scholarly journals mTOR and Aging: An Old Fashioned Dress

2019 ◽  
Vol 20 (11) ◽  
pp. 2774 ◽  
Author(s):  
Giovanni Stallone ◽  
Barbara Infante ◽  
Concetta Prisciandaro ◽  
Giuseppe Grandaliano
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Nutrient Sensing ◽  
Protective Effects ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Age Related ◽  
Signalling Network ◽  
Evolutionarily Conserved ◽  
Mtor Signalling

Aging is a physiologic/pathologic process characterized by a progressive impairment of cellular functions, supported by the alterations of several molecular pathways, leading to an increased cell susceptibility to injury. This deterioration is the primary risk factor for several major human pathologies. Numerous cellular processes, including genomic instability, telomere erosion, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular signal transduction represent common denominators of aging in different organisms. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved nutrient sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast, and mice support the hypothesis that the mTOR signalling network plays a pivotal role in modulating aging. mTOR is emerging as the most robust mediator of the protective effects of various forms of dietary restriction, which has been shown to extend lifespan and slow the onset of age-related diseases across species. Herein we discuss the role of mTor signalling network in the development of classic age-related diseases, focused on cardiovascular system, immune response, and cancer.

scholarly journals Dynein Light Chain 1 Regulates Dynamin-mediated F-Actin Assembly during Sperm Individualization in Drosophila

2005 ◽  
Vol 16 (7) ◽  
pp. 3107-3116 ◽  
Author(s):  
Anindya Ghosh-Roy ◽  
Bela S. Desai ◽  
Krishanu Ray
Keyword(s):  
Light Chain ◽  
Cytoplasmic Dynein ◽  
Actin Dynamics ◽  
Dynein Light Chain ◽  
Actin Assembly ◽  
Cellular Functions ◽  
Directed Movement ◽  
Cellular Processes ◽  
Dynactin Complex

Toward the end of spermiogenesis, spermatid nuclei are compacted and the clonally related spermatids individualize to become mature and active sperm. Studies in Drosophila showed that caudal end-directed movement of a microfilament-rich structure, called investment cone, expels the cytoplasmic contents of individual spermatids. F-actin dynamics plays an important role in this process. Here we report that the dynein light chain 1 (DLC1) of Drosophila is involved in two separate cellular processes during sperm individualization. It is enriched around spermatid nuclei during postelongation stages and plays an important role in the dynein-dynactin–dependent rostral retention of the nuclei during this period. In addition, DDLC1 colocalizes with dynamin along investment cones and regulates F-actin assembly at this organelle by retaining dynamin along the cones. Interestingly, we found that this process does not require the other subunits of cytoplasmic dynein-dynactin complex. Altogether, these observations suggest that DLC1 could independently regulate multiple cellular functions and established a novel role of this protein in F-actin assembly in Drosophila.

scholarly journals Estrogen Receptor and Vascular Aging

2021 ◽  
Vol 2 ◽  
Author(s):  
Morgane Davezac ◽  
Melissa Buscato ◽  
Rana Zahreddine ◽  
Patrick Lacolley ◽  
Daniel Henrion ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Cardiovascular Diseases ◽  
Experimental Studies ◽  
Hormonal Treatment ◽  
Protective Effects ◽  
Age Related ◽  
Nuclear Receptor Family ◽  
The Impact ◽  
Receptor Family

Cardiovascular diseases remain an age-related pathology in both men and women. These pathologies are 3-fold more frequent in men than in women before menopause, although this difference progressively decreases after menopause. The vasculoprotective role of estrogens are well established before menopause, but the consequences of their abrupt decline on the cardiovascular risk at menopause remain debated. In this review, we will attempt to summarize the main clinical and experimental studies reporting the protective effects of estrogens against cardiovascular diseases, with a particular focus on atherosclerosis, and the impact of aging and estrogen deprivation on their endothelial actions. The arterial actions of estrogens, but also part of that of androgens through their aromatization into estrogens, are mediated by the estrogen receptor (ER)α and ERβ. ERs belong to the nuclear receptor family and act by transcriptional regulation in the nucleus, but also exert non-genomic/extranuclear actions. Beside the decline of estrogens at menopause, abnormalities in the expression and/or function of ERs in the tissues, and particularly in arteries, could contribute to the failure of classic estrogens to protect arteries during aging. Finally, we will discuss how recent insights in the mechanisms of action of ERα could contribute to optimize the hormonal treatment of the menopause.

scholarly journals The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1043
Author(s):  
Ivana Bjedov ◽  
Charalampos Rallis
Keyword(s):  
Ribosome Biogenesis ◽  
Complex Trait ◽  
Signalling Pathway ◽  
Target Of Rapamycin ◽  
Cellular Functions ◽  
Pharmacological Interventions ◽  
Age Related ◽  
Energy Sensing ◽  
Mtor Signalling ◽  
Mtor Signalling Pathway

Ageing is a complex trait controlled by genes and the environment. The highly conserved mechanistic target of rapamycin signalling pathway (mTOR) is a major regulator of lifespan in all eukaryotes and is thought to be mediating some of the effects of dietary restriction. mTOR is a rheostat of energy sensing diverse inputs such as amino acids, oxygen, hormones, and stress and regulates lifespan by tuning cellular functions such as gene expression, ribosome biogenesis, proteostasis, and mitochondrial metabolism. Deregulation of the mTOR signalling pathway is implicated in multiple age-related diseases such as cancer, neurodegeneration, and auto-immunity. In this review, we briefly summarise some of the workings of mTOR in lifespan and ageing through the processes of transcription, translation, autophagy, and metabolism. A good understanding of the pathway’s outputs and connectivity is paramount towards our ability for genetic and pharmacological interventions for healthy ageing and amelioration of age-related disease.

scholarly journals The Role of Free Radicals in Autophagy Regulation: Implications for Ageing

2018 ◽  
Vol 2018 ◽  
pp. 1-19 ◽  
Author(s):  
M. Pajares ◽  
A. Cuadrado ◽  
N. Engedal ◽  
Z. Jirsova ◽  
M. Cahova
Keyword(s):  
Control Systems ◽  
Redox Homeostasis ◽  
Biological Macromolecules ◽  
Complex Relationship ◽  
Cellular Functions ◽  
Related Disorder ◽  
Redox Signalling ◽  
Age Related ◽  
Integral Role

Reactive oxygen and nitrogen species (ROS and RNS, resp.) have been traditionally perceived solely as detrimental, leading to oxidative damage of biological macromolecules and organelles, cellular demise, and ageing. However, recent data suggest that ROS/RNS also plays an integral role in intracellular signalling and redox homeostasis (redoxtasis), which are necessary for the maintenance of cellular functions. There is a complex relationship between cellular ROS/RNS content and autophagy, which represents one of the major quality control systems in the cell. In this review, we focus on redox signalling and autophagy regulation with a special interest on ageing-associated changes. In the last section, we describe the role of autophagy and redox signalling in the context of Alzheimer’s disease as an example of a prevalent age-related disorder.

scholarly journals Regulation of circular dorsal ruffles, macropinocytosis, and cell migration by RhoG and its exchange factor, Trio

2017 ◽  
Vol 28 (13) ◽  
pp. 1768-1781 ◽  
Author(s):  
Alejandra Valdivia ◽  
Silvia M. Goicoechea ◽  
Sahezeel Awadia ◽  
Ashtyn Zinn ◽  
Rafael Garcia-Mata
Keyword(s):  
Cell Migration ◽  
Mammalian Cells ◽  
Dorsal Surface ◽  
Receptor Internalization ◽  
Dependent Manner ◽  
Cellular Functions ◽  
Unique Type ◽  
Exchange Factor ◽  
Cellular Processes

Circular dorsal ruffles (CDRs) are actin-rich structures that form on the dorsal surface of many mammalian cells in response to growth factor stimulation. CDRs represent a unique type of structure that forms transiently and only once upon stimulation. The formation of CDRs involves a drastic rearrangement of the cytoskeleton, which is regulated by the Rho family of GTPases. So far, only Rac1 has been consistently associated with CDR formation, whereas the role of other GTPases in this process is either lacking or inconclusive. Here we show that RhoG and its exchange factor, Trio, play a role in the regulation of CDR dynamics, particularly by modulating their size. RhoG is activated by Trio downstream of PDGF in a PI3K- and Src-dependent manner. Silencing RhoG expression decreases the number of cells that form CDRs, as well as the area of the CDRs. The regulation of CDR area by RhoG is independent of Rac1 function. In addition, our results show the RhoG plays a role in the cellular functions associated with CDR formation, including macropinocytosis, receptor internalization, and cell migration. Taken together, our results reveal a novel role for RhoG in the regulation of CDRs and the cellular processes associated with their formation.

scholarly journals Recent progress in research on molecular mechanisms of autophagy in the heart

2015 ◽  
Vol 308 (4) ◽  
pp. H259-H268 ◽  
Author(s):  
Yasuhiro Maejima ◽  
Yun Chen ◽  
Mitsuaki Isobe ◽  
Åsa B. Gustafsson ◽  
Richard N. Kitsis ◽  
...  
Keyword(s):  
Heart Disease ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Degradation Process ◽  
Structure And Function ◽  
Cellular Functions ◽  
Evolutionarily Conserved ◽  
And Function ◽  
Cellular Dysfunction

Dysregulation of autophagy, an evolutionarily conserved process for degradation of long-lived proteins and organelles, has been implicated in the pathogenesis of human disease. Recent research has uncovered pathways that control autophagy in the heart and molecular mechanisms by which alterations in this process affect cardiac structure and function. Although initially thought to be a nonselective degradation process, autophagy, as it has become increasingly clear, can exhibit specificity in the degradation of molecules and organelles, such as mitochondria. Furthermore, it has been shown that autophagy is involved in a wide variety of previously unrecognized cellular functions, such as cell death and metabolism. A growing body of evidence suggests that deviation from appropriate levels of autophagy causes cellular dysfunction and death, which in turn leads to heart disease. Here, we review recent advances in understanding the role of autophagy in heart disease, highlight unsolved issues, and discuss the therapeutic potential of modulating autophagy in heart disease.

Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis

2014 ◽  
Vol 74 (7) ◽  
pp. 1432-1440 ◽  
Author(s):  
Yue Zhang ◽  
Faezeh Vasheghani ◽  
Ying-hua Li ◽  
Meryem Blati ◽  
Kayla Simeone ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Protein Kinase ◽  
Mammalian Target Of Rapamycin ◽  
Adenosine Monophosphate ◽  
Cartilage Degradation ◽  
Chondrocyte Apoptosis ◽  
A Cell ◽  
Mtor Signalling

ObjectivesMammalian target of rapamycin (mTOR) (a serine/threonine protein kinase) is a major repressor of autophagy, a cell survival mechanism. The specific in vivo mechanism of mTOR signalling in OA pathophysiology is not fully characterised. We determined the expression of mTOR and known autophagy genes in human OA cartilage as well as mouse and dog models of experimental OA. We created cartilage-specific mTOR knockout (KO) mice to determine the specific role of mTOR in OA pathophysiology and autophagy signalling in vivo.MethodsInducible cartilage-specific mTOR KO mice were generated and subjected to mouse model of OA. Human OA chondrocytes were treated with rapamycin and transfected with Unc-51–like kinase 1 (ULK1) siRNA to determine mTOR signalling.ResultsmTOR is overexpressed in human OA cartilage as well as mouse and dog experimental OA. Upregulation of mTOR expression co-relates with increased chondrocyte apoptosis and reduced expression of key autophagy genes during OA. Subsequently, we show for the first time that cartilage-specific ablation of mTOR results in increased autophagy signalling and a significant protection from destabilisation of medial meniscus (DMM)-induced OA associated with a significant reduction in the articular cartilage degradation, apoptosis and synovial fibrosis. Furthermore, we show that regulation of ULK1/adenosine monophosphate-activated protein kinase (AMPK) signalling pathway by mTOR may in part be responsible for regulating autophagy signalling and the balance between catabolic and anabolic factors in the articular cartilage.ConclusionsThis study provides a direct evidence of the role of mTOR and its downstream modulation of autophagy in articular cartilage homeostasis.

scholarly journals Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

2019 ◽  
Author(s):  
Kerui Huang ◽  
Ting Miao ◽  
Kai Chang ◽  
Ping Kang ◽  
Qiuhan Jiang ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Inflammatory Cytokine ◽  
Cytokine Signaling ◽  
Over Expression ◽  
Autonomous Regulation ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Age Dependent ◽  
Import Receptor

AbstractAge is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

scholarly journals Nitrosative Stress in Retinal Pathologies: Review

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 543 ◽  
Author(s):  
Antolin Cantó ◽  
Teresa Olivar ◽  
Francisco Javier Romero ◽  
María Miranda
Keyword(s):  
Lipid Membranes ◽  
Nitrosative Stress ◽  
Age Related Macular Degeneration ◽  
Retinal Blood Flow ◽  
Vascular Endothelial ◽  
Nitrogen Species ◽  
Cellular Functions ◽  
Age Related ◽  
Retinal Pathologies

Nitric oxide (NO) is a gas molecule with diverse physiological and cellular functions. In the eye, NO is used to maintain normal visual function as it is involved in photoreceptor light transduction. In addition, NO acts as a rapid vascular endothelial relaxant, is involved in the control of retinal blood flow under basal conditions and mediates the vasodilator responses of different substances such as acetylcholine, bradykinin, histamine, substance P or insulin. However, the retina is rich in polyunsaturated lipid membranes and is sensitive to the action of reactive oxygen and nitrogen species. Products generated from NO (i.e., dinitrogen trioxide (N2O3) and peroxynitrite) have great oxidative damaging effects. Oxygen and nitrogen species can react with biomolecules (lipids, proteins and DNA), potentially leading to cell death, and this is particularly important in the retina. This review focuses on the role of NO in several ocular diseases, including diabetic retinopathy, retinitis pigmentosa, glaucoma or age-related macular degeneration (AMD).

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