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The Aging Stress Response and Its Implication for AMD Pathogenesis.

ABSTRACT: Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5'AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1?), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1? was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including AMPK, IGF1, MTOR, SIRT1 and PPARGC1A.

SUBMITTER: Blasiak J

PROVIDER: S-EPMC7700335 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The Aging Stress Response and Its Implication for AMD Pathogenesis.

Blasiak Janusz J Pawlowska Elzbieta E Sobczuk Anna A Szczepanska Joanna J Kaarniranta Kai K

International journal of molecular sciences 20201122 22

Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5'AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxiso ...[more]

PMID: 33266495

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Project description:Background All animals must be able to adapt to changes in nutrient quality and supply. One striking aspect of this adaptive response is the extension of lifespan when caloric intake is reduced. These animals are also more resistant to various stresses, including starvation. We have characterized the response of adult Drosophila males and females to starvation and sugar conditions using high density microarrays. Results We have organized the regulated genes into specific metabolic and physiologic pathways. Most of the highly regulated genes have a strong sex bias. In addition to expected sex specific changes, such as egg production in females, we found unexpected biases in sensory systems, amino acid and purine metabolism, and signaling pathways. Comparison of starvation to caloric restriction revealed numerous overlaps. Conclusions Our results support the notion that starvation response shares similarities to caloric restriction. They have relevance for sex specific differences in longevity and in response to nutrient conditions which alter lifespan. Nutrient Conditions and Fly handling Larvae were kept on apple juice agar plates with yeast, and the larvae were raised at 25Â°C. For the developmental control larvae were collected 39-41 h AEL, for the developmental time-points at 51-53 hours and every 12 hours until 99-101 hours. Adult flies were kept at 25Â°C in 50 ml PS-tubes flat bottom (Greiner bio-one, Frickenhausen, Germany) on standard fly food (16.5 g yeast, 81,5 g cornmeal, 8 g agar, 100 ml sugar beet sirup and 200 ml 10% Nipagin in EtOH). Flies were collected that had hatched in 24 hours and kept in groups of ~200 flies/tube. After 5 days we separated males and females and put them in groups of 80/28 ml PS-tube. We allowed for one day CO2 recovery on standard fly food before flies were moved to 1) tubes with yeast paste on PBS soaked filter paper (control) 2) tubes with only PBS soaked filter paper (starvation) or 3) tubes with filter paper soaked in PBS with 20% Sucrose (sugar). After 24 or 48 hours flies were shock frozen in liquid nitrogen and stored at - 80Â°C for further handling. Males and females were assayed separately. For females, we performed 24 and 48 starvation, and 24 and 48 hours sugar. For the males only 24 hour starvation was done, since most died upon 48 hour starvation; and 24 and 48 hour sugar. Briefly, flies were collected within a 24 hour period, allowed to stay together for 4 days, separated into males and females, and allowed one day recovery in normal fly food. Afterwards, the flies were placed into three conditions: fresh yeast plus PBS, PBS or PBS plus 20 % sucrose. These experiments essentially parallel the experimental set up of previous larval experiments (7). The starvation and PBS were then compared with yeast (control).

Project description:Background All animals must be able to adapt to changes in nutrient quality and supply. One striking aspect of this adaptive response is the extension of lifespan when caloric intake is reduced. These animals are also more resistant to various stresses, including starvation. We have characterized the response of adult Drosophila males and females to starvation and sugar conditions using high density microarrays. Results We have organized the regulated genes into specific metabolic and physiologic pathways. Most of the highly regulated genes have a strong sex bias. In addition to expected sex specific changes, such as egg production in females, we found unexpected biases in sensory systems, amino acid and purine metabolism, and signaling pathways. Comparison of starvation to caloric restriction revealed numerous overlaps. Conclusions Our results support the notion that starvation response shares similarities to caloric restriction. They have relevance for sex specific differences in longevity and in response to nutrient conditions which alter lifespan. Nutrient Conditions and Fly handling Larvae were kept on apple juice agar plates with yeast, and the larvae were raised at 25°C. For the developmental control larvae were collected 39-41 h AEL, for the developmental time-points at 51-53 hours and every 12 hours until 99-101 hours. Adult flies were kept at 25°C in 50 ml PS-tubes flat bottom (Greiner bio-one, Frickenhausen, Germany) on standard fly food (16.5 g yeast, 81,5 g cornmeal, 8 g agar, 100 ml sugar beet sirup and 200 ml 10% Nipagin in EtOH). Flies were collected that had hatched in 24 hours and kept in groups of ~200 flies/tube. After 5 days we separated males and females and put them in groups of 80/28 ml PS-tube. We allowed for one day CO2 recovery on standard fly food before flies were moved to 1) tubes with yeast paste on PBS soaked filter paper (control) 2) tubes with only PBS soaked filter paper (starvation) or 3) tubes with filter paper soaked in PBS with 20% Sucrose (sugar). After 24 or 48 hours flies were shock frozen in liquid nitrogen and stored at - 80°C for further handling. Males and females were assayed separately. For females, we performed 24 and 48 starvation, and 24 and 48 hours sugar. For the males only 24 hour starvation was done, since most died upon 48 hour starvation; and 24 and 48 hour sugar. Briefly, flies were collected within a 24 hour period, allowed to stay together for 4 days, separated into males and females, and allowed one day recovery in normal fly food. Afterwards, the flies were placed into three conditions: fresh yeast plus PBS, PBS or PBS plus 20 % sucrose. These experiments essentially parallel the experimental set up of previous larval experiments (7). The starvation and PBS were then compared with yeast (control). Keywords: ordered

Project description:Age related macular degeneration (AMD) is one of the leading causes of blindness. Genetics, environmental insult, and age-related factors all play a key role in altering proteostasis, the homeostatic process regulating protein synthesis, degradation and processing. These factors also play a role in the pathogenesis of AMD and it has been well established that cigarette smoking (CS) initiates AMD pathogenic mechanisms. The primary goal of this study is to elucidate whether CS can induce proteostasis/autophagy-impairment in retinal pigment epithelial (RPE) cells. In our preliminary analysis, it was found that cigarette smoke extract (CSE) induces accumulation of ubiquitinated proteins in the insoluble protein fraction (p < 0.01), which was subsequently mitigated through cysteamine (p < 0.01) or fisetin (p < 0.05) treatment. Further, it was verified that these CSE induced ubiquitinated proteins accumulated in the peri-nuclear spaces (p<0.05) that were cleared- off with cysteamine (p < 0.05) or fisetin (p < 0.05). Moreover, CSE-induced aggresome-formation (LC3B-GFP and Ub-RFP co-localization) and autophagy-flux impairment was significantly (p<0.01) mitigated by cysteamine (p<0.05) or fisetin (p<0.05) treatment, indicating the restoration of CSE-mediated autophagy-impairment. CSE treatment was also found to induce intracellular reactive oxygen species (ROS, p < 0.001) while impacting cell viability (p < 0.001), which was quantified using CMH2DCFDA-dye (ROS) and MTS (proliferation) or propodium iodide staining (cell viability) assays, respectively. Moreover, cysteamine and fisetin treatment ameliorated CS-mediated ROS production (p < 0.05) and diminished cell viability (p < 0.05). Lastly, CSE was found to induce cellular senescence (p < 0.001), which was significantly ameliorated by cysteamine (p < 0.001) or fisetin (p < 0.001). In conclusion, our study indicates that CS induced proteostasis/autophagy-impairment regulates mechanisms associated with AMD pathogenesis. Moreover, autophagy-inducing drugs such as cysteamine or fisetin can ameliorate AMD pathogenesis mechanisms that warrant further investigation in pre-clinical murine models.

Dataset Information

The Aging Stress Response and Its Implication for AMD Pathogenesis.

Publications

The Aging Stress Response and Its Implication for AMD Pathogenesis.

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