scholarly journals Compartmentalized Signaling in Aging and Neurodegeneration

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 464
Author(s):  
Giulietta Di Benedetto ◽  
Liliana F. Iannucci ◽  
Nicoletta C. Surdo ◽  
Sofia Zanin ◽  
Filippo Conca ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Function ◽  
Progressive Decline ◽  
Camp Signalling ◽  
Camp Pathway ◽  
Age Related ◽  
Cellular Integrity ◽  
Functional Relevance ◽  
Camp Levels ◽  
Signalling Cascade

The cyclic AMP (cAMP) signalling cascade is necessary for cell homeostasis and plays important roles in many processes. This is particularly relevant during ageing and age-related diseases, where drastic changes, generally decreases, in cAMP levels have been associated with the progressive decline in overall cell function and, eventually, the loss of cellular integrity. The functional relevance of reduced cAMP is clearly supported by the finding that increases in cAMP levels can reverse some of the effects of ageing. Nevertheless, despite these observations, the molecular mechanisms underlying the dysregulation of cAMP signalling in ageing are not well understood. Compartmentalization is widely accepted as the modality through which cAMP achieves its functional specificity; therefore, it is important to understand whether and how this mechanism is affected during ageing and to define which is its contribution to this process. Several animal models demonstrate the importance of specific cAMP signalling components in ageing, however, how age-related changes in each of these elements affect the compartmentalization of the cAMP pathway is largely unknown. In this review, we explore the connection of single components of the cAMP signalling cascade to ageing and age-related diseases whilst elaborating the literature in the context of cAMP signalling compartmentalization.

scholarly journals Updates on Old and Weary Haematopoiesis

2018 ◽  
Vol 19 (9) ◽  
pp. 2567 ◽  
Author(s):  
Joanna Konieczny ◽  
Lorena Arranz
Keyword(s):  
Molecular Mechanisms ◽  
The Elderly ◽  
Progressive Decline ◽  
Cell Functions ◽  
Age Related ◽  
High Incidence ◽  
Hsc Niche ◽  
Blood Formation ◽  
External Stimuli ◽  
Future Work

Blood formation, or haematopoiesis, originates from haematopoietic stem cells (HSCs), whose functions and maintenance are regulated in both cell- and cell non-autonomous ways. The surroundings of HSCs in the bone marrow create a specific niche or microenvironment where HSCs nest that allows them to retain their unique characteristics and respond rapidly to external stimuli. Ageing is accompanied by reduced regenerative capacity of the organism affecting all systems, due to the progressive decline of stem cell functions. This includes blood and HSCs, which contributes to age-related haematological disorders, anaemia, and immunosenescence, among others. Furthermore, chronological ageing is characterised by myeloid and platelet HSC skewing, inflammageing, and expanded clonal haematopoiesis, which may be the result of the accumulation of preleukaemic lesions in HSCs. Intriguingly, haematological malignancies such as acute myeloid leukaemia have a high incidence among elderly patients, yet not all individuals with clonal haematopoiesis develop leukaemias. Here, we discuss recent work on these aspects, their potential underlying molecular mechanisms, and the first cues linking age-related changes in the HSC niche to poor HSC maintenance. Future work is needed for a better understanding of haematopoiesis during ageing. This field may open new avenues for HSC rejuvenation and therapeutic strategies in the elderly.

scholarly journals Protein Posttranslational Modifications: Roles in Aging and Age-Related Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-19 ◽  
Author(s):  
Ana L. Santos ◽  
Ariel B. Lindner
Keyword(s):  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Molecular Processes ◽  
Progressive Decline ◽  
Age Related ◽  
Evolutionarily Conserved ◽  
Protein Posttranslational Modifications ◽  
Aging Models ◽  
The Relationship

Aging is characterized by the progressive decline of biochemical and physiological function in an individual. Consequently, aging is a major risk factor for diseases like cancer, obesity, and type 2 diabetes. The cellular and molecular mechanisms of aging are not well understood, nor is the relationship between aging and the onset of diseases. One of the hallmarks of aging is a decrease in cellular proteome homeostasis, allowing abnormal proteins to accumulate. This phenomenon is observed in both eukaryotes and prokaryotes, suggesting that the underlying molecular processes are evolutionarily conserved. Similar protein aggregation occurs in the pathogenesis of diseases like Alzheimer’s and Parkinson’s. Further, protein posttranslational modifications (PTMs), either spontaneous or physiological/pathological, are emerging as important markers of aging and aging-related diseases, though clear causality has not yet been firmly established. This review presents an overview of the interplay of PTMs in aging-associated molecular processes in eukaryotic aging models. Understanding PTM roles in aging could facilitate targeted therapies or interventions for age-related diseases. In addition, the study of PTMs in prokaryotes is highlighted, revealing the potential of simple prokaryotic models to uncover complex aging-associated molecular processes in the emerging field of microbiogerontology.

scholarly journals Chondrocyte Aging: The Molecular Determinants and Therapeutic Opportunities

2021 ◽  
Vol 9 ◽  
Author(s):  
Thamil Selvee Ramasamy ◽  
Yong Mei Yee ◽  
Ilyas M. Khan
Keyword(s):  
Molecular Mechanisms ◽  
Articular Chondrocytes ◽  
Functional Decline ◽  
Cellular Aging ◽  
Joint Degeneration ◽  
Complex Interplay ◽  
Regenerative Capacity ◽  
Progressive Decline ◽  
Age Related ◽  
Molecular Determinants

Osteoarthritis (OA) is a joint degenerative disease that is an exceedingly common problem associated with aging. Aging is the principal risk factor for OA, but damage-related physiopathology of articular chondrocytes probably drives the mechanisms of joint degeneration by a progressive decline in the homeostatic and regenerative capacity of cells. Cellular aging is the manifestation of a complex interplay of cellular and molecular pathways underpinned by transcriptional, translational, and epigenetic mechanisms and niche factors, and unraveling this complexity will improve our understanding of underlying molecular changes that affect the ability of the articular cartilage to maintain or regenerate itself. This insight is imperative for developing new cell and drug therapies for OA disease that will target the specific causes of age-related functional decline. This review explores the key age-related changes within articular chondrocytes and discusses the molecular mechanisms that are commonly perturbed as cartilage ages and degenerates. Current efforts and emerging potential therapies in treating OA that are being employed to halt or decelerate the aging processes are also discussed.

scholarly journals Fructose modulates GLUT5 mRNA stability in differentiated Caco-2 cells: role of cAMP-signalling pathway and PABP (polyadenylated-binding protein)-interacting protein (Paip) 2

2003 ◽  
Vol 375 (1) ◽  
pp. 167-174 ◽  
Author(s):  
Florence GOUYON ◽  
Cercina ONESTO ◽  
Veronique DALET ◽  
Gilles PAGES ◽  
Armelle LETURQUE ◽  
...  
Keyword(s):  
Mrna Stability ◽  
Protein Complexes ◽  
Binding Protein ◽  
Interacting Protein ◽  
Camp Signalling ◽  
Camp Pathway ◽  
Post Transcriptional Regulation ◽  
Rna Protein Complexes ◽  
Camp Levels

In intestinal cells, levels of the fructose transporter GLUT5 are increased by glucose and to a greater extent by fructose. We investigated the mechanism by which fructose increases GLUT5 expression. In Caco-2 cells, fructose and glucose increased activity of the −2500/+41 GLUT5 promoter to the same extent. cAMP also activated the GLUT5 promoter. However, if a protein kinase A inhibitor was used to block cAMP signalling, extensive GLUT5 mRNA degradation was observed, with no change in basal transcription levels demonstrating the involvement of cAMP in GLUT5 mRNA stability. Indeed, the half-life of GLUT5 mRNA was correlated (R2=0.9913) with cellular cAMP levels. Fructose increased cAMP concentration more than glucose, accounting for the stronger effect of fructose when compared with that of glucose on GLUT5 production. We identified several complexes between GLUT5 3′-UTR RNA (where UTR stands for untranslated region) and cytosolic proteins that might participate in mRNA processing. Strong binding of a 140 kDa complex I was observed in sugar-deprived cells, with levels of binding lower in the presence of fructose and glucose by factors of 12 and 6 respectively. This may account for differences in the effects of fructose and glucose. In contrast, the amounts of two complexes of 96 and 48 kDa increased equally after stimulation with either glucose or fructose. Finally, PABP (polyadenylated-binding protein)-interacting protein 2, a destabilizing partner of PABP, was identified as a component of GLUT5 3′-UTR RNA–protein complexes. We conclude that the post-transcriptional regulation of GLUT5 by fructose involves increases in mRNA stability mediated by the cAMP pathway and Paip2 (PABP-interacting protein 2) binding.

scholarly journals Rewiring of the ubiquitinated proteome determines ageing in C. elegans

Nature ◽  
2021 ◽  
Author(s):  
Seda Koyuncu ◽  
Rute Loureiro ◽  
Hyun Ju Lee ◽  
Prerana Wagle ◽  
Marcus Krueger ◽  
...  
Keyword(s):  
Cell Function ◽  
Insulin Signalling ◽  
Bacterial Colonization ◽  
Regulatory Proteins ◽  
C Elegans ◽  
Intestinal Integrity ◽  
Age Related ◽  
Subsequent Degradation ◽  
Cellular Integrity

AbstractAgeing is driven by a loss of cellular integrity1. Given the major role of ubiquitin modifications in cell function2, here we assess the link between ubiquitination and ageing by quantifying whole-proteome ubiquitin signatures in Caenorhabditis elegans. We find a remodelling of the ubiquitinated proteome during ageing, which is ameliorated by longevity paradigms such as dietary restriction and reduced insulin signalling. Notably, ageing causes a global loss of ubiquitination that is triggered by increased deubiquitinase activity. Because ubiquitination can tag proteins for recognition by the proteasome3, a fundamental question is whether deficits in targeted degradation influence longevity. By integrating data from worms with a defective proteasome, we identify proteasomal targets that accumulate with age owing to decreased ubiquitination and subsequent degradation. Lowering the levels of age-dysregulated proteasome targets prolongs longevity, whereas preventing their degradation shortens lifespan. Among the proteasomal targets, we find the IFB-2 intermediate filament4 and the EPS-8 modulator of RAC signalling5. While increased levels of IFB-2 promote the loss of intestinal integrity and bacterial colonization, upregulation of EPS-8 hyperactivates RAC in muscle and neurons, and leads to alterations in the actin cytoskeleton and protein kinase JNK. In summary, age-related changes in targeted degradation of structural and regulatory proteins across tissues determine longevity.

scholarly journals Oxidative Stress, Mitochondrial Dysfunction, and Aging

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Hang Cui ◽  
Yahui Kong ◽  
Hong Zhang
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Mitochondrial Dna ◽  
Molecular Mechanisms ◽  
Ros Production ◽  
Oxygen Species ◽  
Progressive Decline ◽  
Theories Of Aging ◽  
Age Related ◽  
Potential Impact

Aging is an intricate phenomenon characterized by progressive decline in physiological functions and increase in mortality that is often accompanied by many pathological diseases. Although aging is almost universally conserved among all organisms, the underlying molecular mechanisms of aging remain largely elusive. Many theories of aging have been proposed, including the free-radical and mitochondrial theories of aging. Both theories speculate that cumulative damage to mitochondria and mitochondrial DNA (mtDNA) caused by reactive oxygen species (ROS) is one of the causes of aging. Oxidative damage affects replication and transcription of mtDNA and results in a decline in mitochondrial function which in turn leads to enhanced ROS production and further damage to mtDNA. In this paper, we will present the current understanding of the interplay between ROS and mitochondria and will discuss their potential impact on aging and age-related diseases.

scholarly journals Wine Polyphenols and Neurodegenerative Diseases: An Update on the Molecular Mechanisms Underpinning Their Protective Effects

Beverages ◽  
2018 ◽  
Vol 4 (4) ◽  
pp. 96 ◽  
Author(s):  
Paula Silva ◽  
David Vauzour
Keyword(s):  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Inverse Correlation ◽  
Protective Effects ◽  
Wine Consumption ◽  
Age Related ◽  
Parkinson’S Diseases

Alzheimer’s and Parkinson’s diseases are the most common age-related and predominantly idiopathic neurodegenerative disorders of unknown pathogenesis. Although there are both clinical and neuropathological features of these diseases that are different, they also share some common aetiologies, such as protein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Epidemiological, in vitro and in vivo evidences suggest an inverse correlation between wine consumption and the incidence of neurodegenerative disorders. Wine benefits are, in large part, attributable to the intake of specific polyphenols, which mediate cell function under both normal and pathological conditions. In this review, we aim to provide an overview of the role that wine consumption plays in delaying neurodegenerative disorders. We discuss animal and in vitro studies in support of these actions and we consider how their biological mechanisms at the cellular level may underpin their physiological effects. Together, these data indicate that polyphenols present in wine may hold neuroprotective potential in delaying the onset of neurodegenerative disorders.

Role of membrane lipid rafts in MRP4 (ABCC4)-dependent regulation of the cAMP pathway in blood platelets

2021 ◽  
Author(s):  
Tiphaine Belleville-Rolland ◽  
Alexandre Leuci ◽  
Alexandre MANSOUR ◽  
Benoit Decouture ◽  
Fanny Martin ◽  
...  
Keyword(s):  
Lipid Rafts ◽  
Plasma Membranes ◽  
Blood Platelets ◽  
Membrane Lipid ◽  
Dense Granule ◽  
Effector Proteins ◽  
Platelet Surface ◽  
Camp Signalling ◽  
Camp Pathway ◽  
Camp Levels

Background. Platelet cytosolic cAMP levels are balanced by synthesis, degradation, and efflux. Efflux can occur via MRP4 (multidrug resistant protein-4, ABCC4) present on dense granule and/or plasma membranes. As lipid rafts have been shown to interfere on cAMP homeostasis, we evaluated the relationships between the distribution and activity of MRP4 in lipid rafts and cAMP efflux. Methods. Platelet activation and cAMP homeostasis were analyzed in human and wild-type or MRP4-deleted mouse platelets in the presence of methyl-β-cyclodextrin (MβCD) to disrupt lipid rafts, and of activators of the cAMP signalling pathways. Human platelet MRP4 and effector proteins of the cAMP pathway were analyzed by immunoblots in lipid rafts isolated by differential centrifugation. Results. MβCD dose-dependently inhibited human and mouse platelet aggregation without affecting per se cAMP levels. An additive inhibitory effect existed between the adenylate cyclase (AC) activator forskolin and MβCD that was accompanied by an overincrease of cAMP, and which was significantly enhanced upon MRP4 deletion. Finally, an efflux of cAMP out of resting platelets incubated with PGE1 was observed that was partly dependent on MRP4. Lipid rafts contained a small fraction (≈ 15%) of MRP4 and most of the inhibitory G-protein Gi, whereas Gs protein, AC3, and phosphodiesterases PDE2 and PDE3A were all present as only trace amounts. Conclusion. Our results are in favor of part of MRP4 present at the platelet surface, including in lipid rafts. Lipid raft integrity is necessary for cAMP signalling regulation, although MRP4 and most players of cAMP homeostasis are essentially located outside rafts.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

Molecular Mechanisms of Complement System Proteins and Matrix Metalloproteinases in the Pathogenesis of Age-Related Macular Degeneration

2019 ◽  
Vol 19 (10) ◽  
pp. 705-718 ◽  
Author(s):  
Naima Mansoor ◽  
Fazli Wahid ◽  
Maleeha Azam ◽  
Khadim Shah ◽  
Anneke I. den Hollander ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Macular Degeneration ◽  
Complement System ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Age Related Macular Degeneration ◽  
Genetic Changes ◽  
Complement System Proteins ◽  
Age Related ◽  
Common Genetic Variants

: Age-related macular degeneration (AMD) is an eye disorder affecting predominantly the older people above the age of 50 years in which the macular region of the retina deteriorates, resulting in the loss of central vision. The key factors associated with the pathogenesis of AMD are age, smoking, dietary, and genetic risk factors. There are few associated and plausible genes involved in AMD pathogenesis. Common genetic variants (with a minor allele frequency of >5% in the population) near the complement genes explain 40–60% of the heritability of AMD. The complement system is a group of proteins that work together to destroy foreign invaders, trigger inflammation, and remove debris from cells and tissues. Genetic changes in and around several complement system genes, including the CFH, contribute to the formation of drusen and progression of AMD. Similarly, Matrix metalloproteinases (MMPs) that are normally involved in tissue remodeling also play a critical role in the pathogenesis of AMD. MMPs are involved in the degradation of cell debris and lipid deposits beneath retina but with age their functions get affected and result in the drusen formation, succeeding to macular degeneration. In this review, AMD pathology, existing knowledge about the normal and pathological role of complement system proteins and MMPs in the eye is reviewed. The scattered data of complement system proteins, MMPs, drusenogenesis, and lipofusogenesis have been gathered and discussed in detail. This might add new dimensions to the understanding of molecular mechanisms of AMD pathophysiology and might help in finding new therapeutic options for AMD.

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