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Molecular and Cellular Mechanisms of Aging and Age-related Disorders

by Vladimir I. Titorenko

Int. J. Mol. Sci. 2018, 19(7), 2049; https://doi.org/10.3390/ijms19072049 - 14 Jul 2018

Cited by 12 | Viewed by 3451

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(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Aging and Age-Related Disorders)

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20 pages, 29073 KiB

Open AccessArticle

Aging and Intermittent Fasting Impact on Transcriptional Regulation and Physiological Responses of Adult Drosophila Neuronal and Muscle Tissues

by Sharon Zhang, Eric P. Ratliff, Brandon Molina, Nadja El-Mecharrafie, Jessica Mastroianni, Roxanne W. Kotzebue, Madhulika Achal, Ruth E. Mauntz, Arysa Gonzalez, Ayeh Barekat, William A. Bray, Andrew M. Macias, Daniel Daugherty, Greg L. Harris, Robert A. Edwards and Kim D. Finley

Int. J. Mol. Sci. 2018, 19(4), 1140; https://doi.org/10.3390/ijms19041140 - 10 Apr 2018

Cited by 14 | Viewed by 8463

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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15 pages, 2254 KiB

Open AccessArticle

Characterization of Ageing- and Diet-Related Swine Models of Sarcopenia and Sarcopenic Obesity

by Consolacion Garcia-Contreras, Marta Vazquez-Gomez, Laura Torres-Rovira, Jorge Gonzalez, Esteban Porrini, Magali Gonzalez-Colaço, Beatriz Isabel, Susana Astiz and Antonio Gonzalez-Bulnes

Int. J. Mol. Sci. 2018, 19(3), 823; https://doi.org/10.3390/ijms19030823 - 12 Mar 2018

Cited by 11 | Viewed by 5452

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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11 pages, 2272 KiB

Open AccessArticle

Aged Mouse Cortical Microglia Display an Activation Profile Suggesting Immunotolerogenic Functions

by Tanja Zöller, Abdelraheim Attaai, Phani Sankar Potru, Tamara Ruß and Björn Spittau

Int. J. Mol. Sci. 2018, 19(3), 706; https://doi.org/10.3390/ijms19030706 - 01 Mar 2018

Cited by 38 | Viewed by 7362

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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4367 KiB

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

by Maialen Palomino-Alonso, Mercedes Lachén-Montes, Andrea González-Morales, Karina Ausín, Alberto Pérez-Mediavilla, Joaquín Fernández-Irigoyen and Enrique Santamaría

Int. J. Mol. Sci. 2017, 18(11), 2260; https://doi.org/10.3390/ijms18112260 - 27 Oct 2017

Cited by 10 | Viewed by 4475

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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Open AccessArticle

Electronegative Low-Density Lipoprotein L5 Impairs Viability and NGF-Induced Neuronal Differentiation of PC12 Cells via LOX-1

by Jiz-Yuh Wang, Chiou-Lian Lai, Ching-Tien Lee and Chen-Yen Lin

Int. J. Mol. Sci. 2017, 18(8), 1744; https://doi.org/10.3390/ijms18081744 - 11 Aug 2017

Cited by 12 | Viewed by 7499

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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20 pages, 2485 KiB

Open AccessReview

Activating the Anaphase Promoting Complex to Enhance Genomic Stability and Prolong Lifespan

by Troy A. A. Harkness

Int. J. Mol. Sci. 2018, 19(7), 1888; https://doi.org/10.3390/ijms19071888 - 27 Jun 2018

Cited by 13 | Viewed by 6784

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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14 pages, 796 KiB

Open AccessReview

Some Metabolites Act as Second Messengers in Yeast Chronological Aging

by Karamat Mohammad, Paméla Dakik, Younes Medkour, Mélissa McAuley, Darya Mitrofanova and Vladimir I. Titorenko

Int. J. Mol. Sci. 2018, 19(3), 860; https://doi.org/10.3390/ijms19030860 - 15 Mar 2018

Cited by 16 | Viewed by 5318

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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25 pages, 2251 KiB

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Articular Cartilage Aging-Potential Regenerative Capacities of Cell Manipulation and Stem Cell Therapy

by Magdalena Krajewska-Włodarczyk, Agnieszka Owczarczyk-Saczonek, Waldemar Placek, Adam Osowski and Joanna Wojtkiewicz

Int. J. Mol. Sci. 2018, 19(2), 623; https://doi.org/10.3390/ijms19020623 - 22 Feb 2018

Cited by 19 | Viewed by 9048

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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