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15 pages, 1474 KiB

Open AccessArticle

CLCA2: A Potential Guardian against Premature Senescence and Skin Aging

by Lena Guerrero-Navarro, Ines Martic, Christian Ploner, Pidder Jansen-Dürr and Maria Cavinato

Biomedicines 2024, 12(3), 592; https://doi.org/10.3390/biomedicines12030592 - 06 Mar 2024

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Cellular senescence, a state of irreversible growth arrest, is implicated in various age-related pathologies, including skin aging. In this study, we investigated the role of CLCA2, a calcium-activated chloride channel accessory protein, in cellular senescence and its implications for skin aging. Utilizing UVB [...] Read more.

Cellular senescence, a state of irreversible growth arrest, is implicated in various age-related pathologies, including skin aging. In this study, we investigated the role of CLCA2, a calcium-activated chloride channel accessory protein, in cellular senescence and its implications for skin aging. Utilizing UVB and Nutlin3a-induced senescence models, we observed the upregulation of CLCA2 at both transcriptomic and proteomic levels, suggesting its involvement in senescence pathways. Further analysis revealed that the depletion of CLCA2 led to accelerated senescence onset, characterized by classic senescence markers and a unique secretome profile. In 3D skin equivalent models, SEs constructed with CLCA2 knockdown fibroblasts exhibited features reminiscent of aged skin, underscoring the importance of CLCA2 in maintaining skin homeostasis. Our findings highlight CLCA2 as a novel regulator of cellular senescence and its potential implications for skin aging mechanisms. Full article

(This article belongs to the Special Issue Cellular Senescence: Recent Advances and Discoveries)

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11 pages, 1688 KiB

Open AccessArticle

Mitochondria-Targeted Catalase Does Not Suppress Development of Cellular Senescence during Aging

by Bronwyn A. Mogck, Samantha T. Jezak and Christopher D. Wiley

Biomedicines 2024, 12(2), 414; https://doi.org/10.3390/biomedicines12020414 - 10 Feb 2024

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Abstract

Cellular senescence is a complex stress response marked by stable proliferative arrest and the secretion of biologically active molecules collectively known as the senescence-associated secretory phenotype (SASP). Mitochondria-derived reactive oxygen species (ROS) have been implicated in aging and age-related processes, including senescence. Stressors [...] Read more.

Cellular senescence is a complex stress response marked by stable proliferative arrest and the secretion of biologically active molecules collectively known as the senescence-associated secretory phenotype (SASP). Mitochondria-derived reactive oxygen species (ROS) have been implicated in aging and age-related processes, including senescence. Stressors that increase ROS levels promote both senescence and the SASP, while reducing mitochondrial ROS or mitochondria themselves can prevent senescence or the SASP. Mitochondrially targeted catalase (mCAT), a transgene that reduces mitochondrial levels of ROS, has been shown to extend the lifespan of murine models and protect against the age-related loss of mitochondrial function. However, it remains unclear whether mCAT can prevent senescence or the SASP. In this study, we investigated the impact of mCAT on senescence in cultured cells and aged mice in order to discover if the lifespan-extending activity of mCAT might be due to the reduction in senescent cells or the SASP. Contrary to expectations, we observed that mCAT does not reduce markers of senescence or the SASP in cultured cells. Moreover, mCAT does not prevent the accumulation of senescent cells or the development of the SASP in adipose tissue from aged mice. These results suggest that mitochondrial ROS may not always play a causal role in the development of senescence during natural aging and underscore the need for a nuanced understanding of the intricate relationship between mitochondrial ROS and cellular senescence. Full article

(This article belongs to the Special Issue Cellular Senescence: Recent Advances and Discoveries)

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17 pages, 3120 KiB

Open AccessArticle

Suppression of Bcl3 Disrupts Viability of Breast Cancer Cells through Both p53-Dependent and p53-Independent Mechanisms via Loss of NF-κB Signalling

by Daniel J. Turnham, Hannah Smith and Richard W. E. Clarkson

Biomedicines 2024, 12(1), 143; https://doi.org/10.3390/biomedicines12010143 - 10 Jan 2024

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Abstract

The NF-κB co-factor Bcl3 is a proto-oncogene that promotes breast cancer proliferation, metastasis and therapeutic resistance, yet its role in breast cancer cell survival is unclear. Here, we sought to determine the effect of Bcl3 suppression alone on breast cancer cell viability, with [...] Read more.

The NF-κB co-factor Bcl3 is a proto-oncogene that promotes breast cancer proliferation, metastasis and therapeutic resistance, yet its role in breast cancer cell survival is unclear. Here, we sought to determine the effect of Bcl3 suppression alone on breast cancer cell viability, with a view to informing future studies that aim to target Bcl3 therapeutically. Bcl3 was suppressed by siRNA in breast cancer cell lines before changes in viability, proliferation, apoptosis and senescence were examined. Bcl3 suppression significantly reduced viability and was shown to induce apoptosis in all cell lines tested, while an additional p53-dependent senescence and senescence-associated secretory phenotype was also observed in those cells with functional p53. The role of the Bcl3/NF-κB axis in this senescence response was confirmed via siRNA of the non-canonical NF-κB subunit NFKB2/p52, which resulted in increased cellular senescence and the canonical subunit NFKB1/p50, which induced the senescence-associated secretory phenotype. An analysis of clinical data showed a correlation between reduced relapse-free survival in patients that expressed high levels of Bcl3 and carried a p53 mutation. Together, these data demonstrate a dual role for Bcl3/NF-κB in the maintenance of breast cancer cell viability and suggests that targeting Bcl3 may be more beneficial to patients with tumours that lack functional p53. Full article

(This article belongs to the Special Issue Cellular Senescence: Recent Advances and Discoveries)

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18 pages, 3231 KiB

Open AccessArticle

PURPL and NEAT1 Long Non-Coding RNAs Are Modulated in Vascular Smooth Muscle Cell Replicative Senescence

by Clara Rossi, Marco Venturin, Jakub Gubala, Angelisa Frasca, Alberto Corsini, Cristina Battaglia and Stefano Bellosta

Biomedicines 2023, 11(12), 3228; https://doi.org/10.3390/biomedicines11123228 - 06 Dec 2023

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Abstract

Cellular senescence is characterized by proliferation and migration exhaustion, senescence-associated secretory phenotype (SASP), and oxidative stress. Senescent vascular smooth muscle cells (VSMCs) contribute to cardiovascular diseases and atherosclerotic plaque instability. Since there are no unanimously agreed senescence markers in human VSMCs, to improve [...] Read more.

Cellular senescence is characterized by proliferation and migration exhaustion, senescence-associated secretory phenotype (SASP), and oxidative stress. Senescent vascular smooth muscle cells (VSMCs) contribute to cardiovascular diseases and atherosclerotic plaque instability. Since there are no unanimously agreed senescence markers in human VSMCs, to improve our knowledge, we looked for new possible senescence markers. To this end, we first established and characterized a model of replicative senescence (RS) in human aortic VSMCs. Old cells displayed several established senescence-associated markers. They stained positive for the senescence-associated β-galactosidase, showed a deranged proliferation rate, a dramatically reduced expression of PCNA, an altered migratory activity, increased levels of TP53 and cell-cycle inhibitors p21/p16, and accumulated in the G1 phase. Old cells showed an altered cellular and nuclear morphology, downregulation of the expression of LMNB1 and HMGB1, and increased expression of SASP molecules (IL1β, IL6, IL8, and MMP3). In these senescent VSMCs, among a set of 12 manually selected long non-coding RNAs (lncRNAs), we detected significant upregulation of PURPL and NEAT1. We observed also, for the first time, increased levels of RRAD mRNA. The detection of modulated levels of RRAD, PURPL, and NEAT1 during VSMC senescence could be helpful for future studies on potential anti-aging factors. Full article

(This article belongs to the Special Issue Cellular Senescence: Recent Advances and Discoveries)

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14 pages, 4501 KiB

Open AccessArticle

Circulating Total Extracellular Vesicles Cargo Are Associated with Age-Related Oxidative Stress and Susceptibility to Cardiovascular Diseases: Exploratory Results from Microarray Data

by Laura Reck Cechinel, Rachael Ann Batabyal, Giana Blume Corssac, Madeleine Goldberg, Brennan Harmon, Virgínia Mendes Russo Vallejos, Gisele E. Bruch, André Ricardo Massensini, Adriane Belló-Klein, Alex Sander da Rosa Araujo, Robert J. Freishtat and Ionara Rodrigues Siqueira

Biomedicines 2023, 11(11), 2920; https://doi.org/10.3390/biomedicines11112920 - 28 Oct 2023

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Abstract

Aging is a risk factor for many non-communicable diseases such as cardiovascular and neurodegenerative diseases. Extracellular vesicles and particles (EVP) carry microRNAs that may play a role in age-related diseases and may induce oxidative stress. We hypothesized that aging could impact EVP miRNA [...] Read more.

Aging is a risk factor for many non-communicable diseases such as cardiovascular and neurodegenerative diseases. Extracellular vesicles and particles (EVP) carry microRNAs that may play a role in age-related diseases and may induce oxidative stress. We hypothesized that aging could impact EVP miRNA and impair redox homeostasis, contributing to chronic age-related diseases. Our aims were to investigate the microRNA profiles of circulating total EVPs from aged and young adult animals and to evaluate the pro- and antioxidant machinery in circulating total EVPs. Plasma from 3- and 21-month-old male Wistar rats were collected, and total EVPs were isolated. MicroRNA isolation and microarray expression analysis were performed on EVPs to determine the predicted regulation of targeted mRNAs. Thirty-one mature microRNAs in circulating EVPs were impacted by age and were predicted to target molecules in canonical pathways directly related to cardiovascular diseases and oxidative status. Circulating total EVPs from aged rats had significantly higher NADPH oxidase levels and myeloperoxidase activity, whereas catalase activity was significantly reduced in EVPs from aged animals. Our data shows that circulating total EVP cargo—specifically microRNAs and oxidative enzymes—are involved in redox imbalance in the aging process and can potentially drive cardiovascular aging and, consequently, cardiac disease. Full article

(This article belongs to the Special Issue Cellular Senescence: Recent Advances and Discoveries)

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Review

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32 pages, 1561 KiB

Open AccessReview

Plant Monoterpenes and Essential Oils as Potential Anti-Ageing Agents: Insights from Preclinical Data

by Mónica Zuzarte, Cátia Sousa, Jorge Alves-Silva and Lígia Salgueiro

Biomedicines 2024, 12(2), 365; https://doi.org/10.3390/biomedicines12020365 - 04 Feb 2024

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Abstract

Ageing is a natural process characterized by a time-dependent decline of physiological integrity that compromises functionality and inevitably leads to death. This decline is also quite relevant in major human pathologies, being a primary risk factor in neurodegenerative diseases, metabolic disorders, cardiovascular diseases [...] Read more.

Ageing is a natural process characterized by a time-dependent decline of physiological integrity that compromises functionality and inevitably leads to death. This decline is also quite relevant in major human pathologies, being a primary risk factor in neurodegenerative diseases, metabolic disorders, cardiovascular diseases and musculoskeletal disorders. Bearing this in mind, it is not surprising that research aiming at improving human health during this process has burst in the last decades. Importantly, major hallmarks of the ageing process and phenotype have been identified, this knowledge being quite relevant for future studies towards the identification of putative pharmaceutical targets, enabling the development of preventive/therapeutic strategies to improve health and longevity. In this context, aromatic plants have emerged as a source of potential bioactive volatile molecules, mainly monoterpenes, with many studies referring to their anti-ageing potential. Nevertheless, an integrated review on the current knowledge is lacking, with several research approaches studying isolated ageing hallmarks or referring to an overall anti-ageing effect, without depicting possible mechanisms of action. Herein, we aim to provide an updated systematization of the bioactive potential of volatile monoterpenes on recently proposed ageing hallmarks, and highlight the main mechanisms of action already identified, as well as possible chemical entity–activity relations. By gathering and categorizing the available scattered information, we also aim to identify important research gaps that could help pave the way for future research in the field. Full article

(This article belongs to the Special Issue Cellular Senescence: Recent Advances and Discoveries)

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25 pages, 1620 KiB

Open AccessReview

Cellular Senescence in Liver Cancer: How Dying Cells Become “Zombie” Enemies

by Aurora Gazzillo, Camilla Volponi, Cristiana Soldani, Michela Anna Polidoro, Barbara Franceschini, Ana Lleo, Eduardo Bonavita and Matteo Donadon

Biomedicines 2024, 12(1), 26; https://doi.org/10.3390/biomedicines12010026 (registering DOI) - 21 Dec 2023

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Abstract

Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent [...] Read more.

Liver cancer represents the fourth leading cause of cancer-associated death worldwide. The heterogeneity of its tumor microenvironment (TME) is a major contributing factor of metastasis, relapse, and drug resistance. Regrettably, late diagnosis makes most liver cancer patients ineligible for surgery, and the frequent failure of non-surgical therapeutic options orientates clinical research to the investigation of new drugs. In this context, cellular senescence has been recently shown to play a pivotal role in the progression of chronic inflammatory liver diseases, ultimately leading to cancer. Moreover, the stem-like state triggered by senescence has been associated with the emergence of drug-resistant, aggressive tumor clones. In recent years, an increasing number of studies have emerged to investigate senescence-associated hepatocarcinogenesis and its derived therapies, leading to promising results. In this review, we intend to provide an overview of the recent evidence that unveils the role of cellular senescence in the most frequent forms of primary and metastatic liver cancer, focusing on the involvement of this mechanism in therapy resistance. Full article

(This article belongs to the Special Issue Cellular Senescence: Recent Advances and Discoveries)

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16 pages, 1948 KiB

Open AccessReview

Protein-Bound Uremic Toxins in Senescence and Kidney Fibrosis

by Yi Yang, Milos Mihajlovic and Rosalinde Masereeuw

Biomedicines 2023, 11(9), 2408; https://doi.org/10.3390/biomedicines11092408 - 28 Aug 2023

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Abstract

Chronic kidney disease (CKD) is a progressive condition of kidney dysfunction due to diverse causes of injury. In healthy kidneys, protein-bound uremic toxins (PBUTs) are cleared from the systemic circulation by proximal tubule cells through the concerted action of plasma membrane transporters that [...] Read more.

Chronic kidney disease (CKD) is a progressive condition of kidney dysfunction due to diverse causes of injury. In healthy kidneys, protein-bound uremic toxins (PBUTs) are cleared from the systemic circulation by proximal tubule cells through the concerted action of plasma membrane transporters that facilitate their urinary excretion, but the endogenous metabolites are hardly removed with kidney dysfunction and may contribute to CKD progression. Accumulating evidence suggests that senescence of kidney tubule cells influences kidney fibrosis, the common endpoint for CKD with an excessive accumulation of extracellular matrix (ECM). Senescence is a special state of cells characterized by permanent cell cycle arrest and limitation of proliferation, which promotes fibrosis by releasing senescence-associated secretory phenotype (SASP) factors. The accumulation of PBUTs in CKD causes oxidative stress and increases the production of inflammatory (SASP) factors that could trigger fibrosis. Recent studies gave some clues that PBUTs may also promote senescence in kidney tubular cells. This review provides an overview on how senescence contributes to CKD, the involvement of PBUTs in this process, and how kidney senescence can be studied. Finally, some suggestions for future therapeutic options for CKD while targeting senescence are given. Full article

(This article belongs to the Special Issue Cellular Senescence: Recent Advances and Discoveries)

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