Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction

Jiang, Yi‐Zhou; Yan, F.; Feng, Zhong‐Ping; Lazarovici, Philip; Zheng, Wenhua

doi:10.3390/cells9010100

Cited by 35 publications

(29 citation statements)

References 149 publications

(185 reference statements)

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“…In RPE cells, stimulation of autophagy by rapamycin was found to protect ARPE-19 cells from a lethal dose of H 2 O 2 [ 7 ]. Despite being a potent autophagy activator, many lines of evidences have shown that rapamycin has many adverse effects, such as diabetic-like symptoms, gastrointestinal disorders, and increased risk of infection [ 37 , 38 ]. Therefore, it is important to search for other alternatives with fewer side effects.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Metformin against Hydrogen Peroxide-Induced Oxidative Damage in Human Retinal Pigment Epithelial (RPE) Cells by Enhancing Autophagy through Activation of AMPK Pathway

Zhao¹,

Liu²,

Jiang³

et al. 2020

Oxidative Medicine and Cellular Longevity

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Age-related macular degeneration (AMD) is a leading cause of blindness with limited effective treatment. Although the pathogenesis of this disease is complex and not fully understood, the oxidative damage caused by excessive reactive oxygen species (ROS) in retinal pigment epithelium (RPE) has been considered as a major cause. Autophagy is essential for the degradation of cellular components damaged by ROS, and its dysregulation has been implicated in AMD pathogenesis. Therefore, strategies aiming to boost autophagy could be effective in protecting RPE cells from oxidative damage. Metformin is the first-line anti-type 2 diabetes drug and has been reported to stimulate autophagy in many tissues. We therefore hypothesized that metformin may be able to protect RPE cells against H2O2-induced oxidative damage by autophagy activation. In the present study, we found that metformin attenuated H2O2-induced cell viability loss, apoptosis, elevated ROS levels, and the collapse of the mitochondria membrane potential in D407 cells. Autophagy was stimulated by metformin, and inhibition of autophagy by 3-methyladenine (3-MA) and chloroquine (CQ) or knockdown of Beclin1 and LC3B blocked the protective effects of metformin. In addition, we showed that metformin could activate the AMPK pathway, whereas both pharmacological and genetic inhibitions of AMPK blocked the autophagy-stimulating and protective effects of metformin. Metformin conferred a similar protection against H2O2-induced oxidative damage in primary cultured human RPE cells. Taken together, these results demonstrate that metformin could protect RPE cells from H2O2-induced oxidative damage by stimulating autophagy via the activation of the AMPK pathway, supporting its potential use in the prevention and treatment of AMD.

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Section: Discussionmentioning

confidence: 99%

Protective Effect of Metformin against Hydrogen Peroxide-Induced Oxidative Damage in Human Retinal Pigment Epithelial (RPE) Cells by Enhancing Autophagy through Activation of AMPK Pathway

Zhao¹,

Liu²,

Jiang³

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Human studies support these findings by revealing greater longevity in people with smaller body size (Chmielewski 2016;Samaras 2014;Samaras 2013). Downstream of GH-IGF1, both mTOR (Blagosklonny 2013a;Blagosklonny 2013b;Papadopoli et al 2019;Wilkinson et al 2012) and FOXO (Daitoku and Fukamizu 2007;Jiang et al 2019) cascades are considered as central mechanisms of longevity regulation.…”

Section: Gh/igf/mtor and Gh/igf/foxo Signaling Cascadesmentioning

confidence: 82%

Unbiased Approach for the Identification of Molecular Mechanisms Sensitive to Chemical Exposures

Suvorov

Salemme

McGaunn

et al. 2020

Preprint

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Background: Targeted methods that dominated toxicological research until recently did not allow for screening of all molecular changes involved in toxic response. Therefore, it is difficult to infer if all major mechanisms of toxicity have already been discovered, or if some of them are still overlooked. Objectives: To identify molecular mechanisms sensitive to chemical exposures in an unbiased manner. Methods: We used data on 641,516 unique chemical-gene interactions from the Comparative Toxicogenomic Database. Only data from high-throughput gene expression experiments with human, rat or mouse cells/tissues were extracted. The total number of chemical-gene interactions was calculated for every gene, and used as a measure of gene sensitivity to chemical exposures. These values were further used in enrichment analyses to identify molecular mechanisms sensitive to chemical exposures. Results: Remarkably, use of different input subsets with non-overlapping lists of chemical compounds identified largely the same genes and molecular pathways as most sensitive to chemical exposures, indicative of an unbiased nature of our analysis. One of the most important findings of this study is that almost every known molecular mechanism may be affected by chemical exposures. Predictably, xenobiotic metabolism pathways and mechanisms of cellular response to stress and damage were among the most sensitive. Additionally, our analysis identified a range of highly sensitive molecular pathways, which are not widely recognized by modern toxicology as major targets of toxicants, including lipid metabolism pathways, longevity regulation cascade and cytokine mediated signaling. Discussion: Molecular mechanisms identified as the most sensitive to chemical exposures are relevant for significant public health problems, such as aging, cancer, metabolic and autoimmune disease. Thus, public health system will likely benefit from future research focus on these sensitive molecular mechanisms. Additionally, approach used in this study may guide identification of priority adverse outcome pathways (AOP) for in-vitro and in-silico toxicity testing methods.

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“…In fact, of the > 40 genetic mutations that have been reported to extend lifespan in the mouse and the rat models, approximately one third of them are involved in GH and IIS [164]. Because CR reduces GH and IIS [164], it is generally accepted that CR extends lifespan by limiting GH/IIS signaling and subsequently expressing pro-longevity genes by activating FOXO transcription factors [165]. To date, there are mixed results reported for the question of whether the IIS-FOXO signaling cascade is responsible for CR-mediated lifespan extension.…”

Section: Iis-foxo Signalingmentioning

confidence: 99%

Mechanisms of Lifespan Regulation by Calorie Restriction and Intermittent Fasting in Model Organisms

et al. 2020

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Genetic and pharmacological interventions have successfully extended healthspan and lifespan in animals, but their genetic interventions are not appropriate options for human applications and pharmacological intervention needs more solid clinical evidence. Consequently, dietary manipulations are the only practical and probable strategies to promote health and longevity in humans. Caloric restriction (CR), reduction of calorie intake to a level that does not compromise overall health, has been considered as being one of the most promising dietary interventions to extend lifespan in humans. Although it is straightforward, continuous reduction of calorie or food intake is not easy to practice in real lives of humans. Recently, fasting-related interventions such as intermittent fasting (IF) and time-restricted feeding (TRF) have emerged as alternatives of CR. Here, we review the history of CR and fasting-related strategies in animal models, discuss the molecular mechanisms underlying these interventions, and propose future directions that can fill the missing gaps in the current understanding of these dietary interventions. CR and fasting appear to extend lifespan by both partially overlapping common mechanisms such as the target of rapamycin (TOR) pathway and circadian clock, and distinct independent mechanisms that remain to be discovered. We propose that a systems approach combining global transcriptomic, metabolomic, and proteomic analyses followed by genetic perturbation studies targeting multiple candidate pathways will allow us to better understand how CR and fasting interact with each other to promote longevity.

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Signaling Network of Forkhead Family of Transcription Factors (FOXO) in Dietary Restriction

Cited by 35 publications

References 149 publications

Protective Effect of Metformin against Hydrogen Peroxide-Induced Oxidative Damage in Human Retinal Pigment Epithelial (RPE) Cells by Enhancing Autophagy through Activation of AMPK Pathway

Protective Effect of Metformin against Hydrogen Peroxide-Induced Oxidative Damage in Human Retinal Pigment Epithelial (RPE) Cells by Enhancing Autophagy through Activation of AMPK Pathway

Unbiased Approach for the Identification of Molecular Mechanisms Sensitive to Chemical Exposures

Mechanisms of Lifespan Regulation by Calorie Restriction and Intermittent Fasting in Model Organisms

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