Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophila reveals a species-general network of aging and metabolic genes.

BACKGROUND: Several interventions increase lifespan in model organisms, including reduced insulin/insulin-like growth factor-like signaling (IIS), FOXO transcription factor activation, dietary restriction, and superoxide dismutase (SOD) over-expression. One question is whether these manipulations function through different mechanisms, or whether they intersect on common processes affecting aging. RESULTS: A doxycycline-regulated system was used to over-express manganese-SOD (MnSOD) in adult Drosophila, yielding increases in mean and maximal lifespan of 20%. Increased lifespan resulted from lowered initial mortality rate and required MnSOD over-expression in the adult. Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes and suggesting a true delay in physiological aging, rather than a novel phenotype. Strikingly, cross-dataset comparisons indicated that the pattern of gene expression caused by MnSOD was similar to that observed in long-lived Caenorhabditis elegans insulin-like signaling mutants and to the xenobiotic stress response, thus exposing potential conserved longevity promoting genes and implicating detoxification in Drosophila longevity. CONCLUSION: The data suggest that MnSOD up-regulation and a retrograde signal of reactive oxygen species from the mitochondria normally function as an intermediate step in the extension of lifespan caused by reduced insulin-like signaling in various species. The results implicate a species-conserved net of coordinated genes that affect the rate of senescence by modulating energetic efficiency, purine biosynthesis, apoptotic pathways, endocrine signals, and the detoxification and excretion of metabolites.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophila reveals a species-general network of aging and metabolic genes.

BACKGROUND: Several interventions increase lifespan in model organisms, including reduced insulin/insulin-like growth factor-like signaling (IIS), FOXO transcription factor activation, dietary restriction, and superoxide dismutase (SOD) over-expression. One question is whether these manipulations function through different mechanisms, or whether they intersect on common processes affecting aging. RESULTS: A doxycycline-regulated system was used to over-express manganese-SOD (MnSOD) in adult Drosophila, yielding increases in mean and maximal lifespan of 20%. Increased lifespan resulted from lowered initial mortality rate and required MnSOD over-expression in the adult. Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes and suggesting a true delay in physiological aging, rather than a novel phenotype. Strikingly, cross-dataset comparisons indicated that the pattern of gene expression caused by MnSOD was similar to that observed in long-lived Caenorhabditis elegans insulin-like signaling mutants and to the xenobiotic stress response, thus exposing potential conserved longevity promoting genes and implicating detoxification in Drosophila longevity. CONCLUSION: The data suggest that MnSOD up-regulation and a retrograde signal of reactive oxygen species from the mitochondria normally function as an intermediate step in the extension of lifespan caused by reduced insulin-like signaling in various species. The results implicate a species-conserved net of coordinated genes that affect the rate of senescence by modulating energetic efficiency, purine biosynthesis, apoptotic pathways, endocrine signals, and the detoxification and excretion of metabolites.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Similarities and differences in the gene expression profiles of MnSOD over-expressing and aging in

<p><b>Copyright information:</b></p><p>Taken from "Transcriptional profiling of MnSOD-mediated lifespan extension in reveals a species-general network of aging and metabolic genes"</p><p>http://genomebiology.com/2007/8/12/R262</p><p>Genome Biology 2007;8(12):R262-R262.</p><p>Published online 9 Dec 2007</p><p>PMCID:PMC2246264.</p><p></p> Diagram of sampling points for the transgenic and control flies used in the gene expression profiling studies. For the control, treated (+DOX) and untreated (-DOX) flies were sampled at the 50% survival of the untreated sample, which was also approximately the 50% survival point of the treated flies. For the transgenic line, untreated flies (-DOX) were sampled at their 50% survival and a sample was also taken for DOX treated (+DOX) flies at the same time point (same chronological age). An additional sample was taken for the treated flies (+DOX) at their 50% survival (same 'physiological age'). Venn diagram depicting gene expression changes due to MnSOD over-expression and the overlap with those that occur during normal aging [10]. Yellow highlighting indicates genes whose expression levels are altered at both time points. Green shading indicates genes identified as potential biomarkers of aging. Orange or blue text denotes genes up- or down-regulated, respectively, in a given condition or in the same direction in multiple conditions. Green or purple text denotes genes up- or down-regulated, respectively, in MnSOD over-expressing flies when the direction of change is opposite in old flies. Several representative functional categorizations are noted for the various gene sets. GPCR, GTP-binding protein-coupled receptor; Hsp, heat shock protein; TCA, tricarboxylic acid cycle

MnSOD over-expression during adulthood is necessary and sufficient for lifespan extension and does not result in increased oxidative stress

<p><b>Copyright information:</b></p><p>Taken from "Transcriptional profiling of MnSOD-mediated lifespan extension in reveals a species-general network of aging and metabolic genes"</p><p>http://genomebiology.com/2007/8/12/R262</p><p>Genome Biology 2007;8(12):R262-R262.</p><p>Published online 9 Dec 2007</p><p>PMCID:PMC2246264.</p><p></p> Aconitase enzyme activity measured in mU/mg plotted against age for the following lines: control (a), (b), and (c). The effect of timing of MnSOD induction on lifespan for control (d), (e) and (f)

Longevity promoting genes conserved between mutants and MnSOD over-expressing

<p><b>Copyright information:</b></p><p>Taken from "Transcriptional profiling of MnSOD-mediated lifespan extension in reveals a species-general network of aging and metabolic genes"</p><p>http://genomebiology.com/2007/8/12/R262</p><p>Genome Biology 2007;8(12):R262-R262.</p><p>Published online 9 Dec 2007</p><p>PMCID:PMC2246264.</p><p></p> and ortholog matches that are differentially expressed in response to MnSOD over-expression (both time points) and in mutants in a dependent manner. Expected values from BLASTP are indicated as follows: *5 × 1

Proposed mechanism for MnSOD-mediated mitochondria to nucleus signaling and crosstalk with the IIS pathway

<p><b>Copyright information:</b></p><p>Taken from "Transcriptional profiling of MnSOD-mediated lifespan extension in reveals a species-general network of aging and metabolic genes"</p><p>http://genomebiology.com/2007/8/12/R262</p><p>Genome Biology 2007;8(12):R262-R262.</p><p>Published online 9 Dec 2007</p><p>PMCID:PMC2246264.</p><p></p> The data suggest a model in which MnSOD catalyzed detoxification of superoxide results in increased intracellular hydrogen peroxide levels that mediate various signaling events. Such events include the activation of the JNK and NF-κB pathways. Pathway components that demonstrate increased expression due to MnSOD over-expression are highlighted in yellow. Note that genes up-regulated at both time points are indicated by black text, those up-regulated only at the first time point assayed are indicated by grey text, whereas those up-regulated only at the later time point are denoted by blue text. Solid lines indicate direct interactions, dashed lines indicate indirect interactions, dotted lines indicate translocation events, and '?' indicates hypothetical or speculative elements. The proposed retrograde signal from the mitochondria to the nucleus mediated by hydrogen peroxide is shown in red. Numerous genes are up-regulated as a result of these signaling events and some were also identified as being similarly altered in long-lived IIS mutants, suggesting their role as species-general lifespan effectors. These genes are indicated as are the biological processes that they contribute to. Hydrogen peroxide reversibly inhibits PTEN [105], an upstream inhibitor of IIS, resulting in activation of phosphoinositide 3-kinase (PI3K) signaling. In accordance with this, gene expression levels are up-regulated as are some downstream components of the IIS pathway in response to MnSOD over-expression. Increased IIS activity results in dFOXO inactivation and since MnSOD may be a direct transcriptional target, this suggests that feedback regulation may occur. The proposed feedback loop between MnSOD and the IIS pathway is also shown in red. Crosstalk between TOR and its binding partner, raptor, with the mitochondrion has been suggested [111], although the molecular basis has not been elucidated. As shown here, hydrogen peroxide may participate in this mechanism. ET, electron transport; ILP, insulin-like peptide