scholarly journals Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans

2019 ◽  
Author(s):  
Yue Zhang ◽  
Anne Lanjuin ◽  
Suvagata Roy Chowdhury ◽  
Meeta Mistry ◽  
Carlos G. Silva Garcia ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Lifespan Extension ◽  
Ampk Activation ◽  
Aging Effects ◽  
C Elegans ◽  
Genes Encoding ◽  
The Central Nervous System ◽  
Amp Activated Protein Kinase

AbstractTarget of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK) antagonistically modulate metabolism and aging. However, how they coordinate to determine longevity and if they act via separable mechanisms is unclear. Here, we show that neuronal AMPK is essential for lifespan extension from TORC1 inhibition, and that TORC1 suppression increases lifespan cell non autonomously via distinct mechanisms from global AMPK activation. Lifespan extension by null mutations in genes encoding raga-1 (RagA) or rsks-1 (S6K) is fully suppressed by neuronal-specific rescues. Loss of RAGA-1 increases lifespan via maintaining mitochondrial fusion. Neuronal RAGA-1 abrogation of raga-1 mutant longevity requires UNC-64/syntaxin, and promotes mitochondrial fission cell nonautonomously. Finally, deleting the mitochondrial fission factor DRP-1 renders the animal refractory to the pro-aging effects of neuronal RAGA-1. Our results highlight a new role for neuronal TORC1 in cell nonautonomous regulation of longevity, and suggest TORC1 in the central nervous system might be targeted to promote healthy aging.

scholarly journals Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Yue Zhang ◽  
Anne Lanjuin ◽  
Suvagata Roy Chowdhury ◽  
Meeta Mistry ◽  
Carlos G Silva-García ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Lifespan Extension ◽  
Ampk Activation ◽  
Aging Effects ◽  
C Elegans ◽  
Genes Encoding ◽  
The Central Nervous System ◽  
Amp Activated Protein Kinase

Target of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK) antagonistically modulate metabolism and aging. However, how they coordinate to determine longevity and if they act via separable mechanisms is unclear. Here, we show that neuronal AMPK is essential for lifespan extension from TORC1 inhibition, and that TORC1 suppression increases lifespan cell non autonomously via distinct mechanisms from global AMPK activation. Lifespan extension by null mutations in genes encoding raga-1 (RagA) or rsks-1 (S6K) is fully suppressed by neuronal-specific rescues. Loss of RAGA-1 increases lifespan via maintaining mitochondrial fusion. Neuronal RAGA-1 abrogation of raga-1 mutant longevity requires UNC-64/syntaxin, and promotes mitochondrial fission cell nonautonomously. Finally, deleting the mitochondrial fission factor DRP-1 renders the animal refractory to the pro-aging effects of neuronal RAGA-1. Our results highlight a new role for neuronal TORC1 in cell nonautonomous regulation of longevity, and suggest TORC1 in the central nervous system might be targeted to promote healthy aging.

scholarly journals Peroxiredoxin 5 Inhibits Glutamate-Induced Neuronal Cell Death through the Regulation of Calcineurin-Dependent Mitochondrial Dynamics in HT22 Cells

2019 ◽  
Vol 39 (20) ◽  
Author(s):  
Mi Hye Kim ◽  
Hong Jun Lee ◽  
Sang-Rae Lee ◽  
Hyun-Shik Lee ◽  
Jae-Won Huh ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Glutamate Toxicity ◽  
Ht22 Cells ◽  
Peroxidase Enzyme ◽  
The Central Nervous System

ABSTRACT Glutamate is an essential neurotransmitter in the central nervous system (CNS). However, high glutamate concentrations can lead to neurodegenerative diseases. A hallmark of glutamate toxicity is high levels of reactive oxygen species (ROS), which can trigger Ca2+ influx and dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Peroxiredoxin 5 (Prx5) is a well-known cysteine-dependent peroxidase enzyme. However, the precise effects of Prx5 on glutamate toxicity are still unclear. In this study, we investigated the role of Prx5 in glutamate-induced neuronal cell death. We found that glutamate treatment induces endogenous Prx5 expression and Ca2+/calcineurin-dependent dephosphorylation of Drp1, resulting in mitochondrial fission and neuronal cell death. Our results indicate that Prx5 inhibits glutamate-induced mitochondrial fission through the regulation of Ca2+/calcineurin-dependent dephosphorylation of Drp1, and it does so by scavenging cytosolic and mitochondrial ROS. Therefore, we suggest that Ca2+/calcineurin-dependent mitochondrial dynamics are deeply associated with glutamate-induced neurotoxicity. Consequently, Prx5 may be used as a potential agent for developing therapies against glutamate-induced neurotoxicity and neurodegenerative diseases where it plays a key role.

scholarly journals A Central Role for Neuronal Adenosine 5′-Monophosphate-Activated Protein Kinase in Cancer-Induced Anorexia

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5220-5229 ◽  
Author(s):  
Eduardo R. Ropelle ◽  
José R. Pauli ◽  
Karina G. Zecchin ◽  
Mirian Ueno ◽  
Cláudio T. de Souza ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Food Intake ◽  
Life Span ◽  
Energy Homeostasis ◽  
Ampk Activation ◽  
Chronic Infusion ◽  
The Central Nervous System ◽  
Amp Activated Protein Kinase ◽  
Oxide Synthase ◽  
Cancer Anorexia

The pathogenesis of cancer anorexia is multifactorial and associated with disturbances of the central physiological mechanisms controlling food intake. However, the neurochemical mechanisms responsible for cancer-induced anorexia are unclear. Here we show that chronic infusion of 5-amino-4imidazolecarboxamide-riboside into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-d-glucose promotes hypothalamic AMP-activated protein kinase (AMPK) activation, increases food intake, and prolongs the survival of anorexic tumor-bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals markedly reduced the hypothalamic production of inducible nitric oxide synthase, IL-1β, and TNF-α and modulated the expression of proopiomelanocortin, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and intracerebroventricular treatment with biguanide antidiabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia.

Abstract 568: Deletion of AMP-activated Protein Kinase-alpha Triggers Mitochondrial Fission and Endothelial Dysfunction

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Qqilong Wang ◽  
Zhonglin Xie ◽  
Huaiping Zhu ◽  
Ye Ding ◽  
Ming-Hui Zou
Keyword(s):  
Protein Kinase ◽  
Endothelial Dysfunction ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Chronic Administration ◽  
Mitochondrial Fragmentation ◽  
Aortic Endothelium ◽  
Amp Activated Protein Kinase

Introduction: AMP-activated protein kinase (AMPK) has been reported to regulate mitochondrial biogenesis, function, and turnover. However, the molecular mechanisms by which AMPK regulates mitochondrial dynamics remain poorly characterized. We hypothesized that AMPK deficiency regulates mitochondrial fission that will result in endothelial dysfunction. Methods/Results: Deletion of AMPKα2 resulted in defective autophagy, dynamin-related protein (Drp1) accumulation, and aberrant mitochondrial fragmentation in the aortic endothelium of mice. Furthermore, autophagy inhibition by chloroquine treatment or Atg7 small interfering RNA (siRNA) transfection upregulated Drp1 expression and triggered Drp1-mediated mitochondrial fragmentation. In contrast, autophagy activation by overexpression of Atg7 or chronic administration of rapamycin, the mammalian target of rapamycin kinase inhibitor, promoted Drp1 degradation and attenuated mitochondrial fission in AMPKα2 -/- mice, suggesting that defective autophagy contributes to enhanced Drp1 expression and mitochondrial fragmentation. Interesting, the genetic (Drp1 siRNA) or pharmacological (mdivi-1) inhibition of Drp1 ablated mitochondrial fragmentation in the mouse aortic endothelium and prevented the acetylcholine-induced relaxation of isolated mouse aortas from AMPKα2 -/- mice. This suggests that aberrant Drp1 is responsible for enhanced mitochondrial fission and endothelial dysfunction in AMPKα knockout mice. Conclusions: Our results show that AMPKα deletion promoted mitochondrial fission in vascular endothelial cells by inhibiting the autophagy-dependent degradation of Drp1.

scholarly journals Supplemental Cellular Protection by a Carotenoid Extends Lifespan via Ins/IGF-1 Signaling inCaenorhabditis elegans

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Koumei Yazaki ◽  
Chinatsu Yoshikoshi ◽  
Satoru Oshiro ◽  
Sumino Yanase
Keyword(s):  
Model Organism ◽  
Lifespan Extension ◽  
Cell Organelle ◽  
Wild Type ◽  
Marine Animals ◽  
Cellular Protection ◽  
C Elegans ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
In The Wild

Astaxanthin (AX), which is produced by some marine animals, is a type of carotenoid that has antioxidative properties. In this study, we initially examined the effects of AX on the aging of a model organismC. elegansthat has the conserved intracellular pathways related to mammalian longevity. The continuous treatments with AX (0.1 to 1 mM) from both the prereproductive and young adult stages extended the mean lifespans by about 16–30% in the wild-type and long-lived mutantage-1ofC. elegans. In contrast, the AX-dependent lifespan extension was not observed even in adaf-16null mutant. Especially, the expression of genes encoding superoxide dismutases and catalases increased in two weeks after hatching, and the DAF-16 protein was translocated to the nucleus in the AX-exposed wild type. These results suggest that AX protects the cell organelle mitochondria and nucleus of the nematode, resulting in a lifespan extension via an Ins/IGF-1 signaling pathway during normal aging, at least in part.

scholarly journals Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling

Gerontology ◽  
2017 ◽  
Vol 64 (1) ◽  
pp. 96-104 ◽  
Author(s):  
Collin Yvès Ewald ◽  
Jorge Iván Castillo-Quan ◽  
T. Keith Blackwell
Keyword(s):  
Caenorhabditis Elegans ◽  
Healthy Aging ◽  
Receptor Gene ◽  
Recent Analysis ◽  
Lifespan Extension ◽  
Extension Programs ◽  
Subsequent Work ◽  
C Elegans ◽  
Downstream Processes ◽  
Shed Light

The groundbreaking discovery that lower levels of insulin/IGF-1 signaling (IIS) can induce lifespan extension was reported 24 years ago in the nematode Caenorhabditis elegans. In this organism, mutations in the insulin/IGF-1 receptor gene daf-2 or other genes in this pathway can double lifespan. Subsequent work has revealed that reduced IIS (rIIS) extends lifespan across diverse species, possibly including humans. In C. elegans, IIS also regulates development into the diapause state known as dauer, a quiescent larval form that enables C. elegans to endure harsh environments through morphological adaptation, improved cellular repair, and slowed metabolism. Considerable progress has been made uncovering mechanisms that are affected by C. elegans rIIS. However, from the beginning it has remained unclear to what extent rIIS extends C. elegans lifespan by mobilizing dauer-associated mechanisms in adults. As we discuss, recent work has shed light on this question by determining that rIIS can extend C. elegans lifespan comparably through downstream processes that are either dauer-related or -independent. Importantly, these two lifespan extension programs can be distinguished genetically. It will now be critical to tease apart these programs, because each may involve different longevity-promoting mechanisms that may be relevant to higher organisms. A recent analysis of organismal “healthspan” has questioned the value of C. elegans rIIS as a paradigm for understanding healthy aging, as opposed to simply extending life. We discuss other work that argues strongly that C. elegans rIIS is indeed an invaluable model and consider the likely possibility that dauer-related processes affect parameters associated with health under rIIS conditions. Together, these studies indicate that C. elegans and analyses of rIIS in this organism will continue to provide unexpected and exciting results, and new paradigms that will be valuable for understanding healthy aging in humans.

scholarly journals Ether Lipid Biosynthesis Promotes Lifespan Extension and Enables Diverse Prolongevity Paradigms

2021 ◽  
Author(s):  
Lucydalila Cedillo ◽  
Sainan Li ◽  
Fasih Ahsan ◽  
Sinclair Emans ◽  
Adebanjo Adedoja ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Ether Lipid ◽  
Acid Synthesis ◽  
Epidemiologic Studies ◽  
Lipid Biosynthesis ◽  
Lifespan Extension ◽  
Full Spectrum ◽  
C Elegans ◽  
Transport Chain ◽  
Biosynthetic Machinery

Biguanides, including the world's most commonly prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases, such as cancer. In spite of these promising observations, the full spectrum of the molecular effectors responsible for these health benefits remains elusive. Through unbiased genetic screening in C. elegans, we uncovered a novel role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides govern lifespan extension via a complex effect on the ether lipid landscape requires enzymes responsible for both ether lipid biogenesis and polyunsaturated fatty acid synthesis. Remarkably, loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. Furthermore, overexpression of a single, key ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.

scholarly journals Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Yanan Sun ◽  
Meijiao Li ◽  
Dongfeng Zhao ◽  
Xin Li ◽  
Chonglin Yang ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Food Intake ◽  
Aging Process ◽  
Lifespan Extension ◽  
C Elegans ◽  
Cathepsin Proteases ◽  
Age Dependent ◽  
Genes Encoding ◽  
Degradation Activity ◽  
Lifespan Regulation

Lysosomes play important roles in cellular degradation to maintain cell homeostasis. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in C. elegans. We uncovered age-dependent alterations in lysosomal morphology, motility, acidity and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants daf-2, eat-2 and isp-1, which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in daf-2, eat-2 and isp-1 worms. Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension.

scholarly journals Lysosomal activity regulates Caenorhabditis elegans mitochondrial dynamics through vitamin B12 metabolism

2020 ◽  
Author(s):  
Wei Wei ◽  
Gary Ruvkun
Keyword(s):  
Caenorhabditis Elegans ◽  
Vitamin B12 ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Vitamin B12 Deficiency ◽  
Periodic Pattern ◽  
C Elegans ◽  
Lysosomal Dysfunction ◽  
B12 Deficiency

ABSTRACTMitochondrial fission and fusion are highly regulated by energy demand and physiological conditions to control the production, activity, and movement of these organelles. Mitochondria are arrayed in a periodic pattern in Caenorhabditis elegans muscle, but this pattern is disrupted by mutations in the mitochondrial fission component dynamin. Here we show that the dramatically disorganized mitochondria caused by a mitochondrial fission-defective dynamin mutation is strongly suppressed to a more periodic pattern by a second mutation in lysosomal biogenesis or acidification. Vitamin B12 is normally imported from the bacterial diet via lysosomal degradation of B12-binding proteins and transport of vitamin B12 to the mitochondrion and cytoplasm. We show that the lysosomal dysfunction induced by gene inactivations of lysosomal biogenesis or acidification factors causes vitamin B12 deficiency. Growth of the C. elegans dynamin mutant on an E. coli strain with low vitamin B12 also strongly suppressed the mitochondrial fission defect. Of the two C. elegans enzymes that require B12, gene inactivation of methionine synthase suppressed the mitochondrial fission defect of a dynamin mutation. We show that lysosomal dysfunction induced mitochondrial biogenesis which is mediated by vitamin B12 deficiency and methionine restriction. S-adenosylmethionine, the methyl donor of many methylation reactions, including histones, is synthesized from methionine by S-adenosylmethionine synthase; inactivation of the sams-1 S-adenosylmethionine synthase also suppresses the drp-1 fission defect, suggesting that vitamin B12 regulates mitochondrial biogenesis and then affects mitochondrial fission via chromatin pathways.SIGNIFICANCE STATEMENTThe balance of mitochondrial fission and fusion, two aspects of mitochondrial dynamics, is important for mitochondrial function. Here we show that Caenorhabditis elegans lysosomal activity regulates mitochondrial dynamics by affecting mitochondrial fission through interfering the metabolism of a micronutrient, vitamin B12. Vitamin B12 is exclusively obtained from diets in animals including C. elegans and humans, and its uptake is mediated by the lysosome. We show that lysosomal dysfunction causes vitamin B12 deficiency that leads to reduction of methionine and S-adenosylmethionine to in turn increase mitochondrial biogenesis and fission. Our study provides an insight on the interactions between mitochondrial function and micronutrient metabolism.

scholarly journals Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

2021 ◽  
Author(s):  
Keting Bao ◽  
Jiali Feng ◽  
Wenwen Liu ◽  
Zhifan Mao ◽  
Tianyue Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Animal Model ◽  
Caenorhabditis Elegans ◽  
Stress Resistance ◽  
Lifespan Extension ◽  
Aging Effects ◽  
Hypertonic Stress ◽  
C Elegans ◽  
Promising Application ◽  
Application Prospects

While screening our in-house 1,072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic and anti-aging effects, and could further lead to promising application prospects.

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