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Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 28731

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Dr. Alessandro Attanzio

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Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123 Palermo, Italy
Interests: biochemistry and methodologies; Sicilian foods; bioactive compounds; phytochemicals; bioactivity; cell cultures; chemoprevention; oxidative stress; apoptosis; eryptosis
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Dr. Erica Buoso

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Department of Drug Sciences, University of Pavia, Via Taramelli 12/14, 27100 Pavia, Italy
Interests: transcription and translation regulation in aging and neurodegenerative diseases
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Dr. Fabrizio Biundo

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Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10012, USA
Interests: neurodegenerative diseases; animal behavior; brain pathology; microglia; synaptic plasticity
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Special Issue Information

Dear Colleagues,

Following a very successful first run, we are pleased to announce the launch of a second edition of a Special Issue on the Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions.

Due to the increase of life expectancy, the aging population around the globe has been growing significantly and is estimated to triple by 2050. Aging may be described as a progressive physiological change that leads to a decline of biological functions and of the organism’s ability to adapt to metabolic stress. Aging has many facets that could not be explained by a single theory. To date, genetic and nongenetic theories have been proposed to explain one or more aspects of this biological phenomenon. The genetic theory is centered on shortened telomeres, whereas the nongenetic theory attempts to explain aging in terms of cellular and molecular changes including chemical or physical reactions responsible for rate and course of senescence. These modifications affect tissue structure and cell turnover of the body systems. Accordingly, cellular senescence has been indicated as one of the molecular processes involved in age-related diseases, including cardiovascular diseases, cancer, neurodegenerative diseases and diabetes, which have become a primary health issue challenging the health care system worldwide. During the last decades, internal and external causes of aging have been characterized such as organelles deterioration, and the senescence-associated secretory phenotype (SASP), a cell status characterized by an increased expression and secretion of pro-inflammatory cytokines and chemokines. In addition to these, oxidative stress has also been shown to play an important role in exacerbating senescence by promoting the accumulation of the reactive oxygen and nitrogen species and disrupting the protein turnover.

In light of these considerations, the majority of anti-aging research has focused on dissecting the metabolic pathways associated with senescence and finding therapeutic strategies to slow the progressive decline of age-related pathologies. Among these strategies, a balanced diet including antioxidant phytochemicals, and a healthy lifestyle have also been described to have beneficial effects in fighting aging and its related disorders.

This special issue aims to collect original research articles and reviews that describe molecular pathways of senescence in a context of age-related diseases and could support the development of therapeutic strategies.

Dr. Alessandro Attanzio
Dr. Erica Buoso
Dr. Fabrizio Biundo
Guest Editors

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. Cells 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 2700 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 diseases
senescence
metabolism
epigenetic
inflammaging
hormonal dysfunction
therapeutic strategies
antioxidants
phytochemicals
nutraceutical
lifestyle

Related Special Issue

Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions in Cells (15 articles)

Published Papers (8 papers)

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Research

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15 pages, 2573 KiB

Open AccessArticle

Role of C-Terminal Phosphorylation of Lamin A in DNA Damage and Cellular Senescence

by Ying Ao, Zhuping Wu, Zhiwei Liao, Juncong Lan, Jie Zhang, Pengfei Sun, Baohua Liu and Zimei Wang

Cells 2023, 12(4), 639; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12040639 - 16 Feb 2023

Cited by 2 | Viewed by 1927

Abstract

The nuclear matrix protein lamin A is a multifunctional protein with roles in DNA replication and repair, gene activation, transcriptional regulation, and maintenance of higher-order chromatin structure. Phosphorylation is the main determinant of lamin A mobility in the nucleus and nuclear membrane dissolution during mitosis. However, little is known about the regulation of lamin A phosphorylation during interphase. Interestingly, C-terminal lamin A mutations trigger cellular senescence. Recently, we showed that the C-terminal region of lamin A interacts with casein kinase II (CK2). In the present study, we have expanded on our previous research to further investigate lamin A phosphorylation and elucidate the mechanisms underlying the effect of C-terminal mutations on cellular senescence. Our results indicate that glycogen synthase kinase 3β (GSK3β) and CK2 jointly mediate the phosphorylation of lamin A at C-terminal Ser628 and Ser636 residues. Furthermore, a loss of phosphorylation at either of these two sites affects the nuclear distribution of lamin A, leading to an impaired DNA damage response as well as cellular senescence. Thus, phosphorylation at C-terminal sites in lamin A appears to be important for maintaining genomic stability and preventing cellular senescence. These findings provide insight into how loss of the C-terminal region of lamin A may induce premature aging. Furthermore, enhancement of GSK3β and CK2 activity may represent a possible therapeutic approach for the treatment of aging-related diseases. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II)

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20 pages, 7115 KiB

Open AccessArticle

Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1

by Feliciano Monterrubio-Ledezma, Fernando Navarro-García, Lourdes Massieu, Ricardo Mondragón-Flores, Luz Adriana Soto-Ponce, Jonathan J. Magaña and Bulmaro Cisneros

Cells 2023, 12(2), 275; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12020275 - 10 Jan 2023

Cited by 8 | Viewed by 2773

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by the expression of progerin, a mutant variant of Lamin A. Recently, HGPS studies have gained relevance because unraveling its underlying mechanism would help to understand physiological aging. We previously reported that the CRM1-mediated nuclear protein export pathway is exacerbated in HGPS cells, provoking the mislocalization of numerous protein targets of CRM1. We showed that normalization of this mechanism by pharmacologically inhibiting CRM1 with LMB (specific CRM1 inhibitor), mitigates the senescent phenotype of HGPS cells. Since mitochondrial dysfunction is a hallmark of HGPS, in this study we analyze the effect of LMB on mitochondrial function. Remarkably, LMB treatment induced the recovery of mitochondrial function in HGPS cells, as shown by the improvement in mitochondrial morphology, mitochondrial membrane potential, and ATP levels, which consequently impeded the accumulation of ROS but not mitochondrial superoxide. We provide evidence that the beneficial effect of LMB is mechanistically based on a combinatory effect on mitochondrial biogenesis via upregulation of PGC-1α expression (master transcription cofactor of mitochondrial genes), and mitophagy through the recovery of lysosomal content. The use of exportin CRM1 inhibitors constitutes a promising strategy to treat HGPS and other diseases characterized by mitochondrial impairment. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II)

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13 pages, 3205 KiB

Open AccessArticle

Aging Fibroblasts Adversely Affect Extracellular Matrix Formation via the Senescent Humoral Factor Ependymin-Related Protein 1

by Kento Takaya, Toru Asou and Kazuo Kishi

Cells 2022, 11(23), 3749; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11233749 - 24 Nov 2022

Cited by 4 | Viewed by 1666

Abstract

Skin senescence is characterized by a decrease in extracellular matrix and the accumulation of senescent fibroblasts in the dermis, and their secretion of humoral factors. Ependymin-related protein 1 (EPDR1) is involved in abnormal fibroblast metabolism and collagen deposition, however, its relation to skin aging is unclear. We investigated whether and how EPDR1 is involved in age-related dermal deterioration. When young dermal fibroblasts and senescent cells were co-cultured in a semipermeable membrane separation system, the young fibroblasts showed decreased gene expression of collagen type I α1 chain (COL1A1) and elastin, and increased expression of matrix metalloproteinase (MMP)1 and MMP3. Senescence marker expression and EPDR1 production were increased in the culture medium of senescent cells. Treatment of young fibroblasts with recombinant EPDR1, enhanced matrix-related gene expression and suppressed COL1A1 expression, whereas EPDR1 knockdown had the opposite effects. EPDR1 gene and protein expression were increased in aged skin, compared to young skin. These results suggest that senescent cells affect nearby fibroblasts, in part through EPDR1 secretion, and exert negative effects on matrix production in the dermis. These results may lead to the discovery of potential candidate targets in the development of skin anti-aging therapies. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II)

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17 pages, 2948 KiB

Open AccessArticle

In Vitro Characterization of Doxorubicin-Mediated Stress-Induced Premature Senescence in Human Chondrocytes

by Valeria Kirsch, Jan-Moritz Ramge, Astrid Schoppa, Anita Ignatius and Jana Riegger

Cells 2022, 11(7), 1106; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11071106 - 25 Mar 2022

Cited by 9 | Viewed by 3452

Abstract

Accumulation of senescent chondrocytes is thought to drive inflammatory processes and subsequent cartilage degeneration in age-related as well as posttraumatic osteoarthritis (OA). However, the underlying mechanisms of senescence and consequences on cartilage homeostasis are not completely understood so far. Therefore, suitable in vitro models are needed to study chondrocyte senescence. In this study, we established and evaluated a doxorubicin (Doxo)-based model of stress-induced premature senescence (SIPS) in human articular chondrocytes (hAC). Cellular senescence was determined by the investigation of various senescence associated (SA) hallmarks including β-galactosidase activity, expression of p16, p21, and SA secretory phenotype (SASP) markers (IL-6, IL-8, MMP-13), the presence of urokinase-type plasminogen activator receptor (uPAR), and cell cycle arrest. After seven days, Doxo-treated hAC displayed a SIPS-like phenotype, characterized by excessive secretion of SASP factors, enhanced uPAR-positivity, decreased proliferation rate, and increased β-galactosidase activity. This phenotype was proven to be stable seven days after the removal of Doxo. Moreover, Doxo-treated hAC exhibited increased granularity and flattened or fibroblast-like morphology. Further analysis implies that Doxo-mediated SIPS was driven by oxidative stress as demonstrated by increased ROS levels and NO release. Overall, we provide novel insights into chondrocyte senescence and present a suitable in vitro model for further studies. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II)

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42 pages, 1955 KiB

Open AccessFeature PaperReview

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies

by Roula Khalil, Mona Diab-Assaf and Jean-Marc Lemaitre

Cells 2023, 12(6), 915; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12060915 - 16 Mar 2023

Cited by 8 | Viewed by 7790

Abstract

Life expectancy has drastically increased over the last few decades worldwide, with important social and medical burdens and costs. To stay healthy longer and to avoid chronic disease have become essential issues. Organismal aging is a complex process that involves progressive destruction of tissue functionality and loss of regenerative capacity. One of the most important aging hallmarks is cellular senescence, which is a stable state of cell cycle arrest that occurs in response to cumulated cell stresses and damages. Cellular senescence is a physiological mechanism that has both beneficial and detrimental consequences. Senescence limits tumorigenesis, lifelong tissue damage, and is involved in different biological processes, such as morphogenesis, regeneration, and wound healing. However, in the elderly, senescent cells increasingly accumulate in several organs and secrete a combination of senescence associated factors, contributing to the development of various age-related diseases, including cancer. Several studies have revealed major molecular pathways controlling the senescent phenotype, as well as the ones regulating its interactions with the immune system. Attenuating the senescence-associated secretory phenotype (SASP) or eliminating senescent cells have emerged as attractive strategies aiming to reverse or delay the onset of aging diseases. Here, we review current senotherapies designed to suppress the deleterious effect of SASP by senomorphics or to selectively kill senescent cells by “senolytics” or by immune system-based approaches. These recent investigations are promising as radical new controls of aging pathologies and associated multimorbidities. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II)

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17 pages, 3241 KiB

Open AccessReview

Milk Fat Globule Epidermal Growth Factor VIII Fragment Medin in Age-Associated Arterial Adverse Remodeling and Arterial Disease

by Mingyi Wang, Kimberly R. McGraw and Robert E. Monticone

Cells 2023, 12(2), 253; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12020253 - 07 Jan 2023

Cited by 2 | Viewed by 2798

Abstract

Medin, a small 50-amino acid peptide, is an internal cleaved product from the second discoidin domain of milk fat globule epidermal growth factor VIII (MFG-E8) protein. Medin has been reported as the most common amylogenic protein in the upper part of the arterial system, including aortic, temporal, and cerebral arterial walls in the elderly. Medin has a high affinity to elastic fibers and is closely associated with arterial degenerative inflammation, elastic fiber fragmentation, calcification, and amyloidosis. In vitro, treating with the medin peptide promotes the inflammatory phenotypic shift of both endothelial cells and vascular smooth muscle cells. In vitro, ex vivo, and in vivo studies demonstrate that medin enhances the abundance of reactive oxygen species and reactive nitrogen species produced by both endothelial cells and vascular smooth muscle cells and promotes vascular endothelial dysfunction and arterial stiffening. Immunostaining and immunoblotting analyses of human samples indicate that the levels of medin are increased in the pathogenesis of aortic aneurysm/dissection, temporal arteritis, and cerebrovascular dementia. Thus, medin peptide could be targeted as a biomarker diagnostic tool or as a potential molecular approach to curbing the arterial degenerative inflammatory remodeling that accompanies aging and disease. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II)

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27 pages, 1118 KiB

Open AccessReview

by Lucrezia Irene Maria Campagnoli, Nicoletta Marchesi, Mariapia Vairetti, Alessia Pascale, Andrea Ferrigno and Annalisa Barbieri

Cells 2022, 11(18), 2827; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11182827 - 10 Sep 2022

Cited by 13 | Viewed by 3746

Abstract

Human aging, a natural process characterized by structural and physiological changes, leads to alterations of homeostatic mechanisms, decline of biological functions, and subsequently, the organism becomes vulnerable to external stress or damage. In fact, the elderly population is prone to develop diseases due to deterioration of physiological and biological systems. With aging, the production of reactive oxygen species (ROS) increases, and this causes lipid, protein, and DNA damage, leading to cellular dysfunction and altered cellular processes. Indeed, oxidative stress plays a key role in the pathogenesis of several chronic disorders, including hepatic diseases, such as non-alcoholic fatty liver disease (NAFLD). NAFLD, the most common liver disorder in the Western world, is characterized by intrahepatic lipid accumulation; is highly prevalent in the aging population; and is closely associated with obesity, insulin resistance, hypertension, and dyslipidemia. Among the risk factors involved in the pathogenesis of NAFLD, the dysbiotic gut microbiota plays an essential role, leading to low-grade chronic inflammation, oxidative stress, and production of various toxic metabolites. The intestinal microbiota is a dynamic ecosystem of microbes involved in the maintenance of physiological homeostasis; the alteration of its composition and function, during aging, is implicated in different liver diseases. Therefore, gut microbiota restoration might be a complementary approach for treating NAFLD. The administration of probiotics, which can relieve oxidative stress and elicit several anti-aging properties, could be a strategy to modify the composition and restore a healthy gut microbiota. Indeed, probiotics could represent a valid supplement to prevent and/or help treating some diseases, such as NAFLD, thus improving the already available pharmacological intervention. Moreover, in aging, intervention of prebiotics and fecal microbiota transplantation, as well as probiotics, will provide novel therapeutic approaches. However, the relevant research is limited, and several scientific research works need to be done in the near future to confirm their efficacy. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II)

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24 pages, 14012 KiB

Open AccessReview

Proteostasis Deregulation in Neurodegeneration and Its Link with Stress Granules: Focus on the Scaffold and Ribosomal Protein RACK1

by Mirco Masi, Alessandro Attanzio, Marco Racchi, Benjamin Wolozin, Sofia Borella, Fabrizio Biundo and Erica Buoso

Cells 2022, 11(16), 2590; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11162590 - 19 Aug 2022

Cited by 4 | Viewed by 3047

Abstract

The role of protein misfolding, deposition, and clearance has been the dominant topic in the last decades of investigation in the field of neurodegeneration. The impairment of protein synthesis, along with RNA metabolism and RNA granules, however, are significantly emerging as novel potential targets for the comprehension of the molecular events leading to neuronal deficits. Indeed, defects in ribosome activity, ribosome stalling, and PQC—all ribosome-related processes required for proteostasis regulation—can contribute to triggering stress conditions and promoting the formation of stress granules (SGs) that could evolve in the formation of pathological granules, usually occurring during neurodegenerating effects. In this review, the interplay between proteostasis, mRNA metabolism, and SGs has been explored in a neurodegenerative context with a focus on Alzheimer’s disease (AD), although some defects in these same mechanisms can also be found in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are discussed here. Finally, we highlight the role of the receptor for activated C kinase 1 (RACK1) in these pathologies and note that, besides its well characterized function as a scaffold protein, it has an important role in translation and can associate to stress granules (SGs) determining cell fate in response to diverse stress stimuli. Full article

(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions II)

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