Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK

Su, Yuan; Wang, Tao; Wu, Nan; Li, Diyan; Fan, Xiaolan; Xu, Zhongxian; Mishra, Suchismita; Yang, Mingyao

doi:10.18632/aging.102045

Cited by 117 publications

(93 citation statements)

References 35 publications

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“…As expected, the present studies showed that IMCA promoted the phosphorylation of AMPK in DLD-1 and HCT116 cells (Figures 6(a) and 6(b)). AMPK activation inhibits mTOR activity, which counteracts the elevated expression of SLC7A11 induced by APR246 and the protective cellular responses, and eventually results in cell death [33][34][35]. Furthermore, our results showed that the phosphorylation of mTOR and the downstream target protein P70S6K had been significantly decreased by 50 μM IMCA treatment in DLD-1 and HCT116 cells.…”

Section: Imca Inhibited the Expression Of Slc7a11mentioning

confidence: 57%

IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

Zhang

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

103

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Ferroptosis, implicated in several diseases, is a new form of programmed and nonapoptotic cell death triggered by iron-dependent lipid peroxidation after inactivation of the cystine/glutamate antiporter system xc–, which is composed of solute carrier family 7 membrane 11 (SLC7A11) and solute carrier family 3 membrane 2 (SLC3A2). Therefore, inducing ferroptosis through inhibiting the cystine/glutamate antiporter system xc– may be an effective way to treat cancer. In previous screening tests, we found that the benzopyran derivative 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) significantly inhibited the viability of colorectal cancer cells. However, the impact of IMCA on ferroptosis remains unknown. Hence, this study investigated the effect of IMCA on ferroptosis and elucidated the underlying molecular mechanism. Results showed that IMCA significantly inhibited the cell viability of colorectal cancer cells in vitro and inhibited tumor growth with negligible organ toxicity in vivo. Further studies showed that IMCA significantly induced the ferroptosis of colorectal cancer cells. Mechanistically, IMCA downregulated the expression of SLC7A11 and decreased the contents of cysteine and glutathione, which resulted in reactive oxygen species accumulation and ferroptosis. Furthermore, overexpression of SLC7A11 significantly attenuated the ferroptosis caused by IMCA. In addition, IMCA regulated the activity of the AMPK/mTOR/p70S6k signaling pathway, which is related to the activity of SLC7A11 and ferroptosis. Collectively, our research provided experimental evidences on the activity and mechanism of ferroptosis induced by IMCA and revealed that IMCA might be a promising therapeutic drug for colorectal cancer.

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Section: Imca Inhibited the Expression Of Slc7a11mentioning

confidence: 57%

IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

Zhang

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

103

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“…This study further identified several metabolic pathways that were enriched with metabolites changes, including the sugar and glycerophospholipid metabolism, amino acids, neurotransmitters, and carnitine shuttle [79]. Interestingly, a key tricarboxylic acid cycle (TCA) intermediate metabolite α-ketoglutarate was recently shown to extend lifespan in worms, flies, and mice, which suggested that longevity pathways might be evolutionarily conserved [82][83][84][85].…”

Section: Aging Studies In Model Organismsmentioning

confidence: 83%

Emerging Insights into the Metabolic Alterations in Aging Using Metabolomics

Srivastava

2019

Metabolites

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Metabolomics is the latest 'omics' technology and systems biology science that allows for comprehensive profiling of small-molecule metabolites in biological systems at a specific time and condition. Metabolites are cellular intermediate products of metabolic reactions, which reflect the ultimate response to genomic, transcriptomic, proteomic, or environmental changes in a biological system. Aging is a complex biological process that is characterized by a gradual and progressive decline in molecular, cellular, tissue, organ, and organismal functions, and it is influenced by a combination of genetic, environmental, diet, and lifestyle factors. The precise biological mechanisms of aging remain unknown. Metabolomics has emerged as a powerful tool to characterize the organism phenotypes, identify altered metabolites, pathways, novel biomarkers in aging and disease, and offers wide clinical applications. Here, I will provide a comprehensive overview of our current knowledge on metabolomics led studies in aging with particular emphasis on studies leading to biomarker discovery. Based on the data obtained from model organisms and humans, it is evident that metabolites associated with amino acids, lipids, carbohydrate, and redox metabolism may serve as biomarkers of aging and/or longevity. Current challenges and key questions that should be addressed in the future to advance our understanding of the biological mechanisms of aging are discussed.

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“…for α-ketoglutarate and oxaloacetate, two other TCA cycle intermediates (Williams et al, 2009;Chin et al, 2014;Su et al, 2019). However, such observation needs to be corroborated by evidence in mammals.…”

Section: Me1mentioning

confidence: 98%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

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Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD +-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.

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Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK

Cited by 117 publications

References 35 publications

IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

IMCA Induces Ferroptosis Mediated by SLC7A11 through the AMPK/mTOR Pathway in Colorectal Cancer

Emerging Insights into the Metabolic Alterations in Aging Using Metabolomics

Where Metabolism Meets Senescence: Focus on Endothelial Cells

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