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

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

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 56732

Special Issue Editors

Dr. Alessandro Attanzio

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Guest Editor
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
Special Issues, Collections and Topics in MDPI journals
Dr. Erica Buoso

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Guest Editor
Department of Drug Sciences, University of Pavia, Via Taramelli 12/14, 27100 Pavia, Italy
Interests: transcription and translation regulation in aging and neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Fabrizio Biundo

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Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

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

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Published Papers (15 papers)

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Editorial

Jump to: Research, Review

5 pages, 208 KiB  
Editorial
Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions
by Erica Buoso, Alessandro Attanzio and Fabrizio Biundo
Cells 2022, 11(13), 2029; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11132029 - 26 Jun 2022
Cited by 2 | Viewed by 1601
Abstract
Due to the increase in life expectancy, the aging population around the globe has been growing significantly and is estimated to triple by 2050 [...] Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)

Research

Jump to: Editorial, Review

16 pages, 7019 KiB  
Article
Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy
by Benjamin M. Freyter, Mutaz A. Abd Al-razaq, Anna Isermann, Anne Dietz, Omid Azimzadeh, Liesbeth Hekking, Maria Gomolka and Claudia E. Rübe
Cells 2022, 11(2), 273; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11020273 - 13 Jan 2022
Cited by 9 | Viewed by 2703
Abstract
Irreparable DNA damage following ionizing radiation (IR) triggers prolonged DNA damage response and induces premature senescence. Cellular senescence is a permanent state of cell-cycle arrest characterized by chromatin restructuring, altered nuclear morphology and acquisition of secretory phenotype, which contributes to senescence-related inflammation. However, [...] Read more.
Irreparable DNA damage following ionizing radiation (IR) triggers prolonged DNA damage response and induces premature senescence. Cellular senescence is a permanent state of cell-cycle arrest characterized by chromatin restructuring, altered nuclear morphology and acquisition of secretory phenotype, which contributes to senescence-related inflammation. However, the mechanistic connections for radiation-induced DNA damage that trigger these senescence-associated hallmarks are poorly understood. In our in vitro model of radiation-induced senescence, mass spectrometry-based proteomics was combined with high-resolution imaging techniques to investigate the interrelations between altered chromatin compaction, nuclear envelope destabilization and nucleo-cytoplasmic chromatin blebbing. Our findings confirm the general pathophysiology of the senescence-response, with disruption of nuclear lamin organization leading to extensive chromatin restructuring and destabilization of the nuclear membrane with release of chromatin fragments into the cytosol, thereby activating cGAS-STING-dependent interferon signaling. By serial block-face scanning electron microscopy (SBF-SEM) whole-cell datasets were acquired to investigate the morphological organization of senescent fibroblasts. High-resolution 3-dimensional (3D) reconstruction of the complex nuclear shape allows us to precisely visualize the segregation of nuclear blebs from the main nucleus and their fusion with lysosomes. By multi-view 3D electron microscopy, we identified nanotubular channels formed in lamin-perturbed nuclei of senescent fibroblasts; the potential role of these nucleo-cytoplasmic nanotubes for expulsion of damaged chromatin has to be examined. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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17 pages, 3560 KiB  
Article
Heat Shock Factor 1 Prevents Age-Related Hearing Loss by Decreasing Endoplasmic Reticulum Stress
by Yun Yeong Lee, Eun Sol Gil, In Hye Jeong, Hantai Kim, Jeong Hun Jang and Yun-Hoon Choung
Cells 2021, 10(9), 2454; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092454 - 17 Sep 2021
Cited by 7 | Viewed by 2649
Abstract
Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the [...] Read more.
Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the present study was to identify the role of HSF1 in ARHL. In this study, we demonstrated that the loss of inner and outer hair cells and their supporting cells was predominant in the high-frequency region (basal turn, 32 kHz) in ARHL cochleae. In the aging cochlea, levels of the ER stress marker proteins p-eIF2α and CHOP increased as HSF1 protein levels decreased. The levels of various heat shock proteins (HSPs) also decreased, including HSP70 and HSP40, which were markedly downregulated, and the expression levels of Bax and cleaved caspase-3 apoptosis-related proteins were increased. However, HSF1 overexpression showed significant hearing protection effects in the high-frequency region (basal turn, 32 kHz) by decreasing CHOP and cleaved caspase-3 and increasing the HSP40 and HSP70 proteins. These findings were confirmed by HSF1 functional studies using an auditory cell model. Therefore, we propose that HSF1 can function as a mediator to prevent ARHL by decreasing ER stress-dependent apoptosis in the aging cochlea. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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13 pages, 3620 KiB  
Article
Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia
by Pasquale Mone, Jessica Gambardella, Antonella Pansini, Antonio de Donato, Giuseppe Martinelli, Eugenio Boccalone, Alessandro Matarese, Salvatore Frullone and Gaetano Santulli
Cells 2021, 10(8), 2115; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082115 - 17 Aug 2021
Cited by 42 | Viewed by 3574
Abstract
Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the [...] Read more.
Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8; p < 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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16 pages, 7055 KiB  
Article
Effect of Rho-Associated Kinase Inhibitor and Mesenchymal Stem Cell-Derived Conditioned Medium on Corneal Endothelial Cell Senescence and Proliferation
by Boyoung Jung, Hun Lee, Sumi Kim, Hungwon Tchah and Changmo Hwang
Cells 2021, 10(6), 1463; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061463 - 11 Jun 2021
Cited by 9 | Viewed by 2950
Abstract
This study aims to obtain sufficient corneal endothelial cells for regenerative application. We examined the combinatory effects of Rho-associated kinase (ROCK) inhibitor Y-27632 and mesenchymal stem cell-derived conditioned medium (MSC-CM) on the proliferation and senescence of rabbit corneal endothelial cells (rCECs). rCECs were [...] Read more.
This study aims to obtain sufficient corneal endothelial cells for regenerative application. We examined the combinatory effects of Rho-associated kinase (ROCK) inhibitor Y-27632 and mesenchymal stem cell-derived conditioned medium (MSC-CM) on the proliferation and senescence of rabbit corneal endothelial cells (rCECs). rCECs were cultured in a control medium, a control medium mixed with either Y-27632 or MSC-CM, and a combinatory medium containing Y-27632 and MSC-CM. Cells were analyzed for morphology, cell size, nuclei/cytoplasmic ratio, proliferation capacity and gene expression. rCECs cultured in a combinatory culture medium showed a higher passage number, cell proliferation, and low senescence. rCECs on collagen type I film showed high expression of tight junction. The cell proliferation marker Ki-67 was positively stained either in Y-27632 or MSC-CM-containing media. Genes related to cell proliferation resulted in negligible changes in MKI67, CIP2A, and PCNA in the combinatory medium, suggesting proliferative capacity was maintained. In contrast, all of these genes were significantly downregulated in the other groups. Senescence marker β-galactosidase-positive cells significantly decreased in either MSC-CM and/or Y-27632 mixed media. Senescence-related genes downregulated LMNB1 and MAP2K6, and upregulated MMP2. Cell cycle checkpoint genes such as CDC25C, CDCA2, and CIP2A did not vary in the combinatory medium but were significantly downregulated in either ROCK inhibitor or MSC-CM alone. These results imply the synergistic effect of combinatory culture medium on corneal endothelial cell proliferation and high cell number. This study supports high potential for translation to the development of human corneal endothelial tissue regeneration. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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12 pages, 2821 KiB  
Article
Induction of Stress-Induced Renal Cellular Senescence In Vitro: Impact of Mouse Strain Genetic Diversity
by Chieh Ming Liao, Vera Christine Wulfmeyer, Maxine Swallow, Christine Susanne Falk, Hermann Haller, Ron Korstanje, Anette Melk and Roland Schmitt
Cells 2021, 10(6), 1437; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061437 - 08 Jun 2021
Cited by 4 | Viewed by 2979
Abstract
Cellular senescence, a stress-induced state of irreversible cell cycle arrest, is associated with organ dysfunction and age-related disease. While immortalized cell lines bypass key pathways of senescence, important mechanisms of cellular senescence can be studied in primary cells. Primary tubular epithelial cells (PTEC) [...] Read more.
Cellular senescence, a stress-induced state of irreversible cell cycle arrest, is associated with organ dysfunction and age-related disease. While immortalized cell lines bypass key pathways of senescence, important mechanisms of cellular senescence can be studied in primary cells. Primary tubular epithelial cells (PTEC) derived from mouse kidney are highly susceptible to develop cellular senescence, providing a valuable tool for studying such mechanisms. Here, we tested whether genetic differences between mouse inbred strains have an impact on the development of stress-induced cellular senescence in cultured PTEC. Kidneys from 129S1, B6, NOD, NZO, CAST, and WSB mice were used to isolate PTEC. Cells were monitored for expression of typical senescence markers (SA-β-galactosidase, γ-H2AX+/Ki67−, expression levels of CDKN2A, lamin B1, IL-1a/b, IL-6, G/M-CSF, IFN-g, and KC) at 3 and 10 days after pro-senescent gamma irradiation. Clear differences were found between PTEC from different strains with the highest senescence values for PTEC from WSB mice and the lowest for PTEC from 129S1 mice. PTEC from B6 mice, the most commonly used inbred strain in senescence research, had a senescence score lower than PTEC from WSB and CAST mice but higher than PTEC from NZO and 129S1 mice. These data provide new information regarding the influence of genetic diversity and help explain heterogeneity in existing data. The observed differences should be considered when designing new experiments and will be the basis for further investigation with the goal of identifying candidate loci driving pro- or anti-senescent pathways. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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14 pages, 1343 KiB  
Article
Cellular Senescence and Vitamin D Deficiency Play a Role in the Pathogenesis of Obesity-Associated Subclinical Atherosclerosis: Study of the Potential Protective Role of Vitamin D Supplementation
by Abdulhadi I. Bima, Abdullah S. Mahdi, Fayza F. Al Fayez, Taghreed M. Khawaja, Salwa M. Abo El-Khair and Ayman Z. Elsamanoudy
Cells 2021, 10(4), 920; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040920 - 16 Apr 2021
Cited by 15 | Viewed by 2572
Abstract
The exact link between obesity, vitamin D deficiency, and their relation to cellular senescence in the pathogenesis of subclinical atherosclerosis is still under debate. Therefore, the current study aims to verify the possible role of vitamin D deficiency and cellular senescence in the [...] Read more.
The exact link between obesity, vitamin D deficiency, and their relation to cellular senescence in the pathogenesis of subclinical atherosclerosis is still under debate. Therefore, the current study aims to verify the possible role of vitamin D deficiency and cellular senescence in the pathogenesis of obesity-related subclinical atherosclerosis. Moreover, it aims to investigate the possible protective role of vitamin D supplementation. Fifty-seven male albino rats were enrolled in the study and classified into four groups: negative (10) and positive control groups (10), an obese model group (24), and a vitamin-D-supplemented obese group (13). Aortic tissue samples and fasting blood samples were collected. The following biochemical investigations were performed: serum cholesterol, triglycerides, HDL-C, LDL-C, ALT, AST, CPK, CK-MB, and hs-cTnt. HOMA-IR was calculated. Moreover, serum SMP-30, 25 (OH)Vitamin D3, and eNOS were determined by the ELISA technique. Aortic gene expression of eNOS, SMP-30, and P53 was estimated by real-time qRT-PCR. Serum 25(OH) D3 and SMP-30 were lower in the obese group. In addition, the obese group showed higher serum lipid profile, HOMA-IR, eNOS, ALT, AST, CPK, CK-MB, and hs-cTnt than the control groups, while decreased levels were found in the vitamin-D-treated obese group. Gene expression of eNOS and SMP-30 were in accordance with their serum levels. A positive correlation was found between vitamin D level and SMP-30. In conclusion, obesity is associated with vitamin D deficiency and enhanced cellular senescence. They could play a role in the pathogenesis of obesity-associated subclinical atherosclerosis and endothelial dysfunction. Vitamin D supplements could play a protective role against such obesity-related comorbidity. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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Graphical abstract

20 pages, 4221 KiB  
Article
The MAO Inhibitor Tranylcypromine Alters LPS- and Aβ-Mediated Neuroinflammatory Responses in Wild-type Mice and a Mouse Model of AD
by HyunHee Park, Kyung-Min Han, Hyongjun Jeon, Ji-Soo Lee, Hyunju Lee, Seong Gak Jeon, Jin-Hee Park, Yu Gyung Kim, Yuxi Lin, Young-Ho Lee, Yun Ha Jeong and Hyang-Sook Hoe
Cells 2020, 9(9), 1982; https://doi.org/10.3390/cells9091982 - 28 Aug 2020
Cited by 8 | Viewed by 3629
Abstract
Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate [...] Read more.
Monoamine oxidase (MAO) has been implicated in neuroinflammation, and therapies targeting MAO are of interest for neurodegenerative diseases. The small-molecule drug tranylcypromine, an inhibitor of MAO, is currently used as an antidepressant and in the treatment of cancer. However, whether tranylcypromine can regulate LPS- and/or Aβ-induced neuroinflammation in the brain has not been well-studied. In the present study, we found that tranylcypromine selectively altered LPS-induced proinflammatory cytokine levels in BV2 microglial cells but not primary astrocytes. In addition, tranylcypromine modulated LPS-mediated TLR4/ERK/STAT3 signaling to alter neuroinflammatory responses in BV2 microglial cells. Importantly, tranylcypromine significantly reduced microglial activation as well as proinflammatory cytokine levels in LPS-injected wild-type mice. Moreover, injection of tranylcypromine in 5xFAD mice (a mouse model of AD) significantly decreased microglial activation but had smaller effects on astrocyte activation. Taken together, our results suggest that tranylcypromine can suppress LPS- and Aβ-induced neuroinflammatory responses in vitro and in vivo. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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Review

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26 pages, 1604 KiB  
Review
Cellular Senescence in Adrenocortical Biology and Its Disorders
by Xin Gao, Faping Li, Bin Liu, Yuxiong Wang, Yishu Wang and Honglan Zhou
Cells 2021, 10(12), 3474; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123474 - 09 Dec 2021
Cited by 3 | Viewed by 3959
Abstract
Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. [...] Read more.
Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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11 pages, 2073 KiB  
Review
Pin1 as Molecular Switch in Vascular Endothelium: Notes on Its Putative Role in Age-Associated Vascular Diseases
by Francesca Fagiani, Marieva Vlachou, Daniele Di Marino, Ilaria Canobbio, Alice Romagnoli, Marco Racchi, Stefano Govoni and Cristina Lanni
Cells 2021, 10(12), 3287; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123287 - 24 Nov 2021
Cited by 3 | Viewed by 2541
Abstract
By controlling the change of the backbones of several cellular substrates, the peptidyl-prolyl cis-trans isomerase Pin1 acts as key fine-tuner and amplifier of multiple signaling pathways, thereby inducing several biological consequences, both in physiological and pathological conditions. Data from the literature indicate a [...] Read more.
By controlling the change of the backbones of several cellular substrates, the peptidyl-prolyl cis-trans isomerase Pin1 acts as key fine-tuner and amplifier of multiple signaling pathways, thereby inducing several biological consequences, both in physiological and pathological conditions. Data from the literature indicate a prominent role of Pin1 in the regulating of vascular homeostasis. In this review, we will critically dissect Pin1’s role as conformational switch regulating the homeostasis of vascular endothelium, by specifically modulating nitric oxide (NO) bioavailability. In this regard, Pin1 has been reported to directly control NO production by interacting with bovine endothelial nitric oxide synthase (eNOS) at Ser116-Pro117 (human equivalent is Ser114-Pro115) in a phosphorylation-dependent manner, regulating its catalytic activity, as well as by regulating other intracellular players, such as VEGF and TGF-β, thereby impinging upon NO release. Furthermore, since Pin1 has been found to act as a critical driver of vascular cell proliferation, apoptosis, and inflammation, with implication in many vascular diseases (e.g., diabetes, atherosclerosis, hypertension, and cardiac hypertrophy), evidence indicating that Pin1 may serve a pivotal role in vascular endothelium will be discussed. Understanding the role of Pin1 in vascular homeostasis is crucial in terms of finding a new possible therapeutic player and target in vascular pathologies, including those affecting the elderly (such as small and large vessel diseases and vascular dementia) or those promoting the full expression of neurodegenerative dementing diseases. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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25 pages, 2529 KiB  
Review
Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers
by Mirco Masi, Marco Racchi, Cristina Travelli, Emanuela Corsini and Erica Buoso
Cells 2021, 10(11), 2999; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112999 - 03 Nov 2021
Cited by 18 | Viewed by 4080
Abstract
Cancer is one of the most common causes of death worldwide, and its development is a result of the complex interaction of genetic factors, environmental cues, and aging. Hormone-sensitive cancers depend on the action of one or more hormones for their development and [...] Read more.
Cancer is one of the most common causes of death worldwide, and its development is a result of the complex interaction of genetic factors, environmental cues, and aging. Hormone-sensitive cancers depend on the action of one or more hormones for their development and progression. Sex steroids and corticosteroids can regulate different physiological functions, including metabolism, growth, and proliferation, through their interaction with specific nuclear receptors, that can transcriptionally regulate target genes via their genomic actions. Therefore, interference with hormones’ activities, e.g., deregulation of their production and downstream pathways or the exposition to exogenous hormone-active substances such as endocrine-disrupting chemicals (EDCs), can affect the regulation of their correlated pathways and trigger the neoplastic transformation. Although nuclear receptors account for most hormone-related biologic effects and their slow genomic responses are well-studied, less-known membrane receptors are emerging for their ability to mediate steroid hormones effects through the activation of rapid non-genomic responses also involved in the development of hormone-sensitive cancers. This review aims to collect pre-clinical and clinical data on these extranuclear receptors not only to draw attention to their emerging role in cancer development and progression but also to highlight their dual role as tumor microenvironment players and potential candidate drug targets. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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16 pages, 1717 KiB  
Review
Ocular Neurodegenerative Diseases: Interconnection between Retina and Cortical Areas
by Nicoletta Marchesi, Foroogh Fahmideh, Federica Boschi, Alessia Pascale and Annalisa Barbieri
Cells 2021, 10(9), 2394; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092394 - 12 Sep 2021
Cited by 55 | Viewed by 5440
Abstract
The possible interconnection between the eye and central nervous system (CNS) has been a topic of discussion for several years just based on fact that the eye is properly considered an extension of the brain. Both organs consist of neurons and derived from [...] Read more.
The possible interconnection between the eye and central nervous system (CNS) has been a topic of discussion for several years just based on fact that the eye is properly considered an extension of the brain. Both organs consist of neurons and derived from a neural tube. The visual process involves photoreceptors that receive light stimulus from the external environment and send it to retinal ganglionic cells (RGC), one of the cell types of which the retina is composed. The retina, the internal visual membrane of the eye, processes the visual stimuli in electric stimuli to transfer it to the brain, through the optic nerve. Retinal chronic progressive neurodegeneration, which may occur among the elderly, can lead to different disorders of the eye such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). Mainly in the elderly population, but also among younger people, such ocular pathologies are the cause of irreversible blindness or impaired, reduced vision. Typical neurodegenerative diseases of the CSN are a group of pathologies with common characteristics and etiology not fully understood; some risk factors have been identified, but they are not enough to justify all the cases observed. Furthermore, several studies have shown that also ocular disorders present characteristics of neurodegenerative diseases and, on the other hand, CNS pathologies, i.e., Alzheimer disease (AD) and Parkinson disease (PD), which are causes of morbidity and mortality worldwide, show peculiar alterations at the ocular level. The knowledge of possible correlations could help to understand the mechanisms of onset. Moreover, the underlying mechanisms of these heterogeneous disorders are still debated. This review discusses the characteristics of the ocular illnesses, focusing on the relationship between the eye and the brain. A better comprehension could help in future new therapies, thus reducing or avoiding loss of vision and improve quality of life. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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19 pages, 1843 KiB  
Review
Nano-Based Theranostic Tools for the Detection and Elimination of Senescent Cells
by Jagoda Adamczyk-Grochala and Anna Lewinska
Cells 2020, 9(12), 2659; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122659 - 10 Dec 2020
Cited by 12 | Viewed by 5548
Abstract
The progressive accumulation of apoptosis-resistant and secretory active senescent cells (SCs) in animal and human aged tissues may limit lifespan and healthspan and lead to age-related diseases such as cancer, neurodegenerative disorders, and metabolic syndrome. Thus, SCs are suggested targets in anti-aging therapy. [...] Read more.
The progressive accumulation of apoptosis-resistant and secretory active senescent cells (SCs) in animal and human aged tissues may limit lifespan and healthspan and lead to age-related diseases such as cancer, neurodegenerative disorders, and metabolic syndrome. Thus, SCs are suggested targets in anti-aging therapy. In the last two decades, a number of nanomaterials have gained much attention as innovative tools in theranostic applications due to their unique properties improving target visualization, drug and gene delivery, controlled drug release, effective diagnosis, and successful therapy. Although the healthcare industry has focused on a plethora of applications of nanomaterials, it remains elusive how nanomaterials may modulate cellular senescence, a hallmark of aging. In this review paper, we consider novel nanotechnology-based strategies for healthspan promotion and the prevention of age-related dysfunctions that are based on the delivery of therapeutic compounds capable to preferentially killing SCs (nano-senolytics) and/or modulating a proinflammatory secretome (nano-senomorphics/nano-senostatics). Recent examples of SC-targeted nanomaterials and the mechanisms underlying different aspects of the nanomaterial-mediated senolysis are presented and discussed. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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16 pages, 823 KiB  
Review
Cellular Senescence in Renal and Urinary Tract Disorders
by Yohan Santin, Philippe Lluel, Pascal Rischmann, Xavier Gamé, Jeanne Mialet-Perez and Angelo Parini
Cells 2020, 9(11), 2420; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112420 - 05 Nov 2020
Cited by 7 | Viewed by 3859
Abstract
Cellular senescence is a state of cell cycle arrest induced by repetitive cell mitoses or different stresses, which is implicated in various physiological or pathological processes. The beneficial or adverse effects of senescent cells depend on their transitory or persistent state. Transient senescence [...] Read more.
Cellular senescence is a state of cell cycle arrest induced by repetitive cell mitoses or different stresses, which is implicated in various physiological or pathological processes. The beneficial or adverse effects of senescent cells depend on their transitory or persistent state. Transient senescence has major beneficial roles promoting successful post-injury repair and inhibiting malignant transformation. On the other hand, persistent accumulation of senescent cells has been associated with chronic diseases and age-related illnesses like renal/urinary tract disorders. The deleterious effects of persistent senescent cells have been related, in part, to their senescence-associated secretory phenotype (SASP) characterized by the release of a variety of factors responsible for chronic inflammation, extracellular matrix adverse remodeling, and fibrosis. Recently, an increase in senescent cell burden has been reported in renal, prostate, and bladder disorders. In this review, we will summarize the molecular mechanisms of senescence and their implication in renal and urinary tract diseases. We will also discuss the differential impacts of transient versus persistent status of cellular senescence, as well as the therapeutic potential of senescent cell targeting in these diseases. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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Graphical abstract

31 pages, 2487 KiB  
Review
Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis
by Gisela Machado-Oliveira, Cristiano Ramos, André R. A. Marques and Otília V. Vieira
Cells 2020, 9(10), 2146; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102146 - 23 Sep 2020
Cited by 44 | Viewed by 6358
Abstract
Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive [...] Read more.
Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive structural and functional deterioration of cells, tissues and organs, is intricately linked to age-related diseases. Cell senescence involves coordinated modifications in cellular compartments and has been demonstrated to contribute to different stages of atheroma development. Senescence-based therapeutic strategies are currently being pursued to treat and prevent CVD in humans in the near-future. In addition, distinct experimental settings allowed researchers to unravel potential approaches to regulate anti-apoptotic pathways, facilitate excessive senescent cell clearance and eventually reverse atherogenesis to improve cardiovascular function. However, a deeper knowledge is required to fully understand cellular senescence, to clarify senescence and atherogenesis intertwining, allowing researchers to establish more effective treatments and to reduce the cardiovascular disorders’ burden. Here, we present an objective review of the key senescence-related alterations of the major intracellular organelles and analyze the role of relevant cell types for senescence and atherogenesis. In this context, we provide an updated analysis of therapeutic approaches, including clinically relevant experiments using senolytic drugs to counteract atherosclerosis. Full article
(This article belongs to the Special Issue Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions)
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