Diverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics

Frontiers in Pharmacology ◽

10.3389/fphar.2021.739510 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuki Saito ◽

Takako S. Chikenji

Keyword(s):

Skeletal Muscle ◽

Cellular Senescence ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Neuromuscular Disorders ◽

Muscle Stem Cells ◽

Related Disease ◽

Tissue Degeneration ◽

Cycle Arrest ◽

Age Related

Skeletal muscle undergoes vigorous tissue remodeling after injury. However, aging, chronic inflammatory diseases, sarcopenia, and neuromuscular disorders cause muscle loss and degeneration, resulting in muscular dysfunction. Cellular senescence, a state of irreversible cell cycle arrest, acts during normal embryonic development and remodeling after tissue damage; when these processes are complete, the senescent cells are eliminated. However, the accumulation of senescent cells is a hallmark of aging tissues or pathological contexts and may lead to progressive tissue degeneration. The mechanisms responsible for the effects of senescent cells have not been fully elucidated. Here, we review current knowledge about the beneficial and detrimental effects of senescent cells in tissue repair, regeneration, aging, and age-related disease, especially in skeletal muscle. We also discuss how senescence of muscle stem cells and muscle-resident fibro-adipogenic progenitors affects muscle pathologies or regeneration, and consider the possibility that immunosenescence leads to muscle pathogenesis. Finally, we explore senotherapy, the therapeutic targeting of senescence to treat age-related disease, from the standpoint of improving muscle regeneration.

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Cellular Senescence in the Lung: The Central Role of Senescent Epithelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21093279 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3279 ◽

Cited By ~ 2

Author(s):

Christine Hansel ◽

Verena Jendrossek ◽

Diana Klein

Keyword(s):

Cell Cycle ◽

Cellular Senescence ◽

Inflammatory Diseases ◽

Cancer Tissue ◽

Gene Expressions ◽

Proliferating Cells ◽

Differentiated Cells ◽

Tissue Degeneration ◽

Age Related

Cellular senescence is a key process in physiological dysfunction developing upon aging or following diverse stressors including ionizing radiation. It describes the state of a permanent cell cycle arrest, in which proliferating cells become resistant to growth-stimulating factors. Senescent cells differ from quiescent cells, which can re-enter the cell cycle and from finally differentiated cells: morphological and metabolic changes, restructuring of chromatin, changes in gene expressions and the appropriation of an inflammation-promoting phenotype, called the senescence-associated secretory phenotype (SASP), characterize cellular senescence. The biological role of senescence is complex, since both protective and harmful effects have been described for senescent cells. While initially described as a mechanism to avoid malignant transformation of damaged cells, senescence can even contribute to many age-related diseases, including cancer, tissue degeneration, and inflammatory diseases, particularly when senescent cells persist in damaged tissues. Due to overwhelming evidence about the important contribution of cellular senescence to the pathogenesis of different lung diseases, specific targeting of senescent cells or of pathology-promoting SASP factors has been suggested as a potential therapeutic approach. In this review, we summarize recent advances regarding the role of cellular (fibroblastic, endothelial, and epithelial) senescence in lung pathologies, with a focus on radiation-induced senescence. Among the different cells here, a central role of epithelial senescence is suggested.

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Role of Age-Related Mitochondrial Dysfunction in Sarcopenia

International Journal of Molecular Sciences ◽

10.3390/ijms21155236 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5236 ◽

Cited By ~ 1

Author(s):

Evelyn Ferri ◽

Emanuele Marzetti ◽

Riccardo Calvani ◽

Anna Picca ◽

Matteo Cesari ◽

...

Keyword(s):

Skeletal Muscle ◽

Cellular Senescence ◽

Significant Loss ◽

Muscle Aging ◽

Age Related ◽

Mitochondrial Functions ◽

Health Quality ◽

Skeletal Muscle Aging ◽

And Function

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.

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Cellular Aging Characteristics and Their Association with Age-Related Disorders

Antioxidants ◽

10.3390/antiox9020094 ◽

2020 ◽

Vol 9 (2) ◽

pp. 94 ◽

Cited By ~ 8

Author(s):

Magdalena Rudzińska ◽

Alessandro Parodi ◽

Anastasia V. Balakireva ◽

Olga E. Chepikova ◽

Franco M. Venanzi ◽

...

Keyword(s):

Oxidative Stress ◽

Cellular Senescence ◽

Current Knowledge ◽

Cell Metabolism ◽

Critical Role ◽

Cellular Aging ◽

Molecular Signaling ◽

Age Related ◽

Organelle Communication ◽

Metabolic Dysfunctions

Different molecular signaling pathways, biological processes, and intercellular communication mechanisms control longevity and are affected during cellular senescence. Recent data have suggested that organelle communication, as well as genomic and metabolic dysfunctions, contribute to this phenomenon. Oxidative stress plays a critical role by inducing structural modifications to biological molecules while affecting their function and catabolism and eventually contributing to the onset of age-related dysfunctions. In this scenario, proteins are not adequately degraded and accumulate in the cell cytoplasm as toxic aggregates, increasing cell senescence progression. In particular, carbonylation, defined as a chemical reaction that covalently and irreversibly modifies proteins with carbonyl groups, is considered to be a significant indicator of protein oxidative stress and aging. Here, we emphasize the role and dysregulation of the molecular pathways controlling cell metabolism and proteostasis, the complexity of the mechanisms that occur during aging, and their association with various age-related disorders. The last segment of the review details current knowledge on protein carbonylation as a biomarker of cellular senescence in the development of diagnostics and therapeutics for age-related dysfunctions.

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Cellular senescence contributes to radiation-induced hyposalivation by affecting the stem/progenitor cell niche

Cell Death and Disease ◽

10.1038/s41419-020-03074-9 ◽

2020 ◽

Vol 11 (10) ◽

Cited By ~ 3

Author(s):

Xiaohong Peng ◽

Yi Wu ◽

Uilke Brouwer ◽

Thijmen van Vliet ◽

Boshi Wang ◽

...

Keyword(s):

Salivary Gland ◽

Cellular Senescence ◽

Progenitor Cell ◽

Tissue Degeneration ◽

Cycle Arrest ◽

Radiation Induced ◽

Secretory Phenotype ◽

Cell Niche ◽

Gland Function ◽

Formation Efficiency

Abstract Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.

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Transcriptional Reprogramming of Skeletal Muscle Stem Cells by the Niche Environment

10.1101/2021.05.25.445621 ◽

2021 ◽

Author(s):

Felicia Lazure ◽

Rick Farouni ◽

Korin Sahinyan ◽

Darren M. Blackburn ◽

Aldo Hernandez-Corchado ◽

...

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Tissue Regeneration ◽

Adult Stem Cells ◽

Cell Function ◽

Chromatin Accessibility ◽

Muscle Stem Cells ◽

Age Related ◽

A Genome ◽

Skeletal Muscle Stem Cells

Adult stem cells are indispensable for tissue regeneration. Tissue-specific stem cells reside in a specialized location called their niche, where they are in constant cross talk with neighboring niche cells and circulatory signals from their environment. Aging has a detrimental effect on the number and the regenerative function of various stem cells. However, whether the loss of stem cell function is a cause or consequence of their aging niche is unclear. Using skeletal muscle stem cells (MuSCs) as a model, we decouple cell-intrinsic from niche-mediated extrinsic effects of aging on their transcriptome. By combining in vivo MuSC heterochronic transplantation models and computational methods, we show that on a genome-wide scale, age-related altered genes fall into two distinct categories regarding their response to the niche environment. Genes that are inelastic in their response to the niche exhibit altered chromatin accessibility and are associated with differentially methylated regions (DMRs) between young and aged cells. On the other hand, genes that are restorable by niche exposure exhibit altered transcriptome but show no change in chromatin accessibility or DMRs. Taken together, our data suggest that the niche environment plays a decisive role in controlling the transcriptional activity of MuSCs, and exposure to a young niche can reverse approximately half of all age-associated changes that are not epigenetically encoded. The muscle niche therefore serves as an important therapeutic venue to mitigate the negative consequence of aging on tissue regeneration.

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Insights from In Vivo Studies of Cellular Senescence

Cells ◽

10.3390/cells9040954 ◽

2020 ◽

Vol 9 (4) ◽

pp. 954

Author(s):

Luis I. Prieto ◽

Sara I. Graves ◽

Darren J. Baker

Keyword(s):

Cellular Senescence ◽

Cell Biology ◽

Senescent Cell ◽

In Vivo Studies ◽

Cycle Arrest ◽

Mammalian Cell Lines ◽

Age Related ◽

Cell Accumulation ◽

Secretory Phenotype

Cellular senescence is the dynamic process of durable cell-cycle arrest. Senescent cells remain metabolically active and often acquire a distinctive bioactive secretory phenotype. Much of our molecular understanding in senescent cell biology comes from studies using mammalian cell lines exposed to stress or extended culture periods. While less well understood mechanistically, senescence in vivo is becoming appreciated for its numerous biological implications, both in the context of beneficial processes, such as development, tumor suppression, and wound healing, and in detrimental conditions, where senescent cell accumulation has been shown to contribute to aging and age-related diseases. Importantly, clearance of senescent cells, through either genetic or pharmacological means, has been shown to not only extend the healthspan of prematurely and naturally aged mice but also attenuate pathology in mouse models of chronic disease. These observations have prompted an investigation of how and why senescent cells accumulate with aging and have renewed exploration into the characteristics of cellular senescence in vivo. Here, we highlight our molecular understanding of the dynamics that lead to a cellular arrest and how various effectors may explain the consequences of senescence in tissues. Lastly, we discuss how exploitation of strategies to eliminate senescent cells or their effects may have clinical utility.

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Stilbene Compounds Inhibit Tumor Growth by the Induction of Cellular Senescence and the Inhibition of Telomerase Activity

International Journal of Molecular Sciences ◽

10.3390/ijms20112716 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2716 ◽

Cited By ~ 9

Author(s):

Yu-Hsuan Lee ◽

Yu-Ying Chen ◽

Ya-Ling Yeh ◽

Ying-Jan Wang ◽

Rong-Jane Chen

Keyword(s):

Cellular Senescence ◽

Current Knowledge ◽

Gene Expression Pattern ◽

Telomerase Activity ◽

Clinical Utilization ◽

Cycle Arrest ◽

Suppression Mechanism ◽

Secretory Phenotype ◽

Clinical Potential ◽

Stilbene Compounds

Cellular senescence is a state of cell cycle arrest characterized by a distinct morphology, gene expression pattern, and secretory phenotype. It can be triggered by multiple mechanisms, including those involved in telomere shortening, the accumulation of DNA damage, epigenetic pathways, and the senescence-associated secretory phenotype (SASP), and so on. In current cancer therapy, cellular senescence has emerged as a potent tumor suppression mechanism that restrains proliferation in cells at risk for malignant transformation. Therefore, compounds that stimulate the growth inhibition effects of senescence while limiting its detrimental effects are believed to have great clinical potential. In this review article, we first review the current knowledge of the pro- and antitumorigeneic functions of senescence and summarize the key roles of telomerase in the regulation of senescence in tumors. Second, we review the current literature regarding the anticancer effects of stilbene compounds that are mediated by the targeting of telomerase and cell senescence. Finally, we provide future perspectives on the clinical utilization of stilbene compounds, especially resveratrol and pterostilbene, as novel cancer therapeutic remedies. We conclude and propose that stilbene compounds may induce senescence and may potentially be used as the therapeutic or adjuvant agents for cancers with high telomerase activity.

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The Preconditioning of Berberine Suppresses Hydrogen Peroxide-Induced Premature Senescence via Regulation of Sirtuin 1

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/2391820 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Xiaofei Zhu ◽

Haodi Yue ◽

Xiaofang Guo ◽

Jingyi Yang ◽

Jingshuo Liu ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Cellular Senescence ◽

Sirtuin 1 ◽

Premature Senescence ◽

Low Concentration ◽

Human Diploid Fibroblasts ◽

Cycle Arrest ◽

Age Related ◽

History Of

With a long history of application in Chinese traditional medicine, berberine (BBR) was reported to exhibit healthspan-extending properties in some age-related diseases, such as type 2 diabetes and atherosclerosis. However, the antiaging mechanism of BBR is not completely clear. By means of hydrogen peroxide- (H2O2-) induced premature cellular senescence model, we found that a low-concentration preconditioning of BBR could resist premature senescence in human diploid fibroblasts (HDFs) measured by senescence-associated β-galactosidase (SA-β-gal), accompanied by a decrease in loss of mitochondrial membrane potential and production of intracellular reactive oxygen species (ROS). Moreover, the low-concentration preconditioning of BBR could make cells less susceptible to subsequent H2O2-induced cell cycle arrest and growth inhibition. Experimental results further showed that the low concentration of BBR could induce a slight increase of ROS and upregulate the expression level of sirtuin 1 (SIRT1), an important longevity regulator. H2O2-induced activation of checkpoint kinase 2 (Chk2) was significantly attenuated after the preconditioning of BBR. The present findings implied that the low-concentration preconditioning of BBR could have a mitohormetic effect against cellular senescence triggered by oxidative stress in some age-related diseases through the regulation of SIRT1.

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New Horizons: Novel Approaches to Enhance Healthspan Through Targeting Cellular Senescence and Related Aging Mechanisms

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa728 ◽

2020 ◽

Author(s):

Tamar Tchkonia ◽

Allyson K Palmer ◽

James L Kirkland

Keyword(s):

Cellular Senescence ◽

The Elderly ◽

Protein Accumulation ◽

Unitary Theory ◽

Research Attention ◽

New Horizons ◽

Related Disease ◽

Age Related ◽

Metabolite Generation ◽

Aging Mechanisms

Abstract The elderly population is increasing faster than other segments of the population throughout the world. Age is the leading predictor for most chronic diseases and disorders, multimorbidity, geriatric syndromes, and impaired ability to recover from accidents or illnesses. Enhancing the duration of health and independence, termed healthspan, would be more desirable than extending lifespan merely by prolonging the period of morbidity toward the end of life. The geroscience hypothesis posits that healthspan can be extended by targeting fundamental aging mechanisms, rather than attempting to address each age-related disease one at a time, only so the afflicted individual survives disabled and dies shortly afterward of another age-related disease. These fundamental aging mechanisms include, among others, chronic inflammation, fibrosis, stem cell/ progenitor dysfunction, DNA damage, epigenetic changes, metabolic shifts, destructive metabolite generation, mitochondrial dysfunction, misfolded or aggregated protein accumulation, and cellular senescence. These processes appear to be tightly interlinked, as targeting any one appears to affect many of the rest, underlying our Unitary Theory of Fundamental Aging Mechanisms. Interventions targeting many fundamental aging processes are being developed, including dietary manipulations, metformin, mTOR (mechanistic target of rapamycin) inhibitors, and senolytics, which are in early human trials. These interventions could lead to greater healthspan benefits than treating age-related diseases one at a time. To illustrate these points, we focus on cellular senescence and therapies in development to target senescent cells. Combining interventions targeting aging mechanisms with disease-specific drugs could result in more than additive benefits for currently difficult-to-treat or intractable diseases. More research attention needs to be devoted to targeting fundamental aging processes.

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