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Novel Molecular Mechanisms and Innovative Therapeutic Approaches for Age-Associated Diseases

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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 (30 November 2023) | Viewed by 13167

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Prof. Dr. Stuart Maudsley

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Receptor Biology Lab, Department of Biomedical Sciences, University of Antwerp, 2000 Antwerpen, Belgium
Interests: aging; receptor; G protein-coupled receptor; pharmacology; bioinformatics; proteomics; interactomics; therapeutic; translational
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Dear Colleagues,

The worldwide impact of increased human longevity is seen strongest in the lens of aging-related disease. Aging in some ways can be best considered to be driven by the accumulation of unrepaired cellular damage. Increasing levels of cellular and tissue damage lead to tissue fibrosis, lipid peroxidation, protein glycation, DNA damage, and cellular senescence. All these molecular processes contribute strongly to almost all forms of chronic disease, including cardiovascular disorders, chronic kidney disease, diabetic conditions, neurodegeneration, and musculoskeletal wasting. Given that these pathological conditions are all linked by a common risk factor, i.e., pathological aging, perhaps therapeutic targeting of this process may represent an important new strategy to reduce the future global burden of an increasingly elderly world population. In this Special Issue, we will investigate a broad range of anti-aging therapeutic strategies that can hopefully reduce the rate of aging and thus postpone the onset of major aging-related disease.

Prof. Dr. Stuart Maudsley
Guest Editor

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Keywords

aging
disease
therapeutics
strategy
mechanisms
longevity
health span
lifespan
damage
rejuvenation

Published Papers (7 papers)

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Research

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22 pages, 4269 KiB

Open AccessArticle

Interaction of β_L- and γ-Crystallin with Phospholipid Membrane Using Atomic Force Microscopy

by Nawal K. Khadka, Preston Hazen, Dieter Haemmerle and Laxman Mainali

Int. J. Mol. Sci. 2023, 24(21), 15720; https://doi.org/10.3390/ijms242115720 - 29 Oct 2023

Viewed by 790

Abstract

Highly concentrated lens proteins, mostly β- and γ-crystallin, are responsible for maintaining the structure and refractivity of the eye lens. However, with aging and cataract formation, β- and γ-crystallin are associated with the lens membrane or other lens proteins forming high-molecular-weight proteins, which further associate with the lens membrane, leading to light scattering and cataract development. The mechanism by which β- and γ-crystallin are associated with the lens membrane is unknown. This work aims to study the interaction of β- and γ-crystallin with the phospholipid membrane with and without cholesterol (Chol) with the overall goal of understanding the role of phospholipid and Chol in β- and γ-crystallin association with the membrane. Small unilamellar vesicles made of Chol/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (Chol/POPC) membranes with varying Chol content were prepared using the rapid solvent exchange method followed by probe tip sonication and then dispensed on freshly cleaved mica disk to prepare a supported lipid membrane. The β_L- and γ-crystallin from the cortex of the bovine lens was used to investigate the time-dependent association of β_L- and γ-crystallin with the membrane by obtaining the topographical images using atomic force microscopy. Our study showed that β_L-crystallin formed semi-transmembrane defects, whereas γ-crystallin formed transmembrane defects on the phospholipid membrane. The size of semi-transmembrane defects increases significantly with incubation time when β_L-crystallin interacts with the membrane. In contrast, no significant increase in transmembrane defect size was observed in the case of γ-crystallin. Our result shows that Chol inhibits the formation of membrane defects when β_L- and γ-crystallin interact with the Chol/POPC membrane, where the degree of inhibition depends upon the amount of Chol content in the membrane. At a Chol/POPC mixing ratio of 0.3, membrane defects were observed when both β_L- and γ-crystallin interacted with the membrane. However, at a Chol/POPC mixing ratio of 1, no association of γ-crystallin with the membrane was observed, which resulted in a defect-free membrane, and the severity of the membrane defect was decreased when β_L-crystallin interacted with the membrane. The semi-transmembrane or transmembrane defects formed by the interaction of β_L- and γ-crystallin on phospholipid membrane might be responsible for light scattering and cataract formation. However, Chol suppressed the formation of such defects in the membrane, likely maintaining lens membrane homeostasis and protecting against cataract formation. Full article

(This article belongs to the Special Issue Novel Molecular Mechanisms and Innovative Therapeutic Approaches for Age-Associated Diseases)

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32 pages, 6450 KiB

Open AccessArticle

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

by Stuart Maudsley, Claudia Schrauwen, İrem Harputluoğlu, Deborah Walter, Hanne Leysen and Patricia McDonald

Int. J. Mol. Sci. 2023, 24(10), 8499; https://doi.org/10.3390/ijms24108499 - 09 May 2023

Viewed by 2378

Abstract

G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence. Full article

(This article belongs to the Special Issue Novel Molecular Mechanisms and Innovative Therapeutic Approaches for Age-Associated Diseases)

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12 pages, 795 KiB

Open AccessArticle

Insomnia Impairs Both the Pro-BDNF and the BDNF Levels Similarly to Older Adults with Cognitive Decline: An Exploratory Study

by Sergio Sánchez-García, Karla Moreno-Tamayo, Ricardo Ramírez-Aldana, Carmen García-Peña, Raúl Hernán Medina-Campos, Paola García dela Torre and Nadia Alejandra Rivero-Segura

Int. J. Mol. Sci. 2023, 24(8), 7387; https://doi.org/10.3390/ijms24087387 - 17 Apr 2023

Cited by 4 | Viewed by 1426

Abstract

Sleep disorders, including insomnia, are common during aging, and these conditions have been associated with cognitive decline in older adults. Moreover, during the aging process, neurotransmitters, neurohormones, and neurotrophins decrease significantly, leading to the impairment of cognitive functions. In this sense, BDNF, the most abundant neurotrophic factor in the human brain, has been suggested as a potential target for the prevention and improvement of cognitive decline during aging; however, the current evidence demonstrates that the exogenous administration of BDNF does not improve cognitive function. Hence, in the present study, we quantified pro-BDNF (inactive) and BDNF (active) concentrations in serum samples derived from older individuals with insomnia and/or cognitive decline. We used linear regression to analyze whether clinical or sociodemographic variables impacted the levels of BNDF concentration. We observed that insomnia, rather than cognitive decline, is significantly associated with BDNF concentration, and these effects are independent of other variables. To our knowledge, this is the first study that points to the impact of insomnia on improving the levels of BDNF during aging and suggests that opportune treatment of insomnia may be more beneficial to prevent cognitive decline during aging. Full article

(This article belongs to the Special Issue Novel Molecular Mechanisms and Innovative Therapeutic Approaches for Age-Associated Diseases)

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24 pages, 5196 KiB

Open AccessArticle

The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer’s Disease

by Wayne Chadwick, Stuart Maudsley, William Hull, Enes Havolli, Eugene Boshoff, Mark D. W. Hill, Pascal J. D. Goetghebeur, David C. Harrison, Sohaib Nizami, David C. Bedford, Gareth Coope, Katia Real, Christoph Thiemermann, Peter Maycox, Mark Carlton and Sarah L. Cole

Int. J. Mol. Sci. 2023, 24(8), 6953; https://doi.org/10.3390/ijms24086953 - 09 Apr 2023

Cited by 4 | Viewed by 1296

Abstract

Sporadic Alzheimer’s disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase. Full article

(This article belongs to the Special Issue Novel Molecular Mechanisms and Innovative Therapeutic Approaches for Age-Associated Diseases)

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Review

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17 pages, 558 KiB

Open AccessReview

Immune Diseases Associated with Aging: Molecular Mechanisms and Treatment Strategies

by Mi Eun Kim and Jun Sik Lee

Int. J. Mol. Sci. 2023, 24(21), 15584; https://doi.org/10.3390/ijms242115584 - 25 Oct 2023

Cited by 1 | Viewed by 1849

Abstract

Aging is associated with a decline in immune function, thereby causing an increased susceptibility to various diseases. Herein, we review immune diseases associated with aging, focusing on tumors, atherosclerosis, and immunodeficiency disorders. The molecular mechanisms underlying these conditions are discussed, highlighting telomere shortening, tissue inflammation, and altered signaling pathways, e.g., the mammalian target of the rapamycin (mTOR) pathway, as key contributors to immune dysfunction. The role of the senescence-associated secretory phenotype in driving chronic tissue inflammation and disruption has been examined. Our review underscores the significance of targeting tissue inflammation and immunomodulation for treating immune disorders. In addition, anti-inflammatory medications, including corticosteroids and nonsteroidal anti-inflammatory drugs, and novel approaches, e.g., probiotics and polyphenols, are discussed. Immunotherapy, particularly immune checkpoint inhibitor therapy and adoptive T-cell therapy, has been explored for its potential to enhance immune responses in older populations. A comprehensive analysis of immune disorders associated with aging and underlying molecular mechanisms provides insights into potential treatment strategies to alleviate the burden of these conditions in the aging population. The interplay among immune dysfunction, chronic tissue inflammation, and innovative therapeutic approaches highlights the importance of elucidating these complex processes to develop effective interventions to improve the quality of life in older adults. Full article

(This article belongs to the Special Issue Novel Molecular Mechanisms and Innovative Therapeutic Approaches for Age-Associated Diseases)

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12 pages, 1401 KiB

Open AccessReview

The Tale of DJ-1 (PARK7): A Swiss Army Knife in Biomedical and Psychological Research

by Mo E. Sun and Qingfei Zheng

Int. J. Mol. Sci. 2023, 24(8), 7409; https://doi.org/10.3390/ijms24087409 - 18 Apr 2023

Cited by 3 | Viewed by 1975

Abstract

DJ-1 (also known as PARK7) is a multifunctional enzyme in human beings that is highly conserved and that has also been discovered in diverse species (ranging from prokaryotes to eukaryotes). Its complex enzymatic and non-enzymatic activities (such as anti-oxidation, anti-glycation, and protein quality control), as well as its role as a transcriptional coactivator, enable DJ-1 to serve as an essential regulator in multiple cellular processes (e.g., epigenetic regulations) and make it a promising therapeutic target for diverse diseases (especially cancer and Parkinson’s disease). Due to its nature as a Swiss army knife enzyme with various functions, DJ-1 has attracted a large amount of research interest, from different perspectives. In this review, we give a brief summary of the recent advances with respect to DJ-1 research in biomedicine and psychology, as well as the progress made in attempts to develop DJ-1 into a druggable target for therapy. Full article

(This article belongs to the Special Issue Novel Molecular Mechanisms and Innovative Therapeutic Approaches for Age-Associated Diseases)

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12 pages, 12622 KiB

Open AccessCase Report

Giant Arachnoid Granulations: Diagnostic Workup and Characterization in Three Symptomatic Adults

by Rupal I. Mehta, Rajiv Mangla and Rashi I. Mehta

Int. J. Mol. Sci. 2023, 24(14), 11410; https://doi.org/10.3390/ijms241411410 - 13 Jul 2023

Cited by 1 | Viewed by 2742

Abstract

Giant arachnoid granulations (GAGs) are poorly investigated. Here, we document clinical findings associated with five new GAGs and illustrate the anatomical composition of these structures as well as diagnostic considerations in three symptomatic adults. The GAGs ranged from 1.1 to 3.6 cm (mean, 2.2 cm) in maximum dimension and manifested in middle-aged individuals who presented with long-standing brain mass and/or chronic headache. On imaging examinations, the tissues appeared as irregular parasagittal and/or perisinus structures that demonstrated heterogeneous internal elements. The GAGs abutted dura, extended through calvarial marrow spaces, and impinged on dural venous sinuses, causing their stenosis. The histologic workup of two GAG specimens resected from separate individuals revealed central collagen with pronounced internal vascular proliferation. One specimen additionally exhibited reactive changes within the lesion, including venous thrombosis, hemorrhage, and conspicuous inflammation. The salient immune component consisted of a foam cell-rich infiltrate that obstructed subcapsular and internal sinusoidal GAG spaces. Within this specimen, meningothelial hyperplasia was also appreciated. Notably, proliferated lymphatic vascular elements were additionally observed within the structure, extending into deep central collagen regions and engulfing many extravasated erythrocytes in the subcapsular space. In both surgically treated patients, symptoms resolved completely following resection. This report is the first to definitively depict reactive vascular and immunological changes within GAGs that were clinically associated with headache. The frequency of reactive changes within these meningeal structures is unclear in the literature, as GAGs are rarely sampled and investigated. Further systematic analyses are warranted to elucidate the causes and consequences of GAG genesis and their roles in physiology and disease states. Full article

(This article belongs to the Special Issue Novel Molecular Mechanisms and Innovative Therapeutic Approaches for Age-Associated Diseases)

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