension, we analyzed transcriptomes of DOG-treated and untreated roundworms obtained by RNA-seq at different ages. We found that, depending on age, DOG changes the magnitude of the expression values of about 2 to 24 percent of the genes significantly, although our results reveal that the gross changes introduced by DOG are small compared to the age-induced changes. We found that 27 genes are constantly either up- or down-regulated by DOG over the whole life span, among them several members of the cytochrome P450 family. The monotonic change with age of the temporal expression patterns of the genes was investigated, leading to the result that 21 genes reverse their monotonic behaviour under impaired glycolysis. Put simply, the DOG-treatment reduces the gross transcriptional activity but increases the interconnectedness of gene expression. However, a detailed analysis of network parameters discloses that the introduced changes differ remarkably between individual signalling pathways. We found a reorganization of the hubs of the mTOR pathway when standard diet is replaced by DOG feeding. By constructing correlation based difference networks, we identified those signalling pathways that are most vigorously changed by impaired glycolysis. Taken together, we have found a number of genes and pathways that are potentially involved in the DOG-driven extension of life span of C. elegans. Furthermore, our results demonstrate how the network structure of ageing-relevant signalling pathways is reorganised under impaired glycolysis., PLoS ONE, 8 (10), ISSN:1932-6203

Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. In contrast with recent observations, here we find that overexpression of sir-2.1, the ortholog of mammalian SirT1, does extend Caenorhabditis elegans lifespan. Sirtuins mandatorily convert NAD(+) into nicotinamide (NAM). We here find that NAM and its metabolite, 1-methylnicotinamide (MNA), extend C. elegans lifespan, even in the absence of sir-2.1. We identify a previously unknown C. elegans nicotinamide-N-methyltransferase, encoded by a gene now named anmt-1, to generate MNA from NAM. Disruption and overexpression of anmt-1 have opposing effects on lifespan independent of sirtuins, with loss of anmt-1 fully inhibiting sir-2.1-mediated lifespan extension. MNA serves as a substrate for a newly identified aldehyde oxidase, GAD-3, to generate hydrogen peroxide, which acts as a mitohormetic reactive oxygen species signal to promote C. elegans longevity. Taken together, sirtuin-mediated lifespan extension depends on methylation of NAM, providing an unexpected mechanistic role for sirtuins beyond histone deacetylation.

Arsenite is one of the most toxic chemical substances known and is assumed to exert detrimental effects on viability even at lowest concentrations. By contrast and unlike higher concentrations, we here find that exposure to low-dose arsenite promotes growth of cultured mammalian cells. In the nematode C. elegans, low-dose arsenite promotes resistance against thermal and chemical stressors and extends lifespan of this metazoan, whereas higher concentrations reduce longevity. While arsenite causes a transient increase in reactive oxygen species (ROS) levels in C. elegans, co-exposure to ROS scavengers prevents the lifespan-extending capabilities of arsenite, indicating that transiently increased ROS levels act as transducers of arsenite effects on lifespan, a process known as mitohormesis. This requires two transcription factors, namely DAF-16 and SKN-1, which employ the metallothionein MTL-2 as well as the mitochondrial transporter TIN-9.1 to extend lifespan. Taken together, low-dose arsenite extends lifespan, providing evidence for nonlinear dose-response characteristics of toxin-mediated stress resistance and longevity in a multicellular organism.

Background The African annual fish Nothobranchius furzeri has over recent years been established as a model species for ageing-related studies. This is mainly based on its exceptionally short lifespan and the presence of typical characteristics of vertebrate ageing. To substantiate its role as an alternative vertebrate ageing model, a transcript catalogue is needed, which can serve e.g. as basis for identifying ageing-related genes. Results To build the N. furzeri transcript catalogue, thirteen cDNA libraries were sequenced using Sanger, 454/Roche and Solexa/Illumina technologies yielding about 39 Gb. In total, 19,875 protein-coding genes were identified and annotated. Of these, 71% are represented by at least one transcript contig with a complete coding sequence. Further, transcript levels of young and old fish of the strains GRZ and MZM-0403, which differ in lifespan by twofold, were studied by RNA-seq. In skin and brain, 85 differentially expressed genes were detected; these have a role in cell cycle control and proliferation, inflammation and tissue maintenance. An RNA-seq experiment for zebrafish skin confirmed the ageing-related relevance of the findings in N. furzeri. Notably, analyses of transcript levels between zebrafish and N. furzeri but also between N. furzeri strains differed largely, suggesting that ageing is accelerated in the short-lived N. furzeri strain GRZ compared to the longer-lived strain MZM-0403. Conclusions We provide a comprehensive, annotated N. furzeri transcript catalogue and a first transcriptome-wide insight into N. furzeri ageing. This data will serve as a basis for future functional studies of ageing-related genes.

MicroRNAs are regulators of gene expression. We used miRNA-seq by the Illumina platform to quantify and compare the temporal miRNA expression profiles in the brain of a short-lived (GRZ) and a longer-lived strain (MZM) of the annual fish Nothobranchius furzeri. We used fuzzy-c-means clustering to group miRNAs with similar profiles. In MZM, we found tumor suppressors with known negative interactions with MYC and/or positive interactions with TP53 among up-regulated miRNAs (e.g. miR-23a, miR-26a/b, miR-29a/b and miR-101a) in aged animals. Conversely, we found oncogenes which are MYC targets among down-regulated miRNAs (miR-7a, members of miR cluster 17∼92). These latter were previously shown to be regulated in human replicative aging. In addition, three regulated miRNAs (miR-181c, miR-29a and miR-338) are known to be age-regulated and to globally contribute to regulation of their targets in the human brain. Therefore, there appears to be a degree of evolutionarily conservation in age-dependent miRNA expression between humans and N. furzeri. GRZ showed specific regulation of some miRNAs, notably a marked up-regulation of miR-124, a miRNA important for neuronal differentiation. The two strains differ in their miRNA expression profiles already at sexual maturity. Short lifespan in GRZ could therefore be--at least partially--due to dysregulated miRNA expression.

BACKGROUND: Millions of humans and animals suffer from superficial infections caused by a group of highly specialized filamentous fungi, the dermatophytes, which exclusively infect keratinized host structures. To provide broad insights into the molecular basis of the pathogenicity-associated traits, we report the first genome sequences of two closely phylogenetically related dermatophytes, Arthroderma benhamiae and Trichophyton verrucosum, both of which induce highly inflammatory infections in humans. RESULTS: 97% of the 22.5 megabase genome sequences of A. benhamiae and T. verrucosum are unambiguously alignable and collinear. To unravel dermatophyte-specific virulence-associated traits, we compared sets of potentially pathogenicity-associated proteins, such as secreted proteases and enzymes involved in secondary metabolite production, with those of closely related onygenales (Coccidioides species) and the mould Aspergillus fumigatus. The comparisons revealed expansion of several gene families in dermatophytes and disclosed the peculiarities of the dermatophyte secondary metabolite gene sets. Secretion of proteases and other hydrolytic enzymes by A. benhamiae was proven experimentally by a global secretome analysis during keratin degradation. Molecular insights into the interaction of A. benhamiae with human keratinocytes were obtained for the first time by global transcriptome profiling. Given that A. benhamiae is able to undergo mating, a detailed comparison of the genomes further unraveled the genetic basis of sexual reproduction in this species. CONCLUSIONS: Our results enlighten the genetic basis of fundamental and putatively virulence-related traits of dermatophytes, advancing future research on these medically important pathogens.

Background Cellular senescence is induced either internally, for example by replication exhaustion and cell division, or externally, for example by irradiation. In both cases, cellular damages accumulate which, if not successfully repaired, can result in senescence induction. Recently, we determined the transcriptional changes combined with the transition into replicative senescence in primary human fibroblast strains. Here, by γ-irradiation we induced premature cellular senescence in the fibroblast cell strains (HFF and MRC-5) and determined the corresponding transcriptional changes by high-throughput RNA sequencing. Results Comparing the transcriptomes, we found a high degree of similarity in differential gene expression in replicative as well as in irradiation induced senescence for both cell strains suggesting, in each cell strain, a common cellular response to error accumulation. On the functional pathway level, “Cell cycle” was the only pathway commonly down-regulated in replicative and irradiation-induced senescence in both fibroblast strains, confirming the tight link between DNA repair and cell cycle regulation. However, “DNA repair” and “replication” pathways were down-regulated more strongly in fibroblasts undergoing replicative exhaustion. We also retrieved genes and pathways in each of the cell strains specific for irradiation induced senescence. Conclusion We found the pathways associated with “DNA repair” and “replication” less stringently regulated in irradiation induced compared to replicative senescence. The strong regulation of these pathways in replicative senescence highlights the importance of replication errors for its induction. Electronic supplementary material The online version of this article (doi:10.1186/s40659-016-0095-2) contains supplementary material, which is available to authorized users.

Mutations and genetic variability affect gene expression and lifespan, but the impact of variations in gene expression within individuals on their aging-related mortality is poorly understood. We performed a longitudinal study in the short-lived killifish, Nothobranchius furzeri, and correlated quantitative variations in gene expression during early adult life with lifespan. Shorter- and longer-lived individuals differ in their gene expression before the onset of aging-related mortality; differences in gene expression are more pronounced early in life. We identified mitochondrial respiratory chain complex I as a hub in a module of genes whose expression is negatively correlated with lifespan. Accordingly, partial pharmacological inhibition of complex I by the small molecule rotenone reversed aging-related regulation of gene expression and extended lifespan in N. furzeri by 15%. These results support the use of N. furzeri as a vertebrate model for identifying the protein targets, pharmacological modulators, and individual-to-individual variability associated with aging., Cell Systems, 2 (2), ISSN:2405-4720

SummaryImpaired insulin and IGF-1 signaling (iIIS) in C. elegans daf-2 mutants extends life span more than 2-fold. Constitutively, iIIS increases mitochondrial activity and reduces reactive oxygen species (ROS) levels. By contrast, acute impairment of daf-2 in adult C. elegans reduces glucose uptake and transiently increases ROS. Consistent with the concept of mitohormesis, this ROS signal causes an adaptive response by inducing ROS defense enzymes (SOD, catalase), culminating in ultimately reduced ROS levels despite increased mitochondrial activity. Inhibition of this ROS signal by antioxidants reduces iIIS-mediated longevity by up to 60%. Induction of the ROS signal requires AAK-2 (AMPK), while PMK-1 (p38) and SKN-1 (NRF-2) are needed for the retrograde response. IIIS upregulates mitochondrial L-proline catabolism, and impairment of the latter impairs the life span-extending capacity of iIIS while L-proline supplementation extends C. elegans life span. Taken together, iIIS promotes L-proline metabolism to generate a ROS signal for the adaptive induction of endogenous stress defense to extend life span.