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LySR, a lysosomal surveillance response that extends healthspan [Exp1]

ABSTRACT: Lysosomes are cytoplasmic organelles that are central for the degradation of macromolecules to maintain cellular homeostasis and health. Here, we discovered an adaptive lysosomal transcriptional response that we termed the lysosomal stress response (LySR). Typified by the induction of a large group of transcripts involved in lysosomal function and proteolysis, the LySR can be triggered by silencing of specific vacuolar H+-ATPase subunits in Caenorhabditis elegans. Notably, LySR activation enhances the clearance of protein aggregates in worm models of Alzheimer's and Huntington’s disease and amyotrophic lateral sclerosis, thereby boosting fitness and extending lifespan, a response that is controlled by the GATA transcription factor, ELT-2. Activating the LySR pathway may therefore represent an attractive mechanism to reduce protein aggregation and, as such, extend healthspan.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE196021 | GEO | 2023/02/03

REPOSITORIES: GEO

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LySR, a lysosomal surveillance response that extends healthspan [Exp2]

Project description:Lysosomes are cytoplasmic organelles that are central for the degradation of macromolecules to maintain cellular homeostasis and health. Here, we discovered an adaptive lysosomal transcriptional response that we termed the lysosomal stress response (LySR). Typified by the induction of a large group of transcripts involved in lysosomal function and proteolysis, the LySR can be triggered by silencing of specific vacuolar H+-ATPase subunits in Caenorhabditis elegans. Notably, LySR activation enhances the clearance of protein aggregates in worm models of Alzheimer's and Huntington’s disease and amyotrophic lateral sclerosis, thereby boosting fitness and extending lifespan, a response that is controlled by the GATA transcription factor, ELT-2. Activating the LySR pathway may therefore represent an attractive mechanism to reduce protein aggregation and, as such, extend healthspan.

2023-02-03 | GSE196022 | GEO

A non-classical LysR type transcriptional regulator PA2206 is required for an effective oxidative stress response in Pseudomonas aeruginosa.

Project description:LysR-type transcriptional regulators (LTTRs) are emerging as key circuit components in regulating microbial stress responses and are implicated in modulating oxidative stress in the human opportunistic pathogen Pseudomonas aeruginosa. The oxidative stress response encapsulates several strategies to overcome the deleterious effects of reactive oxygen species. However, many of the regulatory components and associated molecular mechanisms underpinning this key adaptive response remain to be characterised. Comparative analysis of publically available transcriptomic datasets led to the identification of a novel LTTR, PA2206, whose expression was altered in response to a range of host signals in addition to oxidative stress. PA2206 was found to be required for tolerance to H2O2 in vitro and lethality in vivo in the Zebrafish embryo model of infection. Transcriptomic analysis in the presence of H2O2 showed that PA2206 altered the expression of 58 genes, including a large repertoire of oxidative stress and iron responsive genes, independent of the master regulator of oxidative stress, OxyR. Contrary to the classic mechanism of LysR regulation, PA2206 did not autoregulate its own expression and did not influence expression of adjacent or divergently transcribed genes. The PA2214-15 operon was identified as a direct target of PA2206 with truncated promoter fragments revealing binding to the 5M-bM-^@M-^Y-ATTGCCTGGGGTTAT-3M-bM-^@M-^Y LysR box adjacent to the predicted -35 region. PA2206 also interacted with the pvdS promoter suggesting a global dimension to the PA2206 regulon, and suggests PA2206 is an important regulatory component of P. aeruginosa adaptation during oxidative stress. Six samples were analysed in total, three biological replicates of the PA2206 mutant and PA2206 complemented strains. Each biological replicate included three technical replicates.

2013-01-01 | E-GEOD-23367 | biostudies-arrayexpress

A non-classical LysR type transcriptional regulator PA2206 is required for an effective oxidative stress response in Pseudomonas aeruginosa.

Project description:LysR-type transcriptional regulators (LTTRs) are emerging as key circuit components in regulating microbial stress responses and are implicated in modulating oxidative stress in the human opportunistic pathogen Pseudomonas aeruginosa. The oxidative stress response encapsulates several strategies to overcome the deleterious effects of reactive oxygen species. However, many of the regulatory components and associated molecular mechanisms underpinning this key adaptive response remain to be characterised. Comparative analysis of publically available transcriptomic datasets led to the identification of a novel LTTR, PA2206, whose expression was altered in response to a range of host signals in addition to oxidative stress. PA2206 was found to be required for tolerance to H2O2 in vitro and lethality in vivo in the Zebrafish embryo model of infection. Transcriptomic analysis in the presence of H2O2 showed that PA2206 altered the expression of 58 genes, including a large repertoire of oxidative stress and iron responsive genes, independent of the master regulator of oxidative stress, OxyR. Contrary to the classic mechanism of LysR regulation, PA2206 did not autoregulate its own expression and did not influence expression of adjacent or divergently transcribed genes. The PA2214-15 operon was identified as a direct target of PA2206 with truncated promoter fragments revealing binding to the 5’-ATTGCCTGGGGTTAT-3’ LysR box adjacent to the predicted -35 region. PA2206 also interacted with the pvdS promoter suggesting a global dimension to the PA2206 regulon, and suggests PA2206 is an important regulatory component of P. aeruginosa adaptation during oxidative stress.

2013-01-01 | GSE23367 | GEO

A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice.

Project description: Not available

| S-EPMC5609489 | biostudies-literature

Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice.

Project description: Not available

| S-EPMC7304595 | biostudies-literature

A lysosomal surveillance response that extends healthspan

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-02-03 | GSE196023 | GEO

The circadian clock gene period extends healthspan in aging Drosophila melanogaster.

Project description: Not available

| S-EPMC2815745 | biostudies-literature

Mitochondrial chaperone TRAP1 activates the mitochondrial UPR and extends healthspan in Drosophila.

Project description: Not available

| S-EPMC4310785 | biostudies-literature

SRT1720 extends healthspan and lifespan in diet-induced obese mice

Project description:Activation of Sirt1, the mammalian homolog of an NAD+-dependent deacetylase known to modulate lifespan in lower organisms, is thought to hold promise as a strategy for delaying aging in mammals. SRT1720, a novel compound developed as a specific and potent activator of Sirt1, has shown promising effects to glucose homeostasis in short-term studies of rats and mice. Here we show SRT1720 extends both mean and maximum lifespan of mice fed a high-fat diet and has concrete benefits to health including reduced liver steatosis and increased insulin sensitivity and locomotor activity. Gene expression profiles and markers of inflammation and apoptosis were also restored to levels more reflective of standard diet controls. Furthermore, the benefits incurred by SRT1720 occurred in the absence of any observable toxicity. The current findings provide hope that safe and effective treatments may be developed to mitigate age-related diseases and enhance lifespan in humans. Male C57BL/6J mice obtained at 12 weeks of age were maintained on a standard purified mouse diet (AIN-93G) until 56 weeks of age prior to the start of the experiment. Beginning at 56 weeks of age, the SD group was fed a standard AIN-93G diet for the duration of the study. Three separate groups were placed on a high-fat diet (HFD) (AIN-93G modified by the addition of hydrogenated coconut oil to provide 60% of calories from fat) or HFD + 30mg/kg body weight SRT1720 (HFD-L) or 100mg/kg body weight SRT1720 (HFD-H) and remained on those diets throughout the study. All mice were fed ad libitum. Food intake and body weight were measured biweekly for the duration of the study.

2011-08-17 | E-GEOD-19102 | biostudies-arrayexpress

Identification of a novel LysR family transcriptional regulator controlling acquisition of sulfur sources in Acinetobacter baumannii.

Project description:RNA sequencing transcriptomics was performed on a highly multidrug resistant A. baumannii strain belonging to international clone I, AB5075_UW and a transposon insertion inactivated mutant of ABUW_1016 (cbl), which encodes a LysR-type transcriptional regulator.Transcriptomics suggests that Cbl controls expression of the genes involved in acquisition and reduction of various sulfur sources in A. baumannii.

2022-12-15 | GSE183337 | GEO

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