Evidence for premature aging in a Drosophila model of Werner syndrome

Cassidy, Deirdre; Epiney, Derek G.; Salameh, Charlotte; Zhou, Luhan T.; Salomon, Robert N.; Schirmer, Aaron E.; McVey, Mitch; Bolterstein, Elyse

doi:10.1016/j.exger.2019.110733

Cited by 8 publications

(41 citation statements)

References 75 publications

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“…Elevated ambient temperature has been shown to cause physiological and behavioral changes in Drosophila [ 46 , 47 ], increase mutation frequency [ 15 ], and increase ROS levels [ 48 ], providing different mechanisms of DNA damage and stress response. We also tested starvation as a stressor as it has been shown to not only deprive organisms of nutrients, but also reduce DNA repair enzyme functionality due to lower ATP production [ 49 ] and to further examine low body fat in WRNexo Δ [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

“…We hypothesized that WRNexo Δ would be more sensitive to starvation stress based on our previous work showing that WRNexo Δ larvae have lower body fat and WRNexo Δ adult females have lower body weight in comparison to w 1118 controls [ 37 ]. Indeed, we found that both male and female WRNexo Δ adults had shorter lifespans under starvation compared to w 1118 controls ( Figure 3 A and Figure S8 ).…”

Section: Resultsmentioning

confidence: 99%

“…Continuous monitoring of locomotor activity and hourly activity averages were assessed using Drosophila Activity Monitors (DAM2, TriKinetics) as described previously [ 37 ]. Briefly, flies were allowed to mate for 24–48 h post-eclosion before being moved to DAMs.…”

Section: Methodsmentioning

confidence: 99%

“…Our WS model flies are mutant in WRNexo ( WRNexo Δ ), which is homologous to the exonuclease portion of human WRN [ 33 , 34 , 35 ]. While WRNexo lacks a RecQ helicase domain, it has been shown to have functional similarity to human WRN [ 33 , 34 , 35 , 36 , 37 ], providing us with a unique opportunity to investigate the exonuclease-dependent functions of WRN in the absence of the helicase. WRNexo Δ flies have deficiencies in DNA repair [ 38 ] and display phenotypes consistent with accelerated aging observed in WS including shortened lifespan, increased tumor incidence, lower locomotor activity, and low larval body fat [ 37 ].…”

Section: Introductionmentioning

confidence: 99%

“…While WRNexo lacks a RecQ helicase domain, it has been shown to have functional similarity to human WRN [ 33 , 34 , 35 , 36 , 37 ], providing us with a unique opportunity to investigate the exonuclease-dependent functions of WRN in the absence of the helicase. WRNexo Δ flies have deficiencies in DNA repair [ 38 ] and display phenotypes consistent with accelerated aging observed in WS including shortened lifespan, increased tumor incidence, lower locomotor activity, and low larval body fat [ 37 ]. Here, we use our WS fly model to better understand the link between stress response and aging by describing their responses to common stressors (oxidative, thermal, and starvation).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Stress Responses in a Drosophila Model of Werner Syndrome

et al. 2021

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As organisms age, their resistance to stress decreases while their risk of disease increases. This can be shown in patients with Werner syndrome (WS), which is a genetic disease characterized by accelerated aging along with increased risk of cancer and metabolic disease. WS is caused by mutations in WRN, a gene involved in DNA replication and repair. Recent research has shown that WRN mutations contribute to multiple hallmarks of aging including genomic instability, telomere attrition, and mitochondrial dysfunction. However, questions remain regarding the onset and effect of stress on early aging. We used a fly model of WS (WRNexoΔ) to investigate stress response during different life stages and found that stress sensitivity varies according to age and stressor. While larvae and young WRNexoΔ adults are not sensitive to exogenous oxidative stress, high antioxidant activity suggests high levels of endogenous oxidative stress. WRNexoΔ adults are sensitive to stress caused by elevated temperature and starvation suggesting abnormalities in energy storage and a possible link to metabolic dysfunction in WS patients. We also observed higher levels of sleep in aged WRNexoΔ adults suggesting an additional adaptive mechanism to protect against age-related stress. We suggest that stress response in WRNexoΔ is multifaceted and evokes a systemic physiological response to protect against cellular damage. These data further validate WRNexoΔ flies as a WS model with which to study mechanisms of early aging and provide a foundation for development of treatments for WS and similar diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of Stress Responses in a Drosophila Model of Werner Syndrome

et al. 2021

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20(S)-ginsenoside Rg3 promotes myoblast differentiation and protects against myotube atrophy via regulation of the Akt/mTOR/FoxO3 pathway

Wang

Ren

Chen

et al. 2020

Biochemical Pharmacology

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Dietary restriction fails to extend lifespan of Drosophila model of Werner syndrome

Sember,

Chennakesavula,

Beard

et al. 2024

G3: Genes, Genomes, Genetics

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Werner syndrome (WS) is a rare genetic disease in humans, caused by mutations in the WRN gene that encodes a protein containing helicase and exonuclease domains. WS is characterized by symptoms of accelerated aging in multiple tissues and organs, involving increased risk of cancer, heart failure, and metabolic dysfunction. These conditions ultimately lead to the premature mortality of patients with WS. In this study, using the null mutant flies (WRNexoΔ) for the gene WRNexo (CG7670), homologous to the exonuclease domain of WRN in humans, we examined how diets affect the lifespan, stress resistance, and sleep/wake patterns of a Drosophila model of WS. We observed that dietary restriction (DR), one of the most robust non-genetic interventions to extend lifespan in animal models, failed to extend the lifespan of WRNexoΔ mutant flies and even had a detrimental effect in females. Interestingly, the mean lifespan of WRNexoΔ mutant flies was not reduced on a protein-rich diet compared to that of wild-type flies. Compared to wild type control flies, the mutant flies also exhibited altered responses to DR in their resistance to starvation and oxidative stress, as well as changes in sleep/wake patterns. These findings show that the WRN protein is necessary for mediating the effects of DR and suggest that the exonuclease domain of WRN plays an important role in metabolism in addition to its primary role in DNA repair and genome stability.

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Evidence for premature aging in a Drosophila model of Werner syndrome

Cited by 8 publications

References 75 publications

Characterization of Stress Responses in a Drosophila Model of Werner Syndrome

Characterization of Stress Responses in a Drosophila Model of Werner Syndrome

20(S)-ginsenoside Rg3 promotes myoblast differentiation and protects against myotube atrophy via regulation of the Akt/mTOR/FoxO3 pathway

Dietary restriction fails to extend lifespan of Drosophila model of Werner syndrome

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