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Aging and Age-related Disorders: From Molecular Mechanisms to Therapies

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 March 2019) | Viewed by 60939

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Special Issue Editor

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 aging-associated diseases include cardiovascular diseases, chronic obstructive pulmonary disease, chronic kidney disease, diabetes, osteoarthritis, osteoporosis, 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 aging-associated pathology are conserved across phyla.

The focus of this International Journal of Molecular Sciences Special Issue is on molecular and cellular mechanisms, diagnostics and therapies of aging and age-related disorders. The Special 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

Deadline of the First Round: 17 February 2019

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 submissions that pass pre-check are 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.

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Published Papers (8 papers)

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Editorial

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5 pages, 205 KiB  
Editorial
Aging and Age-Related Disorders: From Molecular Mechanisms to Therapies
by Vladimir I. Titorenko
Int. J. Mol. Sci. 2019, 20(13), 3280; https://doi.org/10.3390/ijms20133280 - 03 Jul 2019
Cited by 1 | Viewed by 2273
Abstract
Our understanding of the molecular mechanisms underlying cellular and organismal aging and aging-associated pathology has advanced greatly in recent years [...] Full article

Research

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27 pages, 7308 KiB  
Article
Disordered Expression of shaggy, the Drosophila Gene Encoding a Serine-Threonine Protein Kinase GSK3, Affects the Lifespan in a Transcript-, Stage-, and Tissue-Specific Manner
by Mikhail V. Trostnikov, Natalia V. Roshina, Stepan V. Boldyrev, Ekaterina R. Veselkina, Andrey A. Zhuikov, Anna V. Krementsova and Elena G. Pasyukova
Int. J. Mol. Sci. 2019, 20(9), 2200; https://doi.org/10.3390/ijms20092200 - 04 May 2019
Cited by 9 | Viewed by 3808
Abstract
GSK3 (glycogen synthase kinase 3) is a conserved protein kinase governing numerous regulatory pathways. In Drosophila melanogaster, GSK3 is encoded by shaggy (sgg), which forms 17 annotated transcripts corresponding to 10 protein isoforms. Our goal was to demonstrate how differential [...] Read more.
GSK3 (glycogen synthase kinase 3) is a conserved protein kinase governing numerous regulatory pathways. In Drosophila melanogaster, GSK3 is encoded by shaggy (sgg), which forms 17 annotated transcripts corresponding to 10 protein isoforms. Our goal was to demonstrate how differential sgg transcription affects lifespan, which GSK3 isoforms are important for the nervous system, and which changes in the nervous system accompany accelerated aging. Overexpression of three sgg transcripts affected the lifespan in a stage- and tissue-specific way: sgg-RA and sgg-RO affected the lifespan only when overexpressed in muscles and in embryos, respectively; the essential sgg-RB transcript affected lifespan when overexpressed in all tissues tested. In the nervous system, only sgg-RB overexpression affected lifespan, causing accelerated aging in a neuron-specific way, with the strongest effects in dopaminergic neurons and the weakest effects in GABAergic neurons. Pan-neuronal sgg-RB overexpression violated the properties of the nervous system, including the integrity of neuron bodies; the number, distribution, and structure of mitochondria; cytoskeletal characteristics; and synaptic activity. Such changes observed in young individuals indicated premature aging of their nervous system, which paralleled a decline in survival. Our findings demonstrated the key role of GSK3 in ensuring the link between the pathology of neurons and lifespan. Full article
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10 pages, 658 KiB  
Communication
Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”
by Miodrag Janić, Mojca Lunder, Srdjan Novaković, Petra Škerl and Mišo Šabovič
Int. J. Mol. Sci. 2019, 20(8), 1844; https://doi.org/10.3390/ijms20081844 - 14 Apr 2019
Cited by 17 | Viewed by 3802
Abstract
The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on [...] Read more.
The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed: SIRT1, PRKAA, KLOTHO, NFE2L2, mTOR, and NF-κB. Treatment with fluvastatin and valsartan in combination significantly increased the expression of SIRT1 (1.8-fold; p < 0.0001), PRKAA (1.5-fold; p = 0.262) and KLOTHO (1.7-fold; p < 0.0001), but not NFE2L2, mTOR and NF-κB. Both fluvastatin and valsartan alone significantly, but to a lesser extent, increased the expression of SIRT1, and did not influence the expression of other genes. Five months after treatment discontinuation, genes expression decreased to the basal levels. In addition, analysis with previously obtained results revealed significant correlation between SIRT1 and both increased telomerase activity and improved arterial wall characteristics. We showed that low-dose fluvastatin and valsartan, separately and in combination, substantially increase expression of SIRT1, PRKAA, and KLOTHO genes, which may be attributed to their so far unreported pleiotropic beneficial effects. This approach could be used for prevention of ageing (and longevity genes)–related disorders. Full article
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16 pages, 5632 KiB  
Article
Ultrastructural and Molecular Analysis of Ribose-Induced Glycated Reconstructed Human Skin
by Roberta Balansin Rigon, Sabine Kaessmeyer, Christopher Wolff, Christian Hausmann, Nan Zhang, Michaela Sochorová, Andrej Kováčik, Rainer Haag, Kateřina Vávrová, Martina Ulrich, Monika Schäfer-Korting and Christian Zoschke
Int. J. Mol. Sci. 2018, 19(11), 3521; https://doi.org/10.3390/ijms19113521 - 08 Nov 2018
Cited by 13 | Viewed by 5442
Abstract
Aging depicts one of the major challenges in pharmacology owing to its complexity and heterogeneity. Thereby, advanced glycated end-products modify extracellular matrix proteins, but the consequences on the skin barrier function remain heavily understudied. Herein, we utilized transmission electron microscopy for the ultrastructural [...] Read more.
Aging depicts one of the major challenges in pharmacology owing to its complexity and heterogeneity. Thereby, advanced glycated end-products modify extracellular matrix proteins, but the consequences on the skin barrier function remain heavily understudied. Herein, we utilized transmission electron microscopy for the ultrastructural analysis of ribose-induced glycated reconstructed human skin (RHS). Molecular and functional insights substantiated the ultrastructural characterization and proved the relevance of glycated RHS beyond skin aging. In particular, electron microscopy mapped the accumulation and altered spatial orientation of fibrils and filaments in the dermal compartment of glycated RHS. Moreover, the epidermal basement membrane appeared thicker in glycated than in non-glycated RHS, but electron microscopy identified longitudinal clusters of the finest collagen fibrils instead of real thickening. The stratum granulosum contained more cell layers, the morphology of keratohyalin granules decidedly differed, and the stratum corneum lipid order increased in ribose-induced glycated RHS, while the skin barrier function was almost not affected. In conclusion, dermal advanced glycated end-products markedly changed the epidermal morphology, underlining the importance of matrix–cell interactions. The phenotype of ribose-induced glycated RHS emulated aged skin in the dermis, while the two to three times increased thickness of the stratum granulosum resembled poorer cornification. Full article
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Review

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43 pages, 4048 KiB  
Review
Quiescence Entry, Maintenance, and Exit in Adult Stem Cells
by Karamat Mohammad, Paméla Dakik, Younes Medkour, Darya Mitrofanova and Vladimir I. Titorenko
Int. J. Mol. Sci. 2019, 20(9), 2158; https://doi.org/10.3390/ijms20092158 - 01 May 2019
Cited by 63 | Viewed by 8525
Abstract
Cells of unicellular and multicellular eukaryotes can respond to certain environmental cues by arresting the cell cycle and entering a reversible state of quiescence. Quiescent cells do not divide, but can re-enter the cell cycle and resume proliferation if exposed to some signals [...] Read more.
Cells of unicellular and multicellular eukaryotes can respond to certain environmental cues by arresting the cell cycle and entering a reversible state of quiescence. Quiescent cells do not divide, but can re-enter the cell cycle and resume proliferation if exposed to some signals from the environment. Quiescent cells in mammals and humans include adult stem cells. These cells exhibit improved stress resistance and enhanced survival ability. In response to certain extrinsic signals, adult stem cells can self-renew by dividing asymmetrically. Such asymmetric divisions not only allow the maintenance of a population of quiescent cells, but also yield daughter progenitor cells. A multistep process of the controlled proliferation of these progenitor cells leads to the formation of one or more types of fully differentiated cells. An age-related decline in the ability of adult stem cells to balance quiescence maintenance and regulated proliferation has been implicated in many aging-associated diseases. In this review, we describe many traits shared by different types of quiescent adult stem cells. We discuss how these traits contribute to the quiescence, self-renewal, and proliferation of adult stem cells. We examine the cell-intrinsic mechanisms that allow establishing and sustaining the characteristic traits of adult stem cells, thereby regulating quiescence entry, maintenance, and exit. Full article
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28 pages, 752 KiB  
Review
Age-Associated Changes in the Immune System and Blood–Brain Barrier Functions
by Michelle A. Erickson and William A. Banks
Int. J. Mol. Sci. 2019, 20(7), 1632; https://doi.org/10.3390/ijms20071632 - 02 Apr 2019
Cited by 96 | Viewed by 8204
Abstract
Age is associated with altered immune functions that may affect the brain. Brain barriers, including the blood–brain barrier (BBB) and blood–CSF barrier (BCSFB), are important interfaces for neuroimmune communication, and are affected by aging. In this review, we explore novel mechanisms by which [...] Read more.
Age is associated with altered immune functions that may affect the brain. Brain barriers, including the blood–brain barrier (BBB) and blood–CSF barrier (BCSFB), are important interfaces for neuroimmune communication, and are affected by aging. In this review, we explore novel mechanisms by which the aging immune system alters central nervous system functions and neuroimmune responses, with a focus on brain barriers. Specific emphasis will be on recent works that have identified novel mechanisms by which BBB/BCSFB functions change with age, interactions of the BBB with age-associated immune factors, and contributions of the BBB to age-associated neurological disorders. Understanding how age alters BBB functions and responses to pathological insults could provide important insight on the role of the BBB in the progression of cognitive decline and neurodegenerative disease. Full article
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12 pages, 955 KiB  
Review
Causes and Mechanisms of Hematopoietic Stem Cell Aging
by Jungwoon Lee, Suk Ran Yoon, Inpyo Choi and Haiyoung Jung
Int. J. Mol. Sci. 2019, 20(6), 1272; https://doi.org/10.3390/ijms20061272 - 13 Mar 2019
Cited by 44 | Viewed by 11217
Abstract
Many elderly people suffer from hematological diseases known to be highly age-dependent. Hematopoietic stem cells (HSCs) maintain the immune system by producing all blood cells throughout the lifetime of an organism. Recent reports have suggested that HSCs are susceptible to age-related stress and [...] Read more.
Many elderly people suffer from hematological diseases known to be highly age-dependent. Hematopoietic stem cells (HSCs) maintain the immune system by producing all blood cells throughout the lifetime of an organism. Recent reports have suggested that HSCs are susceptible to age-related stress and gradually lose their self-renewal and regeneration capacity with aging. HSC aging is driven by cell-intrinsic and -extrinsic factors that result in the disruption of the immune system. Thus, the study of HSC aging is important to our understanding of age-related immune diseases and can also provide potential strategies to improve quality of life in the elderly. In this review, we delineate our understanding of the phenotypes, causes, and molecular mechanisms involved in HSC aging. Full article
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33 pages, 397 KiB  
Review
Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks
by Rüdiger Hardeland
Int. J. Mol. Sci. 2019, 20(5), 1223; https://doi.org/10.3390/ijms20051223 - 11 Mar 2019
Cited by 205 | Viewed by 16825
Abstract
Aging and various age-related diseases are associated with reductions in melatonin secretion, proinflammatory changes in the immune system, a deteriorating circadian system, and reductions in sirtuin-1 (SIRT1) activity. In non-tumor cells, several effects of melatonin are abolished by inhibiting SIRT1, indicating mediation by [...] Read more.
Aging and various age-related diseases are associated with reductions in melatonin secretion, proinflammatory changes in the immune system, a deteriorating circadian system, and reductions in sirtuin-1 (SIRT1) activity. In non-tumor cells, several effects of melatonin are abolished by inhibiting SIRT1, indicating mediation by SIRT1. Melatonin is, in addition to its circadian and antioxidant roles, an immune stimulatory agent. However, it can act as either a pro- or anti-inflammatory regulator in a context-dependent way. Melatonin can stimulate the release of proinflammatory cytokines and other mediators, but also, under different conditions, it can suppress inflammation-promoting processes such as NO release, activation of cyclooxygenase-2, inflammasome NLRP3, gasdermin D, toll-like receptor-4 and mTOR signaling, and cytokine release by SASP (senescence-associated secretory phenotype), and amyloid-β toxicity. It also activates processes in an anti-inflammatory network, in which SIRT1 activation, upregulation of Nrf2 and downregulation of NF-κB, and release of the anti-inflammatory cytokines IL-4 and IL-10 are involved. A perhaps crucial action may be the promotion of macrophage or microglia polarization in favor of the anti-inflammatory phenotype M2. In addition, many factors of the pro- and anti-inflammatory networks are subject to regulation by microRNAs that either target mRNAs of the respective factors or upregulate them by targeting mRNAs of their inhibitor proteins. Full article
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