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

Curtis, Christina; Landis, Gary N.; Folk, Donna G.; Wehr, Nancy B.; Hoe, Nicholas; Waskar, Morris; Abdueva, Diana; Skvortsov, Dmitriy; Ford, Daniel; Luu, Allan; Badrinath, Ananth; Levine, Rodney L.; Bradley, Timothy J.; Tavaré, Simon; Tower, John

doi:10.1186/gb-2007-8-12-r262

Cited by 124 publications

(120 citation statements)

References 131 publications

(173 reference statements)

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“…One popular suggestion is that long-lived animals have enhanced protection and repair mechanisms that prevent against cellular damage induced by reactive oxygen species (Curtis et al 2007;Kregel and Zhang 2007;Beckman and Ames 1998). While there is currently considerable debate on the exact role of ROS-induced oxidative stress in ageing (Gems and Doonan 2009;Perez et al 2009;Speakman and Selman 2011), evidence from long-lived invertebrate IIS mutants suggests that increased antioxidant protection and/or reduced oxidative stress can be associated with longevity.…”

Section: Introductionmentioning

confidence: 99%

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

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Withers

Selman

2012

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Insulin receptor substrate-1 null (Irs1 −/− ) mice are long lived and importantly they also demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls. Currently, the molecular mechanisms that underlie lifespan extension in long-lived mice are unclear although protection against oxidative damage may be important. Here, we determined both the activities of several intracellular antioxidants and levels of oxidative damage in brain, skeletal muscle, and liver of Irs1 −/− and WT mice at 80, 450, and 700 days of age, predicting that long-lived Irs1 −/− mice would be protected against oxidative damage. We measured activities of both intracellular superoxide dismutases (SOD); cytosolic (CuZnSOD) and mitochondrial (MnSOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), and reduced glutathione (GHS). Of these, only hepatic CAT was significantly altered (increased) in Irs1 −/− mice. In addition, the levels of protein oxidation (protein carbonyl content) and lipid peroxidation (4-hydroxynonenal) were unaltered in Irs1 −/− mice, although the hepatic GSH/ GSSG ratio, indicating an oxidized environment, was significantly lower in long-lived Irs1 −/− mice. Overall, our results do not support the premise that lifespan extension in Irs1 −/− mice is associated with greater tissue antioxidant protection or reduced oxidative damage.

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Section: Introductionmentioning

confidence: 99%

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

Page

Withers

Selman

2012

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“…Numbers above the shaded diagonal denote overlapping genes between lists, below the diagonal are P values, and shaded is the number of unique genes in the lists. The data include genes responding to aging in C (AC) and LS lines (ALS); genes significantly different between C and LS lines at the same chronological age (Ch) and same physiological age (P), and the overlap between the two (OL) (present study); genes responding to aging (Landis) (23); genes responding to a life-span-extending over-expression of MnSOD at the same chronological age (MnSOD Ch) and same physiological age (MnSOD P) (Curtis et al 2007); genes correlated with variance in life span (Lifespan) and starvation (Starv) in isofemale lines (27); genes responding to selection for increased longevity (Long), starvation resistance (Starv sel), heat knock-down (KD), and by rearing at constant 30°C (Sørensen et al 2007); and genes responding to a brief heat shock (Heat) (Kristensen et al 2005) NS non-significant…”

Section: Age-dependent Transcriptome Changesmentioning

confidence: 99%

“…We investigated the transcriptional selection response in young, middleaged, and old flies, and contrasting expression in C and LS lines at the same chronological age and when the same proportion of a cohort had died (same physiological age), elaborating on the design of Curtis et al (Fig. 1) (Curtis et al 2007). The genes that had significantly different transcript abundance between the C and LS lines at the same chronological age belonged to one of two categories: candidates for affecting longevity, playing a causal role in the prolonged life span of the LS lines, or biomarkers of physiological age, reflecting the proposed delayed senescence of LS lines.…”

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confidence: 99%

Flies selected for longevity retain a young gene expression profile

Sarup

Sørensen

Loeschcke

2010

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We investigated correlated responses in the transcriptomes of longevity-selected lines of Drosophila melanogaster to identify pathways that affect life span in metazoan systems. We evaluated the gene expression profile in young, middle-aged, and old male flies, finding that 530 genes were differentially expressed between selected and control flies when measured at the same chronological age. The longevity-selected flies consistently showed expression profiles more similar to control flies one age class younger than control flies of the same age. This finding is in accordance with a younger gene expression profile in longevity-selected lines. Among the genes downregulated in longevity-selected lines, we found a clear over-representation of genes involved in immune functions, supporting the hypothesis of a lifeshortening effect of an overactive immune system, known as inflammaging. We judged the physiological age as the level of cumulative mortality. Eighty-four genes were differentially expressed between the control and longevity-selected lines at the same physiological age, and the overlap between the same chronological and physiological age gene lists included 40 candidate genes for increased longevity. Among these candidates were genes with roles in starvation resistance, immune response regulation, and several that have not yet been linked to longevity. Investigating these genes would provide new knowledge of the pathways that affect life span in invertebrates and, potentially, mammals.

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“…HSPs can counteract proteo-toxicity and favor stress resistance to the organism which may be causally linked to an increase in life span vis-à-vis positive impact on the aging-related functional declines (Tower 2009(Tower , 2011. Genome-wide studies on age-associated gene expression changes in flies have shown the upregulation of heat shock genes (hsps) (Curtis et al 2007;Landis et al 2012). In addition, modulated expression of hsps (hsp70, hsp27, and hsp22) has been reported to alter life span in flies (Kim et al 2010;Liao et al 2008;Tatar et al 1997) and higher level of HSPs is reported in longerlived mammals and birds (Salway et al 2011).…”

mentioning

confidence: 99%

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Pandey

Vimal

Chandra

et al. 2014

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Dichloroacetic acid (DCA), a water disinfection by-product, has attained emphasis due to its prospect for clinical use against different diseases including cancer along with negative impact on organisms. However, these reports are based on the toxicological as well clinical data using comparatively higher concentrations of DCA without much of environmental relevance. Here, we evaluate cellular as well as organismal effects of DCA at environmentally and mild clinically relevant concentrations (0.02-20.0 μg/ml) using an established model organism, Drosophila melanogaster. Flies were fed on food mixed with test concentrations of DCA for 12-48 h to examine the induction of reactive oxygen species (ROS) generation, oxidative stress (OS), heat shock genes (hsps) and cell death along with organismal responses. We also examined locomotor performance, ROS generation, glutathione (GSH) depletion, expression of GSH-synthesizing genes (gclc and gclm), and hsps at different days (0, 10, 20, 30, 40, 50) of the age in flies after prolonged DCA exposure. We observed mild OS and induction of antioxidant defense system in 20.0 μg/ml DCA-exposed organism after 24 h. After prolonged exposure to DCA, exposed organism exhibited improved survival, elevated expression of hsp27, gclc, and gclm concomitant with lower ROS generation and GSH depletion and improved locomotor performance. Conversely, hsp27 knockdown flies exhibited reversal of the above end points. The study provides evidence for the attenuation of cellular and functional decline in aged Drosophila after prolonged DCA exposure and the effect of hsp27 modulation which further incites studies towards the therapeutic application of DCA.

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

Cited by 124 publications

References 131 publications

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

Flies selected for longevity retain a young gene expression profile

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

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