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Aging and Senescence

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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 (31 May 2021) | Viewed by 55897

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Special Issue Editor

Prof. Dr. Giovanni Di Bernardo

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Guest Editor

Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy
Interests: senescence; mesenchymal stromal cells; cell cycle; adipogenesis; apoptosis; differentiation; aging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Aging is a natural process that occurs during the lifespan of an organism and involves cellular, physiological, and social changes. Cellular senescence refers to a phenomenon in which permanent cell growth arrest is induced, for example, as a response to excessive extracellular or intracellular stress. The involved cells change and acquire a new phenotype which, by and large, defines the senescent status. Senescent cells secrete senescence-associated secretory phenotype (SASP) proteins to carry out several functions, such as sensitizing surrounding cells to senescence, immunomodulation, and impairing or fostering cancer growth and wound healing, promoting tissue remodeling. Recent studies are increasingly revealing that this event is involved in aging and age-associate diseases, considering that tissue regeneration and DNA damage repair decline with age. Irrespective, during aging, the mechanisms and effectors that drive a gradual decay of physiological function still remain underinvestigated. In this context, a recent debate in the scientific community is questioning whether aging is an adaptive action or simply a consequence of the stochastic accumulation of deleterious phenomena. The primary aspect of this Special Issue is to supply a contribution of significant works in the field of “Aging and Senescence”, focusing on biological processes of cellular senescence and the demonstration that this physiological mechanism contributes to the onset of multiple diseases associated with aging.

Topics of this Special Issue include, but are not limited to:

Organismal aging and senescence
The key role of cellular senescence in driving of aging
Senescence-associated secretory phenotype (SASP) proteins and their contribution to physiological and pathological effects in organisms
How genetic or pharmacological removal of senescent cells improves longevity and promotes health span
Stem cells and aging

Prof. Giovanni Di Bernardo
Guest Editor

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Keywords

aging
inflammaging
replicative senescence
senescence-associated secretory phenotype (SASP)
age-associated diseases

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Published Papers (12 papers)

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Research

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16 pages, 5227 KiB

Open AccessArticle

Licochalcone D Ameliorates Oxidative Stress-Induced Senescence via AMPK Activation

by Nagarajan Maharajan, Chitra Devi Ganesan, Changjong Moon, Chul-Ho Jang, Won-Keun Oh and Gwang-Won Cho

Int. J. Mol. Sci. 2021, 22(14), 7324; https://doi.org/10.3390/ijms22147324 - 7 Jul 2021

Cited by 28 | Viewed by 3428

Abstract

Increased oxidative stress is a crucial factor for the progression of cellular senescence and aging. The present study aimed to investigate the effects of licochalcone D (Lico D) on oxidative stress-induced senescence, both in vitro and in vivo, and explore its potential mechanisms. Hydrogen peroxide (200 µM for double time) and D-galactose (D-Gal) (150 mg/kg) were used to induce oxidative stress in human bone marrow-mesenchymal stem cells (hBM-MSCs) and mice, respectively. We performed the SA-β-gal assay and evaluated the senescence markers, activation of AMPK, and autophagy. Lico D potentially reduced oxidative stress-induced senescence by upregulating AMPK-mediated activation of autophagy in hBM-MSCs. D-Gal treatment significantly increased the expression levels of senescence markers, such as p53 and p21, in the heart and hippocampal tissues, while this effect was reversed in the Lico D-treated animals. Furthermore, a significant increase in AMPK activation was observed in both tissues, while the activation of autophagy was only observed in the heart tissue. Interestingly, we found that Lico D significantly reduced the expression levels of the receptors for advanced glycation end products (RAGE) in the hippocampal tissue. Taken together, our findings highlight the antioxidant, anti-senescent, and cardioprotective effects of Lico D and suggest that the activation of AMPK and autophagy ameliorates the oxidative stress-induced senescence. Full article

(This article belongs to the Special Issue Aging and Senescence)

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15 pages, 4871 KiB

Open AccessArticle

p16-3MR: A Novel Model to Study Cellular Senescence in Cigarette Smoke-Induced Lung Injuries

by Gagandeep Kaur, Isaac K. Sundar and Irfan Rahman

Int. J. Mol. Sci. 2021, 22(9), 4834; https://doi.org/10.3390/ijms22094834 - 3 May 2021

Cited by 10 | Viewed by 5431

Abstract

Cellular senescence and lung aging are associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). COPD progresses with aging, and chronic smoking is the key susceptibility factor in lung pathological changes concurrent with mitochondrial dysfunction and biological aging. However, these processes involving cigarette smoke (CS)-mediated lung cellular senescence are difficult to distinguish. One of the impediments to studying cellular senescence in relation to age-related lung pathologies is the lack of a suitable in vivo model. In view of this, we provide evidence that supports the suitability of p16-3MR mice to studying cellular senescence in CS-mediated and age-related lung pathologies. p16-3MR mice have a trimodal reporter fused to the promoter of the p16^INK4a gene that enables detection, isolation, and selective elimination of senescent cells, thus making them a suitable model to study cellular senescence. To determine their suitability in CS-mediated lung pathologies, we exposed young (12–14 months) and old (17–20 months) p16-3MR mice to 30 day CS exposure and studied the expression of senescent genes (p16, p21, and p53) and SASP-associated markers (MMP9, MMP12, PAI-1, and FN-1) in air- and CS-exposed mouse lungs. Our results showed that this model could detect cellular senescence using luminescence and isolate cells undergoing senescence with the help of tissue fluorescence in CS-exposed young and old mice. Our results from the expression of senescence markers and SASP-associated genes in CS-exposed young and old p16-3MR mice were comparable with increased lung cellular senescence and SASP in COPD. We further showed alteration in the; (i) tissue luminescence and fluorescence, (ii) mRNA and protein expressions of senescent markers and SASP genes, and (iii) SA-β-gal activity in CS-exposed young and old p16-3MR mice as compared to their air controls. Overall, we showed that p16-3MR is a competent model for studying the cellular senescence in CS-induced pathologies. Hence, the p16-3MR reporter mouse model may be used as a novel tool for understanding the pathobiology of cellular senescence and other underlying mechanisms involved in COPD and fibrosis. Full article

(This article belongs to the Special Issue Aging and Senescence)

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15 pages, 3282 KiB

Open AccessArticle

CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence

by Vinoth Kumar Rethineswaran, Da Yeon Kim, Yeon-Ju Kim, WoongBi Jang, Seung Taek Ji, Le Thi Hong Van, Ly Thanh Truong Giang, Jong Seong Ha, Jisoo Yun, Jinsup Jung and Sang-Mo Kwon

Int. J. Mol. Sci. 2021, 22(9), 4796; https://doi.org/10.3390/ijms22094796 - 30 Apr 2021

Cited by 4 | Viewed by 4193 | Correction

Abstract

Endothelial progenitor cells (EPCs) are specialized cells in circulating blood, well known for their ability to form new vascular structures. Aging and various ailments such as diabetes, atherosclerosis and cardiovascular disease make EPCs vulnerable to decreasing in number, which affects their migration, proliferation and angiogenesis. Myocardial ischemia is also linked to a reduced number of EPCs and their endothelial functional role, which hinders proper blood circulation to the myocardium. The current study shows that an aminopyrimidine derivative compound (CHIR99021) induces the inhibition of GSK-3β in cultured late EPCs. GSK-3β inhibition subsequently inhibits mTOR by blocking the phosphorylation of TSC2 and lysosomal localization of mTOR. Furthermore, suppression of GSK-3β activity considerably increased lysosomal activation and autophagy. The activation of lysosomes and autophagy by GSK-3β inhibition not only prevented replicative senescence of the late EPCs but also directed their migration, proliferation and angiogenesis. To conclude, our results demonstrate that lysosome activation and autophagy play a crucial role in blocking the replicative senescence of EPCs and in increasing their endothelial function. Thus, the findings provide an insight towards the treatment of ischemia-associated cardiovascular diseases based on the role of late EPCs. Full article

(This article belongs to the Special Issue Aging and Senescence)

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13 pages, 2784 KiB

Open AccessArticle

Different Stages of Quiescence, Senescence, and Cell Stress Identified by Molecular Algorithm Based on the Expression of Ki67, RPS6, and Beta-Galactosidase Activity

by Nicola Alessio, Domenico Aprile, Salvatore Cappabianca, Gianfranco Peluso, Giovanni Di Bernardo and Umberto Galderisi

Int. J. Mol. Sci. 2021, 22(6), 3102; https://doi.org/10.3390/ijms22063102 - 18 Mar 2021

Cited by 38 | Viewed by 4922

Abstract

During their life span, cells have two possible states: a non-cycling, quiescent state (G0) and a cycling, activated state. Cells may enter a reversible G0 state of quiescence or, alternatively, they may undergo an irreversible G0 state. The latter may be a physiological differentiation or, following a stress event, a senescent status. Discrimination among the several G0 states represents a significant investigation, since quiescence, differentiation, and senescence are progressive phenomena with intermediate transitional stages. We used the expression of Ki67, RPS6, and beta-galactosidase to identify healthy cells that progressively enter and leave quiescence through G0-entry, G0 and G0-alert states. We then evaluated how cells may enter senescence following a genotoxic stressful event. We identified an initial stress stage with the expression of beta-galactosidase and Ki67 proliferation marker. Cells may recover from stress events or become senescent passing through early and late senescence states. Discrimination between quiescence and senescence was based on the expression of RPS6, a marker of active protein synthesis that is present in senescent cells but absent in quiescent cells. Even taking into account that fixed G0 states do not exist, our molecular algorithm may represent a method for identifying turning points of G0 transitional states that continuously change. Full article

(This article belongs to the Special Issue Aging and Senescence)

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13 pages, 3370 KiB

Open AccessArticle

The Interaction of the Senescent and Adjacent Breast Cancer Cells Promotes the Metastasis of Heterogeneous Breast Cancer Cells through Notch Signaling

by Na Zhang, Jiafei Ji, Dandan Zhou, Xuan Liu, Xinglin Zhang, Yingqi Liu, Weifang Xiang, Meida Wang, Lian Zhang, Guannan Wang, Baiqu Huang, Jun Lu and Yu Zhang

Int. J. Mol. Sci. 2021, 22(2), 849; https://doi.org/10.3390/ijms22020849 - 15 Jan 2021

Cited by 19 | Viewed by 3262

Abstract

Chemotherapy is one of the most common strategies for tumor treatment but often associated with post-therapy tumor recurrence. While chemotherapeutic drugs are known to induce tumor cell senescence, the roles and mechanisms of senescence in tumor recurrence remain unclear. In this study, we used doxorubicin to induce senescence in breast cancer cells, followed by culture of breast cancer cells with conditional media of senescent breast cancer cells (indirect co-culture) or directly with senescent breast cancer cells (direct co-culture). We showed that breast cancer cells underwent the epithelial–mesenchymal transition (EMT) to a greater extent and had stronger migration and invasion ability in the direct co-culture compared with that in the indirect co-culture model. Moreover, in the direct co-culture model, non-senescent breast cancer cells facilitated senescent breast cancer cells to escape and re-enter into the cell cycle. Meanwhile, senescent breast cancer cells regained tumor cell characteristics and underwent EMT after direct co-culture. We found that the Notch signaling was activated in both senescent and non-senescent breast cancer cells in the direct co-culture group. Notably, the EMT process of senescent and adjacent breast cancer cells was blocked upon inhibition of Notch signaling with N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT) in the direct co-cultures. In addition, DAPT inhibited the lung metastasis of the co-cultured breast cancer cells in vivo. Collectively, data arising from this study suggest that both senescent and adjacent non-senescent breast cancer cells developed EMT through activating Notch signaling under conditions of intratumoral heterogeneity caused by chemotherapy, which infer the possibility that Notch inhibitors used in combination with chemotherapeutic agents may become an effective treatment strategy. Full article

(This article belongs to the Special Issue Aging and Senescence)

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10 pages, 2241 KiB

Open AccessArticle

Mathematical Connection between Short Telomere Induced Senescence Calculation and Mortality Rate Data

by Jerry B. Torrance and Steve Goldband

Int. J. Mol. Sci. 2020, 21(21), 7959; https://doi.org/10.3390/ijms21217959 - 27 Oct 2020

Cited by 4 | Viewed by 2502

Abstract

The last 20 years have seen a surge in scientific activity and promising results in the study of aging and longevity. Many researchers have focused on telomeres, which are composed of a series of TTAGGG repeat nucleotide sequences at the ends of each chromosome. Measurements of the length of these telomere strands show that they decrease in length with increasing age, leading many authors to propose that when the length of these telomere strands decreases sufficiently, the cells enter into a state of replicative senescence, eventually leading to disease and death. These ideas are supported by evidence that short telomere length is correlated with increased mortality. In this paper, we extend this idea to make an actual calculation of the predicted mortality rate caused by short telomere length induced senescence (STLIS). We derive a simple equation for the mathematical relationship between telomere length and mortality rate. Using only three parameters based on telomere length measurement data of Canadians, we have calculated both the magnitude and the age dependence of the mortality rate for both men and women. We show that these calculated data are in good quantitative agreement with the actual number of Canadians that die. This agreement demonstrates the quantitative correlation between the mortality calculated by the STLIS model and the mortality of the major diseases of aging (e.g., cardiovascular disease, many cancers and diabetes mellitus), which dominate human mortality. This result represents significant progress in our understanding of the factors behind the cause of aging. Full article

(This article belongs to the Special Issue Aging and Senescence)

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14 pages, 2954 KiB

Open AccessArticle

Effects of p-Cresol on Senescence, Survival, Inflammation, and Odontoblast Differentiation in Canine Dental Pulp Stem Cells

by Mohammed Zayed and Koichiro Iohara

Int. J. Mol. Sci. 2020, 21(18), 6931; https://doi.org/10.3390/ijms21186931 - 21 Sep 2020

Cited by 4 | Viewed by 2626

Abstract

Aging, defined by a decrease in the physical and functional integrity of the tissues, leads to age-associated degenerative diseases. There is a relation between aged dental pulp and the senescence of dental pulp stem cells (DPSCs). Therefore, it is important to investigate the molecular processes underlying the senescence of DPSCs to elucidate the dental pulp aging mechanisms. p-Cresol (PC), a uremic toxin, is strongly related to cellular senescence. Here, age-related phenotypic changes including senescence, apoptosis, inflammation, and declining odontoblast differentiation in PC-treated canine DPSCs were investigated. Under the PC condition, cellular senescence was induced by decreased proliferation capacity and increased cell size, senescence-associated β-galactosidase (SA-β-gal) activity, and senescence markers p21, IL-1β, IL-8, and p53. Exposure to PC could stimulate inflammation by the increased expression of IL-6 and cause the distraction of the cell cycle by the increased level of Bax protein and decreased Bcl-2. The levels of odontoblast differentiation markers, dentin sialophosphoprotein (DSPP), dentin matrix protein 1, and osterix, were decreased. Consistent with those findings, the alizarin red staining, alkaline phosphatase, and DSPP protein level were decreased during the odontoblast differentiation process. Taken together, these findings indicate that PC could induce cellular senescence in DPSCs, which may demonstrate the changes in aging dental pulp. Full article

(This article belongs to the Special Issue Aging and Senescence)

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Review

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18 pages, 519 KiB

Open AccessReview

Flavonoids in Skin Senescence Prevention and Treatment

by Anna Domaszewska-Szostek, Monika Puzianowska-Kuźnicka and Alina Kuryłowicz

Int. J. Mol. Sci. 2021, 22(13), 6814; https://doi.org/10.3390/ijms22136814 - 25 Jun 2021

Cited by 58 | Viewed by 8152

Abstract

Skin aging is associated with the accumulation of senescent cells and is related to many pathological changes, including decreased protection against pathogens, increased susceptibility to irritation, delayed wound healing, and increased cancer susceptibility. Senescent cells secrete a specific set of pro-inflammatory mediators, referred to as a senescence-associated secretory phenotype (SASP), which can cause profound changes in tissue structure and function. Thus, drugs that selectively eliminate senescent cells (senolytics) or neutralize SASP (senostatics) represent an attractive therapeutic strategy for age-associated skin deterioration. There is growing evidence that plant-derived compounds (flavonoids) can slow down or even prevent aging-associated deterioration of skin appearance and function by targeting cellular pathways crucial for regulating cellular senescence and SASP. This review summarizes the senostatic and senolytic potential of flavonoids in the context of preventing skin aging. Full article

(This article belongs to the Special Issue Aging and Senescence)

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14 pages, 578 KiB

Open AccessReview

Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process

by Fiqri D. Khaidizar, Yasumasa Bessho and Yasukazu Nakahata

Int. J. Mol. Sci. 2021, 22(7), 3709; https://doi.org/10.3390/ijms22073709 - 2 Apr 2021

Cited by 23 | Viewed by 6617

Abstract

Aging is a phenomenon underlined by complex molecular and biochemical changes that occur over time. One of the metabolites that is gaining strong research interest is nicotinamide adenine dinucleotide, NAD⁺, whose cellular level has been shown to decrease with age in various tissues of model animals and humans. Administration of NAD⁺ precursors, nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), to supplement NAD⁺ production through the NAD⁺ salvage pathway has been demonstrated to slow down aging processes in mice. Therefore, NAD⁺ is a critical metabolite now understood to mitigate age-related tissue function decline and prevent age-related diseases in aging animals. In human clinical trials, administration of NAD⁺ precursors to the elderly is being used to address systemic age-associated physiological decline. Among NAD⁺ biosynthesis pathways in mammals, the NAD⁺ salvage pathway is the dominant pathway in most of tissues, and NAMPT is the rate limiting enzyme of this pathway. However, only a few activators of NAMPT, which are supposed to increase NAD⁺, have been developed so far. In this review, we will focus on the importance of NAD⁺ and the possible application of an activator of NAMPT to promote successive aging. Full article

(This article belongs to the Special Issue Aging and Senescence)

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23 pages, 3740 KiB

Open AccessReview

Accelerated Aging and Age-Related Diseases (CVD and Neurological) Due to Air Pollution and Traffic Noise Exposure

by Omar Hahad, Katie Frenis, Marin Kuntic, Andreas Daiber and Thomas Münzel

Int. J. Mol. Sci. 2021, 22(5), 2419; https://doi.org/10.3390/ijms22052419 - 28 Feb 2021

Cited by 40 | Viewed by 6286

Abstract

The World Health Organization estimates that only approximately 25% of diversity in longevity is explained by genetic factors, while the other 75% is largely determined by interactions with the physical and social environments. Indeed, aging is a multifactorial process that is influenced by a range of environmental, sociodemographic, and biopsychosocial factors, all of which might act in concert to determine the process of aging. The global average life expectancy increased fundamentally over the past century, toward an aging population, correlating with the development and onset of age-related diseases, mainly from cardiovascular and neurological nature. Therefore, the identification of determinants of healthy and unhealthy aging is a major goal to lower the burden and socioeconomic costs of age-related diseases. The role of environmental factors (such as air pollution and noise exposure) as crucial determinants of the aging process are being increasingly recognized. Here, we critically review recent findings concerning the pathomechanisms underlying the aging process and their correlates in cardiovascular and neurological disease, centered on oxidative stress and inflammation, as well as the influence of prominent environmental pollutants, namely air pollution and traffic noise exposure, which is suggested to accelerate the aging process. Insight into these types of relationships and appropriate preventive strategies are urgently needed to promote healthy aging. Full article

(This article belongs to the Special Issue Aging and Senescence)

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15 pages, 891 KiB

Open AccessReview

Bcl-xL as a Modulator of Senescence and Aging

by Cristina Mas-Bargues, Consuelo Borrás and Jose Viña

Int. J. Mol. Sci. 2021, 22(4), 1527; https://doi.org/10.3390/ijms22041527 - 3 Feb 2021

Cited by 21 | Viewed by 5442

Abstract

Many features of aging result from the incapacity of cells to adapt to stress conditions. When cells are overwhelmed by stress, they can undergo senescence to avoid unrestricted growth of damaged cells. Recent findings have proven that cellular senescence is more than that. A specific grade of senescence promotes embryo development, tissue remodeling and wound healing. However, constant stresses and a weakening immune system can lead to senescence chronicity with aging. The accumulation of senescent cells is directly related to tissue dysfunction and age-related pathologies. Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models. In this review, we aim to discuss how Bcl-xL could modulate senescence-associated harmful effects in centenarians, protecting them from the burden of accumulation of senescent cells. Full article

(This article belongs to the Special Issue Aging and Senescence)

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