bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒10‒24
twenty-five papers selected by
Maria Grazia Vizioli
Mayo Clinic
  1. The metabolic roots of senescence: mechanisms and opportunities for intervention.
  2. Cellular Senescence and its Impact on the Circadian Clock.
  3. Promises and challenges of senolytics in skin regeneration, pathology and ageing.
  4. The role of cellular senescence in cardiac disease: basic biology and clinical relevance.
  5. Shear stress-induced cellular senescence blunts liver regeneration through Notch-Sirt1-P21/P16 axis.
  6. Recent advances in the discovery of senolytics.
  7. Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src.
  8. Platelet-Derived Growth Factor Induces SASP-Associated Gene Expression in Human Multipotent Mesenchymal Stromal Cells but Does Not Promote Cell Senescence.
  9. Role of mismatch repair in aging.
  10. Many chronological aging clocks can be found throughout the epigenome: Implications for quantifying biological aging.
  11. Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review.
  12. Complete loss of miR-200 family induces EMT associated cellular senescence in gastric cancer.
  13. The Role of AhR in the Hallmarks of Brain Aging: Friend and Foe.
  14. cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence.
  15. Telomeres and Age-Related Diseases.
  16. Cellular Senescence limits Translational Readthrough.
  17. Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age.
  18. Mitochondrial Contributions to Hematopoietic Stem Cell Aging.
  19. Noncanonical Wnt5a signaling regulates tendon stem/progenitor cells senescence.
  20. Senescent Thyrocytes, Similarly to Thyroid Tumor Cells, Elicit M2-like Macrophage Polarization In Vivo.
  21. Lung cancer cells expressing a shortened CDK16 3'UTR escape senescence through impaired miR-485-5p targeting.
  22. Prospective Selective Mechanism of Emerging Senolytic Agents Derived from Flavonoids.
  23. Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases.
  24. NAMPT reduction-induced NAD+ insufficiency contributes to the compromised oocyte quality from obese mice.
  25. Interleukin 6 reduces vascular smooth muscle cell apoptosis via Prep1 and is associated with aging.
  1. Nat Metab. 2021 Oct;3(10): 1290-1301
    The metabolic roots of senescence: mechanisms and opportunities for intervention.
    Christopher D Wiley, Judith Campisi.
      Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.
    DOI:  https://doi.org/10.1038/s42255-021-00483-8
  2. J Biochem. 2021 Oct 20. pii: mvab115. [Epub ahead of print]
    Cellular Senescence and its Impact on the Circadian Clock.
    Rezwana Ahmed, Hasan Mahmud Reza, Kazuyuki Shinohara, Yasukazu Nakahata.
      Aging is one of the greatest risk factors for chronic non-communicable diseases, and cellular senescence is one of the major causes of aging and age-related diseases. The persistent presence of senescent cells in late life seems to cause disarray in a tissue-specific manner. Aging disrupts the circadian clock system, which results in the development of many age-related diseases such as metabolic syndrome, cancer, cardiac diseases, and sleep disorders and an increased susceptibility to infections. In this review, we first discuss cellular senescence and some of its basic characteristics and detrimental roles. Then, we discuss a relatively unexplored topic on the link between cellular senescence and the circadian clock and attempt to determine whether cellular senescence could be the underlying factor for circadian clock disruption.
    Keywords:  NAD+; aging; cellular senescence; circadian clock; metabolites
    DOI:  https://doi.org/10.1093/jb/mvab115
  3. Mech Ageing Dev. 2021 Oct 19. pii: S0047-6374(21)00160-3. [Epub ahead of print] 111588
    Promises and challenges of senolytics in skin regeneration, pathology and ageing.
    Vera Pils, Nadja Ring, Karla Valdivieso, Ingo Lämmermann, Florian Gruber, Markus Schosserer, Johannnes Grillari, Mikolaj Ogrodnik.
      The research of the last two decades has defined a crucial role of cellular senescence in both the physiology and pathology of skin, and senescent cells have been detected in conditions including development, regeneration, aging, and disease. The pathophysiology of cellular senescence in skin is complex as the phenotype of senescence pertains to several different cell types including fibroblasts, keratinocytes and melanocytes, among others. Paradoxically, the transient presence of senescent cells is believed to be beneficial in the context of development and wound healing, while the chronic presence of senescent cells is detrimental in the context of aging, diseases, and chronic wounds, which afflict predominantly the elderly. Identifying strategies to prevent senescence induction or reduce senescent burden in the skin could broadly benefit the aging population. Senolytics, drugs known to specifically eliminate senescent cells while preserving non-senescent cells, are being intensively studied for use in the clinical setting. Here, we review recent research on skin senescence, the methods for detection of senescent cells and describe promises and challenges related to the application of senolytic drugs.
    Keywords:  aging; inflammation; molecular biology of aging; senescence; senolytics; skin regeneration
    DOI:  https://doi.org/10.1016/j.mad.2021.111588
  4. Nat Rev Cardiol. 2021 Oct 19.
    The role of cellular senescence in cardiac disease: basic biology and clinical relevance.
    Mozhdeh Mehdizadeh, Martin Aguilar, Eric Thorin, Gerardo Ferbeyre, Stanley Nattel.
      Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing and ageing. Senescent cells have a complex senescence-associated secretory phenotype (SASP), involving a range of pro-inflammatory factors with important paracrine and autocrine effects on cell and tissue biology. Clinical evidence and experimental studies link cellular senescence, senescent cell accumulation, and the production and release of SASP components with age-related cardiac pathologies such as heart failure, myocardial ischaemia and infarction, and cancer chemotherapy-related cardiotoxicity. However, the precise role of senescent cells in these conditions is unclear and, in some instances, both detrimental and beneficial effects have been reported. The involvement of cellular senescence in other important entities, such as cardiac arrhythmias and remodelling, is poorly understood. In this Review, we summarize the basic biology of cellular senescence and discuss what is known about the role of cellular senescence and the SASP in heart disease. We then consider the various approaches that are being developed to prevent the accumulation of senescent cells and their consequences. Many of these strategies are applicable in vivo and some are being investigated for non-cardiac indications in clinical trials. We end by considering important knowledge gaps, directions for future research and the potential implications for improving the management of patients with heart disease.
    DOI:  https://doi.org/10.1038/s41569-021-00624-2
  5. Hepatology. 2021 Oct 23.
    Shear stress-induced cellular senescence blunts liver regeneration through Notch-Sirt1-P21/P16 axis.
    Juan-Li Duan, Bai Ruan, Ping Song, Zhi-Qiang Fang, Zhen-Sheng Yue, Jing-Jing Liu, Guo-Rui Dou, Hua Han, Lin Wang.
      BACKGROUND & AIMS: The mechanisms involved in liver regeneration after partial hepatectomy (PHx) are complicated. Cellular senescence, once linked to aging, plays a pivotal role in wound repair. However, the regulatory effects of cellular senescence on liver regeneration have not been fully elucidated.APPROACH & RESULTS: Mice subjected to PHx were analyzed 14 days after surgery. The incomplete remodeling of liver sinusoids affected shear stress-induced eNOS signaling on day 14, resulting in the accumulation of senescent liver sinusoidal endothelial cells (LSECs). Removing macrophages to augment LSEC senescence led to a malfunction of the regenerating liver. A dynamic fluctuation in Notch activity accompanied senescent LSEC accumulation during liver regeneration. Endothelial Notch activation by using Cdh5-CreERT NICeCA mice triggered LSEC senescence and senescence-associated secretory phenotype (SASP), which disrupted liver regeneration. Blocking the Notch by γ-secretase inhibitor (GSI) diminished senescence and promoted LSEC expansion. Mechanically, Notch-Hes1 signaling inhibited Sirt1 transcription by binding to its promoter region. Activation of Sirt1 by SRT1720 neutralized the up-regulation of P53, P21, and P16 caused by Notch activation, and eliminated Notch-driven LSEC senescence. Finally, Sirt1 activator promoted liver regeneration by abrogating LSEC senescence and improving sinusoid remodeling.
    CONCLUSIONS: Shear stress-induced LSEC senescence driven by Notch interferes with liver regeneration after PHx. Sirt1 inhibition accelerates liver regeneration by abrogating Notch-driven senescence, providing a potential opportunity to target senescent cells and facilitate liver repair after injury.
    Keywords:  Liver regeneration; Liver sinusoidal endothelial cells; Notch; Senescence; Sirt1
    DOI:  https://doi.org/10.1002/hep.32209
  6. Mech Ageing Dev. 2021 Oct 14. pii: S0047-6374(21)00159-7. [Epub ahead of print] 111587
    Recent advances in the discovery of senolytics.
    Lei Zhang, Louise E Pitcher, Vaishali Prahalad, Laura J Niedernhofer, Paul D Robbins.
      The demonstration in model organisms that cellular senescence drives aging and age-related disease has led to widespread efforts to identify compounds able to selectively kill senescent cells, termed senolytics. Approaches used to identify senolytics include bioinformatic analysis of senescent cell anti-apoptotic pathways (SCAPs) for drug development and screening of drugs libraries on different senescent cell types in culture. Alternatively, cytotoxic compounds can be made specific to senescent cells through a prodrug strategy such as linking the compound to a galactose moiety where toxicity is activated by lysosomal β-galactosidase. Identified senolytics can then be optimized through medicinal chemistry or linking to E3 targeting moieties to facilitate proteolysis of their targets. This review will provide an overview of approaches to identify senolytics and an update of the classes of senolytics identified to date.
    Keywords:  PROTACs; Senescence; aging; drug screening; prodrugs; senolytics
    DOI:  https://doi.org/10.1016/j.mad.2021.111587
  7. Signal Transduct Target Ther. 2021 Oct 22. 6(1): 354
    Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src.
    Xian Xiao, Meiqian Xu, Hongliang Yu, Liping Wang, Xiaoxia Li, Janusz Rak, Shihua Wang, Robert Chunhua Zhao.
      Senescent endothelial cells (ECs) could impair the integrity of the blood vessel endothelium, leading to vascular aging and a series of diseases, such as atherosclerosis, diabetes. Preventing or mitigating EC senescence might serve as a promising therapeutic paradigm for these diseases. Recent studies showed that small extracellular vesicles (sEV) have the potential to transfer bioactive molecules into recipient cells and induce phenotypic changes. Since mesenchymal stem cells (MSCs) have long been postulated as an important source cell in regenerative medicine, herein we investigated the role and mechanism of MSC-derived sEV (MSC-sEV) on EC senescence. In vitro results showed that MSC-sEV reduced senescent biomarkers, decreased senescence-associated secretory phenotype (SASP), rescued angiogenesis, migration and other dysfunctions in senescent EC induced by oxidative stress. In the In vivo natural aging and type-2 diabetes mouse wound-healing models (both of which have senescent ECs), MSC-sEV promoted wound closure and new blood vessel formation. Mechanically, miRNA microarray showed that miR-146a was highly expressed in MSC-sEV and also upregulated in EC after MSC-sEV treatment. miR-146a inhibitors abolished the stimulatory effects of MSC-sEV on senescence. Moreover, we found miR-146a could suppress Src phosphorylation and downstream targets VE-cadherin and Caveolin-1. Collectively, our data indicate that MSC-sEV mitigated endothelial cell senescence and stimulate angiogenesis through miR-146a/Src.
    DOI:  https://doi.org/10.1038/s41392-021-00765-3
  8. Biomedicines. 2021 Sep 22. pii: 1290. [Epub ahead of print]9(10):
    Platelet-Derived Growth Factor Induces SASP-Associated Gene Expression in Human Multipotent Mesenchymal Stromal Cells but Does Not Promote Cell Senescence.
    Olga Grigorieva, Mikhail Arbatskiy, Ekaterina Novoseletskaya, Uliana Dyachkova, Alexander Ishkin, Natalia Kalinina, Anastasia Efimenko.
      Activation of multipotent mesenchymal stromal cells (MSCs) is a central part of tissue response to damage. Platelet-derived growth factor (PDGF-BB), which is abundantly released in the damaged area, potently stimulates the proliferation and migration of MSCs. Recent evidence indicates that tissue injury is associated with the accumulation of senescent cells, including ones of MSC origin. Therefore, we hypothesized that PDGF-BB induces MSC senescence. To evaluate mechanisms of early activation of MSCs by PDGF-BB, we performed transcriptome profiling of human MSCs isolated from adipose tissue after exposure to PDGF-BB for 12 and 24 h. We demonstrated that PDGF-BB induced the expression of several genes encoding the components of senescence-associated secretory phenotype (SASP) in MSCs such as plasminogen activator inhibitor-1 (PAI-1), urokinase-type plasminogen activator and its receptor (uPA and uPAR), and some matrix metalloproteases. However, further experimental validation of transcriptomic data clearly indicated that PDGF-BB exerted mitogenic and pro-migratory effects on MSCs, and augmented their pro-angiogenic activity, but did not significantly stimulate MSC senescence.
    Keywords:  cellular senescence; multipotent mesenchymal stromal cells; platelet-derived growth factor; transcriptome
    DOI:  https://doi.org/10.3390/biomedicines9101290
  9. Int J Biol Sci. 2021 ;17(14): 3923-3935
    Role of mismatch repair in aging.
    Jie Wen, Yangyang Wang, Minghao Yuan, Zhenting Huang, Qian Zou, Yinshuang Pu, Bin Zhao, Zhiyou Cai.
      A common feature of aging is the accumulation of genetic damage throughout life. DNA damage can lead to genomic instability. Many diseases associated with premature aging are a result of increased accumulation of DNA damage. In order to minimize these damages, organisms have evolved a complex network of DNA repair mechanisms, including mismatch repair (MMR). In this review, we detail the effects of MMR on genomic instability and its role in aging emphasizing on the association between MMR and the other hallmarks of aging, serving to drive or amplify these mechanisms. These hallmarks include telomere attrition, epigenetic alterations, mitochondrial dysfunction, altered nutrient sensing and cell senescence. The close relationship between MMR and these markers may provide prevention and treatment strategies, to reduce the incidence of age-related diseases and promote the healthy aging of human beings.
    Keywords:  aging; epigenetic alterations; genomic instability; mismatch repair; mitochondrial dysfunction; telomere attrition
    DOI:  https://doi.org/10.7150/ijbs.64953
  10. Aging Cell. 2021 Oct 16. e13492
    Many chronological aging clocks can be found throughout the epigenome: Implications for quantifying biological aging.
    Hunter L Porter, Chase A Brown, Xiavan Roopnarinesingh, Cory B Giles, Constantin Georgescu, Willard M Freeman, Jonathan D Wren.
      Epigenetic alterations are a hallmark of aging and age-related diseases. Computational models using DNA methylation data can create "epigenetic clocks" which are proposed to reflect "biological" aging. Thus, it is important to understand the relationship between predictive clock sites and aging biology. To do this, we examined over 450,000 methylation sites from 9,699 samples. We found ~20% of the measured genomic cytosines can be used to make many different epigenetic clocks whose age prediction performance surpasses that of telomere length. Of these predictive sites, the average methylation change over a lifetime was small (~1.5%) and these sites were under-represented in canonical regions of epigenetic regulation. There was only a weak association between "accelerated" epigenetic aging and disease. We also compare tissue-specific and pan-tissue clock performance. This is critical to applying clocks both to new sample sets in basic research, as well as understanding if clinically available tissues will be feasible samples to evaluate "epigenetic aging" in unavailable tissues (e.g., brain). Despite the reproducible and accurate age predictions from DNA methylation data, these findings suggest they may have limited utility as currently designed in understanding the molecular biology of aging and may not be suitable as surrogate endpoints in studies of anti-aging interventions. Purpose-built clocks for specific tissues age ranges or phenotypes may perform better for their specific purpose. However, if purpose-built clocks are necessary for meaningful predictions, then the utility of clocks and their application in the field needs to be considered in that context.
    Keywords:  Aging; bioinformatics; epigenetic clocks; epigenetics
    DOI:  https://doi.org/10.1111/acel.13492
  11. Biomolecules. 2021 Oct 07. pii: 1478. [Epub ahead of print]11(10):
    Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review.
    Urban Alehagen, Trine B Opstad, Jan Alexander, Anders Larsson, Jan Aaseth.
      Selenium (Se) is an essential dietary trace element that plays an important role in the prevention of inflammation, cardiovascular diseases, infections, and cancer. Selenoproteins contain selenocysteine in the active center and include, i.a., the enzymes thioredoxin reductases (TXNRD1-3), glutathione peroxidases (GPX1-4 and GPX6) and methionine sulfoxide reductase, involved in immune functions, metabolic homeostasis, and antioxidant defense. Ageing is an inevitable process, which, i.a., involves an imbalance between antioxidative defense and reactive oxygen species (ROS), changes in protein and mitochondrial renewal, telomere attrition, cellular senescence, epigenetic alterations, and stem cell exhaustion. These conditions are associated with mild to moderate inflammation, which always accompanies the process of ageing and age-related diseases. In older individuals, Se, by being a component in protective enzymes, operates by decreasing ROS-mediated inflammation, removing misfolded proteins, decreasing DNA damage, and promoting telomere length. Se-dependent GPX1-4 and TXNRD1-3 directly suppress oxidative stress. Selenoprotein H in the cell nucleus protects DNA, and selenoproteins residing in the endoplasmic reticulum (ER) assist in the removal of misfolded proteins and protection against ER stress. In this review, we highlight the role of adequate Se status for human ageing and prevention of age-related diseases, and further its proposed role in preservation of telomere length in middle-aged and elderly individuals.
    Keywords:  ageing; cancer; cardiovascular; selenium; sirtuins; telomeres
    DOI:  https://doi.org/10.3390/biom11101478
  12. Oncogene. 2021 Oct 19.
    Complete loss of miR-200 family induces EMT associated cellular senescence in gastric cancer.
    Liang Yu, Can Cao, Xu Li, Mili Zhang, Qisheng Gu, Hugh Gao, Jesse J Balic, Duogang Xu, Lei Zhang, Le Ying, Dakang Xu, Yuqin Yang, Di Wu, Baokun He, Brendan J Jenkins, Youdong Liu, Jikun Li.
      The EMT (epithelial-to-mesenchymal-transition) subtype of gastric cancer (GC) is associated with poor treatment responses and unfavorable clinical outcomes. Despite the broad physiological roles of the micro-RNA (miR)-200 family, they largely serve to maintain the overall epithelial phenotype. However, during late-stage gastric tumorigenesis, members of the miR-200 family are markedly suppressed, resulting in the transition to the mesenchymal state and the acquisition of invasive properties. As such, the miR-200 family represents a robust molecular marker of EMT, and subsequently, disease severity and prognosis. Most reports have studied the effect of single miR-200 family member knockdown. Here, we employ a multiplex CRISPR/Cas9 system to generate a complete miR-200 family knockout (FKO) to investigate their collective and summative role in regulating key cellular processes during GC pathogenesis. Genetic deletion of all miR-200s in the human GC cell lines induced potent morphological alterations, G1/S cell cycle arrest, increased senescence-associated β-galactosidase (SA-β-Gal) activity, and aberrant metabolism, collectively resembling the senescent phenotype. Coupling RNA-seq data with publicly available datasets, we revealed a clear separation of senescent and non-senescent states amongst FKO cells and control cells, respectively. Further analysis identified key senescence-associated secretory phenotype (SASP) components in FKO cells and a positive feedback loop for maintenance of the senescent state controlled by activation of TGF-β and TNF-α pathways. Finally, we showed that miR-200 FKO associated senescence in cancer epithelial cells significantly recruited stromal cells in the tumor microenvironment. Our work has identified a new role of miR-200 family members which function as an integrated unit serving to link senescence with EMT, two major conserved biological processes.
    DOI:  https://doi.org/10.1038/s41388-021-02067-y
  13. Cells. 2021 Oct 13. pii: 2729. [Epub ahead of print]10(10):
    The Role of AhR in the Hallmarks of Brain Aging: Friend and Foe.
    Emmanuel S Ojo, Shelley A Tischkau.
      In recent years, aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered to be involved in aging phenotypes across several species. This receptor is a highly conserved biosensor that is activated by numerous exogenous and endogenous molecules, including microbiota metabolites, to mediate several physiological and toxicological functions. Brain aging hallmarks, which include glial cell activation and inflammation, increased oxidative stress, mitochondrial dysfunction, and cellular senescence, increase the vulnerability of humans to various neurodegenerative diseases. Interestingly, many studies have implicated AhR signaling pathways in the aging process and longevity across several species. This review provides an overview of the impact of AhR pathways on various aging hallmarks in the brain and the implications for AhR signaling as a mechanism in regulating aging-related diseases of the brain. We also explore how the nature of AhR ligands determines the outcomes of several signaling pathways in brain aging processes.
    Keywords:  AhR endogenous/exogenous ligands; aryl hydrocarbon receptor; brain aging hallmarks; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cells10102729
  14. Protein Cell. 2021 Oct 22.
    cGAS guards against chromosome end-to-end fusions during mitosis and facilitates replicative senescence.
    Xiaocui Li, Xiaojuan Li, Chen Xie, Sihui Cai, Mengqiu Li, Heping Jin, Shu Wu, Jun Cui, Haiying Liu, Yong Zhao.
      As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.
    Keywords:  DNA damage response; cGAS; chromosome end-to-end fusion; genome stability; mitosis; non-homologous end joining; telomeres
    DOI:  https://doi.org/10.1007/s13238-021-00879-y
  15. Biomedicines. 2021 Sep 27. pii: 1335. [Epub ahead of print]9(10):
    Telomeres and Age-Related Diseases.
    Hans-Jürgen Gruber, Maria Donatella Semeraro, Wilfried Renner, Markus Herrmann.
      Telomeres are at the non-coding ends of linear chromosomes. Through a complex 3-dimensional structure, they protect the coding DNA and ensure appropriate separation of chromosomes. Aging is characterized by a progressive shortening of telomeres, which compromises their structure and function. Because of their protective function for genomic DNA, telomeres appear to play an important role in the development and progression of many age-related diseases, such as cardiovascular disease (CVD), malignancies, dementia, and osteoporosis. Despite substantial evidence that links telomere length with these conditions, the nature of these observations remains insufficiently understood. Therefore, future studies should address the question of causality. Furthermore, analytical methods should be further improved with the aim to provide informative and comparable results. This review summarize the actual knowledge of telomere biology and the possible implications of telomere dysfunction for the development and progression of age-related diseases. Furthermore, we provide an overview of analytical techniques for the measurement of telomere length and telomerase activity.
    Keywords:  age; disease; telomere
    DOI:  https://doi.org/10.3390/biomedicines9101335
  16. Biol Open. 2021 Oct 22. pii: bio.058688. [Epub ahead of print]
    Cellular Senescence limits Translational Readthrough.
    Neylen Del Toro, Frédéric Lessard, Jacob Bouchard, Nasrin Mobasheri, Jordan Guillon, Sebastian Igelmann, Sarah Tardif, Tony Buffard, Véronique Bourdeau, Léa Brakier-Gingras, Gerardo Ferbeyre.
      The origin and evolution of cancer cells is considered to be mainly fueled by DNA mutations. Although translation errors could also expand the cellular proteome, their role in cancer biology remains poorly understood. Tumor suppressors called caretakers block cancer initiation and progression by preventing DNA mutations and/or stimulating DNA repair. If translational errors contribute to tumorigenesis, then caretakers genes should prevent such errors in normal cells in response to oncogenic stimuli. Here, we show that the process of cellular senescence induced by oncogenes, tumor suppressors or chemotherapeutic drugs is associated to a reduction in translational readthrough (TR) measured using reporters containing termination codons withing the context of both normal translation termination or programmed TR. Senescence reduced both basal TR and TR stimulated by aminoglycosides. Mechanistically, the reduction of TR during senescence is controlled by the RB tumor suppressor pathway. Cells that escape from cellular senescence either induced by oncogenes or chemotherapy have an increased TR. Also, breast cancer cells that escape from therapy-induced senescence express high levels of AGO1x, a TR isoform of AGO1 linked to breast cancer progression. We propose that senescence and the RB pathway reduce TR limiting proteome diversity and the expression of TR proteins required for cancer cell proliferation.
    Keywords:  Retinoblastoma (RB) tumor suppressor; Senescence; Translation termination; Translational readthrough
    DOI:  https://doi.org/10.1242/bio.058688
  17. Aging Cell. 2021 Oct 23. e13499
    Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age.
    Sun Y Maybury-Lewis, Abigail K Brown, Mitchell Yeary, Anna Sloutskin, Shleshma Dhakal, Tamar Juven-Gershon, Ashley E Webb.
      Neural stem cells (NSCs) in the adult and aged brain are largely quiescent, and require transcriptional reprogramming to re-enter the cell cycle. However, the mechanisms underlying these changes and how they are altered with age remain undefined. Here, we identify the chromatin accessibility differences between primary neural stem/progenitor cells in quiescent and activated states. These distinct cellular states exhibit shared and unique chromatin profiles, both associated with gene regulation. Accessible chromatin states specific to activation or quiescence are active enhancers bound by key pro-neurogenic and quiescence factors. In contrast, shared sites are enriched for core promoter elements associated with translation and metabolism. Unexpectedly, through integrated analysis, we find that many sites that become accessible during NSC activation are linked to gene repression and associated with pro-quiescence factors, revealing a novel mechanism that may preserve quiescence re-entry. Furthermore, we report that in aged NSCs, chromatin regions associated with metabolic and transcriptional functions bound by key pro-quiescence transcription factors lose accessibility, suggesting a novel mechanism of age-associated NSC dysfunction. Together, our findings reveal how accessible chromatin states regulate the transcriptional switch between NSC quiescence and activation, and how this switch is affected with age.
    Keywords:  aging; chromatin accessibility; neural stem cells; stem cell activation
    DOI:  https://doi.org/10.1111/acel.13499
  18. Int J Mol Sci. 2021 Oct 15. pii: 11117. [Epub ahead of print]22(20):
    Mitochondrial Contributions to Hematopoietic Stem Cell Aging.
    Claudia Morganti, Keisuke Ito.
      Mitochondrial dysfunction and stem cell exhaustion are two hallmarks of aging. In the hematopoietic system, aging is linked to imbalanced immune response and reduced regenerative capacity in hematopoietic stem cells (HSCs), as well as an increased predisposition to a spectrum of diseases, including myelodysplastic syndrome and acute myeloid leukemia. Myeloid-biased differentiation and loss of polarity are distinct features of aged HSCs, which generally exhibit enhanced mitochondrial oxidative phosphorylation and increased production of reactive oxygen species (ROS), suggesting a direct role for mitochondria in the degenerative process. Here, we provide an overview of current knowledge of the mitochondrial mechanisms that contribute to age-related phenotypes in HSCs. These include mitochondrial ROS production, alteration/activation of mitochondrial metabolism, the quality control pathway of mitochondria, and inflammation. Greater understanding of the key machineries of HSC aging will allow us to identify new therapeutic targets for preventing, delaying, or even reversing aspects of this process.
    Keywords:  ROS; aging; hematopoiesis; hematopoietic stem cell; inflammation; mitochondrial metabolism; stem cell exhaustion
    DOI:  https://doi.org/10.3390/ijms222011117
  19. Stem Cell Res Ther. 2021 Oct 18. 12(1): 544
    Noncanonical Wnt5a signaling regulates tendon stem/progenitor cells senescence.
    Minhao Chen, Yingjuan Li, Longfei Xiao, Guangchun Dai, Panpan Lu, Yunfeng Rui.
      BACKGROUND: The structural and functional properties of tendon decline with age, and these changes contribute to tendon disorder. Tendon stem/progenitor cells (TSPCs) play a vital role in tendon repair, regeneration and homeostasis maintaining. Although studies have demonstrated that tendon aging is closely associated with the altered TSPCs function on senescence, the cellular and molecular mechanisms of TSPCs senescence remain largely unknown. This study was designed to investigate the role of Wnt5a in TSPCs senescence.METHODS: TSPCs were isolated from 2-month-old and 20-month-old male C57BL/6 mice. The expression of Wnt5a was determined by RNA sequencing, qRT-PCR and western blotting. TSPCs were then treated with Wnt5a shRNA or recombinant Wnt5a or AG490 or IFN-γ or Ror2-siRNA. Western blotting, β-gal staining, qRT-PCR, immunofluorescence staining and cell cycle analysis were used for confirming the role of Wnt5a in TSPCs senescence.
    RESULTS: We found a canonical to noncanonical Wnt signaling shift due to enhanced expression of Wnt5a in aged TSPCs. Functionally, we demonstrated that inhibition of Wnt5a attenuated TSPCs senescence, age-related cell polarity and the senescence-associated secretory phenotype (SASP) expression in aged TSPCs. Mechanistically, the JAK-STAT signaling pathway was activated in aged TSPCs, while Wnt5a knockdown inhibited the JAK-STAT signaling pathway, suggesting that Wnt5a modulates TSPCs senescence via JAK-STAT signaling pathway. Moreover, knockdown of Ror2 inhibited Wnt5a-induced activation of the JAK-STAT signaling pathway, which indicates that Wnt5a potentiates JAK-STAT signaling pathway through Ror2, and Ror2 acts as the functional receptor of Wnt5a in TSPCs senescence.
    CONCLUSION: Our results demonstrate a critical role of noncanonical Wnt5a signaling in TSPCs senescence, and Wnt5a could be an attractive therapeutic target for antagonizing tendon aging.
    Keywords:  JAK–STAT; Ror2; Senescence; Tendon-derived stem/progenitor cells; Wnt5a
    DOI:  https://doi.org/10.1186/s13287-021-02605-1
  20. Biology (Basel). 2021 Sep 30. pii: 985. [Epub ahead of print]10(10):
    Senescent Thyrocytes, Similarly to Thyroid Tumor Cells, Elicit M2-like Macrophage Polarization In Vivo.
    Mara Mazzoni, Giuseppe Mauro, Lucia Minoli, Loredana Cleris, Maria Chiara Anania, Tiziana Di Marco, Emanuela Minna, Sonia Pagliardini, Maria Grazia Rizzetti, Giacomo Manenti, Maria Grazia Borrello, Eugenio Scanziani, Angela Greco.
      Inflammation plays a critical role in thyroid cancer onset and progression. We previously characterized the in vitro interplay between macrophages and senescent human thyrocytes and thyroid tumor-derived cell lines, modeling the early and the late thyroid tumor phases, respectively. We reported that both models are able to induce pro-tumoral M2-like macrophage polarization, through the activation of the COX2-PGE2 axis. Here, we investigated the presence of macrophage infiltrating cells in mouse xenografts derived from the above described cells models. We showed that subcutaneous injection in immunodeficient mice of both senescent human thyrocytes and thyroid tumor-derived cell lines elicits macrophage recruitment. Furthermore, considering the type of macrophage infiltrate, we observed a stronger infiltration of Arginase I positive cells (M2-like). Overall, these results demonstrate the in vivo capability of senescent and tumor thyroid cells to recruit and polarize macrophages, suggesting that the promotion of a pro-tumoral microenvironment through tumor associated macrophages may occurs in late as well as in early thyroid tumor stages, favoring tumor onset and progression.
    Keywords:  inflammation; macrophages; mouse xenografts; senescence; thyrocytes; thyroid carcinoma
    DOI:  https://doi.org/10.3390/biology10100985
  21. Mol Oncol. 2021 Oct 23.
    Lung cancer cells expressing a shortened CDK16 3'UTR escape senescence through impaired miR-485-5p targeting.
    Qi Jia, Baiyun Xie, Zhaozhao Zhao, Leihuan Huang, Gang Wei, Ting Ni.
      Inducing senescence in cancer cells is an emerging strategy for cancer therapy. The dysregulation and mutation of genes encoding cyclin-dependent kinases (CDKs) have been implicated in various human cancers. However, whether CDK can induce cancer cell senescence remains poorly understood. We observed that CDK16 expression was high in multiple cancer types, including lung cancer, whereas various replicative senescence models displayed low CDK16 expression. CDK16 knockdown caused senescence-associated phenotypes in lung cancer cell lines. Interestingly, the CDK16 3' untranslated region (UTR) was shortened in cancer and lengthened in senescence models, which was regulated by alternative polyadenylation (APA). The longer 3'UTR [using the distal polyA (pA) site] generated less protein than the shorter one (using the proximal pA site). Since microRNAs (miRNAs) usually bind to the 3'UTR of target genes to suppress their expression, we investigated whether miRNAs targeting the region between the shortened and longer 3'UTR are responsible for the reduced expression. We found that miR-485-5p targeted the 3'UTR between the distal and proximal pA site and caused senescence-associated phenotypes by reducing protein production from the longer CDK16 transcript. Of note, CDK16 knockdown led to a reduced expression of MYC proto-oncogene, bHLH transcription factor (MYC) and CD274 molecule (PD-L1), which in turn enhanced the tumor-suppressive effects of senescent cancer cells. The present study discovered that CDK16, whose expression is under the regulation of APA and miR-485-5p, is a potential target for pro-senescence lung cancer therapy.
    Keywords:   CDK16 ; 3′UTR; APA; cancer cell senescence; miR-485-5p
    DOI:  https://doi.org/10.1002/1878-0261.13125
  22. J Agric Food Chem. 2021 Oct 18.
    Prospective Selective Mechanism of Emerging Senolytic Agents Derived from Flavonoids.
    Yijun Wang, Yufeng He, Margaret P Rayman, Jinsong Zhang.
      Senescent cells (SCs) are associated with the onset and development of multiple chronic diseases. Selective clearance of SCs by senolytic drugs is a potential therapeutic option for a number of age-related diseases. Among senolytic candidates, only dasatinib with quercetin and fisetin meet the rigorous criteria for senolytic drugs, according to a modified version of Koch's postulates. It is astonishing that two of the three agents, i.e., quercetin and fisetin, are flavonoids, although the mechanism by which they preferentially eliminate SCs is unclear. Herein, we propose a possible selective mechanism; prooxidant activities of quercetin or fisetin are inevitably involved in killing apoptosis-resistant SCs. Among the dietary flavonoids, quercetin is a potent redox-active flavonoid with strong prooxidant activities, and transition metals, such as copper and iron, hugely amplify its prooxidant activities. Fisetin, which has higher senolytic activities than quercetin, has higher prooxidant effects than quercetin in the absence or presence of copper. It appears that the prooxidant activity of flavonoids is an important consideration for screening senolytics. SCs accumulate high levels of copper and iron, and the selective mechanism of quercetin or fisetin is probably associated with copper/iron-promoted oxidative damage in SCs. Copper and iron dramatically enhanced the prooxidant effects of the flavonoid, epigallocatechin-3-gallate, having shown a depletion effect on SCs in rats and high therapeutic efficacy in patients with idiopathic pulmonary fibrosis, largely caused by SCs. Further investigation to evaluate whether epigallocatechin-3-gallate is a senolytic drug, according to Koch's postulates, is warranted.
    Keywords:  copper; fisetin; iron; quercetin; senescent cells; senolytic
    DOI:  https://doi.org/10.1021/acs.jafc.1c04379
  23. Cells. 2021 Oct 16. pii: 2772. [Epub ahead of print]10(10):
    Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases.
    Claudio Pinto, Elisabetta Ninfole, Antonio Benedetti, Marco Marzioni, Luca Maroni.
      Autophagy is a "housekeeping" lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.
    Keywords:  FXR; Rubicon; UDCA; ageing; autophagy; cholangiopathies; cholestasis
    DOI:  https://doi.org/10.3390/cells10102772
  24. Aging Cell. 2021 Oct 18. e13496
    NAMPT reduction-induced NAD+ insufficiency contributes to the compromised oocyte quality from obese mice.
    Hengjie Wang, Shuai Zhu, Xinghan Wu, Yuan Liu, Juan Ge, Qiang Wang, Ling Gu.
      Maternal obesity is associated with multiple adverse reproductive outcomes, whereas the underlying molecular mechanisms are still not fully understood. Here, we found the reduced nicotinamide phosphoribosyl transferase (NAMPT) expression and lowered nicotinamide adenine dinucleotide (NAD+ ) content in oocytes from obese mice. Next, by performing morpholino knockdown assay and pharmacological inhibition, we revealed that NAMPT deficiency not only severely disrupts maturational progression and meiotic apparatus, but also induces the metabolic dysfunction in oocytes. Furthermore, overexpression analysis demonstrated that NAMPT insufficiency induced NAD+ loss contributes to the compromised developmental potential of oocytes and early embryos from obese mice. Importantly, in vitro supplement and in vivo administration of nicotinic acid (NA) was able to ameliorate the obesity-associated meiotic defects and oxidative stress in oocytes. Our results indicate a role of NAMPT in modulating oocyte meiosis and metabolism, and uncover the beneficial effects of NA treatment on oocyte quality from obese mice.
    Keywords:  meiosis; metabolism; nicotinamide phosphoribosyl transferase; obesity; oocyte
    DOI:  https://doi.org/10.1111/acel.13496
  25. FASEB J. 2021 Nov;35(11): e21989
    Interleukin 6 reduces vascular smooth muscle cell apoptosis via Prep1 and is associated with aging.
    Ilaria Cimmino, Francesco Prisco, Sonia Orso, Ayewa L Agognon, Pasquale Liguoro, Davide De Biase, Nunzianna Doti, Menotti Ruvo, Orlando Paciello, Francesco Beguinot, Pietro Formisano, Francesco Oriente.
      Aging exacerbates neointimal formation by reducing apoptosis of vascular smooth muscle cells (VSMCs) and induces inflammation within vascular wall. Prep1 is a homeodomain transcription factor which stimulates the expression of proinflammatory cytokines in aortic endothelial cell models and plays a primary role in the regulation of apoptosis. In this study, we have investigated the role of Prep1 in aorta of Prep1 hypomorphic heterozygous mice (Prep1i/+ ) and in VSMCs, and its correlation with aging. Histological analysis from Prep1i/+ aortas revealed a 25% reduction in medial smooth muscle cell density compared to WT animals. This result paralleled higher apoptosis, caspase 3, caspase 9 and p53 levels in Prep1i/+ mice and lower Bcl-xL. Prep1 overexpression in VSMCs decreased apoptosis by 25% and caspase 3 and caspase 9 expression by 40% and 37%. In parallel, Bcl-xL inhibition by BH3I-1 and p53 induction by etoposide reverted the antiapoptotic effect of Prep1. Experiments performed in aorta from 18 months old WT mice showed a significant increase in Prep1, p16INK4 , p21Waf1 and interleukin 6 (IL-6) compared to youngest animals. Similar results have been observed in H2 O2 -induced senescent VSMCs. Interestingly, the synthetic Prep1 inhibitory peptide Prep1 (54-72) reduced the antiapoptotic effects mediated by IL-6, particularly in senescent VSMCs. These results indicate that IL-6-Prep1 signaling reduces apoptosis, by modulating Bcl-xL and p53 both in murine aorta and in VSMCs. In addition, age-dependent increase in IL-6 and Prep1 in senescent VSMCs and in old mice may be involved in the aging-related vascular dysfunction.
    Keywords:  Prep1; aging; apoptosis; interleukin 6; vascular smooth muscle cells
    DOI:  https://doi.org/10.1096/fj.202100943R
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