scholarly journals The Evolution of the Hallmarks of Aging

2021 ◽  
Vol 12 ◽  
Author(s):  
Maël Lemoine
Keyword(s):  
Molecular Mechanisms ◽  
Nutrient Sensing ◽  
Human Aging ◽  
Comprehensive Understanding ◽  
Abnormal Protein ◽  
Transcriptional Alterations ◽  
Theory Of Aging ◽  
Unicellular Organisms ◽  
Biology Of Aging ◽  
Progressive Accumulation

The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the “hallmarks of aging,” i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging – the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called “layers of aging.” A difference should be made between the first four layers of unicellular aging, present in some unicellular organisms and in all multicellular opisthokonts, that stem and strike “from the inside” of individual cells and span from increasingly abnormal protein folding to deregulated nutrient sensing, and the last four layers of metacellular aging, progressively appearing in metazoans, that strike the cells of a multicellular organism “from the outside,” i.e., because of other cells, and span from transcriptional alterations to the disruption of intercellular communication. The evolution of metazoans and eumetazoans probably solved the problem of aging along with the problem of unicellular aging. However, metacellular aging originates in the mechanisms by which the effects of unicellular aging are kept under control – e.g., the exhaustion of stem cells that contribute to replace damaged somatic cells. In bilaterians, additional functions have taken a toll on generally useless potentially limited lifespan to increase the fitness of organisms at the price of a progressively less efficient containment of the damage of unicellular aging. In the end, this picture suggests that geroscience should be more efficient in targeting conditions of metacellular aging rather than unicellular aging itself.

The biochemistry and cell biology of aging: metabolic regulation through mitochondrial signaling

2014 ◽  
Vol 306 (6) ◽  
pp. E581-E591 ◽  
Author(s):  
Yun Chau Long ◽  
Theresa May Chin Tan ◽  
Inoue Takao ◽  
Bor Luen Tang
Keyword(s):  
Cell Biology ◽  
Metabolic Regulation ◽  
Nutrient Sensing ◽  
Cellular Aging ◽  
Retrograde Signaling ◽  
Unfolded Protein ◽  
Mitochondrial Retrograde Signaling ◽  
Long Time ◽  
Biology Of Aging ◽  
Protein Response

Cellular and organ metabolism affects organismal lifespan. Aging is characterized by increased risks for metabolic disorders, with age-associated degenerative diseases exhibiting varying degrees of mitochondrial dysfunction. The traditional view of the role of mitochondria generated reactive oxygen species (ROS) in cellular aging, assumed to be causative and simply detrimental for a long time now, is in need of reassessment. While there is little doubt that high levels of ROS are detrimental, mounting evidence points toward a lifespan extension effect exerted by mild to moderate ROS elevation. Dietary caloric restriction, inhibition of insulin-like growth factor-I signaling, and inhibition of the nutrient-sensing mechanistic target of rapamycin are robust longevity-promoting interventions. All of these appear to elicit mitochondrial retrograde signaling processes (defined as signaling from the mitochondria to the rest of the cell, for example, the mitochondrial unfolded protein response, or UPRmt). The effects of mitochondrial retrograde signaling may even spread to other cells/tissues in a noncell autonomous manner by yet unidentified signaling mediators. Multiple recent publications support the notion that an evolutionarily conserved, mitochondria-initiated signaling is central to the genetic and epigenetic regulation of cellular aging and organismal lifespan.

scholarly journals Methotrexate Toxicity: Molecular Mechanisms and Management

2021 ◽  
pp. 204-217
Author(s):  
Riyadh S. Almalki ◽  
Hala Eweis ◽  
Fatemah Kamal ◽  
Dina Kutbi
Keyword(s):  
Side Effects ◽  
Cancer Chemotherapy ◽  
Pulmonary Toxicity ◽  
Molecular Mechanisms ◽  
Hematological Toxicity ◽  
Comprehensive Understanding ◽  
First Line ◽  
Cutaneous Toxicity ◽  
Gi Toxicity ◽  
Line Drug

Methotrexate (MTX) is the most widely used drug in cancer chemotherapy and is considered to be the first-line drug for the treatment of a number of rheumatic and non-rheumatic disorders. The pulmonary toxicity, hepatotoxicity of MTX are two of its major side effects. Other toxicities such as endocrinological toxicity, GI toxicity, cutaneous toxicity, hematological toxicity, fatal malfunction or loss, and malignancy can also occur, but at a significantly lower rate of prevalence. This review aims to provide a comprehensive understanding of the molecular mechanisms of methotrexate toxic effects and Lastly, we discussed the management of this toxicity.

scholarly journals Molecular Mechanisms Involved in the Multicellular Growth of Ustilaginomycetes

2020 ◽  
Vol 8 (7) ◽  
pp. 1072
Author(s):  
Domingo Martínez-Soto ◽  
Lucila Ortiz-Castellanos ◽  
Mariana Robledo-Briones ◽  
Claudia Geraldine León-Ramírez
Keyword(s):  
Molecular Mechanisms ◽  
Developmental Process ◽  
Culture Media ◽  
Morphological Plasticity ◽  
Model Organisms ◽  
Fruiting Bodies ◽  
Daughter Cells ◽  
Plant Infection ◽  
Polarized Cell Growth ◽  
Unicellular Organisms

Multicellularity is defined as the developmental process by which unicellular organisms became pluricellular during the evolution of complex organisms on Earth. This process requires the convergence of genetic, ecological, and environmental factors. In fungi, mycelial and pseudomycelium growth, snowflake phenotype (where daughter cells remain attached to their stem cells after mitosis), and fruiting bodies have been described as models of multicellular structures. Ustilaginomycetes are Basidiomycota fungi, many of which are pathogens of economically important plant species. These fungi usually grow unicellularly as yeasts (sporidia), but also as simple multicellular forms, such as pseudomycelium, multicellular clusters, or mycelium during plant infection and under different environmental conditions: Nitrogen starvation, nutrient starvation, acid culture media, or with fatty acids as a carbon source. Even under specific conditions, Ustilago maydis can form basidiocarps or fruiting bodies that are complex multicellular structures. These fungi conserve an important set of genes and molecular mechanisms involved in their multicellular growth. In this review, we will discuss in-depth the signaling pathways, epigenetic regulation, required polyamines, cell wall synthesis/degradation, polarized cell growth, and other cellular-genetic processes involved in the different types of Ustilaginomycetes multicellular growth. Finally, considering their short life cycle, easy handling in the laboratory and great morphological plasticity, Ustilaginomycetes can be considered as model organisms for studying fungal multicellularity.

Resistance to antifungal therapies

2017 ◽  
Vol 61 (1) ◽  
pp. 157-166 ◽  
Author(s):  
Rajendra Prasad ◽  
Atanu Banerjee ◽  
Abdul Haseeb Shah
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Therapeutic Interventions ◽  
Medical Professionals ◽  
Comprehensive Understanding ◽  
Novel Targets

The evolution of antifungal resistance among fungal pathogens has rendered the limited arsenal of antifungal drugs futile. Considering the recent rise in the number of nosocomial fungal infections in immunocompromised patients, the emerging clinical multidrug resistance (MDR) has become a matter of grave concern for medical professionals. Despite advances in therapeutic interventions, it has not yet been possible to devise convincing strategies to combat antifungal resistance. Comprehensive understanding of the molecular mechanisms of antifungal resistance is essential for identification of novel targets that do not promote or delay emergence of drug resistance. The present study discusses features and limitations of the currently available antifungals, mechanisms of antifungal resistance and highlights the emerging therapeutic strategies that could be deployed to combat MDR.

scholarly journals A Mep2-dependent Transcriptional Profile Links Permease Function to Gene Expression during Pseudohyphal Growth in Saccharomyces cerevisiae

2008 ◽  
Vol 19 (7) ◽  
pp. 3028-3039 ◽  
Author(s):  
Julian C. Rutherford ◽  
Gordon Chua ◽  
Timothy Hughes ◽  
Maria E. Cardenas ◽  
Joseph Heitman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Map Kinase ◽  
Molecular Mechanisms ◽  
Nutrient Sensing ◽  
Transcriptional Profile ◽  
Regulatory Function ◽  
Pseudohyphal Growth ◽  
Epistasis Analysis ◽  
Map Kinase Pathway ◽  
Kinase Pathway

The ammonium permease Mep2 is required for the induction of pseudohyphal growth, a process in Saccharomyces cerevisiae that occurs in response to nutrient limitation. Mep2 has both a transport and a regulatory function, supporting models in which Mep2 acts as a sensor of ammonium availability. Potentially similar ammonium permease-dependent regulatory cascades operate in other fungi, and they may also function in animals via the homologous Rh proteins; however, little is known about the molecular mechanisms that mediate ammonium sensing. We show that Mep2 is localized to the cell surface during pseudohyphal growth, and it is required for both filamentous and invasive growth. Analysis of site-directed Mep2 mutants in residues lining the ammonia-conducting channel reveal separation of function alleles (transport and signaling defective; transport-proficient/signaling defective), indicating transport is necessary but not sufficient to sense ammonia. Furthermore, Mep2 overexpression enhances differentiation under normally repressive conditions and induces a transcriptional profile that is consistent with activation of the mitogen-activated protein (MAP) kinase pathway. This finding is supported by epistasis analysis establishing that the known role of the MAP kinase pathway in pseudohyphal growth is linked to Mep2 function. Together, these data strengthen the model that Mep2-like proteins are nutrient sensing transceptors that govern cellular differentiation.

scholarly journals Stepping inside the realm of epigenetic modifiers

2015 ◽  
Vol 6 (2) ◽  
pp. 119-136 ◽  
Author(s):  
Roy Blum
Keyword(s):  
Modus Operandi ◽  
Regulate Gene Expression ◽  
Daughter Cells ◽  
Differentiated Cells ◽  
Epigenetic Modifiers ◽  
Eukaryotic Chromatin ◽  
Transcriptional Alterations ◽  
Numerous Cell ◽  
Unicellular Organisms ◽  
Unique Composition

AbstractThe ability to regulate gene expression in response to environmental alterations is vital for the endurance of all cells. However, unlike bacteria and unicellular organisms, cells of multicellular eukaryotes have developed this competency in a highly sophisticated manner, which ultimately allows for multiple lineages of differentiated cells. To maintain stability and generate progeny, differentiated cells must remain lineage-committed through numerous cell generations, and therefore their transcriptional modus operandi ought to be memorized and transmittable. To preserve the specialized characteristics of differentiated cells, it is crucial that transcriptional alterations that are triggered by specific external or intrinsic stimuli can last also after stimuli fading and propagate onto daughter cells. The unique composition of DNA and histones, and their ability to acquire a variety of epigenetic modifications, enables eukaryotic chromatin to assimilate cellular plasticity and molecular memory. The most well-studied types of epigenetic modifiers are covalently modifying DNA or histones, mostly in a reversible manner. Additional epigenetic mechanisms include histone variant replacement, energy-utilizing remodeling factors, and noncoding transcripts assembled with modifying complexes. Working with multifunctional complexes including transcription factors, epigenetic modifiers have the potential to dictate a variety of transcriptional programs underlying all cellular lineages, while utilizing in each the same source DNA as their substrates.

scholarly journals The molecular evolution of the vertebrate behavioural repertoire

2016 ◽  
Vol 371 (1685) ◽  
pp. 20150051 ◽  
Author(s):  
Seth G. N. Grant
Keyword(s):  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Behavioural Disorders ◽  
Major Question ◽  
Unicellular Eukaryotes ◽  
General Importance ◽  
Duplication Events ◽  
Genomic Studies ◽  
Unicellular Organisms ◽  
Behavioural Repertoire

How the sophisticated vertebrate behavioural repertoire evolved remains a major question in biology. The behavioural repertoire encompasses the set of individual behavioural components that an organism uses when adapting and responding to changes in its external world. Although unicellular organisms, invertebrates and vertebrates share simple reflex responses, the fundamental mechanisms that resulted in the complexity and sophistication that is characteristic of vertebrate behaviours have only recently been examined. A series of behavioural genetic experiments in mice and humans support a theory that posited the importance of synapse proteome expansion in generating complexity in the behavioural repertoire. Genome duplication events, approximately 550 Ma, produced expansion in the synapse proteome that resulted in increased complexity in synapse signalling mechanisms that regulate components of the behavioural repertoire. The experiments demonstrate the importance to behaviour of the gene duplication events, the diversification of paralogues and sequence constraint. They also confirm the significance of comparative proteomic and genomic studies that identified the molecular origins of synapses in unicellular eukaryotes and the vertebrate expansion in proteome complexity. These molecular mechanisms have general importance for understanding the repertoire of behaviours in different species and for human behavioural disorders arising from synapse gene mutations.

scholarly journals Glucose intake hampers PKA-regulated HSP90 chaperone activity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yu-Chen Chen ◽  
Pei-Heng Jiang ◽  
Hsuan-Ming Chen ◽  
Chang-Han Chen ◽  
Yi-Ting Wang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Protein Quality ◽  
Glucose Sensing ◽  
Nutrient Sensing ◽  
Heat Sensitivity ◽  
Functional Screening ◽  
Quantitative Mass Spectrometry ◽  
Glucose Intake ◽  
Gradual Loss ◽  
Hsp90 Chaperone

Aging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan. Functional screening of 135 potential regulators uncovered that Ids2 is activated by PP2C under CR and inactivated by PKA under glucose intake. ids2Δ or ids2 phosphomimetic cells displayed heat sensitivity and lifespan shortening. Ids2 serves as a co-chaperone to form a complex with Hsc82 or the redundant Hsp82, and phosphorylation impedes its association with chaperone HSP90. Thus, PP2C and PKA may orchestrate glucose sensing and protein folding to enable cells to maintain protein quality for sustained longevity.

scholarly journals Reflexões sobre a Biogerontologia como uma Ciência Generalista, Integrativa e Interativa

2001 ◽  
Vol 3 ◽  
Author(s):  
Ivana Beatrice Mânica da Cruz ◽  
Carla Helena Augustin Schwanke
Keyword(s):  
Human Aging ◽  
Biology Of Aging

Resumo: O texto compila conceitos e informações relacionados com um ramo recente da biologia do desenvolvimento, denominado biogerontologia ou biologia do envelhecimento. Reflexões sobre o conjunto de conhecimentos relatado, associado a aspectos sociais, antropológicos e psicológicos são feitas. A síntese do texto, preconiza a importância de rompermos com a ignorância a respeito das modificações associadas ao envelhecimento humano como uma forma de manejar de modo adequado este período da vida auxiliando, deste modo, na diminuição da marginalização e isolamento do idoso que acontece na nossa sociedade. Palavras-chave: Biogerontologia. Envelhecimento. Abstract: The text resumes concepts and informations related to a recent branch of the biology of development, named biogerontology or biology of aging. Reflections about the knowledge, associated to social, antropological and psicological aspects are made. The synthesis of the text precognize the importance of breaking the ignorance about the modifications related to human aging as a way to handle in a good way this time of life, and, in this way help to lower the arginalization and isolation of the elder that happens in our society. Keywords: Biogerontology. Agement.

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