bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒12‒26
23 papers selected by
Maria Grazia Vizioli
Mayo Clinic
  1. Aging disrupts circadian gene regulation and function in macrophages.
  2. Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.
  3. CDK5RAP2 loss-of-function causes premature cell senescence via the GSK3β/β-catenin-WIP1 pathway.
  4. Impact of zinc on DNA integrity and age-related inflammation.
  5. Human MSC-Derived Exosomes Reduce Cellular Senescence in Renal Epithelial Cells.
  6. Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration.
  7. Cellular Senescence in Adrenocortical Biology and Its Disorders.
  8. tRNA biogenesis and specific aminoacyl-tRNA synthetases regulate senescence stability under the control of mTOR.
  9. Peroxiredoxin 6 protects irradiated cells from oxidative stress and shapes their senescence-associated cytokine landscape.
  10. Cytosolic Self-DNA-A Potential Source of Chronic Inflammation in Aging.
  11. Increased MFG-E8 at neuromuscular junctions is an exacerbating factor for sarcopenia-associated denervation.
  12. Is Evidence Supporting the Subtelomere-Telomere Theory of Aging?
  13. Age-dependent expression changes of circadian system-related genes reveal a potentially conserved link to aging.
  14. Senescence Alterations in Pulmonary Hypertension.
  15. nc886, a Non-Coding RNA, Is a New Biomarker and Epigenetic Mediator of Cellular Senescence in Fibroblasts.
  16. Immunosenescence and Autoimmunity: Exploiting the T-Cell Receptor Repertoire to Investigate the Impact of Aging on Multiple Sclerosis.
  17. Cellular Senescence: Mechanisms and Therapeutic Potential.
  18. The effect of lactoferrin in aging: role and potential.
  19. Protocol for assessing senescence-associated lung pathologies in mice.
  20. Late-life exercise mitigates skeletal muscle epigenetic aging.
  21. Senescent Cells in Cancer: Wanted or Unwanted Citizens.
  22. Resolvin D1 Suppresses H2O2-Induced Senescence in Fibroblasts by Inducing Autophagy through the miR-1299/ARG2/ARL1 Axis.
  23. Metabolic reprogramming during hyperammonemia targets mitochondrial function and postmitotic senescence.
  1. Nat Immunol. 2021 Dec 23.
    Aging disrupts circadian gene regulation and function in macrophages.
    Eran Blacher, Connie Tsai, Lev Litichevskiy, Zohar Shipony, Chinyere Agbaegbu Iweka, Kai Markus Schneider, Bayarsaikhan Chuluun, H Craig Heller, Vilas Menon, Christoph A Thaiss, Katrin I Andreasson.
      Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.
    DOI:  https://doi.org/10.1038/s41590-021-01083-0
  2. Front Aging Neurosci. 2021 ;13 766306
    Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons.
    Sandra Lizbeth Morales-Rosales, Roberto Santín-Márquez, Pedro Posadas-Rodriguez, Ruth Rincon-Heredia, Teresa Montiel, Raúl Librado-Osorio, Armando Luna-López, Nadia Alejandra Rivero-Segura, Claudio Torres, Agustina Cano-Martínez, Alejandro Silva-Palacios, Paulina Cortés-Hernández, Julio Morán, Lourdes Massieu, Mina Konigsberg.
      The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron. In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide [stress-induced premature senescence (SIPS)]. Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state [reduced glutathione/oxidized glutathione (GSH/GSSG)], the mitochondrial morphology, and the proteins and membrane potential were determined. Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.
    Keywords:  aging; astrocyte; cellular senescence; mitochondria; redox state
    DOI:  https://doi.org/10.3389/fnagi.2021.766306
  3. Cell Death Dis. 2021 Dec 20. 13(1): 9
    CDK5RAP2 loss-of-function causes premature cell senescence via the GSK3β/β-catenin-WIP1 pathway.
    Xidi Wang, Patrick Sipila, Zizhen Si, Jesusa L Rosales, Xu Gao, Ki-Young Lee.
      Developmental disorders characterized by small body size have been linked to CDK5RAP2 loss-of-function mutations, but the mechanisms underlying which remain obscure. Here, we demonstrate that knocking down CDK5RAP2 in human fibroblasts triggers premature cell senescence that is recapitulated in Cdk5rap2an/an mouse embryonic fibroblasts and embryos, which exhibit reduced body weight and size, and increased senescence-associated (SA)-β-gal staining compared to Cdk5rap2+/+ and Cdk5rap2+/an embryos. Interestingly, CDK5RAP2-knockdown human fibroblasts show increased p53 Ser15 phosphorylation that does not correlate with activation of p53 kinases, but rather correlates with decreased level of the p53 phosphatase, WIP1. Ectopic WIP1 expression reverses the senescent phenotype in CDK5RAP2-knockdown cells, indicating that senescence in these cells is linked to WIP1 downregulation. CDK5RAP2 interacts with GSK3β, causing increased inhibitory GSK3β Ser9 phosphorylation and inhibiting the activity of GSK3β, which phosphorylates β-catenin, tagging β-catenin for degradation. Thus, loss of CDK5RAP2 decreases GSK3β Ser9 phosphorylation and increases GSK3β activity, reducing nuclear β-catenin, which affects the expression of NF-κB target genes such as WIP1. Consequently, loss of CDK5RAP2 or β-catenin causes WIP1 downregulation. Inhibition of GSK3β activity restores β-catenin and WIP1 levels in CDK5RAP2-knockdown cells, reducing p53 Ser15 phosphorylation and preventing senescence in these cells. Conversely, inhibition of WIP1 activity increases p53 Ser15 phosphorylation and senescence in CDK5RAP2-depleted cells lacking GSK3β activity. These findings indicate that loss of CDK5RAP2 promotes premature cell senescence through GSK3β/β-catenin downregulation of WIP1. Premature cell senescence may contribute to reduced body size associated with CDK5RAP2 loss-of-function.
    DOI:  https://doi.org/10.1038/s41419-021-04457-2
  4. Free Radic Biol Med. 2021 Dec 15. pii: S0891-5849(21)01108-4. [Epub ahead of print]178 391-397
    Impact of zinc on DNA integrity and age-related inflammation.
    Emily Ho, Carmen P Wong, Janet C King.
      Dr. Bruce Ames was a pioneer in understanding the role of oxidative stress and DNA damage, and in the 1990s began to make connections between micronutrient deficiencies and DNA damage. Zinc is an essential micronutrient for human health and a key component for the function of numerous cellular processes. In particular, zinc plays a critical role in cellular antioxidant defense, the maintenance of DNA integrity and is also essential for the normal development and function of the immune system. This review highlights the work helping connect zinc deficiency to oxidative stress, susceptibility to DNA damage and chronic inflammation that was initiated while working with Dr. Ames. This review outlines the body of work in this area, from cells to humans. The article also reviews the unique challenges of maintaining zinc status as we age and the interplay between zinc deficiency and age-related inflammation and immune dysfunction. Several micronutrient deficiencies, including zinc deficiency, can drastically affect the risk of many chronic diseases and underscores the importance of adequate nutrition for healthy aging.
    Keywords:  Aging; DNA damage; Inflammation; Oxidative stress; Zinc
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.12.256
  5. Int J Mol Sci. 2021 Dec 17. pii: 13562. [Epub ahead of print]22(24):
    Human MSC-Derived Exosomes Reduce Cellular Senescence in Renal Epithelial Cells.
    Chieh Ming Liao, Tianjiao Luo, Juliane von der Ohe, Blanca de Juan Mora, Roland Schmitt, Ralf Hass.
      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.
    Keywords:  MSC; PTEC; SASP; aging; exosome; kidney; senescence
    DOI:  https://doi.org/10.3390/ijms222413562
  6. Aging Cell. 2021 Dec 24. e13541
    Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration.
    Ali Fathi, Sakthikumar Mathivanan, Linghai Kong, Andrew J Petersen, Cole R K Harder, Jasper Block, Julia Marie Miller, Anita Bhattacharyya, Daifeng Wang, Su-Chun Zhang.
      Modeling age-related neurodegenerative disorders with human stem cells are difficult due to the embryonic nature of stem cell-derived neurons. We developed a chemical cocktail to induce senescence of iPSC-derived neurons to address this challenge. We first screened small molecules that induce embryonic fibroblasts to exhibit features characteristic of aged fibroblasts. We then optimized a cocktail of small molecules that induced senescence in fibroblasts and cortical neurons without causing DNA damage. The utility of the "senescence cocktail" was validated in motor neurons derived from ALS patient iPSCs which exhibited protein aggregation and axonal degeneration substantially earlier than those without cocktail treatment. Our "senescence cocktail" will likely enhance the manifestation of disease-related phenotypes in neurons derived from iPSCs, enabling the generation of reliable drug discovery platforms.
    Keywords:  cell senescence; disease modeling; neural differentiation; neurodegeneration
    DOI:  https://doi.org/10.1111/acel.13541
  7. Cells. 2021 Dec 09. pii: 3474. [Epub ahead of print]10(12):
    Cellular Senescence in Adrenocortical Biology and Its Disorders.
    Xin Gao, Faping Li, Bin Liu, Yuxiong Wang, Yishu Wang, Honglan Zhou.
      Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders.
    Keywords:  adrenal cortex; aging; cellular senescence; compact and clear cells
    DOI:  https://doi.org/10.3390/cells10123474
  8. PLoS Genet. 2021 Dec 20. 17(12): e1009953
    tRNA biogenesis and specific aminoacyl-tRNA synthetases regulate senescence stability under the control of mTOR.
    Jordan Guillon, Hugo Coquelet, Géraldine Leman, Bertrand Toutain, Coralie Petit, Cécile Henry, Alice Boissard, Catherine Guette, Olivier Coqueret.
      Oncogenes or chemotherapy treatments trigger the induction of suppressive pathways such as apoptosis or senescence. Senescence was initially defined as a definitive arrest of cell proliferation but recent results have shown that this mechanism is also associated with cancer progression and chemotherapy resistance. Senescence is therefore much more heterogeneous than initially thought. How this response varies is not really understood, it has been proposed that its outcome relies on the secretome of senescent cells and on the maintenance of their epigenetic marks. Using experimental models of senescence escape, we now described that the stability of this proliferative arrest relies on specific tRNAs and aminoacyl-tRNA synthetases. Following chemotherapy treatment, the DNA binding of the type III RNA polymerase was reduced to prevent tRNA transcription and induce a complete cell cycle arrest. By contrast, during senescence escape, specific tRNAs such as tRNA-Leu-CAA and tRNA-Tyr-GTA were up-regulated. Reducing tRNA transcription appears necessary to control the strength of senescence since RNA pol III inhibition through BRF1 depletion maintained senescence and blocked the generation of escaping cells. mTOR inhibition also prevented chemotherapy-induced senescence escape in association with a reduction of tRNA-Leu-CAA and tRNA-Tyr-GTA expression. Further confirming the role of the tRNA-Leu-CAA and tRNA-Tyr-GTA, results showed that their corresponding tRNA ligases, LARS and YARS, were necessary for senescence escape. This effect was specific since the CARS ligase had no effect on persistence. By contrast, the down-regulation of LARS and YARS reduced the emergence of persistent cells and this was associated with the modulation of E2F1 target genes expression. Overall, these findings highlight a new regulation of tRNA biology during senescence and suggest that specific tRNAs and ligases contribute to the strength and heterogeneity of this tumor suppressive pathway.
    DOI:  https://doi.org/10.1371/journal.pgen.1009953
  9. Redox Biol. 2021 Dec 11. pii: S2213-2317(21)00372-4. [Epub ahead of print]49 102212
    Peroxiredoxin 6 protects irradiated cells from oxidative stress and shapes their senescence-associated cytokine landscape.
    Barbora Salovska, Alexandra Kondelova, Kristyna Pimkova, Zuzana Liblova, Miroslav Pribyl, Ivo Fabrik, Jiri Bartek, Marie Vajrychova, Zdenek Hodny.
      Cellular senescence is a complex stress response defined as an essentially irreversible cell cycle arrest mediated by the inhibition of cell cycle-specific cyclin dependent kinases. The imbalance in redox homeostasis and oxidative stress have been repeatedly observed as one of the hallmarks of the senescent phenotype. However, a large-scale study investigating protein oxidation and redox signaling in senescent cells in vitro has been lacking. Here we applied a proteome-wide analysis using SILAC-iodoTMT workflow to quantitatively estimate the level of protein sulfhydryl oxidation and proteome level changes in ionizing radiation-induced senescence (IRIS) in hTERT-RPE-1 cells. We observed that senescent cells mobilized the antioxidant system to buffer the increased oxidation stress. Among the antioxidant proteins with increased relative abundance in IRIS, a unique 1-Cys peroxiredoxin family member, peroxiredoxin 6 (PRDX6), was identified as an important contributor to protection against oxidative stress. PRDX6 silencing increased ROS production in senescent cells, decreased their resistance to oxidative stress-induced cell death, and impaired their viability. Subsequent SILAC-iodoTMT and secretome analysis after PRDX6 silencing showed the downregulation of PRDX6 in IRIS affected protein secretory pathways, decreased expression of extracellular matrix proteins, and led to unexpected attenuation of senescence-associated secretory phenotype (SASP). The latter was exemplified by decreased secretion of pro-inflammatory cytokine IL-6 which was also confirmed after treatment with an inhibitor of PRDX6 iPLA2 activity, MJ33. In conclusion, by combining different methodological approaches we discovered a novel role of PRDX6 in senescent cell viability and SASP development. Our results suggest PRDX6 could have a potential as a drug target for senolytic or senomodulatory therapy.
    Keywords:  Cellular senescence; Interleukin 6; Peroxiredoxin 6; Redox proteomics; SILAC-iodoTMT; Senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.redox.2021.102212
  10. Cells. 2021 Dec 15. pii: 3544. [Epub ahead of print]10(12):
    Cytosolic Self-DNA-A Potential Source of Chronic Inflammation in Aging.
    Mansour Akbari, Daryl P Shanley, Vilhelm A Bohr, Lene Juel Rasmussen.
      Aging is the consequence of a lifelong accumulation of stochastic damage to tissues and cellular components. Advancing age closely associates with elevated markers of innate immunity and low-grade chronic inflammation, probably reflecting steady increasing incidents of cellular and tissue damage over the life course. The DNA sensing cGAS-STING signaling pathway is activated by misplaced cytosolic self-DNA, which then initiates the innate immune responses. Here, we hypothesize that the stochastic release of various forms of DNA from the nucleus and mitochondria, e.g., because of DNA damage, altered nucleus integrity, and mitochondrial damage, can result in chronic activation of inflammatory responses that characterize the aging process. This cytosolic self-DNA-innate immunity axis may perturb tissue homeostasis and function that characterizes human aging and age-associated pathology. Proper techniques and experimental models are available to investigate this axis to develop therapeutic interventions.
    Keywords:  DNA repair; aging; cGAS-STING; cytosolic self-DNA; inflammation; mitochondria
    DOI:  https://doi.org/10.3390/cells10123544
  11. Aging Cell. 2021 Dec 24. e13536
    Increased MFG-E8 at neuromuscular junctions is an exacerbating factor for sarcopenia-associated denervation.
    Madoka Ikemoto-Uezumi, Heying Zhou, Tamaki Kurosawa, Yuki Yoshimoto, Masashi Toyoda, Nobuo Kanazawa, Tatsu Nakazawa, Mitsuhiro Morita, Kunihiro Tsuchida, Akiyoshi Uezumi.
      Sarcopenia is an important health problem associated with adverse outcomes. Although the etiology of sarcopenia remains poorly understood, factors apart from muscle fibers, including humoral factors, might be involved. Here, we used cytokine antibody arrays to identify humoral factors involved in sarcopenia and found a significant increase in levels of milk fat globule epidermal growth factor 8 (MFG-E8) in skeletal muscle of aged mice, compared with young mice. We found that the increase in MFG-E8 protein at arterial walls and neuromuscular junctions (NMJs) in muscles of aged mice. High levels of MFG-E8 at NMJs and an age-related increase in arterial MFG-E8 have also been identified in human skeletal muscle. In NMJs, MFG-E8 is localized on the surface of terminal Schwann cells, which are important accessory cells for the maintenance of NMJs. We found that increased MFG-E8 at NMJs precedes age-related denervation and is more prominent in sarcopenia-susceptible fast-twitch than in sarcopenia-resistant slow-twitch muscle. Comparison between fast and slow muscles further revealed that arterial MFG-E8 can be uncoupled from sarcopenic phenotype. A genetic deficiency in MFG-E8 attenuated age-related denervation of NMJs and muscle weakness, providing evidence of a pathogenic role of increased MFG-E8. Thus, our study revealed a mechanism by which increased MFG-E8 at NMJs leads to age-related NMJ degeneration and suggests that targeting MFG-E8 could be a promising therapeutic approach to prevent sarcopenia.
    Keywords:  MFG-E8; aging; denervation; neuromuscular junction; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.13536
  12. Biochemistry (Mosc). 2021 Dec;86(12): 1526-1539
    Is Evidence Supporting the Subtelomere-Telomere Theory of Aging?
    Giacinto Libertini, Olga Shubernetskaya, Graziamaria Corbi, Nicola Ferrara.
      The telomere theory tries to explain cellular mechanisms of aging as mainly caused by telomere shortening at each duplication. The subtelomere-telomere theory overcomes various shortcomings of telomere theory by highlighting the essential role of subtelomeric DNA in aging mechanisms. The present work illustrates and deepens the correspondence between assumptions and implications of subtelomere-telomere theory and experimental results. In particular, it is investigated the evidence regarding the relationships between aging and (i) epigenetic modifications; (ii) oxidation and inflammation; (iii) telomere protection; (iv) telomeric heterochromatin hood; (v) gradual cell senescence; (vi) cell senescence; and (vii) organism decline with telomere shortening. The evidence appears broadly in accordance or at least compatible with the description and implications of the subtelomere-telomere theory. In short, phenomena of cellular aging, by which the senescence of the whole organism is determined in various ways, appear substantially dependent on epigenetic modifications regulated by the subtelomere-telomere-telomeric hood-telomerase system. These phenomena appear to be not random, inevitable, and irreversible but rather induced and regulated by genetically determined mechanisms, and modifiable and reversible by appropriate methods. All this supports the thesis that aging is a genetically programmed and regulated phenoptotic phenomenon and is against the opposite thesis of aging as caused by random and inevitable degenerative factors.
    Keywords:  aging; cell senescence; epigenetic changes; gradual cell senescence; phenoptosis; subtelomere; telomere; telomeric heterochromatin hood
    DOI:  https://doi.org/10.1134/S0006297921120026
  13. Aging (Albany NY). 2021 Dec 19. 13(undefined):
    Age-dependent expression changes of circadian system-related genes reveal a potentially conserved link to aging.
    Emanuel Barth, Akash Srivastava, Diane Wengerodt, Milan Stojiljkovic, Hubertus Axer, Otto W Witte, Alexandra Kretz, Manja Marz.
      The circadian clock system influences the biology of life by establishing circadian rhythms in organisms, tissues, and cells, thus regulating essential biological processes based on the day/night cycle. Circadian rhythms change over a lifetime due to maturation and aging, and disturbances in the control of the circadian system are associated with several age-related pathologies. However, the impact of chronobiology and the circadian system on healthy organ and tissue aging remains largely unknown. Whether aging-related changes of the circadian system's regulation follow a conserved pattern across different species and tissues, hence representing a common driving force of aging, is unclear. Based on a cross-sectional transcriptome analysis covering 329 RNA-Seq libraries, we provide indications that the circadian system is subjected to aging-related gene alterations shared between evolutionarily distinct species, such as Homo sapiens, Mus musculus, Danio rerio, and Nothobranchius furzeri. We discovered differentially expressed genes by comparing tissue-specific transcriptional profiles of mature, aged, and old-age individuals and report on six genes (per2, dec2, cirp, klf10, nfil3, and dbp) of the circadian system, which show conserved aging-related expression patterns in four organs of the species examined. Our results illustrate how the circadian system and aging might influence each other in various tissues over a long lifespan and conceptually complement previous studies tracking short-term diurnal and nocturnal gene expression oscillations.
    Keywords:  RNA-Seq; aging; circadian clock system; circadian rhythm; inter-species comparison; longevity
    DOI:  https://doi.org/10.18632/aging.203788
  14. Cells. 2021 Dec 08. pii: 3456. [Epub ahead of print]10(12):
    Senescence Alterations in Pulmonary Hypertension.
    Inés Roger, Javier Milara, Nada Belhadj, Julio Cortijo.
      Cellular senescence is the arrest of normal cell division and is commonly associated with aging. The interest in the role of cellular senescence in lung diseases derives from the observation of markers of senescence in chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (IPF), and pulmonary hypertension (PH). Accumulation of senescent cells and the senescence-associated secretory phenotype in the lung of aged patients may lead to mild persistent inflammation, which results in tissue damage. Oxidative stress due to environmental exposures such as cigarette smoke also promotes cellular senescence, together with additional forms of cellular stress such as mitochondrial dysfunction and endoplasmic reticulum stress. Growing recent evidence indicate that senescent cell phenotypes are observed in pulmonary artery smooth muscle cells and endothelial cells of patients with PH, contributing to pulmonary artery remodeling and PH development. In this review, we analyze the role of different senescence cell phenotypes contributing to the pulmonary artery remodeling process in different PH clinical entities. Different molecular pathway activation and cellular functions derived from senescence activation will be analyzed and discussed as promising targets to develop future senotherapies as promising treatments to attenuate pulmonary artery remodeling in PH.
    Keywords:  SASP; pulmonary hypertension; senescence; senolytics
    DOI:  https://doi.org/10.3390/cells10123456
  15. Int J Mol Sci. 2021 Dec 20. pii: 13673. [Epub ahead of print]22(24):
    nc886, a Non-Coding RNA, Is a New Biomarker and Epigenetic Mediator of Cellular Senescence in Fibroblasts.
    Yuna Kim, Hyanggi Ji, Eunae Cho, Nok-Hyun Park, Kyeonghwan Hwang, Wonseok Park, Kwang-Soo Lee, Deokhoon Park, Eunsun Jung.
      Functional studies of organisms and human models have revealed that epigenetic changes can significantly impact the process of aging. Non-coding RNA (ncRNA), one of epigenetic regulators, plays an important role in modifying the expression of mRNAs and their proteins. It can mediate the phenotype of cells. It has been reported that nc886 (=vtRNA2-1 or pre-miR-886), a long ncRNA, can suppress tumor formation and photo-damages of keratinocytes caused by UVB. The aim of this study was to determine the role of nc886 in replicative senescence of fibroblasts and determine whether substances capable of controlling nc886 expression could regulate cellular senescence. In replicative senescence fibroblasts, nc886 expression was decreased while methylated nc886 was increased. There were changes of senescence biomarkers including SA-β-gal activity and expression of p16INK4A and p21Waf1/Cip1 in senescent cells. These findings indicate that the decrease of nc886 associated with aging is related to cellular senescence of fibroblasts and that increasing nc886 expression has potential to suppress cellular senescence. AbsoluTea Concentrate 2.0 (ATC) increased nc886 expression and ameliorated cellular senescence of fibroblasts by inhibiting age-related biomarkers. These results indicate that nc886 has potential as a new target for anti-aging and that ATC can be a potent epigenetic anti-aging ingredient.
    Keywords:  epigenetic regulation; fibroblasts; green tea extract; nc886; replicative senescence
    DOI:  https://doi.org/10.3390/ijms222413673
  16. Front Immunol. 2021 ;12 799380
    Immunosenescence and Autoimmunity: Exploiting the T-Cell Receptor Repertoire to Investigate the Impact of Aging on Multiple Sclerosis.
    Roberta Amoriello, Alice Mariottini, Clara Ballerini.
      T-cell receptor (TCR) repertoire diversity is a determining factor for the immune system capability in fighting infections and preventing autoimmunity. During life, the TCR repertoire diversity progressively declines as a physiological aging progress. The investigation of TCR repertoire dynamics over life represents a powerful tool unraveling the impact of immunosenescence in health and disease. Multiple Sclerosis (MS) is a demyelinating, inflammatory, T-cell mediated autoimmune disease of the Central Nervous System in which age is crucial: it is the most widespread neurological disease among young adults and, furthermore, patients age may impact on MS progression and treatments outcome. Crossing knowledge on the TCR repertoire dynamics over MS patients' life is fundamental to investigate disease mechanisms, and the advent of high- throughput sequencing (HTS) has significantly increased our knowledge on the topic. Here we report an overview of current literature about the impact of immunosenescence and age-related TCR dynamics variation in autoimmunity, including MS.
    Keywords:  T cell receptor (TCR); aging; autoimmune diseases; disease modifying therapies (DMTs); multiple sclerosis
    DOI:  https://doi.org/10.3389/fimmu.2021.799380
  17. Biomedicines. 2021 Nov 25. pii: 1769. [Epub ahead of print]9(12):
    Cellular Senescence: Mechanisms and Therapeutic Potential.
    Zehuan Liao, Han Lin Yeo, Siaw Wen Wong, Yan Zhao.
      Cellular senescence is a complex and multistep biological process which cells can undergo in response to different stresses. Referring to a highly stable cell cycle arrest, cellular senescence can influence a multitude of biological processes-both physiologically and pathologically. While phenotypically diverse, characteristics of senescence include the expression of the senescence-associated secretory phenotype, cell cycle arrest factors, senescence-associated β-galactosidase, morphogenesis, and chromatin remodelling. Persistent senescence is associated with pathologies such as aging, while transient senescence is associated with beneficial programmes, such as limb patterning. With these implications, senescence-based translational studies, namely senotherapy and pro-senescence therapy, are well underway to find the cure to complicated diseases such as cancer and atherosclerosis. Being a subject of major interest only in the recent decades, much remains to be studied, such as regarding the identification of unique biomarkers of senescent cells. This review attempts to provide a comprehensive understanding of the diverse literature on senescence, and discuss the knowledge we have on senescence thus far.
    Keywords:  aging; cancer; senescence; senotherapy
    DOI:  https://doi.org/10.3390/biomedicines9121769
  18. Food Funct. 2021 Dec 20.
    The effect of lactoferrin in aging: role and potential.
    Bing Li, Bo Zhang, Xudong Liu, Yidan Zheng, Kuntong Han, Henan Liu, Changjing Wu, Jin Li, Shuhua Fan, Weifeng Peng, Fuli Zhang, Xiaomeng Liu.
      Aging is frequently accompanied by various types of physiological deterioration, which increases the risk of human pathologies. Global public health efforts to increase human lifespan have increasingly focused on lowering the risk of aging-related diseases, such as diabetes, neurodegenerative diseases, cardiovascular disease, and cancers. Dietary intervention is a promising approach to maintaining human health during aging. Lactoferrin (LF) is known for its physiologically pleiotropic properties. Anti-aging interventions of LF have proven to be safe and effective for various pharmacological activities, such as anti-oxidation, anti-cellular senescence, anti-inflammation, and anti-carcinogenic. Moreover, LF has a pivotal role in modulating the major signaling pathways that influence the longevity of organisms. Thus, LF is expected to be able to attenuate the process of aging and greatly ameliorate its effects.
    DOI:  https://doi.org/10.1039/d1fo02750f
  19. STAR Protoc. 2021 Dec 17. 2(4): 100993
    Protocol for assessing senescence-associated lung pathologies in mice.
    Koichiro Kawaguchi, Michihiro Hashimoto, Ryuta Mikawa, Azusa Asai, Tadashi Sato, Masataka Sugimoto.
      Cellular senescence underlies tissue aging and aging-associated pathologies, as well as lung pathology. We and others have shown that elimination of senescent cells alleviates pulmonary diseases such as fibrosis and emphysema in animal models. We herein describe a protocol for assessing senescence-dependent lung phenotypes in mice. This protocol describes the use of ARF-DTR mice for semi-genetic elimination of lung senescent cells, followed by a pulmonary function test and the combination with pulmonary disease models to study lung pathologies. For complete details on the use and execution of this protocol, please refer to Hashimoto et al. (2016), Kawaguchi et al. (2021), and Mikawa et al. (2018).
    Keywords:  Cell Biology; Health Sciences; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2021.100993
  20. Aging Cell. 2021 Dec 21. e13527
    Late-life exercise mitigates skeletal muscle epigenetic aging.
    Kevin A Murach, Andrea L Dimet-Wiley, Yuan Wen, Camille R Brightwell, Christine M Latham, Cory M Dungan, Christopher S Fry, Stanley J Watowich.
      There are functional benefits to exercise in muscle, even when performed late in life, but the contributions of epigenetic factors to late-life exercise adaptation are poorly defined. Using reduced representation bisulfite sequencing (RRBS), ribosomal DNA (rDNA) and mitochondrial-specific examination of methylation, targeted high-resolution methylation analysis, and DNAge™ epigenetic aging clock analysis with a translatable model of voluntary murine endurance/resistance exercise training (progressive weighted wheel running, PoWeR), we provide evidence that exercise may mitigate epigenetic aging in skeletal muscle. Late-life PoWeR from 22-24 months of age modestly but significantly attenuates an age-associated shift toward promoter hypermethylation. The epigenetic age of muscle from old mice that PoWeR-trained for eight weeks was approximately eight weeks younger than 24-month-old sedentary counterparts, which represents ~8% of the expected murine lifespan. These data provide a molecular basis for exercise as a therapy to attenuate skeletal muscle aging.
    Keywords:   Rbm10 ; Timm8a1 ; Horvath clock; PoWeR; rDNA
    DOI:  https://doi.org/10.1111/acel.13527
  21. Cells. 2021 Nov 26. pii: 3315. [Epub ahead of print]10(12):
    Senescent Cells in Cancer: Wanted or Unwanted Citizens.
    Sven E Niklander, Daniel W Lambert, Keith D Hunter.
      Over recent decades, the field of cellular senescence has attracted considerable attention due to its association with aging, the development of age-related diseases and cancer. Senescent cells are unable to proliferate, as the pathways responsible for initiating the cell cycle are irreversibly inhibited. Nevertheless, senescent cells accumulate in tissues and develop a pro-inflammatory secretome, known as the senescence-associated secretory phenotype (SASP), which can have serious deleterious effects if not properly regulated. There is increasing evidence suggesting senescent cells contribute to different stages of carcinogenesis in different anatomical sites, mainly due to the paracrine effects of the SASP. Thus, a new therapeutic field, known as senotherapeutics, has developed. In this review, we aim to discuss the molecular mechanisms underlying the senescence response and its relationship with cancer development, focusing on the link between senescence-related inflammation and cancer. We will also discuss different approaches to target senescent cells that might be of use for cancer treatment.
    Keywords:  SASP; cancer; carcinogenesis; senescence; senolytics; senomorphics
    DOI:  https://doi.org/10.3390/cells10123315
  22. Antioxidants (Basel). 2021 Nov 30. pii: 1924. [Epub ahead of print]10(12):
    Resolvin D1 Suppresses H2O2-Induced Senescence in Fibroblasts by Inducing Autophagy through the miR-1299/ARG2/ARL1 Axis.
    Hyun Ji Kim, Boram Kim, Hyung Jung Byun, Lu Yu, Tuan Minh Nguyen, Thi Ha Nguyen, Phuong Anh Do, Eun Ji Kim, Kyung Ah Cheong, Kyung Sung Kim, Hiệu Huy Phùng, Mostafizur Rahman, Ji Yun Jang, Seung Bae Rho, Gyeoung Jin Kang, Mi Kyung Park, Ho Lee, Kyeong Lee, Jungsook Cho, Hyo Kyung Han, Sang Geon Kim, Ai Young Lee, Chang Hoon Lee.
      ARG2 has been reported to inhibit autophagy in vascular endothelial cells and keratinocytes. However, studies of its mechanism of action, its role in skin fibroblasts, and the possibility of promoting autophagy and inhibiting cellular senescence through ARG2 inhibition are lacking. We induced cellular senescence in dermal fibroblasts by using H2O2. H2O2-induced fibroblast senescence was inhibited upon ARG2 knockdown and promoted upon ARG2 overexpression. The microRNA miR-1299 suppressed ARG2 expression, thereby inhibiting fibroblast senescence, and miR-1299 inhibitors promoted dermal fibroblast senescence by upregulating ARG2. Using yeast two-hybrid assay, we found that ARG2 binds to ARL1. ARL1 knockdown inhibited autophagy and ARL1 overexpression promoted it. Resolvin D1 (RvD1) suppressed ARG2 expression and cellular senescence. These data indicate that ARG2 stimulates dermal fibroblast cell senescence by inhibiting autophagy after interacting with ARL1. In addition, RvD1 appears to promote autophagy and inhibit dermal fibroblast senescence by inhibiting ARG2 expression. Taken together, the miR-1299/ARG2/ARL1 axis emerges as a novel mechanism of the ARG2-induced inhibition of autophagy. Furthermore, these results indicate that miR-1299 and pro-resolving lipids, including RvD1, are likely involved in inhibiting cellular senescence by inducing autophagy.
    Keywords:  ARG2; ARL1; H2O2; autophagy; cell senescence; fibroblast; miR-1299
    DOI:  https://doi.org/10.3390/antiox10121924
  23. JCI Insight. 2021 Dec 22. pii: e154089. [Epub ahead of print]6(24):
    Metabolic reprogramming during hyperammonemia targets mitochondrial function and postmitotic senescence.
    Avinash Kumar, Nicole Welch, Saurabh Mishra, Annette Bellar, Rafaella Nasciemento Silva, Ling Li, Shashi Shekhar Singh, Mary Sharkoff, Alexis Kerr, Aruna Kumar Chelluboyina, Jinendiran Sekar, Amy H Attaway, Charles Hoppel, Belinda Willard, Gangarao Davuluri, Srinivasan Dasarathy.
      Ammonia is a cytotoxic metabolite with pleiotropic molecular and metabolic effects, including senescence induction. During dysregulated ammonia metabolism, which occurs in chronic diseases, skeletal muscle becomes a major organ for nonhepatocyte ammonia uptake. Muscle ammonia disposal occurs in mitochondria via cataplerosis of critical intermediary metabolite α-ketoglutarate, a senescence-ameliorating molecule. Untargeted and mitochondrially targeted data were analyzed by multiomics approaches. These analyses were validated experimentally to dissect the specific mitochondrial oxidative defects and functional consequences, including senescence. Responses to ammonia lowering in myotubes and in hyperammonemic portacaval anastomosis rat muscle were studied. Whole-cell transcriptomics integrated with whole-cell, mitochondrial, and tissue proteomics showed distinct temporal clusters of responses with enrichment of oxidative dysfunction and senescence-related pathways/proteins during hyperammonemia and after ammonia withdrawal. Functional and metabolic studies showed defects in electron transport chain complexes I, III, and IV; loss of supercomplex assembly; decreased ATP synthesis; increased free radical generation with oxidative modification of proteins/lipids; and senescence-associated molecular phenotype-increased β-galactosidase activity and expression of p16INK, p21, and p53. These perturbations were partially reversed by ammonia lowering. Dysregulated ammonia metabolism caused reversible mitochondrial dysfunction by transcriptional and translational perturbations in multiple pathways with a distinct skeletal muscle senescence-associated molecular phenotype.
    Keywords:  Cell Biology; Cellular senescence; Hepatology; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.154089
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