Controversies and Recent Advances in Senescence and Aging

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

Deadline for manuscript submissions: closed (1 May 2022) | Viewed by 78412

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Institute of Biology Valrose, University of Nice Sophia Antipolis, 06107 Nice, France
Interests: PPARs; cancer; development; angiogenesis; transcriptional regulation; tumor angiogenesis; mechanisms of tumor progression; cancer treatment
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Special Issue Information

Dear Colleagues,

Aging could be viewed as a gradual and continuous decline in the function of cells, tissues, or the whole organism resulting from genetic, external, and lifestyle-associated factors. Alternatively, aging might be perceived as dysregulation of “normal” developmental processes. Aging is the leading predictive factor of chronic diseases that account for most of the morbidity and mortality worldwide (e.g., neurodegeneration; cardiovascular, pulmonary, renal, and bone diseases; and cancers). Oxidative stress and reactive oxygen species generation, overproduction of inflammatory cytokines, activation of oncogenes, DNA damage, telomere shortening, and the accumulation of senescent cells are all widely accepted mechanisms contributing to aging. Senescence is mainly thought to be provoked by negative cellular stress, but might also be induced by physiological developmental stimuli. It was described 50 years ago in fibroblasts in culture, and is characterized as irreversible cell cycle arrest independent of quiescence and terminal differentiation. However, more recent observations suggest that the status of developmental and cancer senescent cells might not be irreversible. Aside from cell cycle arrest, senescent cells are characterized by morphological changes and molecular damage, metabolic alterations, and a specific secretory phenotype. The cyclin-dependent kinase inhibitors p16Ink4a, p19Arf, and p21Waf1/Cip1 have been implicated in senescence, but currently, no single marker is available to identify a cell as specifically senescent in vivo. One the one hand, senescent cells might contribute to embryonic tissue development and participate in tissue repair and tumor suppression. On the other hand they are involved in detrimental tissue decline during aging. Thus, the application of senolytic or senostatic drugs to halt or reverse age-related pathologies could represent an interesting therapeutic option. In several animal models, the elimination of senescent cells has been shown to promote healthy aging, while in a different model, the elimination of p16Ink4a-expressing cells resulted in the impairment of the health-span and liver disease. Given the pleiotropic actions of senescent cells, a deeper understanding is needed to develop further approaches and recommendations for healthy aging. All contributions shedding additional light and providing significant or provocative findings in these fascinating topics are welcome in this Special issue of Cells.

Dr. Nicole Wagner
Dr. Kay-Dietrich Wagner
Guest Editors

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Keywords

  • aging
  • senescence
  • development
  • senolytics/senostatics
  • p16Ink4a
  • p19Arf
  • p21Waf1/Cip1
  • SASP
  • tissue repair
  • tumor suppression

Published Papers (17 papers)

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Editorial

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6 pages, 234 KiB  
Editorial
Controversies and Recent Advances in Senescence and Aging
by Nicole Wagner and Kay-Dietrich Wagner
Cells 2023, 12(6), 902; https://doi.org/10.3390/cells12060902 - 15 Mar 2023
Viewed by 1481
Abstract
Aging is the leading predictive factor of many chronic diseases that account for most of the morbidity and mortality worldwide, i [...] Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)

Research

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19 pages, 2441 KiB  
Article
Short-Chain Fatty Acids Impair Neutrophil Antiviral Function in an Age-Dependent Manner
by Francisco J. Carrillo-Salinas, Siddharth Parthasarathy, Laura Moreno de Lara, Anna Borchers, Christina Ochsenbauer, Alexander Panda and Marta Rodriguez-Garcia
Cells 2022, 11(16), 2515; https://doi.org/10.3390/cells11162515 - 13 Aug 2022
Cited by 6 | Viewed by 2100
Abstract
Half of the people living with HIV are women. Younger women remain disproportionally affected in endemic areas, but infection rates in older women are rising worldwide. The vaginal microbiome influences genital inflammation and HIV infection risk. Multiple factors, including age, induce vaginal microbial [...] Read more.
Half of the people living with HIV are women. Younger women remain disproportionally affected in endemic areas, but infection rates in older women are rising worldwide. The vaginal microbiome influences genital inflammation and HIV infection risk. Multiple factors, including age, induce vaginal microbial alterations, characterized by high microbial diversity that generate high concentrations of short-chain fatty acids (SCFAs), known to modulate neutrophil function. However, how SCFAs may modulate innate anti-HIV protection by neutrophils is unknown. To investigate SCFA-mediated alterations of neutrophil function, blood neutrophils from younger and older women were treated with SCFAs (acetate, butyrate and propionate) at concentrations within the range reported during bacterial vaginosis, and phenotype, migration and anti-HIV responses were evaluated. SCFA induced phenotypical changes preferentially in neutrophils from older women. Butyrate decreased CD66b and increased CD16 and CD62L expression, indicating low activation and prolonged survival, while propionate increased CD54 and CXCR4 expression, indicating a mature aged phenotype. Furthermore, acetate and butyrate significantly inhibited neutrophil migration in vitro and specifically reduced α-defensin release in older women, molecules with anti-HIV activity. Following HIV stimulation, SCFA treatment delayed NET release and dampened chemokine secretion compared to untreated neutrophils in younger and older women. Our results demonstrate that SCFAs can impair neutrophil-mediated anti-HIV responses. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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10 pages, 962 KiB  
Article
Dual Oxidase, a Hydrogen-Peroxide-Producing Enzyme, Regulates Neuronal Oxidative Damage and Animal Lifespan in Drosophila melanogaster
by Minwoo Baek, Wijeong Jang and Changsoo Kim
Cells 2022, 11(13), 2059; https://doi.org/10.3390/cells11132059 - 29 Jun 2022
Cited by 2 | Viewed by 1780
Abstract
Reducing the oxidative stress in neurons extends lifespan in Drosophila melanogaster, highlighting the crucial role of neuronal oxidative damage in lifespan determination. However, the source of the reactive oxygen species (ROS) that provoke oxidative stress in neurons is not clearly defined. Here, [...] Read more.
Reducing the oxidative stress in neurons extends lifespan in Drosophila melanogaster, highlighting the crucial role of neuronal oxidative damage in lifespan determination. However, the source of the reactive oxygen species (ROS) that provoke oxidative stress in neurons is not clearly defined. Here, we identify dual oxidase (duox), a calcium-activated ROS-producing enzyme, as a lifespan determinant. Due to the lethality of duox homozygous mutants, we employed a duox heterozygote that exhibited normal appearance and movement. We found that duox heterozygous male flies, which were isogenized with control flies, demonstrated extended lifespan. Neuronal knockdown experiments further suggested that duox is crucial to oxidative stress in neurons. Our findings suggest duox to be a source of neuronal oxidative stress associated with animal lifespan. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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16 pages, 3225 KiB  
Article
Influences of Long-Term Exercise and High-Fat Diet on Age-Related Telomere Shortening in Rats
by Maria Donatella Semeraro, Gunter Almer, Wilfried Renner, Hans-Jürgen Gruber and Markus Herrmann
Cells 2022, 11(10), 1605; https://doi.org/10.3390/cells11101605 - 10 May 2022
Cited by 6 | Viewed by 1923
Abstract
(1) Obesity and exercise are believed to modify age-related telomere shortening by regulating telomerase and shelterins. Existing studies are inconsistent and limited to peripheral blood mononuclear cells (PBMCs) and selected solid tissues. (2) Female Sprague Dawley (SD) rats received either standard diet (ND) [...] Read more.
(1) Obesity and exercise are believed to modify age-related telomere shortening by regulating telomerase and shelterins. Existing studies are inconsistent and limited to peripheral blood mononuclear cells (PBMCs) and selected solid tissues. (2) Female Sprague Dawley (SD) rats received either standard diet (ND) or high-fat diet (HFD). For 10 months, half of the animals from both diet groups performed 30 min running at 30 cm/s on five consecutive days followed by two days of rest (exeND, exeHFD). The remaining animals served as sedentary controls (coND, coHFD). Relative telomere length (RTL) and mRNA expression of telomerase (TERT) and the shelterins TERF-1 and TERF-2 were mapped in PBMCs and nine solid tissues. (3) At study end, coND and coHFD animals showed comparable RTL in most tissues with no systematic differences in TERT, TERF-1 and TERF-2 expression. Only visceral fat of coHFD animals showed reduced RTL and lower expression of TERT, TERF-1 and TERF-2. Exercise had heterogeneous effects on RTL in exeND and exeHFD animals with longer telomeres in aorta and large intestine, but shorter telomeres in PBMCs and liver. Telomere-regulating genes showed inconsistent expression patterns. (4) In conclusion, regular exercise or HFD cannot systematically modify RTL by regulating the expression of telomerase and shelterins. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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13 pages, 10497 KiB  
Article
Multinucleated Retinal Pigment Epithelial Cells Adapt to Vision and Exhibit Increased DNA Damage Response
by Qin Ke, Lili Gong, Xingfei Zhu, Ruili Qi, Ming Zou, Baoxin Chen, Wei Liu, Shan Huang, Yizhi Liu and David Wan-Cheng Li
Cells 2022, 11(9), 1552; https://doi.org/10.3390/cells11091552 - 05 May 2022
Cited by 5 | Viewed by 2219
Abstract
Multinucleated retinal pigment epithelium (RPE) cells have been reported in humans and other mammals. Rodents have an extremely high percentage of multinucleated cells (more than 80%). Both mouse and human multinucleated RPE cells exhibit specific regional distributions that are potentially correlated with photoreceptor [...] Read more.
Multinucleated retinal pigment epithelium (RPE) cells have been reported in humans and other mammals. Rodents have an extremely high percentage of multinucleated cells (more than 80%). Both mouse and human multinucleated RPE cells exhibit specific regional distributions that are potentially correlated with photoreceptor density. However, detailed investigations of multinucleated RPE in different species and their behavior after DNA damage are missing. Here, we compared the composition of multinucleated RPE cells in nocturnal and diurnal animals that possess distinct rod and cone proportions. We further investigated the reactive oxygen species (ROS) production and DNA damage response in mouse mononucleated and multinucleated RPE cells and determined the effect of p53 dosage on the DNA damage response in these cells. Our results revealed an unrealized association between multinucleated RPE cells and nocturnal vision. In addition, we found multinucleated RPE cells exhibited increased ROS production and DNA damage after X-ray irradiation. Furthermore, haploinsufficiency of p53 led to increased DNA damage frequency after irradiation, and mononucleated RPE cells were more sensitive to a change in p53 dosage. In conclusion, this study provides novel information on in vivo PRE topography and the DNA damage response, which may reflect specific requirements for vision adaption and macular function. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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15 pages, 9441 KiB  
Article
Detection of Cellular Senescence in Human Primary Melanocytes and Malignant Melanoma Cells In Vitro
by Tom Zimmermann, Michaela Pommer, Viola Kluge, Chafia Chiheb, Susanne Muehlich and Anja-Katrin Bosserhoff
Cells 2022, 11(9), 1489; https://doi.org/10.3390/cells11091489 - 28 Apr 2022
Cited by 7 | Viewed by 2529
Abstract
Detection and quantification of senescent cells remain difficult due to variable phenotypes and the absence of highly specific and reliable biomarkers. It is therefore widely accepted to use a combination of multiple markers and cellular characteristics to define senescent cells in vitro. The [...] Read more.
Detection and quantification of senescent cells remain difficult due to variable phenotypes and the absence of highly specific and reliable biomarkers. It is therefore widely accepted to use a combination of multiple markers and cellular characteristics to define senescent cells in vitro. The exact choice of these markers is a subject of ongoing discussion and usually depends on objective reasons such as cell type and treatment conditions, as well as subjective considerations including feasibility and personal experience. This study aims to provide a comprehensive comparison of biomarkers and cellular characteristics used to detect senescence in melanocytic systems. Each marker was assessed in primary human melanocytes that overexpress mutant BRAFV600E, as it is commonly found in melanocytic nevi, and melanoma cells after treatment with the chemotherapeutic agent etoposide. The combined use of these two experimental settings is thought to allow profound conclusions on the choice of senescence biomarkers when working with melanocytic systems. Further, this study supports the development of standardized senescence detection and quantification by providing a comparative analysis that might also be helpful for other cell types and experimental conditions. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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17 pages, 2562 KiB  
Article
Natural Product Library Screens Identify Sanguinarine Chloride as a Potent Inhibitor of Telomerase Expression and Activity
by Siyu Yan, Song Lin, Kexin Chen, Shanshan Yin, Haoyue Peng, Nanshuo Cai, Wenbin Ma, Zhou Songyang and Yan Huang
Cells 2022, 11(9), 1485; https://doi.org/10.3390/cells11091485 - 28 Apr 2022
Cited by 8 | Viewed by 2163
Abstract
Reverse transcriptase hTERT is essential to telomerase function in stem cells, as well as in 85–90% of human cancers. Its high expression in stem cells or cancer cells has made telomerase/hTERT an attractive therapeutic target for anti-aging and anti-tumor applications. In this study, [...] Read more.
Reverse transcriptase hTERT is essential to telomerase function in stem cells, as well as in 85–90% of human cancers. Its high expression in stem cells or cancer cells has made telomerase/hTERT an attractive therapeutic target for anti-aging and anti-tumor applications. In this study, we screened a natural product library containing 800 compounds using an endogenous hTERT reporter. Eight candidates have been identified, in which sanguinarine chloride (SC) and brazilin (Braz) were selected due to their leading inhibition. SC could induce an acute and strong suppressive effect on the expression of hTERT and telomerase activity in multiple cancer cells, whereas Braz selectively inhibited telomerase in certain types of cancer cells. Remarkably, SC long-term treatment could cause telomere attrition and cell growth retardation, which lead to senescence features in cancer cells, such as the accumulation of senescence-associated β-galactosidase (SA-β-gal)-positive cells, the upregulation of p16/p21/p53 pathways and telomere dysfunction-induced foci (TIFs). Additionally, SC exhibited excellent capabilities of anti-tumorigenesis, both in vitro and in vivo. In the mechanism, the compound down-regulated several active transcription factors including p65, a subunit of NF-κB complex, and reintroducing p65 could alleviate its suppression of the hTERT/telomerase. Moreover, SC could directly bind hTERT and inhibit telomerase activity in vitro. In conclusion, we identified that SC not only down-regulates the hTERT gene’s expression, but also directly affects telomerase/hTERT. The dual function makes this compound an attractive drug candidate for anti-tumor therapy. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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20 pages, 40216 KiB  
Article
Dynamic Spatiotemporal Expression Pattern of the Senescence-Associated Factor p16Ink4a in Development and Aging
by Hasan Safwan-Zaiter, Nicole Wagner, Jean-François Michiels and Kay-Dietrich Wagner
Cells 2022, 11(3), 541; https://doi.org/10.3390/cells11030541 - 04 Feb 2022
Cited by 13 | Viewed by 3043
Abstract
A plethora of factors have been attributed to underly aging, including oxidative stress, telomere shortening and cellular senescence. Several studies have shown a significant role of the cyclin-dependent kinase inhibitor p16ink4a in senescence and aging. However, its expression in development has been less [...] Read more.
A plethora of factors have been attributed to underly aging, including oxidative stress, telomere shortening and cellular senescence. Several studies have shown a significant role of the cyclin-dependent kinase inhibitor p16ink4a in senescence and aging. However, its expression in development has been less well documented. Therefore, to further clarify a potential role of p16 in development and aging, we conducted a developmental expression study of p16, as well as of p19ARF and p21, and investigated their expression on the RNA level in brain, heart, liver, and kidney of mice at embryonic, postnatal, adult, and old ages. P16 expression was further assessed on the protein level by immunohistochemistry. Expression of p16 was highly dynamic in all organs in embryonic and postnatal stages and increased dramatically in old mice. Expression of p19 and p21 was less variable and increased to a moderate extent at old age. In addition, we observed a predominant expression of p16 mRNA and protein in liver endothelial cells versus non-endothelial cells of old mice, which suggests a functional role specifically in liver endothelium of old subjects. Thus, p16 dynamic spatiotemporal expression might implicate p16 in developmental and physiological processes in addition to its well-known function in the build-up of senescence. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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Review

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19 pages, 1217 KiB  
Review
Effects of Air Pollution on Cellular Senescence and Skin Aging
by Ines Martic, Pidder Jansen-Dürr and Maria Cavinato
Cells 2022, 11(14), 2220; https://doi.org/10.3390/cells11142220 - 17 Jul 2022
Cited by 24 | Viewed by 6689
Abstract
The human skin is exposed daily to different environmental factors such as air pollutants and ultraviolet (UV) light. Air pollution is considered a harmful environmental risk to human skin and is known to promote aging and inflammation of this tissue, leading to the [...] Read more.
The human skin is exposed daily to different environmental factors such as air pollutants and ultraviolet (UV) light. Air pollution is considered a harmful environmental risk to human skin and is known to promote aging and inflammation of this tissue, leading to the onset of skin disorders and to the appearance of wrinkles and pigmentation issues. Besides this, components of air pollution can interact synergistically with ultraviolet light and increase the impact of damage to the skin. However, little is known about the modulation of air pollution on cellular senescence in skin cells and how this can contribute to skin aging. In this review, we are summarizing the current state of knowledge about air pollution components, their involvement in the processes of cellular senescence and skin aging, as well as the current therapeutic and cosmetic interventions proposed to prevent or mitigate the effects of air pollution in the skin. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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20 pages, 1433 KiB  
Review
Age-Related Lysosomal Dysfunctions
by Lena Guerrero-Navarro, Pidder Jansen-Dürr and Maria Cavinato
Cells 2022, 11(12), 1977; https://doi.org/10.3390/cells11121977 - 20 Jun 2022
Cited by 10 | Viewed by 3712
Abstract
Organismal aging is normally accompanied by an increase in the number of senescent cells, growth-arrested metabolic active cells that affect normal tissue function. These cells present a series of characteristics that have been studied over the last few decades. The damage in cellular [...] Read more.
Organismal aging is normally accompanied by an increase in the number of senescent cells, growth-arrested metabolic active cells that affect normal tissue function. These cells present a series of characteristics that have been studied over the last few decades. The damage in cellular organelles disbalances the cellular homeostatic processes, altering the behavior of these cells. Lysosomal dysfunction is emerging as an important factor that could regulate the production of inflammatory molecules, metabolic cellular state, or mitochondrial function. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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26 pages, 879 KiB  
Review
The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis
by Kay-Dietrich Wagner and Nicole Wagner
Cells 2022, 11(12), 1966; https://doi.org/10.3390/cells11121966 - 19 Jun 2022
Cited by 31 | Viewed by 6071
Abstract
It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. [...] Read more.
It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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16 pages, 1766 KiB  
Review
Cellular Senescence in Aging Lungs and Diseases
by Arbi Aghali, Maunick Lefin Koloko Ngassie, Christina M. Pabelick and Y. S. Prakash
Cells 2022, 11(11), 1781; https://doi.org/10.3390/cells11111781 - 29 May 2022
Cited by 17 | Viewed by 4764
Abstract
Cellular senescence represents a state of irreversible cell cycle arrest occurring naturally or in response to exogenous stressors. Following the initial arrest, progressive phenotypic changes define conditions of cellular senescence. Understanding molecular mechanisms that drive senescence can help to recognize the importance of [...] Read more.
Cellular senescence represents a state of irreversible cell cycle arrest occurring naturally or in response to exogenous stressors. Following the initial arrest, progressive phenotypic changes define conditions of cellular senescence. Understanding molecular mechanisms that drive senescence can help to recognize the importance of such pathways in lung health and disease. There is increasing interest in the role of cellular senescence in conditions such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) in the context of understanding pathophysiology and identification of novel therapies. Herein, we discuss the current knowledge of molecular mechanisms and mitochondrial dysfunction regulating different aspects of cellular senescence-related to chronic lung diseases to develop rational strategies for modulating the senescent cell phenotype in the lung for therapeutic benefit. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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25 pages, 883 KiB  
Review
Induction of Accelerated Aging in a Mouse Model
by Nanshuo Cai, Yifan Wu and Yan Huang
Cells 2022, 11(9), 1418; https://doi.org/10.3390/cells11091418 - 22 Apr 2022
Cited by 15 | Viewed by 8319
Abstract
With the global increase of the elderly population, the improvement of the treatment for various aging-related diseases and the extension of a healthy lifespan have become some of the most important current medical issues. In order to understand the developmental mechanisms of aging [...] Read more.
With the global increase of the elderly population, the improvement of the treatment for various aging-related diseases and the extension of a healthy lifespan have become some of the most important current medical issues. In order to understand the developmental mechanisms of aging and aging-related disorders, animal models are essential to conduct relevant studies. Among them, mice have become one of the most prevalently used model animals for aging-related studies due to their high similarity to humans in terms of genetic background and physiological structure, as well as their short lifespan and ease of reproduction. This review will discuss some of the common and emerging mouse models of accelerated aging and related chronic diseases in recent years, with the aim of serving as a reference for future application in fundamental and translational research. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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14 pages, 1384 KiB  
Review
Pyroptosis and Sarcopenia: Frontier Perspective of Disease Mechanism
by Hongfu Jin, Wenqing Xie, Miao He, Hengzhen Li, Wenfeng Xiao and Yusheng Li
Cells 2022, 11(7), 1078; https://doi.org/10.3390/cells11071078 - 23 Mar 2022
Cited by 16 | Viewed by 4337
Abstract
With global ageing, sarcopenia, as an age-related disease, has brought a heavy burden to individuals and society. Increasing attention has been given to further exploring the morbidity mechanism and intervention measures for sarcopenia. Pyroptosis, also known as cellular inflammatory necrosis, is a kind [...] Read more.
With global ageing, sarcopenia, as an age-related disease, has brought a heavy burden to individuals and society. Increasing attention has been given to further exploring the morbidity mechanism and intervention measures for sarcopenia. Pyroptosis, also known as cellular inflammatory necrosis, is a kind of regulated cell death that plays a role in the ageing progress at the cellular level. It is closely related to age-related diseases such as cardiovascular diseases, Alzheimer’s disease, osteoarthritis, and sarcopenia. In the process of ageing, aggravated oxidative stress and poor skeletal muscle perfusion in ageing muscle tissues can activate the nod-like receptor (NLRP) family to trigger pyroptosis. Chronic inflammation is a representative characteristic of ageing. The levels of inflammatory factors such as TNF-α may activate the signaling pathways of pyroptosis by the NF-κB-GSDMD axis, which remains to be further studied. Autophagy is a protective mechanism in maintaining the integrity of intracellular organelles and the survival of cells in adverse conditions. The autophagy of skeletal muscle cells can inhibit the activation of the pyroptosis pathway to some extent. A profound understanding of the mechanism of pyroptosis in sarcopenia may help to identify new therapeutic targets in the future. This review article focuses on the role of pyroptosis in the development and progression of sarcopenia. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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25 pages, 1132 KiB  
Review
Aging of the Immune System: Focus on Natural Killer Cells Phenotype and Functions
by Ashley Brauning, Michael Rae, Gina Zhu, Elena Fulton, Tesfahun Dessale Admasu, Alexandra Stolzing and Amit Sharma
Cells 2022, 11(6), 1017; https://doi.org/10.3390/cells11061017 - 17 Mar 2022
Cited by 49 | Viewed by 10762
Abstract
Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer’s and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its [...] Read more.
Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer’s and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease. One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging (“inflammaging”). NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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23 pages, 2159 KiB  
Review
Molecular Mechanisms of Alveolar Epithelial Stem Cell Senescence and Senescence-Associated Differentiation Disorders in Pulmonary Fibrosis
by Xiaojing Hong, Lihui Wang, Kexiong Zhang, Jun Liu and Jun-Ping Liu
Cells 2022, 11(5), 877; https://doi.org/10.3390/cells11050877 - 03 Mar 2022
Cited by 13 | Viewed by 4808
Abstract
Pulmonary senescence is accelerated by unresolved DNA damage response, underpinning susceptibility to pulmonary fibrosis. Recently it was reported that the SARS-Cov-2 viral infection induces acute pulmonary epithelial senescence followed by fibrosis, although the mechanism remains unclear. Here, we examine roles of alveolar epithelial [...] Read more.
Pulmonary senescence is accelerated by unresolved DNA damage response, underpinning susceptibility to pulmonary fibrosis. Recently it was reported that the SARS-Cov-2 viral infection induces acute pulmonary epithelial senescence followed by fibrosis, although the mechanism remains unclear. Here, we examine roles of alveolar epithelial stem cell senescence and senescence-associated differentiation disorders in pulmonary fibrosis, exploring the mechanisms mediating and preventing pulmonary fibrogenic crisis. Notably, the TGF-β signalling pathway mediates alveolar epithelial stem cell senescence by mechanisms involving suppression of the telomerase reverse transcriptase gene in pulmonary fibrosis. Alternatively, telomere uncapping caused by stress-induced telomeric shelterin protein TPP1 degradation mediates DNA damage response, pulmonary senescence and fibrosis. However, targeted intervention of cellular senescence disrupts pulmonary remodelling and fibrosis by clearing senescent cells using senolytics or preventing senescence using telomere dysfunction inhibitor (TELODIN). Studies indicate that the development of senescence-associated differentiation disorders is reprogrammable and reversible by inhibiting stem cell replicative senescence in pulmonary fibrosis, providing a framework for targeted intervention of the molecular mechanisms of alveolar stem cell senescence and pulmonary fibrosis. Abbreviations: DPS, developmental programmed senescence; IPF, idiopathic pulmonary fibrosis; OIS, oncogene-induced replicative senescence; SADD, senescence-associated differentiation disorder; SALI, senescence-associated low-grade inflammation; SIPS, stress-induced premature senescence; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TIFs, telomere dysfunction-induced foci; TIS, therapy-induced senescence; VIS, virus-induced senescence. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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20 pages, 1676 KiB  
Review
Synergistic Anti-Ageing through Senescent Cells Specific Reprogramming
by Rui Chen and Thomas Skutella
Cells 2022, 11(5), 830; https://doi.org/10.3390/cells11050830 - 28 Feb 2022
Cited by 7 | Viewed by 9511
Abstract
In this review, we seek a novel strategy for establishing a rejuvenating microenvironment through senescent cells specific reprogramming. We suggest that partial reprogramming can produce a secretory phenotype that facilitates cellular rejuvenation. This strategy is desired for specific partial reprogramming under control to [...] Read more.
In this review, we seek a novel strategy for establishing a rejuvenating microenvironment through senescent cells specific reprogramming. We suggest that partial reprogramming can produce a secretory phenotype that facilitates cellular rejuvenation. This strategy is desired for specific partial reprogramming under control to avoid tumour risk and organ failure due to loss of cellular identity. It also alleviates the chronic inflammatory state associated with ageing and secondary senescence in adjacent cells by improving the senescence-associated secretory phenotype. This manuscript also hopes to explore whether intervening in cellular senescence can improve ageing and promote damage repair, in general, to increase people’s healthy lifespan and reduce frailty. Feasible and safe clinical translational protocols are critical in rejuvenation by controlled reprogramming advances. This review discusses the limitations and controversies of these advances’ application (while organizing the manuscript according to potential clinical translation schemes) to explore directions and hypotheses that have translational value for subsequent research. Full article
(This article belongs to the Special Issue Controversies and Recent Advances in Senescence and Aging)
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