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Aging and Senescence 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (24 March 2022) | Viewed by 78184

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Prof. Dr. Umberto Galderisi

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Department of Experimental Medicine, Luigi Vanvitelli Campania University, 80138 Naples, Italy
Interests: stem cell; MUSE cells; cellular biology
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Prof. Dr. Giovanni Di Bernardo

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Guest Editor

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

Special Issue Information

Dear Colleagues,

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

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

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

Prof. Dr. Umberto Galderisi
Prof. Dr. Giovanni Di Bernardo
Guest Editors

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Keywords

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

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Published Papers (11 papers)

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Research

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11 pages, 1544 KiB

Open AccessArticle

Long Non-Coding RNA KCNQ1OT1 Regulates Protein Kinase CK2 Via miR-760 in Senescence and Calorie Restriction

by Yoonsung Lee and Young-Seuk Bae

Int. J. Mol. Sci. 2022, 23(3), 1888; https://doi.org/10.3390/ijms23031888 - 8 Feb 2022

Cited by 5 | Viewed by 2496

Abstract

Long non-coding RNAs (lncRNAs) play important biological roles. Here, the roles of the lncRNA KCNQ1OT1 in cellular senescence and calorie restriction were determined. KCNQ1OT1 knockdown mediated various senescence markers (increased senescence-associated β-galactosidase staining, the p53-p21^Cip1/WAF1 pathway, H3K9 trimethylation, and expression of the senescence-associated secretory phenotype) and reactive oxygen species generation via CK2α downregulation in human cancer HCT116 and MCF-7 cells. Additionally, KCNQ1OT1 was downregulated during replicative senescence, and its silencing induced senescence in human lung fibroblast IMR-90 cells. Additionally, an miR-760 mimic suppressed KCNQ1OT1-mediated CK2α upregulation, indicating that KCNQ1OT1 upregulated CK2α by sponging miR-760. Finally, the KCNQ1OT1–miR-760 axis was involved in both lipopolysaccharide-mediated CK2α reduction and calorie restriction (CR)-mediated CK2α induction in these cells. Therefore, for the first time, this study demonstrates that the KCNQ1OT1–miR-760–CK2α pathway plays essential roles in senescence and CR, thereby suggesting that KCNQ1OT1 is a novel therapeutic target for an alternative treatment that mimics the effects of anti-aging and CR. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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15 pages, 2879 KiB

Open AccessArticle

Human MSC-Derived Exosomes Reduce Cellular Senescence in Renal Epithelial Cells

by Chieh Ming Liao, Tianjiao Luo, Juliane von der Ohe, Blanca de Juan Mora, Roland Schmitt and Ralf Hass

Int. J. Mol. Sci. 2021, 22(24), 13562; https://doi.org/10.3390/ijms222413562 - 17 Dec 2021

Cited by 29 | Viewed by 5020

Abstract

Cellular senescence of renal tubular cells is associated with chronic diseases and age-related kidney disorders. Therapies to antagonize senescence are, therefore, explored as novel approaches in nephropathy. Exosomes derived from human mesenchymal stroma-/stem-like cells (MSC) entail the transfer of multiple bioactive molecules, exhibiting profound regenerative potential in various tissues, including therapeutic effects in kidney diseases. Here, we first demonstrate that exosomes promote proliferation and reduce senescence in aged MSC cultures. For potential therapeutic perspectives in organ rejuvenation, we used MSC-derived exosomes to antagonize senescence in murine kidney primary tubular epithelial cells (PTEC). Exosome treatment efficiently reduced senescence while diminishing the transcription of senescence markers and senescence-associated secretory phenotype (SASP) factors. Concomitantly, we observed less DNA damage foci and more proliferating cells. These data provide new information regarding the therapeutic property of MSC exosomes in the development of renal senescence, suggesting a contribution to a new chapter of regenerative vehicles in senotherapy. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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13 pages, 3504 KiB

Open AccessArticle

Senolytic Therapy for Cerebral Ischemia-Reperfusion Injury

by Songhyun Lim, Tae Jung Kim, Young-Ju Kim, Cheesue Kim, Sang-Bae Ko and Byung-Soo Kim

Int. J. Mol. Sci. 2021, 22(21), 11967; https://doi.org/10.3390/ijms222111967 - 4 Nov 2021

Cited by 48 | Viewed by 5310

Abstract

Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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20 pages, 3807 KiB

Open AccessArticle

Induction of Premature Cell Senescence Stimulated by High Doses of Antioxidants Is Mediated by Endoplasmic Reticulum Stress

by Olga Lyublinskaya, Julia Kornienko, Julia Ivanova, Natalia Pugovkina, Larisa Alekseenko, Ekaterina Lyublinskaya, Irina Tyuryaeva, Irina Smirnova, Tatiana Grinchuk, Mariia Shorokhova, Anna Krasnenko, Nikolay Plotnikov and Nikolay Nikolsky

Int. J. Mol. Sci. 2021, 22(21), 11851; https://doi.org/10.3390/ijms222111851 - 31 Oct 2021

Cited by 7 | Viewed by 2773

Abstract

In our previous study, we found that high doses of several substances with antioxidant capacities (Tempol, resveratrol, diphenyleneiodonium) can cause genotoxic stress and induce premature senescence in the human mesenchymal stem cells (MSCs). Here, using whole-transcriptome analysis, we revealed the signs of endoplasmic reticulum stress and unfolded protein response (UPR) in MSCs stressed with Tempol and resveratrol. In addition, we found the upregulation of genes, coding the UPR downstream target APC/C, and E3 ubiquitin ligase that regulate the stability of cell cycle proteins. We performed the molecular analysis, which further confirmed the untimely degradation of APC/C targets (cyclin A, geminin, and Emi1) in MSCs treated with antioxidants. Human fibroblasts responded to antioxidant applications similarly. We conclude that endoplasmic reticulum stress and impaired DNA synthesis regulation can be considered as potential triggers of cell damage and premature senescence stimulated by high-dose antioxidant treatments. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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13 pages, 2870 KiB

Open AccessArticle

Biomolecular Evaluation of Piceatannol’s Effects in Counteracting the Senescence of Mesenchymal Stromal Cells: A New Candidate for Senotherapeutics?

by Nicola Alessio, Tiziana Squillaro, Ida Lettiero, Giovanni Galano, Roberto De Rosa, Gianfranco Peluso, Umberto Galderisi and Giovanni Di Bernardo

Int. J. Mol. Sci. 2021, 22(21), 11619; https://doi.org/10.3390/ijms222111619 - 27 Oct 2021

Cited by 10 | Viewed by 2353

Abstract

Several investigations on senescence and its causative role in aging have underscored the importance of developing senotherapeutics, a field focused on killing senescent cells and/or preventing their accumulation within tissues. Using polyphenols in counteracting senescence may facilitate the development of senotherapeutics given their presence in the human diet, their confirmed tolerability and absence of severe side effects, and their role in preventing senescence and inducing the death of senescent cells. Against that background, we evaluated the effect of piceatannol, a natural polyphenol, on the senescence of mesenchymal stromal cells (MSCs), which play a key role in the body’s homeostasis. Among our results, piceatannol reduced the number of senescent cells both after genotoxic stress that induced acute senescence and in senescent replicative cultures. Such senotherapeutics activity, moreover, promoted the recovery of cell proliferation and the stemness properties of MSCs. Altogether, our findings demonstrate piceatannol’s effectiveness in counteracting senescence by targeting its associated pathways and detecting and affecting P53-dependent and P53-independent senescence. Our study thus suggests that, given piceatannol’s various mechanisms to accomplish its pleiotropic activities, it may be able to counteract any senescent phenotypes. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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Review

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18 pages, 1370 KiB

Open AccessReview

Blood–Brain Barrier Dysfunction and Astrocyte Senescence as Reciprocal Drivers of Neuropathology in Aging

by Marcela K. Preininger and Daniela Kaufer

Int. J. Mol. Sci. 2022, 23(11), 6217; https://doi.org/10.3390/ijms23116217 - 1 Jun 2022

Cited by 34 | Viewed by 5109

Abstract

As the most abundant cell types in the brain, astrocytes form a tissue-wide signaling network that is responsible for maintaining brain homeostasis and regulating various brain activities. Here, we review some of the essential functions that astrocytes perform in supporting neurons, modulating the immune response, and regulating and maintaining the blood–brain barrier (BBB). Given their importance in brain health, it follows that astrocyte dysfunction has detrimental effects. Indeed, dysfunctional astrocytes are implicated in age-related neuropathology and participate in the onset and progression of neurodegenerative diseases. Here, we review two mechanisms by which astrocytes mediate neuropathology in the aging brain. First, age-associated blood–brain barrier dysfunction (BBBD) causes the hyperactivation of TGFβ signaling in astrocytes, which elicits a pro-inflammatory and epileptogenic phenotype. Over time, BBBD-associated astrocyte dysfunction results in hippocampal and cortical neural hyperexcitability and cognitive deficits. Second, senescent astrocytes accumulate in the brain with age and exhibit a decreased functional capacity and the secretion of senescent-associated secretory phenotype (SASP) factors, which contribute to neuroinflammation and neurotoxicity. Both BBBD and senescence progressively increase during aging and are associated with increased risk of neurodegenerative disease, but the relationship between the two has not yet been established. Thus, we discuss the potential relationship between BBBD, TGFβ hyperactivation, and senescence with respect to astrocytes in the context of aging and disease and identify future areas of investigation in the field. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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26 pages, 1571 KiB

Open AccessReview

Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs

by Natalie Kudlova, Juan Bautista De Sanctis and Marian Hajduch

Int. J. Mol. Sci. 2022, 23(8), 4168; https://doi.org/10.3390/ijms23084168 - 10 Apr 2022

Cited by 54 | Viewed by 13959

Abstract

Cellular senescence is defined as irreversible cell cycle arrest caused by various processes that render viable cells non-functional, hampering normal tissue homeostasis. It has many endogenous and exogenous inducers, and is closely connected with age, age-related pathologies, DNA damage, degenerative disorders, tumor suppression and activation, wound healing, and tissue repair. However, the literature is replete with contradictory findings concerning its triggering mechanisms, specific biomarkers, and detection protocols. This may be partly due to the wide range of cellular and in vivo animal or human models of accelerated aging that have been used to study senescence and test senolytic drugs. This review summarizes recent findings concerning senescence, presents some widely used cellular and animal senescence models, and briefly describes the best-known senolytic agents. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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31 pages, 2939 KiB

Open AccessReview

Cell Senescence and Central Regulators of Immune Response

by Sergey M. Lunin, Elena G. Novoselova, Olga V. Glushkova, Svetlana B. Parfenyuk, Tatyana V. Novoselova and Maxim O. Khrenov

Int. J. Mol. Sci. 2022, 23(8), 4109; https://doi.org/10.3390/ijms23084109 - 7 Apr 2022

Cited by 9 | Viewed by 4329

Abstract

Pathways regulating cell senescence and cell cycle underlie many processes associated with ageing and age-related pathologies, and they also mediate cellular responses to exposure to stressors. Meanwhile, there are central mechanisms of the regulation of stress responses that induce/enhance or weaken the response of the whole organism, such as hormones of the hypothalamic–pituitary–adrenal (HPA) axis, sympathetic and parasympathetic systems, thymic hormones, and the pineal hormone melatonin. Although there are many analyses considering relationships between the HPA axis and organism ageing, we found no systematic analyses of relationships between the neuroendocrine regulators of stress and inflammation and intracellular mechanisms controlling cell cycle, senescence, and apoptosis. Here, we provide a review of the effects of neuroendocrine regulators on these mechanisms. Our analysis allowed us to postulate a multilevel system of central regulators involving neurotransmitters, glucocorticoids, melatonin, and the thymic hormones. This system finely regulates the cell cycle and metabolic/catabolic processes depending on the level of systemic stress, stage of stress response, and energy capabilities of the body, shifting the balance between cell cycle progression, cell cycle stopping, senescence, and apoptosis. These processes and levels of regulation should be considered when studying the mechanisms of ageing and the proliferation on the level of the whole organism. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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17 pages, 4795 KiB

Open AccessReview

Flavonoids—Natural Gifts to Promote Health and Longevity

by Xiaolan Fan, Ziqiang Fan, Ziyue Yang, Tiantian Huang, Yingdong Tong, Deying Yang, Xueping Mao and Mingyao Yang

Int. J. Mol. Sci. 2022, 23(4), 2176; https://doi.org/10.3390/ijms23042176 - 16 Feb 2022

Cited by 63 | Viewed by 5739

Abstract

The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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27 pages, 1862 KiB

Open AccessReview

Genes and Longevity of Lifespan

by May Nasser Bin-Jumah, Muhammad Shahid Nadeem, Sadaf Jamal Gilani, Fahad A. Al-Abbasi, Inam Ullah, Sami I. Alzarea, Mohammed M. Ghoneim, Sultan Alshehri, Aziz Uddin, Bibi Nazia Murtaza and Imran Kazmi

Int. J. Mol. Sci. 2022, 23(3), 1499; https://doi.org/10.3390/ijms23031499 - 28 Jan 2022

Cited by 23 | Viewed by 9471

Abstract

Aging is a complex process indicated by low energy levels, declined physiological activity, stress induced loss of homeostasis leading to the risk of diseases and mortality. Recent developments in medical sciences and an increased availability of nutritional requirements has significantly increased the average human lifespan worldwide. Several environmental and physiological factors contribute to the aging process. However, about 40% human life expectancy is inherited among generations, many lifespan associated genes, genetic mechanisms and pathways have been demonstrated during last decades. In the present review, we have evaluated many human genes and their non-human orthologs established for their role in the regulation of lifespan. The study has included more than fifty genes reported in the literature for their contributions to the longevity of life. Intact genomic DNA is essential for the life activities at the level of cell, tissue, and organ. Nucleic acids are vulnerable to oxidative stress, chemotherapies, and exposure to radiations. Efficient DNA repair mechanisms are essential for the maintenance of genomic integrity, damaged DNA is not replicated and transferred to next generations rather the presence of deleterious DNA initiates signaling cascades leading to the cell cycle arrest or apoptosis. DNA modifications, DNA methylation, histone methylation, histone acetylation and DNA damage can eventually lead towards apoptosis. The importance of calorie restriction therapy in the extension of lifespan has also been discussed. The role of pathways involved in the regulation of lifespan such as DAF-16/FOXO (forkhead box protein O1), TOR and JNK pathways has also been particularized. The study provides an updated account of genetic factors associated with the extended lifespan and their interactive contributory role with cellular pathways. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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42 pages, 987 KiB

Open AccessReview

Mechanisms and Regulation of Cellular Senescence

by Lauréline Roger, Fanny Tomas and Véronique Gire

Int. J. Mol. Sci. 2021, 22(23), 13173; https://doi.org/10.3390/ijms222313173 - 6 Dec 2021

Cited by 152 | Viewed by 19718

Abstract

Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state. Full article

(This article belongs to the Special Issue Aging and Senescence 2.0)

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