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Special Issue "Molecular and Cellular Mechanisms of Aging and Age-Related Disorders"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2018)

Special Issue Editor

Guest Editor
Dr. Vladimir Titorenko

Biology Department, Concordia University, Montreal, Quebec, Canada
Website | E-Mail
Phone: (514) 848-2424 extension 3424
Interests: aging; cancer; lipid metabolism; mitochondria; cell cycle; proteomics; lipidomics

Special Issue Information

Dear Colleagues,

Aging of unicellular and multicellular eukaryotic organisms is a convoluted biological phenomenon, which is manifested as an age-related functional decline caused by a progressive dysregulation of certain cellular and organismal processes. Many chronic diseases are associated with human aging. These age-related diseases include arthritis, diabetes, heart disease, kidney disease, liver dysfunction, sarcopenia, stroke, neurodegenerative diseases (including Parkinson's, Alzheimer's and Huntington's diseases), and many forms of cancer. Studies in yeast, roundworms, fruit flies, fishes, mice, primates and humans have provided evidence that the major aspects and basic mechanisms of aging and age-related pathology are conserved across phyla. The focus of this International Journal of Molecular Sciences Special Issue is on molecular and cellular mechanisms of aging and age-related disorders. The Issue will highlight the strategies used by evolutionarily diverse organisms for coordinating various longevity-defining cellular processes in space and time, critically evaluate the molecular and cellular mechanisms underlying such coordination, and outline the most important unanswered questions and directions for future research in this vibrant and rapidly evolving field.

Dr. Vladimir Titorenko
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aging
  • age-related disorders
  • aging-delaying interventions
  • signaling pathways
  • hormesis
  • metabolism
  • mitochondria
  • cellular proteostasis
  • interorganellar communications

Related Special Issue

Published Papers (9 papers)

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Editorial

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Open AccessEditorial
Molecular and Cellular Mechanisms of Aging and Age-related Disorders
Int. J. Mol. Sci. 2018, 19(7), 2049; https://doi.org/10.3390/ijms19072049
Received: 11 July 2018 / Accepted: 13 July 2018 / Published: 14 July 2018
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(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)

Research

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Open AccessArticle
Aging and Intermittent Fasting Impact on Transcriptional Regulation and Physiological Responses of Adult Drosophila Neuronal and Muscle Tissues
Int. J. Mol. Sci. 2018, 19(4), 1140; https://doi.org/10.3390/ijms19041140
Received: 5 March 2018 / Revised: 29 March 2018 / Accepted: 30 March 2018 / Published: 10 April 2018
Cited by 2 | PDF Full-text (29073 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The progressive decline of the nervous system, including protein aggregate formation, reflects the subtle dysregulation of multiple functional pathways. Our previous work has shown intermittent fasting (IF) enhances longevity, maintains adult behaviors and reduces aggregates, in part, by promoting autophagic function in the [...] Read more.
The progressive decline of the nervous system, including protein aggregate formation, reflects the subtle dysregulation of multiple functional pathways. Our previous work has shown intermittent fasting (IF) enhances longevity, maintains adult behaviors and reduces aggregates, in part, by promoting autophagic function in the aging Drosophila brain. To clarify the impact that IF-treatment has upon aging, we used high throughput RNA-sequencing technology to examine the changing transcriptome in adult Drosophila tissues. Principle component analysis (PCA) and other analyses showed ~1200 age-related transcriptional differences in head and muscle tissues, with few genes having matching expression patterns. Pathway components showing age-dependent expression differences were involved with stress response, metabolic, neural and chromatin remodeling functions. Middle-aged tissues also showed a significant increase in transcriptional drift-variance (TD), which in the CNS included multiple proteolytic pathway components. Overall, IF-treatment had a demonstrably positive impact on aged transcriptomes, partly ameliorating both fold and variance changes. Consistent with these findings, aged IF-treated flies displayed more youthful metabolic, behavioral and basal proteolytic profiles that closely correlated with transcriptional alterations to key components. These results indicate that even modest dietary changes can have therapeutic consequences, slowing the progressive decline of multiple cellular systems, including proteostasis in the aging nervous system. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)
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Open AccessArticle
Characterization of Ageing- and Diet-Related Swine Models of Sarcopenia and Sarcopenic Obesity
Int. J. Mol. Sci. 2018, 19(3), 823; https://doi.org/10.3390/ijms19030823
Received: 23 January 2018 / Revised: 28 February 2018 / Accepted: 7 March 2018 / Published: 12 March 2018
Cited by 1 | PDF Full-text (2254 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Sarcopenia and sarcopenic obesity are currently considered major global threats for health and well-being. However, there is a lack of adequate preclinical models for their study. The present trial evaluated the suitability of aged swine by determining changes in adiposity, fatty acids composition, [...] Read more.
Sarcopenia and sarcopenic obesity are currently considered major global threats for health and well-being. However, there is a lack of adequate preclinical models for their study. The present trial evaluated the suitability of aged swine by determining changes in adiposity, fatty acids composition, antioxidant status and lipid peroxidation, development of metabolic disturbances and structural changes in tissues and organs. Iberian sows with clinical evidence of aging-related sarcopenia were fed a standard diet fulfilling their maintenance requirements or an obesogenic diet for 100 days. Aging and sarcopenia were related to increased lipid accumulation and cellular dysfunction at both adipose tissue and non-adipose ectopic tissues (liver and pancreas). Obesity concomitant to sarcopenia aggravates the condition by increasing visceral adiposity and causing dyslipidemia, insulin resistance and lipotoxicity in non-adipose tissues. These results support that the Iberian swine model represents certain features of sarcopenia and sarcopenic obesity in humans, paving the way for future research on physiopathology of these conditions and possible therapeutic targets. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)
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Open AccessArticle
Aged Mouse Cortical Microglia Display an Activation Profile Suggesting Immunotolerogenic Functions
Int. J. Mol. Sci. 2018, 19(3), 706; https://doi.org/10.3390/ijms19030706
Received: 31 January 2018 / Revised: 21 February 2018 / Accepted: 25 February 2018 / Published: 1 March 2018
Cited by 7 | PDF Full-text (2272 KB) | HTML Full-text | XML Full-text
Abstract
Microglia are the resident immune cells of the central nervous system (CNS) and participate in physiological and pathological processes. Their unique developmental nature suggests age-dependent structural and functional impairments that might contribute to neurodegenerative diseases. In the present study, we addressed the age-dependent [...] Read more.
Microglia are the resident immune cells of the central nervous system (CNS) and participate in physiological and pathological processes. Their unique developmental nature suggests age-dependent structural and functional impairments that might contribute to neurodegenerative diseases. In the present study, we addressed the age-dependent changes in cortical microglia gene expression patterns and the expression of M1- and M2-like activation markers. Iba1 immunohistochemistry, isolation of cortical microglia followed by fluorescence-activated cell sorting and RNA isolation to analyze transcriptional changes in aged cortical microglia was performed. We provide evidence that aging is associated with decreased numbers of cortical microglia and the establishment of a distinct microglia activation profile including upregulation of Ifi204, Lilrb4, Arhgap, Oas1a, Cd244 and Ildr2. Moreover, flow cytometry revealed that aged cortical microglia express increased levels of Cd206 and Cd36. The data presented in the current study indicate that aged mouse cortical microglia adopt a distinct activation profile, which suggests immunosuppressive and immuno-tolerogenic functions. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)
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Graphical abstract

Open AccessArticle
Network-Driven Proteogenomics Unveils an Aging-Related Imbalance in the Olfactory IκBα-NFκB p65 Complex Functionality in Tg2576 Alzheimer’s Disease Mouse Model
Int. J. Mol. Sci. 2017, 18(11), 2260; https://doi.org/10.3390/ijms18112260
Received: 27 September 2017 / Revised: 23 October 2017 / Accepted: 25 October 2017 / Published: 27 October 2017
Cited by 2 | PDF Full-text (4367 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Olfaction is often deregulated in Alzheimer’s disease (AD) patients, and is also impaired in transgenic Tg2576 AD mice, which overexpress the Swedish mutated form of human amyloid precursor protein (APP). However, little is known about the molecular mechanisms that accompany the neurodegeneration of [...] Read more.
Olfaction is often deregulated in Alzheimer’s disease (AD) patients, and is also impaired in transgenic Tg2576 AD mice, which overexpress the Swedish mutated form of human amyloid precursor protein (APP). However, little is known about the molecular mechanisms that accompany the neurodegeneration of olfactory structures in aged Tg2576 mice. For that, we have applied proteome- and transcriptome-wide approaches to probe molecular disturbances in the olfactory bulb (OB) dissected from aged Tg2576 mice (18 months of age) as compared to those of age matched wild-type (WT) littermates. Some over-represented biological functions were directly relevant to neuronal homeostasis and processes of learning, cognition, and behavior. In addition to the modulation of CAMP responsive element binding protein 1 (CREB1) and APP interactomes, an imbalance in the functionality of the IκBα-NFκB p65 complex was observed during the aging process in the OB of Tg2576 mice. At two months of age, the phosphorylated isoforms of olfactory IκBα and NFκB p65 were inversely regulated in transgenic mice. However, both phosphorylated proteins were increased at 6 months of age, while a specific drop in IκBα levels was detected in 18-month-old Tg2576 mice, suggesting a transient activation of NFκB in the OB of Tg2576 mice. Taken together, our data provide a metabolic map of olfactory alterations in aged Tg2576 mice, reflecting the progressive effect of APP overproduction and β-amyloid (Aβ) accumulation on the OB homeostasis in aged stages. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)
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Graphical abstract

Open AccessArticle
Electronegative Low-Density Lipoprotein L5 Impairs Viability and NGF-Induced Neuronal Differentiation of PC12 Cells via LOX-1
Int. J. Mol. Sci. 2017, 18(8), 1744; https://doi.org/10.3390/ijms18081744
Received: 20 July 2017 / Revised: 5 August 2017 / Accepted: 7 August 2017 / Published: 11 August 2017
Cited by 1 | PDF Full-text (5997 KB) | HTML Full-text | XML Full-text
Abstract
There have been striking associations of cardiovascular diseases (e.g., atherosclerosis) and hypercholesterolemia with increased risk of neurodegeneration including Alzheimer’s disease (AD). Low-density lipoprotein (LDL), a cardiovascular risk factor, plays a crucial role in AD pathogenesis; further, L5, a human plasma LDL fraction with [...] Read more.
There have been striking associations of cardiovascular diseases (e.g., atherosclerosis) and hypercholesterolemia with increased risk of neurodegeneration including Alzheimer’s disease (AD). Low-density lipoprotein (LDL), a cardiovascular risk factor, plays a crucial role in AD pathogenesis; further, L5, a human plasma LDL fraction with high electronegativity, may be a factor contributing to AD-type dementia. Although L5 contributing to atherosclerosis progression has been studied, its role in inducing neurodegeneration remains unclear. Here, PC12 cell culture was used for treatments with human LDLs (L1, L5, or oxLDL), and subsequently cell viability and nerve growth factor (NGF)-induced neuronal differentiation were assessed. We identified L5 as a neurotoxic LDL, as demonstrated by decreased cell viability in a time- and concentration-dependent manner. Contrarily, L1 had no such effect. L5 caused cell damage by inducing ATM/H2AX-associated DNA breakage as well as by activating apoptosis via lectin-like oxidized LDL receptor-1 (LOX-1) signaling to p53 and ensuring cleavage of caspase-3. Additionally, sublethal L5 long-termly inhibited neurite outgrowth in NGF-treated PC12 cells, as evidenced by downregulation of early growth response factor-1 and neurofilament-M. This inhibitory effect was mediated via an interaction between L5 and LOX-1 to suppress NGF-induced activation of PI3k/Akt cascade, but not NGF receptor TrkA and downstream MAPK pathways. Together, our data suggest that L5 creates a neurotoxic stress via LOX-1 in PC12 cells, thereby leading to impairment of viability and NGF-induced differentiation. Atherogenic L5 likely contributes to neurodegenerative disorders. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)
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Review

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Open AccessReview
Activating the Anaphase Promoting Complex to Enhance Genomic Stability and Prolong Lifespan
Int. J. Mol. Sci. 2018, 19(7), 1888; https://doi.org/10.3390/ijms19071888
Received: 15 May 2018 / Revised: 19 June 2018 / Accepted: 20 June 2018 / Published: 27 June 2018
Cited by 3 | PDF Full-text (2485 KB) | HTML Full-text | XML Full-text
Abstract
In aging cells, genomic instability is now recognized as a hallmark event. Throughout life, cells encounter multiple endogenous and exogenous DNA damaging events that are mostly repaired, but inevitably DNA mutations, chromosome rearrangements, and epigenetic deregulation begins to mount. Now that people are [...] Read more.
In aging cells, genomic instability is now recognized as a hallmark event. Throughout life, cells encounter multiple endogenous and exogenous DNA damaging events that are mostly repaired, but inevitably DNA mutations, chromosome rearrangements, and epigenetic deregulation begins to mount. Now that people are living longer, more and more late life time is spent suffering from age-related disease, in which genomic instability plays a critical role. However, several major questions remain heavily debated, such as the following: When does aging start? How long can we live? In order to minimize the impact of genomic instability on longevity, it is important to understand when aging starts, and to ensure repair mechanisms remain optimal from the very start to the very end. In this review, the interplay between the stress and nutrient response networks, and the regulation of homeostasis and genomic stability, is discussed. Mechanisms that link these two networks are predicted to be key lifespan determinants. The Anaphase Promoting Complex (APC), a large evolutionarily conserved ubiquitin ligase, can potentially serve this need. Recent work demonstrates that the APC maintains genomic stability, mounts a stress response, and increases longevity in yeast. Furthermore, inhibition of APC activity by glucose and nutrient response factors indicates a tight link between the APC and the stress/nutrient response networks. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)
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Open AccessReview
Some Metabolites Act as Second Messengers in Yeast Chronological Aging
Int. J. Mol. Sci. 2018, 19(3), 860; https://doi.org/10.3390/ijms19030860
Received: 8 February 2018 / Revised: 12 March 2018 / Accepted: 13 March 2018 / Published: 15 March 2018
Cited by 4 | PDF Full-text (796 KB) | HTML Full-text | XML Full-text
Abstract
The concentrations of some key metabolic intermediates play essential roles in regulating the longevity of the chronologically aging yeast Saccharomyces cerevisiae. These key metabolites are detected by certain ligand-specific protein sensors that respond to concentration changes of the key metabolites by altering [...] Read more.
The concentrations of some key metabolic intermediates play essential roles in regulating the longevity of the chronologically aging yeast Saccharomyces cerevisiae. These key metabolites are detected by certain ligand-specific protein sensors that respond to concentration changes of the key metabolites by altering the efficiencies of longevity-defining cellular processes. The concentrations of the key metabolites that affect yeast chronological aging are controlled spatially and temporally. Here, we analyze mechanisms through which the spatiotemporal dynamics of changes in the concentrations of the key metabolites influence yeast chronological lifespan. Our analysis indicates that a distinct set of metabolites can act as second messengers that define the pace of yeast chronological aging. Molecules that can operate both as intermediates of yeast metabolism and as second messengers of yeast chronological aging include reduced nicotinamide adenine dinucleotide phosphate (NADPH), glycerol, trehalose, hydrogen peroxide, amino acids, sphingolipids, spermidine, hydrogen sulfide, acetic acid, ethanol, free fatty acids, and diacylglycerol. We discuss several properties that these second messengers of yeast chronological aging have in common with second messengers of signal transduction. We outline how these second messengers of yeast chronological aging elicit changes in cell functionality and viability in response to changes in the nutrient, energy, stress, and proliferation status of the cell. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)
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Open AccessReview
Articular Cartilage Aging-Potential Regenerative Capacities of Cell Manipulation and Stem Cell Therapy
Int. J. Mol. Sci. 2018, 19(2), 623; https://doi.org/10.3390/ijms19020623
Received: 28 January 2018 / Revised: 11 February 2018 / Accepted: 16 February 2018 / Published: 22 February 2018
Cited by 2 | PDF Full-text (2251 KB) | HTML Full-text | XML Full-text
Abstract
Changes in articular cartilage during the aging process are a stage of natural changes in the human body. Old age is the major risk factor for osteoarthritis but the disease does not have to be an inevitable consequence of aging. Chondrocytes are particularly [...] Read more.
Changes in articular cartilage during the aging process are a stage of natural changes in the human body. Old age is the major risk factor for osteoarthritis but the disease does not have to be an inevitable consequence of aging. Chondrocytes are particularly prone to developing age-related changes. Changes in articular cartilage that take place in the course of aging include the acquisition of the senescence-associated secretory phenotype by chondrocytes, a decrease in the sensitivity of chondrocytes to growth factors, a destructive effect of chronic production of reactive oxygen species and the accumulation of the glycation end products. All of these factors affect the mechanical properties of articular cartilage. A better understanding of the underlying mechanisms in the process of articular cartilage aging may help to create new therapies aimed at slowing or inhibiting age-related modifications of articular cartilage. This paper presents the causes and consequences of cellular aging of chondrocytes and the biological therapeutic outlook for the regeneration of age-related changes of articular cartilage. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)
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