bims-senagi Biomed News
on Senescence and aging
Issue of 2022‒01‒23
forty-nine papers selected by
Maria Grazia Vizioli
Mayo Clinic
  1. Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche.
  2. Spatially Confined Intervention of Cellular Senescence by a Lysosomal Metabolism Targeting Molecular Prodrug for Broad-Spectrum Senotherapy.
  3. Inhibition of IKKβ/NF-κB signaling facilitates tendinopathy healing by rejuvenating inflamm-aging induced tendon-derived stem/progenitor cell senescence.
  4. WNT/beta-catenin signalling interrupts a senescence-induction cascade in human mesenchymal stem cells that restricts their expansion.
  5. Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy.
  6. The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease.
  7. Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile.
  8. The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients' Lymphocytes Favoring Chemotherapy Efficacy.
  9. Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell mediated reduction of therapy induced senescent cells.
  10. The biological clean-ups that could combat age-related disease.
  11. ER reductive stress caused by Ero1α S-nitrosation accelerates senescence.
  12. GDF15, an emerging key player in human aging.
  13. Single-cell Transcriptomic Profiling of the Hypothalamic Median Eminence during Aging.
  14. Exploring New Kingdoms: The Role of Extracellular Vesicles in Oxi-Inflamm-Aging Related to Cardiorenal Syndrome.
  15. Ribosomal DNA and the nucleolus at the heart of aging.
  16. Metabolomic Profiles of Mouse Tissues Reveal an Interplay between Aging and Energy Metabolism.
  17. Epigenetic aging of the demographically non-aging naked mole-rat.
  18. Cellular senescence: all roads lead to mitochondria.
  19. Mesenchymal Stem Cell Senescence and Osteogenesis.
  20. Proper control of R-loop homeostasis is required for maintenance of gene expression and neuronal function during aging.
  21. Targeting Epigenetic Mechanisms in Vascular Aging.
  22. DJ-1 depletion prevents immunoaging in T-cell compartments.
  23. MOB3A bypasses BRAF and RAS oncogene-induced senescence by engaging the Hippo pathway.
  24. cGAS and cancer therapy: a double-edged sword.
  25. TLR4 downregulation by the RNA-binding protein PUM1 alleviates cellular aging and osteoarthritis.
  26. Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7.
  27. Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis.
  28. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.
  29. Mitophagy mechanisms in neuronal physiology and pathology during ageing.
  30. Sex-dependent effects of chronic exercise on cognitive flexibility but not hippocampal Bdnf in aging mice.
  31. Tissue engineering strategies to bioengineer the ageing skin phenotype in vitro.
  32. Preventing age-related motor unit loss; is exercise the answer?
  33. High fat diet-induced brain damaging effects through autophagy-mediated senescence, inflammation and apoptosis mitigated by ginsenoside F1-enhanced mixture.
  34. Muscle mitochondrial energetics predicts mobility decline in well-functioning older adults: The baltimore longitudinal study of aging.
  35. Does the human lifespan have a limit?
  36. Carving the senescent phenotype by the chemical reactivity of catecholamines: An integrative review.
  37. DNA methylation signatures in Blood DNA of Hutchinson-Gilford Progeria syndrome.
  38. Hindlimb Immobilization Increases IL-1β and Cdkn2a Expression in Skeletal Muscle Fibro-Adipogenic Progenitor Cells: A Link Between Senescence and Muscle Disuse Atrophy.
  39. Adaptive capacity to dietary Vitamin B12 levels is maintained by a gene-diet interaction that ensures optimal life span.
  40. Novel SARS-CoV-2 therapeutic targets: RNA proofreading complex and virus-induced senescence.
  41. CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal.
  42. How the COVID-19 pandemic might age us.
  43. Mild calorie restriction, but not 17α-estradiol, extends ovarian reserve and fertility in female mice.
  44. Retrotransposons as a Source of DNA Damage in Neurodegeneration.
  45. Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models.
  46. Senolytic drugs: Beyond the promise and the hype.
  47. Correlation between telomere length and biomarkers of oxidative stress in human aging.
  48. Astrocyte immunosenescence and deficits in interleukin 10 signaling in the aged brain disrupt the regulation of microglia following innate immune activation.
  49. The cGAS/STING Pathway: A Novel Target for Cancer Therapy.
  1. Stem Cell Reports. 2021 Dec 28. pii: S2213-6711(21)00649-4. [Epub ahead of print]
    Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche.
    Michael P Fatt, Lina M Tran, Gisella Vetere, Mekayla A Storer, Jaclin V Simonetta, Freda D Miller, Paul W Frankland, David R Kaplan.
      Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on CNS neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Genetic ablation of senescent cells similarly activated hippocampal NPCs. This acute burst of neurogenesis had long-term effects in middle-aged mice. One month post-ABT-263, adult-born hippocampal neuron numbers increased and hippocampus-dependent spatial memory was enhanced. These data support a model where senescent niche cells negatively influence neighboring non-senescent NPCs during aging, and ablation of these senescent cells partially restores neurogenesis and hippocampus-dependent cognition.
    Keywords:  ABT-263; aging; hippcampus; neural stem cells; neurogenesis; senescence; senescence-associated secretory phenotype; senolytic; spatial memory
    DOI:  https://doi.org/10.1016/j.stemcr.2021.12.010
  2. Angew Chem Int Ed Engl. 2022 Jan 17.
    Spatially Confined Intervention of Cellular Senescence by a Lysosomal Metabolism Targeting Molecular Prodrug for Broad-Spectrum Senotherapy.
    Yanlan Liu, Yinghao Xia, Jili Li, Linlin Wang, Xiyuan Luo, Yuqi Xie.
      Specific intervention of senescent cells (SnCs) is emerging as a powerful means to counteract aging and age-related diseases. Canonical methods are generally designed to target SnC-associated signaling pathways, which are however dynamically changing and highly heterogeneous in SnCs, significantly limiting the effectiveness. Here, we present a tailor-made molecular prodrug targeting lysosome dysfunction, a unique feature shared by virtually all types of SnCs.The prodrug comprises three modules all targeting the altered lysosomal programs in SnCs, namely, a recognizing unit towards the elevated lysosome content, a linker cleavable by the activated lysosomal enzyme, and a lysosomotropic agent targeting the increased lysosomal membrane sensitivity. This spatially confined design enables killing broad-spectrum SnCs, with high specificity over non-SnCs. Along with in vivo benefits, this work offers a way to significantly expand the applicability of senotherapy in a wide range of diseases.
    Keywords:  Cellular senescence; age-related diseases; molecular senolytics; organelle targeting; prodrug
    DOI:  https://doi.org/10.1002/anie.202115764
  3. Mol Ther Nucleic Acids. 2022 Mar 08. 27 562-576
    Inhibition of IKKβ/NF-κB signaling facilitates tendinopathy healing by rejuvenating inflamm-aging induced tendon-derived stem/progenitor cell senescence.
    Chongyang Wang, Zhekun Zhou, Wei Song, Zhuochang Cai, Zhenyu Ding, Daoyun Chen, Fangfang Xia, Yaohua He.
      Degenerative rotator cuff tendinopathy (RCT) is a chronic tendon disease caused by degeneration and inflammation, which often affects the elderly population. Mesenchymal stem cell senescence is generally recognized as an important pathophysiological mechanism in many age-related skeletal diseases. Herein, we collected human tendon-derived stem/progenitor cells (TSPCs) from degenerative supraspinatus tendons and found that TSPC senescence is closely related to RCT. We further identified that nuclear factor κB (NF-κB) pathway activation is involved in age-related inflammation (inflamm-aging) of degenerative RCT. Moreover, whole genome RNA sequencing revealed that in vitro inhibition of the I kappa B kinase β (IKKβ)/NF-κB signaling pathway could reverse the aged TSPC phenotype with decreased TSPC senescence and increased tenogenic potential. To achieve effective in vivo inhibition of IKKβ/NF-κB signaling, we fabricated IKKβ small interfering RNA (siRNA)-loaded gold nanoclusters (AuNC-siRNA) for efficient and convenient intra-articular delivery of IKKβ siRNA. We found that AuNC-siRNA prevented inflamm-aging-induced TSPC senescence and dysfunction in a degenerative RCT aged rat model. Together, these data show that inflamm-aging causes degenerative RCT through inducing TSPC senescence, which can be reversed by blocking the IKKβ/NF-κB pathway in vivo. Thus, our study provides a promising therapeutic strategy for degenerative RCT via intra-articular delivery of IKKβ siRNA using AuNCs.
    Keywords:  NF-κB; cellular senescence; inflamm-aging; rotator cuff; tendinopathy
    DOI:  https://doi.org/10.1016/j.omtn.2021.12.026
  4. Cell Mol Life Sci. 2022 Jan 20. 79(2): 82
    WNT/beta-catenin signalling interrupts a senescence-induction cascade in human mesenchymal stem cells that restricts their expansion.
    Johannes Lehmann, Roberto Narcisi, Natasja Franceschini, Danai Chatzivasileiou, Cindy G Boer, Wendy J L M Koevoet, Diana Putavet, Dubravka Drabek, Rien van Haperen, Peter L J de Keizer, Gerjo J V M van Osch, Derk Ten Berge.
      Senescence, the irreversible cell cycle arrest of damaged cells, is accompanied by a deleterious pro-inflammatory senescence-associated secretory phenotype (SASP). Senescence and the SASP are major factors in aging, cancer, and degenerative diseases, and interfere with the expansion of adult cells in vitro, yet little is known about how to counteract their induction and deleterious effects. Paracrine signals are increasingly recognized as important senescence triggers and understanding their regulation and mode of action may provide novel opportunities to reduce senescence-induced inflammation and improve cell-based therapies. Here, we show that the signalling protein WNT3A counteracts the induction of paracrine senescence in cultured human adult mesenchymal stem cells (MSCs). We find that entry into senescence in a small subpopulation of MSCs triggers a secretome that causes a feed-forward signalling cascade that with increasing speed induces healthy cells into senescence. WNT signals interrupt this cascade by repressing cytokines that mediate this induction of senescence. Inhibition of those mediators by interference with NF-κB or interleukin 6 signalling reduced paracrine senescence in absence of WNT3A and promoted the expansion of MSCs. Our work reveals how WNT signals can antagonize senescence and has relevance not only for expansion of adult cells but can also provide new insights into senescence-associated inflammatory and degenerative diseases.
    Keywords:  Cell cycle; Multipotent stromal cells; Paracrine senescence; Secondary senescence
    DOI:  https://doi.org/10.1007/s00018-021-04035-x
  5. Cells. 2022 Jan 13. pii: 273. [Epub ahead of print]11(2):
    Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy.
    Benjamin M Freyter, Mutaz A Abd Al-Razaq, Anna Isermann, Anne Dietz, Omid Azimzadeh, Liesbeth Hekking, Maria Gomolka, Claudia E Rübe.
      Irreparable DNA damage following ionizing radiation (IR) triggers prolonged DNA damage response and induces premature senescence. Cellular senescence is a permanent state of cell-cycle arrest characterized by chromatin restructuring, altered nuclear morphology and acquisition of secretory phenotype, which contributes to senescence-related inflammation. However, the mechanistic connections for radiation-induced DNA damage that trigger these senescence-associated hallmarks are poorly understood. In our in vitro model of radiation-induced senescence, mass spectrometry-based proteomics was combined with high-resolution imaging techniques to investigate the interrelations between altered chromatin compaction, nuclear envelope destabilization and nucleo-cytoplasmic chromatin blebbing. Our findings confirm the general pathophysiology of the senescence-response, with disruption of nuclear lamin organization leading to extensive chromatin restructuring and destabilization of the nuclear membrane with release of chromatin fragments into the cytosol, thereby activating cGAS-STING-dependent interferon signaling. By serial block-face scanning electron microscopy (SBF-SEM) whole-cell datasets were acquired to investigate the morphological organization of senescent fibroblasts. High-resolution 3-dimensional (3D) reconstruction of the complex nuclear shape allows us to precisely visualize the segregation of nuclear blebs from the main nucleus and their fusion with lysosomes. By multi-view 3D electron microscopy, we identified nanotubular channels formed in lamin-perturbed nuclei of senescent fibroblasts; the potential role of these nucleo-cytoplasmic nanotubes for expulsion of damaged chromatin has to be examined.
    Keywords:  cGAS-STING signaling; cellular senescence; chromatin reorganization; cytosolic chromatin fragments (CCF); ionizing radiation; nuclear blebbing; radiation-induced senescence; serial block-face scanning electron microscopy (SBF-SEM); transmission electron microscopy (TEM)
    DOI:  https://doi.org/10.3390/cells11020273
  6. Int J Mol Sci. 2022 Jan 07. pii: 652. [Epub ahead of print]23(2):
    The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease.
    Cornelius Engelmann, Frank Tacke.
      Non-alcoholic fatty liver disease (NAFLD) represents an increasing global health burden. Cellular senescence develops in response to cellular injury, leading not only to cell cycle arrest but also to alterations of the cellular phenotype and metabolic functions. In this review, we critically discuss the currently existing evidence for the involvement of cellular senescence in NAFLD in order to identify areas requiring further exploration. Hepatocyte senescence can be a central pathomechanism as it may foster intracellular fat accumulation, fibrosis and inflammation, also due to secretion of senescence-associated inflammatory mediators. However, in some non-parenchymal liver cell types, such as hepatic stellate cells, senescence may be beneficial by reducing the extracellular matrix deposition and thereby reducing fibrosis. Deciphering the detailed interaction between NAFLD and cellular senescence will be essential to discover novel therapeutic targets halting disease progression.
    Keywords:  NAFLD; NASH; SASP; fibrosis; mitochondrial dysfunction; senescence associated secretory phenotype
    DOI:  https://doi.org/10.3390/ijms23020652
  7. Aging (Albany NY). 2022 Jan 18. 14(undefined):
    Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile.
    Adam Krzystyniak, Malgorzata Wesierska, Gregory Petrazzo, Agnieszka Gadecka, Magdalena Dudkowska, Anna Bielak-Zmijewska, Grazyna Mosieniak, Izabela Figiel, Jakub Wlodarczyk, Ewa Sikora.
      Aging is associated with cognitive decline and accumulation of senescent cells in various tissues and organs. Senolytic agents such as dasatinib and quercetin (D+Q) in combination have been shown to target senescent cells and ameliorate symptoms of aging-related disorders in mouse models. However, the mechanisms by which senolytics improve cognitive impairments have not been fully elucidated particularly in species other than mice. To study the effect of senolytics on aging-related multifactorial cognitive dysfunctions we tested the spatial memory of male Wistar rats in an active allothetic place avoidance task. Here we report that 8 weeks treatment with D+Q alleviated learning deficits and memory impairment observed in aged animals. Furthermore, treatment with D+Q resulted in a reduction of the peripheral inflammation measured by the levels of serum inflammatory mediators (including members of senescent cell secretome) in aged rats. Significant improvements in cognitive abilities observed in aged rats upon treatment with D+Q were associated with changes in the dendritic spine morphology of the apical dendritic tree from the hippocampal CA1 neurons and changes in the level of histone H3 trimethylation at lysine 9 and 27 in the hippocampus. The beneficial effects of D+Q on learning and memory in aged rats were long-lasting and persisted at least 5 weeks after the cessation of the drugs administration. Our results expand and provide new insights to the existing knowledge associated with effects of senolytics on alleviating age-related associated cognitive dysfunctions.
    Keywords:  SASP; aging; brain; cognition; hippocampus; memory; plasticity; senescence
    DOI:  https://doi.org/10.18632/aging.203835
  8. Cells. 2022 Jan 15. pii: 294. [Epub ahead of print]11(2):
    The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients' Lymphocytes Favoring Chemotherapy Efficacy.
    Annibale Alessandro Puca, Valentina Lopardo, Francesco Montella, Paola Di Pietro, Daniela Cesselli, Irene Giulia Rolle, Michela Bulfoni, Veronica Di Sarno, Giorgio Iaconetta, Pietro Campiglia, Carmine Vecchione, Antonio Paolo Beltrami, Elena Ciaglia.
      Glioblastoma (GBM) is the most common primary brain cancer with the median age at diagnosis around 64 years, thus pointing to aging as an important risk factor. Indeed, aging, by increasing the senescence burden, is configured as a negative prognostic factor for GBM stage. Furthermore, several anti-GBM therapies exist, such as temozolomide (TMZ) and etoposide (ETP), that unfortunately trigger senescence and the secretion of proinflammatory senescence-associated secretory phenotype (SASP) factors that are responsible for the improper burst of (i) tumorigenesis, (ii) cancer metastasis, (iii) immunosuppression, and (iv) tissue dysfunction. Thus, adjuvant therapies that limit senescence are urgently needed. The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene previously demonstrated a modulatory activity in restoring age-related immune dysfunction and in balancing the low-grade inflammatory status of elderly people. Based on the above findings, we tested LAV-BPIFB4 senotherapeutic effects on senescent glioblastoma U87-MG cells and on T cells from GBM patients. We interrogated SA-β-gal and HLA-E senescence markers, SASP factors, and proliferation and apoptosis assays. The results highlighted a LAV-BPIFB4 remodeling of the senescent phenotype of GBM cells, enhancement of their sensitivity to temozolomide and a selective reduction of the T cells' senescence from GBM patients. Overall, these findings candidate LAV-BPIFB4 as an adjuvant therapy for GBM.
    Keywords:  PBMCs; chemotherapy; glioma; longevity; senescence
    DOI:  https://doi.org/10.3390/cells11020294
  9. Mol Ther. 2022 Jan 17. pii: S1525-0016(22)00025-9. [Epub ahead of print]
    Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell mediated reduction of therapy induced senescent cells.
    Pallavi Chaturvedi, Varghese George, Niraj Shrestha, Meng Wang, Michael J Dee, Xiaoyun Zhu, Bai Liu, Jack Egan, Francesca D'Eramo, Catherine Spanoudis, Victor Gallo, Christian Echeverri, Lijing You, Lin Kong, Byron Fang, Emily K Jeng, Peter R Rhode, Hing C Wong.
      Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we showed that the immunotherapeutic HCW9218, comprising TGF-β receptor II and IL-15/IL-15 receptor α domains, enhanced metabolic and cytotoxic activities of immune cells and reduced TIS tumor cells in vivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduced the immunosuppressive tumor microenvironment and enhanced immune-cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggested that HCW9218-activated natural killer cells played a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhanced efficacy of tumor antigen-specific and anti-PDL-1 antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreased TIS cells and lowered SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.
    Keywords:  CD8(+) T cells; IL-15; Immunotherapy; NK cells; TGF-β antagonist; checkpoint blockade; chemotherapy; therapeutic antibody; therapy-induced senescence
    DOI:  https://doi.org/10.1016/j.ymthe.2022.01.025
  10. Nature. 2022 Jan;601(7893): S15-S17
    The biological clean-ups that could combat age-related disease.
    Elie Dolgin.
      
    Keywords:  Ageing; Biotechnology; Drug discovery
    DOI:  https://doi.org/10.1038/d41586-022-00075-w
  11. Free Radic Biol Med. 2022 Jan 13. pii: S0891-5849(22)00017-X. [Epub ahead of print]
    ER reductive stress caused by Ero1α S-nitrosation accelerates senescence.
    Xinhua Qiao, Yingmin Zhang, Aojun Ye, Yini Zhang, Ting Xie, Zhenyu Lv, Cang Shi, Dongli Wu, Boyu Chu, Xun Wu, Weiqi Zhang, Ping Wang, Guang-Hui Liu, Chih-Chen Wang, Lei Wang, Chang Chen.
      Oxidative stress in aging has attracted much attention; however, the role of reductive stress in aging remains largely unknown. Here, we report that the endoplasmic reticulum (ER) undergoes reductive stress during replicative senescence, as shown by specific glutathione and H2O2 fluorescent probes. We constructed an ER-specific reductive stress cell model by ER-specific catalase overexpression and observed accelerated senescent phenotypes accompanied by disrupted proteostasis and a compromised ER unfolded protein response (UPR). Mechanistically, S-nitrosation of the pivotal ER sulfhydryl oxidase Ero1α led to decreased activity, therefore resulting in reductive stress in the ER. Inhibition of inducible nitric oxide synthase decreased the level of Ero1α S-nitrosation and decreased cellular senescence. Moreover, the expression of constitutively active Ero1α restored an oxidizing state in the ER and successfully rescued the senescent phenotypes. Our results uncover a new mechanism of senescence promoted by ER reductive stress and provide proof-of-concept that maintaining the oxidizing power of the ER and organelle-specific precision redox regulation could be valuable future geroprotective strategies.
    Keywords:  Aging; Endoplasmic reticulum (ER); Ero1α; Proteostasis; Reductive stress; S-Nitrosation/S-nitrosylation; Senescence; Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.01.006
  12. Ageing Res Rev. 2022 Jan 17. pii: S1568-1637(22)00011-3. [Epub ahead of print] 101569
    GDF15, an emerging key player in human aging.
    Maria Conte, Cristina Giuliani, Antonio Chiariello, Vincenzo Iannuzzi, Claudio Franceschi, Stefano Salvioli.
      Growth differentiation factor 15 (GDF15) is recently emerging not only as a stress-related mitokine, but also as a key player in the aging process, being the most up-regulated protein with age and associated with a variety of age-related diseases (ARDs). Many data indicate that GDF15 has protective roles in several tissues during different stress and aging, thus playing a beneficial role in apparent contrast with the observed association with many ARDs. A possible detrimental role for this protein is then hypothesised to emerge with age. Therefore, GDF15 can be considered as a pleiotropic factor with beneficial activities that can turn detrimental in old age possibly when it is chronically elevated. In this review, we summarize the current knowledge on the biology of GDF15 during aging. We also propose GDF15 as a part of a dormancy program, where it may play as a mediator of defence processes aimed to protect from inflammatory damage and other stresses, according to the life history theory.
    Keywords:  GDF15; age-related diseases; dormancy program; inflammaging; metabolism; stress
    DOI:  https://doi.org/10.1016/j.arr.2022.101569
  13. J Genet Genomics. 2022 Jan 12. pii: S1673-8527(22)00004-2. [Epub ahead of print]
    Single-cell Transcriptomic Profiling of the Hypothalamic Median Eminence during Aging.
    Zhen-Hua Chen, Si Li, Mingrui Xu, Candace C Liu, Hongying Ye, Ben Wang, Qing-Feng Wu.
      Aging is a slow and progressive natural process that compromises the normal functions of cells, tissues, organs and systems. The aging of the hypothalamic median eminence (ME), a structural gate linking neural and endocrine systems, may impair hormone release, energy homeostasis and central sensing of circulating molecules, leading to systemic and reproductive aging. However, the molecular and cellular features of ME aging remain largely unknown. Here we describe the transcriptional landscape of young and middle-aged mouse ME at single-cell resolution, revealing the common and cell-type-specific transcriptional changes with age. The transcriptional changes in cell-intrinsic programs, cell-cell crosstalk and cell-extrinsic factors highlight five molecular features of ME aging and also implicate several potentially druggable targets at cellular, signaling and molecular levels. Importantly, our results suggest that vascular and leptomeningeal cells (VLMCs) may lead the asynchronized aging process among diverse cell types and drive local inflammation and cellular senescence via a unique secretome. Together, our study uncovers how intrinsic and extrinsic features of each cell type in the hypothalamic ME are changed by the aging process, which will facilitate our understanding of brain aging and provide clues for efficient anti-aging intervention at the middle-aged stage.
    Keywords:  Hypothalamic median eminence; Single-cell transcriptomic analysis; Vascular and leptomeningeal cells; aging
    DOI:  https://doi.org/10.1016/j.jgg.2022.01.001
  14. Antioxidants (Basel). 2021 Dec 29. pii: 78. [Epub ahead of print]11(1):
    Exploring New Kingdoms: The Role of Extracellular Vesicles in Oxi-Inflamm-Aging Related to Cardiorenal Syndrome.
    Cristina Mas-Bargues, Matilde Alique, María Teresa Barrús-Ortiz, Consuelo Borrás, Raquel Rodrigues-Díez.
      The incidence of age associated chronic diseases has increased in recent years. Although several diverse causes produce these phenomena, abundant evidence shows that oxidative stress plays a central role. In recent years, numerous studies have focused on elucidating the role of oxidative stress in the development and progression of both aging and chronic diseases, opening the door to the discovery of new underlying mechanisms and signaling pathways. Among them, senolytics and senomorphics, and extracellular vesicles offer new therapeutic strategies to slow the development of aging and its associated chronic diseases by decreasing oxidative stress. In this review, we aim to discuss the role of extracellular vesicles in human cardiorenal syndrome development and their possible role as biomarkers, targets, or vehicles of drugs to treat this syndrome.
    Keywords:  age-related pathologies; aging; extracellular vesicles; inflammation; oxi-inflamm-aging; oxidative stress; senescence; senolytics
    DOI:  https://doi.org/10.3390/antiox11010078
  15. Trends Biochem Sci. 2022 Jan 18. pii: S0968-0004(21)00276-0. [Epub ahead of print]
    Ribosomal DNA and the nucleolus at the heart of aging.
    Eirini Kasselimi, Dafni-Eleftheria Pefani, Stavros Taraviras, Zoi Lygerou.
      The rRNA genes [ribosomal DNA (rDNA)] are organized in a prominent nuclear compartment, the nucleolus. It is now well established that the nucleolus functions beyond ribosome biosynthesis, regulating several physiological cellular responses. The nucleoli constitute dynamic genomic/nuclear hubs and demonstrate unique inherent characteristics, rendering them ideal to sense, signal, and respond to various intrinsic and environmental insults. Here, we discuss emerging findings supporting direct links between rDNA/nucleolar instability and cellular senescence/organismal aging from yeast to mammals. Moreover, we highlight evidence that nucleolar functionality and rDNA architecture impact on meiotic/transgenerational rejuvenation, thus revealing causality underlying connections between rDNA/nucleolar instability and aging.
    Keywords:  aging; life span; nucleolus; rejuvenation; replicative senescence; ribosomal DNA
    DOI:  https://doi.org/10.1016/j.tibs.2021.12.007
  16. Metabolites. 2021 Dec 26. pii: 17. [Epub ahead of print]12(1):
    Metabolomic Profiles of Mouse Tissues Reveal an Interplay between Aging and Energy Metabolism.
    Qishun Zhou, Jakob Kerbl-Knapp, Fangrong Zhang, Melanie Korbelius, Katharina Barbara Kuentzel, Nemanja Vujić, Alena Akhmetshina, Gerd Hörl, Margret Paar, Ernst Steyrer, Dagmar Kratky, Tobias Madl.
      Energy metabolism, including alterations in energy intake and expenditure, is closely related to aging and longevity. Metabolomics studies have recently unraveled changes in metabolite composition in plasma and tissues during aging and have provided critical information to elucidate the molecular basis of the aging process. However, the metabolic changes in tissues responsible for food intake and lipid storage have remained unexplored. In this study, we aimed to investigate aging-related metabolic alterations in these tissues. To fill this gap, we employed NMR-based metabolomics in several tissues, including different parts of the intestine (duodenum, jejunum, ileum) and brown/white adipose tissues (BAT, WAT), of young (9-10 weeks) and old (96-104 weeks) wild-type (mixed genetic background of 129/J and C57BL/6) mice. We, further, included plasma and skeletal muscle of the same mice to verify previous results. Strikingly, we found that duodenum, jejunum, ileum, and WAT do not metabolically age. In contrast, plasma, skeletal muscle, and BAT show a strong metabolic aging phenotype. Overall, we provide first insights into the metabolic changes of tissues essential for nutrient uptake and lipid storage and have identified biomarkers for metabolites that could be further explored, to study the molecular mechanisms of aging.
    Keywords:  NMR spectroscopy; aging; energy metabolism; fat; intestine; metabolomics; mice
    DOI:  https://doi.org/10.3390/metabo12010017
  17. Nat Commun. 2022 Jan 17. 13(1): 355
    Epigenetic aging of the demographically non-aging naked mole-rat.
    Csaba Kerepesi, Margarita V Meer, Julia Ablaeva, Vince G Amoroso, Sang-Goo Lee, Bohan Zhang, Maxim V Gerashchenko, Alexandre Trapp, Sun Hee Yim, Ake T Lu, Morgan E Levine, Andrei Seluanov, Steve Horvath, Thomas J Park, Vera Gorbunova, Vadim N Gladyshev.
      The naked mole-rat (NMR) is an exceptionally long-lived rodent that shows no increase of mortality with age, defining it as a demographically non-aging mammal. Here, we perform bisulfite sequencing of the blood of > 100 NMRs, assessing > 3 million common CpG sites. Unsupervised clustering based on sites whose methylation correlates with age reveals an age-related methylome remodeling, and we also observe a methylome information loss, suggesting that NMRs age. We develop an epigenetic aging clock that accurately predicts the NMR age. We show that these animals age much slower than mice and much faster than humans, consistent with their known maximum lifespans. Interestingly, patterns of age-related changes of clock sites in Tert and Prpf19 differ between NMRs and mice, but there are also sites conserved between the two species. Together, the data indicate that NMRs, like other mammals, epigenetically age even in the absence of demographic aging of this species.
    DOI:  https://doi.org/10.1038/s41467-022-27959-9
  18. FEBS J. 2022 Jan 20.
    Cellular senescence: all roads lead to mitochondria.
    Hélène Martini, João F Passos.
      Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and a pro-inflammatory phenotype, commonly known as the Senescence-Associated secretory Phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues, drives tissue dysfunction and several age-related conditions. This has spurred the academic community and industry to identify new therapeutic interventions targeting this process. Mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence which plays important roles not only in the senescence growth arrest but also in the development of the SASP and resistance to cell-death. Here, we review the evidence that supports a role for mitochondria in the development of senescence and describe the underlying mechanisms. Finally, we propose that a detailed road map of mitochondrial biology in senescence will be crucial to guide the future development of senotherapies.
    Keywords:  Mitochondria; SASP; aging; senescence
    DOI:  https://doi.org/10.1111/febs.16361
  19. Medicina (Kaunas). 2021 Dec 31. pii: 61. [Epub ahead of print]58(1):
    Mesenchymal Stem Cell Senescence and Osteogenesis.
    Artaria Tjempakasari, Heri Suroto, Djoko Santoso.
      Mesenchymal stem cells (MSCs) are stem cells with the potential ability to differentiate into various cells and the ability to self-renew and resemble fibroblasts. These cells can adhere to plastic to facilitate the culture process. MSCs can be used in research into tissue biotechnology and rejuvenation medicine. MSCs are also beneficial in recipient tissue and differentiate as a breakthrough strategy through paracrine activity. Many databases have shown MSC-based treatment can be beneficial in the reduction of osteogenesis induced by senescence. In this article, we will discuss the potential effect of MSCs in senescence cells related to osteogenesis.
    Keywords:  MSCs senescence; cellular senescence; mesenchymal stem cells; osteogenesis
    DOI:  https://doi.org/10.3390/medicina58010061
  20. Aging Cell. 2022 Jan 20. e13554
    Proper control of R-loop homeostasis is required for maintenance of gene expression and neuronal function during aging.
    Juan Jauregui-Lozano, Spencer Escobedo, Alyssa Easton, Nadia A Lanman, Vikki M Weake, Hana Hall.
      Age-related loss of cellular function and increased cell death are characteristic hallmarks of aging. While defects in gene expression and RNA metabolism have been linked with age-associated human neuropathies, it is not clear how the changes that occur in aging neurons contribute to loss of gene expression homeostasis. R-loops are RNA-DNA hybrids that typically form co-transcriptionally via annealing of the nascent RNA to the template DNA strand, displacing the non-template DNA strand. Dysregulation of R-loop homeostasis has been associated with both transcriptional impairment and genome instability. Importantly, a growing body of evidence links R-loop accumulation with cellular dysfunction, increased cell death, and chronic disease onset. Here, we characterized the R-loop landscape in aging Drosophila melanogaster photoreceptor neurons and showed that bulk R-loop levels increased with age. Further, genome-wide mapping of R-loops revealed that transcribed genes accumulated R-loops over gene bodies during aging, which correlated with decreased expression of long and highly expressed genes. Importantly, while photoreceptor-specific down-regulation of Top3β, a DNA/RNA topoisomerase associated with R-loop resolution, lead to decreased visual function, over-expression of Top3β or nuclear-localized RNase H1, which resolves R-loops, enhanced positive light response during aging. Together, our studies highlight the functional link between dysregulation of R-loop homeostasis, gene expression, and visual function during aging.
    Keywords:   Drosophila ; R-loop; aging; eye; neurons; photoreceptors; transcription; visual
    DOI:  https://doi.org/10.1111/acel.13554
  21. Front Cardiovasc Med. 2021 ;8 806988
    Targeting Epigenetic Mechanisms in Vascular Aging.
    Zhongxiao Lin, Qian Ding, Xinzhi Li, Yuliang Feng, Hao He, Chuoji Huang, YiZhun Zhu.
      Environment, diseases, lack of exercise, and aged tendency of population have becoming crucial factors that induce vascular aging. Vascular aging is unmodifiable risk factor for diseases like diabetes, hypertension, atherosclerosis, and hyperlipidemia. Effective interventions to combat this vascular function decline is becoming increasingly urgent as the rising hospitalization rate caused by vascular aging-related diseases. Fortunately, recent transformative omics approaches have enabled us to examine vascular aging mechanisms at unprecedented levels and precision, which make our understanding of slowing down or reversing vascular aging become possible. Epigenetic viz. DNA methylation, histone modifications, and non-coding RNA-based mechanisms, is a hallmark of vascular aging, its deregulation leads to aberrant transcription changes in tissues. Epigenetics mechanisms by mediating covalent modifications to DNA and histone proteins, consequently, influence the sensitivity and activities of signaling pathways in cells and tissues. A growing body of evidence supports correlations between epigenetic changes and vascular aging. In this article, we will provide a comprehensive overview of epigenetic changes associated with vascular aging based on the recent findings with a focus on molecular mechanisms of action, strategies to reverse epigenetic changes, and future perspectives.
    Keywords:  DNA methylation; chromatin architecture; epigenetics regulation; histone modifications; vascular aging
    DOI:  https://doi.org/10.3389/fcvm.2021.806988
  22. EMBO Rep. 2022 Jan 17. e53302
    DJ-1 depletion prevents immunoaging in T-cell compartments.
    Ni Zeng, Christophe M Capelle, Alexandre Baron, Takumi Kobayashi, Severine Cire, Vera Tslaf, Cathy Leonard, Djalil Coowar, Haruhiko Koseki, Astrid M Westendorf, Jan Buer, Dirk Brenner, Rejko Krüger, Rudi Balling, Markus Ollert, Feng Q Hefeng.
      Decline in immune function during aging increases susceptibility to different aging-related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here, we show that loss of DJ-1 encoded by PARK7/DJ-1, causing early-onset familial Parkinson's disease (PD), unexpectedly diminished signs of immunoaging in T-cell compartments of both human and mice. Compared with two gender-matched unaffected siblings of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled non-senescent T cells. The observation was further consolidated by the results in 45-week-old DJ-1 knockout mice. Our data demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Mechanistically, DJ-1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T-cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases.
    Keywords:  CD8 T cells; PARK7/DJ-1; aging; immune aging; immunosenescence
    DOI:  https://doi.org/10.15252/embr.202153302
  23. Mol Cancer Res. 2022 Jan 19. pii: molcanres.0767.2021. [Epub ahead of print]
    MOB3A bypasses BRAF and RAS oncogene-induced senescence by engaging the Hippo pathway.
    Kendall Dutchak, Sam Garnett, Mary Nicoll, Angeline de Bruyns, David Dankort.
      Oncogenic activation of the RTK-RAS-RAF-MEK-ERK pathway occurs in ~25% of all human cancers, yet activated RAS, BRAF or MEK expression in primary cells leads to a prolonged and predominantly irreversible cell cycle arrest termed oncogene-induced senescence (OIS). OIS acts as an intrinsic tumor suppressor mechanism, serving as a barrier to tumor progression. Screening a library of activated kinases and kinase-regulatory proteins we identified MOB3A, a Mps-one binder coactivator (MOB) protein family member, whose constitutive expression permits proliferation and suppresses senescence in response to oncogenic RAS and BRAF signals. MOB3A is one of seven human MOB genes, which are highly conserved from yeast to human and that function to activate the Hippo pathway kinases (MST/LATS) or NDR kinases. Here we show that within the MOB family of genes MOB3A and C are unique in their ability to allow primary cell proliferation in the face of sustained oncogene signaling. Unlike the canonical MOB1A/B proteins, MOB3A inhibits Hippo/MST/LATS signaling and constitutive MOB3A membrane localization phenocopies OIS bypass seen with elevated YAP expression. Moreover, inhibition of MOB3 family member expression results in decreased proliferation and tumor growth of cancer cell lines. Together these data identify MOB3A's role in bypass of oncogene induced senescence and its role as a Hippo pathway inhibitor. Implications: These results suggest that MOB3 targeting to re-engage the Hippo pathway, or direct targeting of YAP/TAZ, may be viable therapeutic strategies potential for RAS-pathway driven tumours.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0767
  24. Acta Pharmacol Sin. 2022 Jan 18.
    cGAS and cancer therapy: a double-edged sword.
    Jia-Min Du, Mei-Jia Qian, Tao Yuan, Rui-Han Chen, Qiao-Jun He, Bo Yang, Qi Ling, Hong Zhu.
      Cyclic guanosine monophosphate-adenosine monophosphate adenosine synthetase (cGAS) is a DNA sensor that detects and binds to cytosolic DNA to generate cyclic GMP-AMP (cGAMP). As a second messenger, cGAMP mainly activates the adapter protein STING, which induces the production of type I interferons (IFNs) and inflammatory cytokines. Mounting evidence shows that cGAS is extensively involved in the innate immune response, senescence, and tumor immunity, thereby exhibiting a tumor-suppressive function, most of which is mediated by the STING pathway. In contrast, cGAS can also act as an oncogenic factor, mostly by increasing genomic instability through inhibitory effects on DNA repair, suggesting its utility as an antitumor target. This article reviews the roles and the underlying mechanisms of cGAS in cancer, particularly focusing on its dual roles in carcinogenesis and tumor progression, which are probably attributable to its classical and nonclassical functions, as well as approaches targeting cGAS for cancer therapy.
    Keywords:  cGAS; tumor suppression; tumor promotion; cancer therapy
    DOI:  https://doi.org/10.1038/s41401-021-00839-6
  25. Cell Death Differ. 2022 Jan 16.
    TLR4 downregulation by the RNA-binding protein PUM1 alleviates cellular aging and osteoarthritis.
    Dong Suk Yoon, Kyoung-Mi Lee, Yoorim Choi, Eun Ae Ko, Na-Hyun Lee, Sehee Cho, Kwang Hwan Park, Jung-Hwan Lee, Hae-Won Kim, Jin Woo Lee.
      Dysfunction of mRNA or RNA-binding proteins (RBPs) causes cellular aging and age-related degenerative diseases; however, information regarding the mechanism through which RBP-mediated posttranscriptional regulation affects cellular aging and related disease processes is limited. In this study, PUM1 was found to be associated with the self-renewal capacity and aging process of human mesenchymal stem cells (MSC). PUM1 interacted with the 3'-untranslated region of Toll-like receptor 4 (TLR4) to suppress TLR4 mRNA translation and regulate the activity of nuclear factor-κB (NF-κB), a master regulator of the aging process in MSCs. PUM1 overexpression protected MSCs against H2O2-induced cellular senescence by suppressing TLR4-mediated NF-κB activity. TLR4-mediated NF-κB activation is a key regulator in osteoarthritis (OA) pathogenesis. PUM1 overexpression enhanced the chondrogenic potential of MSCs even under the influence of inflammation-inducing factors, such as lipopolysaccharide (LPS) or interleukin-1β (IL-1β), whereas the chondrogenic potential was reduced following the PUM1 knockdown-mediated TLR4 activation. PUM1 levels decreased under inflammatory conditions in vitro and during OA progression in human and mouse disease models. PUM1 knockdown in human chondrocytes promoted chondrogenic phenotype loss, whereas PUM1 overexpression protected the cells from inflammation-mediated disruption of the chondrogenic phenotype. Gene therapy using a lentiviral vector encoding mouse PUM1 showed promise in preserving articular cartilage integrity in OA mouse models. In conclusion, PUM1 is a novel suppressor of MSC aging, and the PUM1-TLR4 regulatory axis represents a potential therapeutic target for OA.
    DOI:  https://doi.org/10.1038/s41418-021-00925-6
  26. Ann Rheum Dis. 2022 Jan 20. pii: annrheumdis-2021-221513. [Epub ahead of print]
    Mechanical overloading promotes chondrocyte senescence and osteoarthritis development through downregulating FBXW7.
    Haiyan Zhang, Yan Shao, Zihao Yao, Liangliang Liu, Hongbo Zhang, Jianbin Yin, Haoyu Xie, Kai Li, Pinglin Lai, Hua Zeng, Guozhi Xiao, Chun Zeng, Daozhang Cai, Xiaochun Bai.
      OBJECTIVES: To investigate the role of mechanical stress in cartilage ageing and identify the mechanistic association during osteoarthritis (OA) progression.METHODS: F-box and WD repeat domain containing 7 (FBXW7) ubiquitin ligase expression and chondrocyte senescence were examined in vitro, in experimental OA mice and in human OA cartilage. Mice with Fbxw7 knockout in chondrocytes were generated and adenovirus-expressing Fbxw7 (AAV-Fbxw7) was injected intra-articularly in mice. Destabilised medial meniscus surgery was performed to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score and the changes in chondrocyte senescence were determined. mRNA sequencing was performed in articular cartilage from Fbxw7 knockout and control mice.
    RESULTS: Mechanical overloading accelerated senescence in cultured chondrocytes and in mice articular cartilage. FBXW7 was downregulated by mechanical overloading in primary chondrocytes and mice cartilage, and decreased in the cartilage of patients with OA, aged mice and OA mice. FBXW7 deletion in chondrocytes induced chondrocyte senescence and accelerated cartilage catabolism in mice, as manifested by an upregulation of p16INK4A, p21 and Colx and downregulation of Col2a1 and ACAN, which resulted in the exacerbation of OA. By contrast, intra-articular injection of adenovirus expressing Fbxw7 alleviated OA in mice. Mechanistically, mechanical overloading decreased Fbxw7 mRNA transcription and FBXW7-mediated MKK7 degradation, which consequently stimulated JNK signalling. In particular, inhibition of JNK activity by DTP3, a MKK7 inhibitor, ameliorated chondrocyte senescence and cartilage degeneration CONCLUSIONS: FBXW7 is a key factor in the association between mechanical overloading and chondrocyte senescence and cartilage ageing in the pathology of OA.
    Keywords:  chondrocytes; osteoarthritis; therapeutics
    DOI:  https://doi.org/10.1136/annrheumdis-2021-221513
  27. Nature. 2022 Jan 19.
    Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis.
    Kevin C Stein, Fabián Morales-Polanco, Joris van der Lienden, T Kelly Rainbolt, Judith Frydman.
      Ageing is accompanied by a decline in cellular proteostasis, which underlies many age-related protein misfolding diseases1,2. Yet, how ageing impairs proteostasis remains unclear. As nascent polypeptides represent a substantial burden on the proteostasis network3, we hypothesized that altered translational efficiency during ageing could help to drive the collapse of proteostasis. Here we show that ageing alters the kinetics of translation elongation in both Caenorhabditis elegans and Saccharomyces cerevisiae. Ribosome pausing was exacerbated at specific positions in aged yeast and worms, including polybasic stretches, leading to increased ribosome collisions known to trigger ribosome-associated quality control (RQC)4-6. Notably, aged yeast cells exhibited impaired clearance and increased aggregation of RQC substrates, indicating that ageing overwhelms this pathway. Indeed, long-lived yeast mutants reduced age-dependent ribosome pausing, and extended lifespan correlated with greater flux through the RQC pathway. Further linking altered translation to proteostasis collapse, we found that nascent polypeptides exhibiting age-dependent ribosome pausing in C. elegans were strongly enriched among age-dependent protein aggregates. Notably, ageing increased the pausing and aggregation of many components of proteostasis, which could initiate a cycle of proteostasis collapse. We propose that increased ribosome pausing, leading to RQC overload and nascent polypeptide aggregation, critically contributes to proteostasis impairment and systemic decline during ageing.
    DOI:  https://doi.org/10.1038/s41586-021-04295-4
  28. Nature. 2022 Jan 19.
    The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.
    Jeremy Di Domizio, Muhammet F Gulen, Fanny Saidoune, Vivek V Thacker, Ahmad Yatim, Kunal Sharma, Théo Nass, Emmanuella Guenova, Martin Schaller, Curdin Conrad, Christine Goepfert, Laurence De Leval, Christophe von Garnier, Sabina Berezowska, Anaëlle Dubois, Michel Gilliet, Andrea Ablasser.
      Coronavirus disease 2019 (COVID-19), caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is characterized by significant lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) play an essential role in the pathogenesis of COVID-193-5. While rapid induction of type I IFNs limits virus propagation, sustained elevation of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here, we identify the cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING)-pathway, which controls immunity to cytosolic DNA, as a critical driver of aberrant type I IFN responses in COVID-1918. Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples of COVID-19 patients with prominent tissue destruction and associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, SARS-CoV-2 infection activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, leading to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a novel principle for the development of host-directed therapeutics.
    DOI:  https://doi.org/10.1038/s41586-022-04421-w
  29. Biophys Rev. 2021 Dec;13(6): 955-965
    Mitophagy mechanisms in neuronal physiology and pathology during ageing.
    Maria Markaki, Dikaia Tsagkari, Nektarios Tavernarakis.
      Ageing in diverse species ranging from the simple nematode Caenorhabditis elegans to humans is associated with a marked decrease of neuronal function and increased susceptibility to neurodegeneration. Accumulating findings also indicate that alterations in neuronal functionality with age are associated with a decline in mitochondrial integrity and function. The rate at which a mitochondrial population is refreshed is determined by the coordination of mitochondrial biogenesis with mitophagy, a selective type of autophagy targeting damaged or superfluous mitochondria for degradation. Coupling of these opposing processes is crucial for maintaining cellular energy homeostasis, which eventually contributes to health span. Here, we focus on the role of mitophagy in nervous system function in the context of normal physiology and disease. First, we consider the progress that has been made over the last decade in elucidating the mechanisms that govern and regulate mitophagy, placing emphasis on the PINK1/Parkin-mediated mitophagy. We further discuss the contribution of mitophagy to the maintenance of neuronal homeostasis and health as well as recent findings implicating impaired mitophagy in age-related decline of the nervous system function and consequently in the pathogenesis of neurodegenerative diseases.
    Keywords:  Ageing; Energy homeostasis; Mitophagy; Neurodegeneration; Neuron; Neuronal health
    DOI:  https://doi.org/10.1007/s12551-021-00894-7
  30. Neuronal Signal. 2022 Apr;6(1): NS20210053
    Sex-dependent effects of chronic exercise on cognitive flexibility but not hippocampal Bdnf in aging mice.
    Annabel K Short, Viet Bui, Isabel C Zbukvic, Anthony J Hannan, Terence Y Pang, Jee Hyun Kim.
      Cognitive impairments associated with advanced age involve alterations in the hippocampus that changes with experience throughout life. The hippocampus is critical for cognitive flexibility involved with extinction and reinstatement of conditioned fear. It is widely accepted that regular exercise can be beneficial for hippocampal function. Therefore, we asked whether chronic voluntary exercise in middle-aged mice can improve extinction and/or reinstatement of conditioned fear compared with standard-housing. Eight-month-old male and female C57Bl/6J mice had access to a running wheel or remained in standard-housing until 11 months of age. Alongside control standard-housed young adult (3-month-old) mice, they received tone-footshock pairings, which were subsequently extinguished with tone-alone presentations the next day. Half of the mice then received a reminder in the form of a single footshock. Male and female 11-month-old mice housed in standard conditions exhibited impaired reinstatement compared with young adult mice. However, for males that had access to a running wheel from 8 months of age, the reminder treatment rescued reinstatement ability. This was not observed in females. Additionally, exercise during middle age in both sexes increased expression of brain-derived neurotrophic factor (Bdnf) mRNA in the hippocampus, specifically exon 4 mRNA. These results show that, at least for males, physical exercise is beneficial for reducing age-related decline in cognitive abilities. Despite not affecting reinstatement, exercise also increased Bdnf gene expression in the female hippocampus, which could potentially benefit other forms of hippocampus-dependent cognition.
    Keywords:  aging; bdnf; cognition; fear; neurotrophic factors; sex
    DOI:  https://doi.org/10.1042/NS20210053
  31. Aging Cell. 2022 Jan 17. e13550
    Tissue engineering strategies to bioengineer the ageing skin phenotype in vitro.
    Lydia Costello, Teresa Dicolandrea, Ryan Tasseff, Robert Isfort, Charlie Bascom, Thomas von Zglinicki, Stefan Przyborski.
      Human skin ageing is a complex and heterogeneous process, which is influenced by genetically determined intrinsic factors and accelerated by cumulative exposure to extrinsic stressors. In the current world ageing demographic, there is a requirement for a bioengineered ageing skin model, to further the understanding of the intricate molecular mechanisms of skin ageing, and provide a distinct and biologically relevant platform for testing actives and formulations. There have been many recent advances in the development of skin models that recapitulate aspects of the ageing phenotype in vitro. This review encompasses the features of skin ageing, the molecular mechanisms that drive the ageing phenotype, and tissue engineering strategies that have been utilised to bioengineer ageing skin in vitro.
    Keywords:  ageing; bioengineered tissue; human; in vitro; molecular biology of aging; skin
    DOI:  https://doi.org/10.1111/acel.13550
  32. Exp Gerontol. 2022 Jan 18. pii: S0531-5565(22)00003-1. [Epub ahead of print] 111695
    Preventing age-related motor unit loss; is exercise the answer?
    Mathew Piasecki, Daniel W Stashuk.
      
    DOI:  https://doi.org/10.1016/j.exger.2022.111695
  33. J Ginseng Res. 2022 Jan;46(1): 79-90
    High fat diet-induced brain damaging effects through autophagy-mediated senescence, inflammation and apoptosis mitigated by ginsenoside F1-enhanced mixture.
    Jingang Hou, Byeongmin Jeon, Jongin Baek, Yeejin Yun, Daeun Kim, Boyoon Chang, Sungyeon Kim, Sunchang Kim.
      Background: Herbal medicines are popular approaches to capably prevent and treat obesity and its related diseases. Excessive exposure to dietary lipids causes oxidative stress and inflammation, which possibly induces cellular senescence and contribute the damaging effects in brain. The potential roles of selective enhanced ginsenoside in regulating high fat diet (HFD)-induced brain damage remain unknown.Methods: The protection function of Ginsenoside F1-enhanced mixture (SGB121) was evaluated by in vivo and in vitro experiments. Human primary astrocytes and SH-SY5Y cells were treated with palmitic acid conjugated Bovine Serum Albumin, and the effects of SGB121 were determined by MTT and lipid uptake assays. For in vivo tests, C57BL/6J mice were fed with high fat diet for 3 months with or without SGB121 administration. Thereafter, immunohistochemistry, western blot, PCR and ELISA assays were conducted with brain tissues.
    Results and conclusion: SGB121 selectively suppressed HFD-induced oxidative stress and cellular senescence in brain, and reduced subsequent inflammation responses manifested by abrogated secretion of IL-6, IL-1β and TNFα via NF-κB signaling pathway. Interestingly, SGB121 protects against HFD-induced damage by improving mitophagy and endoplasmic reticulum-stress associated autophagy flux and inhibiting apoptosis. In addition, SGB121 regulates lipid uptake and accumulation by FATP4 and PPARα. SGB121 significantly abates excessively phosphorylated tau protein in the cortex and GFAP activation in corpus callosum. Together, our results suggest that SGB121 is able to favor the resistance of brain to HFD-induced damage, therefore provide explicit evidence of the potential to be a functional food.
    Keywords:  Autophagy; Brain damage; High fat diet; SGB121; Senescence
    DOI:  https://doi.org/10.1016/j.jgr.2021.04.002
  34. Aging Cell. 2022 Jan 20. e13552
    Muscle mitochondrial energetics predicts mobility decline in well-functioning older adults: The baltimore longitudinal study of aging.
    Qu Tian, Brendan A Mitchell, Marta Zampino, Kenneth W Fishbein, Richard G Spencer, Luigi Ferrucci.
      BACKGROUND: Muscle mitochondrial dysfunction is associated with poor mobility in aging. Whether mitochondrial dysfunction predicts subsequent mobility decline is unknown.METHODS: We examined 380 cognitively normal participants aged 60 and older (53%women, 22%Black) who were well-functioning (gait speed ≥ 1.0 m/s) and free of Parkinson's disease and stroke at baseline and had data on baseline skeletal muscle oxidative capacity and one or more mobility assessments during an average 2.5 years. Muscle oxidative capacity was measured by phosphorus magnetic resonance spectroscopy as the post-exercise recovery rate of phosphocreatine (kPCr ). Mobility was measured by four walking tests. Associations of baseline kPCr with mobility changes were examined using linear mixed-effects models, adjusted for covariates. In a subset, we examined whether changes in muscle strength and mass affected these associations by adjusting for longitudinal muscle strength, lean mass, and fat mass.
    RESULTS: Lower baseline kPCr was associated with greater decline in all four mobility measures (β, p-value: (0.036, 0.020) 6-m usual gait speed; (0.029, 0.038) 2.5-min usual gait speed; (0.034, 0.011) 6-m rapid gait speed; (-0.042, <0.001) 400-m time). In the subset, further adjustment for longitudinal muscle strength, lean mass, and fat mass attenuated longitudinal associations with changes in mobility (Δβ reduced 26-63%).
    CONCLUSION: Among initially well-functioning older adults, worse muscle mitochondrial function predicts mobility decline, and part of this longitudinal association is explained by decline in muscle strength and mass. Our findings suggest that worse mitochondrial function contributes to mobility decline with aging. These findings need to be verified in studies correlating longitudinal changes in mitochondrial function, muscle, and mobility performance.
    Keywords:  magnetic resonance spectroscopy; mitochondrial energetics; mobility decline; skeletal muscle; walking speed
    DOI:  https://doi.org/10.1111/acel.13552
  35. Nature. 2022 Jan;601(7893): S2-S4
    Does the human lifespan have a limit?
    Michael Eisenstein.
      
    Keywords:  Ageing; Society
    DOI:  https://doi.org/10.1038/d41586-022-00070-1
  36. Ageing Res Rev. 2022 Jan 17. pii: S1568-1637(22)00012-5. [Epub ahead of print] 101570
    Carving the senescent phenotype by the chemical reactivity of catecholamines: An integrative review.
    Aleksei G Golubev.
      Macromolecules damaged by covalent modifications produced by chemically reactive metabolites accumulate in the slowly renewable components of living bodies and compromise their functions. Among such metabolites, catecholamines (CA) are unique, compared with the ubiquitous oxygen, ROS, glucose and methylglyoxal, in that their high chemical reactivity is confined to a limited set of cell types, including the dopaminergic and noradrenergic neurons and their direct targets, which suffer from CA propensities for autoxidation yielding toxic quinones, and for Pictet-Spengler reactions with carbonyl-containing compounds, which yield mitochondrial toxins. The functions progressively compromised because of that include motor performance, cognition, reward-driven behaviors, emotional tuning, and the neuroendocrine control of reproduction. The phenotypic manifestations of the resulting disorders culminate in such conditions as Parkinson's and Alzheimer's diseases, hypertension, sarcopenia, and menopause. The reasons to suspect that CA play some special role in aging accumulated since early 1970-ies. Published reviews address the role of CA hazardousness in the development of specific aging-associated diseases. The present integrative review explores how the bizarre discrepancy between CA hazardousness and biological importance could have emerged in evolution, how much does the chemical reactivity of CA contribute to the senescent phenotype in mammals, and what can be done with it.
    Keywords:  aging; catecholamines; circulatory system; cognitive decline; gonadotropins; neurodegenerative diseases; neuromelanin; stem cell niches; steroid hormones
    DOI:  https://doi.org/10.1016/j.arr.2022.101570
  37. Aging Cell. 2022 Jan 19. e13555
    DNA methylation signatures in Blood DNA of Hutchinson-Gilford Progeria syndrome.
    Yosra Bejaoui, Aleem Razzaq, Noha A Yousri, Junko Oshima, Andre Megarbane, Abeer Qannan, Ramya Pottabatula, Tanvir Alam, George M Martin, Henning F Horn, Thomas Haaf, Steve Horvath, Nady El Hajj.
      Hutchinson-Gilford Progeria Syndrome (HGPS) is an extremely rare genetic disorder caused by mutations in the LMNA gene and characterized by premature and accelerated aging beginning in childhood. In this study, we performed the first genome-wide methylation analysis on blood DNA of 15 patients with progeroid laminopathies using Infinium Methylation EPIC arrays including 8 patients with classical HGPS. We could observe DNA methylation alterations at 61 CpG sites as well as 32 significant regions following a 5 Kb tiling analysis. Differentially methylated probes were enriched for phosphatidylinositol biosynthetic process, phospholipid biosynthetic process, sarcoplasm, sarcoplasmic reticulum, phosphatase regulator activity, glycerolipid biosynthetic process, glycerophospholipid biosynthetic process, and phosphatidylinositol metabolic process. Differential methylation analysis at the level of promoters and CpG islands revealed no significant methylation changes in blood DNA of progeroid laminopathy patients. Nevertheless, we could observe significant methylation differences in classic HGPS when specifically looking at probes overlapping solo-WCGW partially methylated domains. Comparing aberrantly methylated sites in progeroid laminopathies, classic Werner syndrome, and Down syndrome revealed a common significantly hypermethylated region in close vicinity to the transcription start site of a long non-coding RNA located anti-sense to the Catenin Beta Interacting Protein 1 gene (CTNNBIP1). By characterizing epigenetically altered sites, we identify possible pathways/mechanisms that might have a role in the accelerated aging of progeroid laminopathies.
    Keywords:  DNA methylation; Hutchinson-Gilford Progeria syndrome; accelerated aging; epigenetic clock; progeroid laminopathies
    DOI:  https://doi.org/10.1111/acel.13555
  38. Front Cell Dev Biol. 2021 ;9 790437
    Hindlimb Immobilization Increases IL-1β and Cdkn2a Expression in Skeletal Muscle Fibro-Adipogenic Progenitor Cells: A Link Between Senescence and Muscle Disuse Atrophy.
    Emily Parker, Andrew Khayrullin, Andrew Kent, Bharati Mendhe, Khairat Bahgat Youssef El Baradie, Kanglun Yu, Jeanene Pihkala, Yutao Liu, Meghan McGee-Lawrence, Maribeth Johnson, Jie Chen, Mark Hamrick.
      Loss of muscle mass and strength contributes to decreased independence and an increased risk for morbidity and mortality. A better understanding of the cellular and molecular mechanisms underlying muscle atrophy therefore has significant clinical and therapeutic implications. Fibro-adipogenic progenitors (FAPs) are a skeletal muscle resident stem cell population that have recently been shown to play vital roles in muscle regeneration and muscle hypertrophy; however, the role that these cells play in muscle disuse atrophy is not well understood. We investigated the role of FAPs in disuse atrophy in vivo utilizing a 2-week single hindlimb immobilization model. RNA-seq was performed on FAPs isolated from the immobilized and non-immobilized limb. The RNAseq data show that IL-1β is significantly upregulated in FAPs following 2 weeks of immobilization, which we confirmed using droplet-digital PCR (ddPCR). We further validated the RNA-seq and ddPCR data from muscle in situ using RNAscope technology. IL-1β is recognized as a key component of the senescence-associated secretory phenotype, or SASP. We then tested the hypothesis that FAPs from the immobilized limb would show elevated senescence measured by cyclin-dependent kinase inhibitor 2A (Cdkn2a) expression as a senescence marker. The ddPCR and RNAscope data both revealed increased Cdkn2a expression in FAPs with immobilization. These data suggest that the gene expression profile of FAPs is significantly altered with disuse, and that disuse itself may drive senescence in FAPs further contributing to muscle atrophy.
    Keywords:  RNA-seq; SASP; atrophy; disuse; progenitor cell
    DOI:  https://doi.org/10.3389/fcell.2021.790437
  39. Aging Cell. 2022 Jan;21(1): e13518
    Adaptive capacity to dietary Vitamin B12 levels is maintained by a gene-diet interaction that ensures optimal life span.
    Tripti Nair, Rahul Chakraborty, Praveen Singh, Sabnam Sahin Rahman, Akash Kumar Bhaskar, Shantanu Sengupta, Arnab Mukhopadhyay.
      Diet regulates complex life-history traits such as longevity. For optimal lifespan, organisms employ intricate adaptive mechanisms whose molecular underpinnings are less known. We show that Caenorhabditis elegans FLR-4 kinase prevents lifespan differentials on the bacterial diet having higher Vitamin B12 levels. The flr-4 mutants are more responsive to the higher B12 levels of Escherichia coli HT115 diet, and consequently, have enhanced flux through the one-carbon cycle. Mechanistically, a higher level of B12 transcriptionally downregulates the phosphoethanolamine methyltransferase pmt-2 gene, which modulates phosphatidylcholine (PC) levels. Pmt-2 downregulation activates cytoprotective gene expression through the p38-MAPK pathway, leading to increased lifespan only in the mutant. Evidently, preventing bacterial B12 uptake or inhibiting one-carbon metabolism reverses all the above phenotypes. Conversely, supplementation of B12 to E. coli OP50 or genetically reducing PC levels in the OP50-fed mutant extends lifespan. Together, we reveal how worms maintain adaptive capacity to diets having varying micronutrient content to ensure a normal lifespan.
    Keywords:   Caenorhabditis elegans ; flr-4 ; Vitamin B12; gene expression; life span; one-carbon metabolism; osmotic stress; p38-MAPK
    DOI:  https://doi.org/10.1111/acel.13518
  40. Cell Death Differ. 2022 Jan 17.
    Novel SARS-CoV-2 therapeutic targets: RNA proofreading complex and virus-induced senescence.
    Liangyu Lin, Ying Wang, Qing Li, Mingyuan Hu, Yufang Shi.
      
    DOI:  https://doi.org/10.1038/s41418-021-00909-6
  41. EMBO J. 2022 Jan 17. e108599
    CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal.
    Lisa Crozier, Reece Foy, Brandon L Mouery, Robert H Whitaker, Andrea Corno, Christos Spanos, Tony Ly, Jeanette Gowen Cook, Adrian T Saurin.
      CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are approved to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a cytostatic arrest in G1 causes long-lasting effects on tumour growth. Here, we demonstrate that a prolonged G1 arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. Upon release from that arrest, many cells fail to complete DNA replication and exit the cell cycle in a p53-dependent manner. If cells fail to withdraw from the cell cycle following DNA replication problems, they enter mitosis and missegregate chromosomes causing excessive DNA damage, which further limits their proliferative potential. These effects are observed in a range of tumour types, including breast cancer, implying that genotoxic stress is a common outcome of CDK4/6 inhibition. This unanticipated ability of CDK4/6 inhibitors to induce DNA damage now provides a rationale to better predict responsive tumour types and effective combination therapies, as demonstrated by the fact that CDK4/6 inhibition induces sensitivity to chemotherapeutics that also cause replication stress.
    Keywords:  CDK6; Palbociclib; cyclin-dependent kinase; replication stress; senescence
    DOI:  https://doi.org/10.15252/embj.2021108599
  42. Nature. 2022 01;601(7893): S5-S7
    How the COVID-19 pandemic might age us.
    Emily Sohn.
      
    Keywords:  Ageing; SARS-CoV-2; Society
    DOI:  https://doi.org/10.1038/d41586-022-00071-0
  43. Exp Gerontol. 2022 Jan 13. pii: S0531-5565(21)00451-4. [Epub ahead of print]159 111669
    Mild calorie restriction, but not 17α-estradiol, extends ovarian reserve and fertility in female mice.
    José V V Isola, Bianka M Zanini, Jessica D Hense, Joao A Alvarado-Rincón, Driele N Garcia, Giulia C Pereira, Arnaldo D Vieira, Thais L Oliveira, Tiago Collares, Bernardo G Gasperin, Michael B Stout, Augusto Schneider.
      Calorie restriction (CR) (25-40%) is the most commonly studied strategy for curtailing age-related disease and has also been found to extend reproductive lifespan in female mice. However, the effects of mild CR (10%), which is sustainable, on ovarian aging has not yet been addressed. 17α-estradiol (17α-E2) is another intervention shown to positively modulate healthspan and lifespan in mice but its effects on female reproduction remain unclear. We evaluated the effects of mild CR (10%) and 17α-E2 treatment on ovarian reserve and female fertility over a 24-week period, and compared these effects with the more commonly employed 30% CR regimen. Both 10% and 30% CR elicited positive effects on the preservation of ovarian reserve, whereas 17α-E2 did not alter parameters associated with ovarian function. Following refeeding, both 10% and 30% increased fertility as evidenced by greater pregnancy rates. In aligned with the ovarian reserve data, 17α-E2 also failed to improve fertility. Collectively, these data indicate that 10% CR is effective in preserving ovarian function and fertility, while 17α-E2 does not appear to have therapeutic potential for delaying ovarian aging.
    Keywords:  Follicular progression; Menopause; Ovarian aging; Pro-longevity interventions
    DOI:  https://doi.org/10.1016/j.exger.2021.111669
  44. Front Aging Neurosci. 2021 ;13 786897
    Retrotransposons as a Source of DNA Damage in Neurodegeneration.
    Eugenie Peze-Heidsieck, Tom Bonnifet, Rania Znaidi, Camille Ravel-Godreuil, Olivia Massiani-Beaudoin, Rajiv L Joshi, Julia Fuchs.
      The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), still remains elusive and no curative treatment is available. Age is the major risk factor for PD and AD, but the molecular link between aging and neurodegeneration is not fully understood. Aging is defined by several hallmarks, some of which partially overlap with pathways implicated in NDs. Recent evidence suggests that aging-associated epigenetic alterations can lead to the derepression of the LINE-1 (Long Interspersed Element-1) family of transposable elements (TEs) and that this derepression might have important implications in the pathogenesis of NDs. Almost half of the human DNA is composed of repetitive sequences derived from TEs and TE mobility participated in shaping the mammalian genomes during evolution. Although most TEs are mutated and no longer mobile, more than 100 LINE-1 elements have retained their full coding potential in humans and are thus retrotransposition competent. Uncontrolled activation of TEs has now been reported in various models of neurodegeneration and in diseased human brain tissues. We will discuss in this review the potential contribution of LINE-1 elements in inducing DNA damage and genomic instability, which are emerging pathological features in NDs. TEs might represent an important molecular link between aging and neurodegeneration, and a potential target for urgently needed novel therapeutic disease-modifying interventions.
    Keywords:  Alzheimer’s disease; DNA damage; LINE-1; Parkinson’s disease; aging; genomic instability; neurodegenerative diseases; transposable elements (TEs)
    DOI:  https://doi.org/10.3389/fnagi.2021.786897
  45. Nat Aging. 2021 Dec;1(12): 1162-1174
    Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models.
    Hong Seok Shim, James W Horner, Chang-Jiun Wu, Jiexi Li, Zheng D Lan, Shan Jiang, Xueping Xu, Wen-Hao Hsu, Tomasz Zal, Ivonne I Flores, Pingna Deng, Yuan-Ta Lin, Li-Huei Tsai, Y Alan Wang, Ronald A DePinho.
      Amyloid-induced neurodegeneration plays a central role in Alzheimer's disease (AD) pathogenesis. Here, we show that telomerase reverse transcriptase (TERT) haploinsufficiency decreases BDNF and increases amyloid-β (Aβ) precursor in murine brain. Moreover, prior to disease onset, the TERT locus sustains accumulation of repressive epigenetic marks in murine and human AD neurons, implicating TERT repression in amyloid-induced neurodegeneration. To test the impact of sustained TERT expression on AD pathobiology, AD mouse models were engineered to maintain physiological levels of TERT in adult neurons, resulting in reduced Aβ accumulation, improved spine morphology, and preserved cognitive function. Mechanistically, integrated profiling revealed that TERT interacts with β-catenin and RNA polymerase II at gene promoters and upregulates gene networks governing synaptic signaling and learning processes. These TERT-directed transcriptional activities do not require its catalytic activity nor telomerase RNA. These findings provide genetic proof-of-concept for somatic TERT gene activation therapy in attenuating AD progression including cognitive decline.
    DOI:  https://doi.org/10.1038/s43587-021-00146-z
  46. Mech Ageing Dev. 2022 Jan 12. pii: S0047-6374(22)00013-6. [Epub ahead of print] 111631
    Senolytic drugs: Beyond the promise and the hype.
    Diana Jurk, João F Passos.
      
    DOI:  https://doi.org/10.1016/j.mad.2022.111631
  47. Rejuvenation Res. 2022 Jan 19.
    Correlation between telomere length and biomarkers of oxidative stress in human aging.
    Somu Yadav, Pawan Kumar Maurya.
      The telomere length (TL) has increasingly been used as a biomarker of human aging because it has been shown to predict the chances of survival and longevity. Oxidative stress is presumed to be a major cause of telomere shortening but the importance of oxidative stress as a determinant of telomere shortening remains less clear and has recently been questioned. We analyzed 105 healthy subjects of both sexes between the ages of 20-77 years. The TL, and, biomarkers of oxidative stress were estimated as per standard protocols. A significant (p<0.001) age-dependent decline in TL was observed. TL was positively correlated with the ferric reducing ability of plasma (FRAP value) (r=0.8811) and reduced glutathione (GSH) (r=0.8209) while negatively correlated with malondialdehyde (MDA) (r=-0.7191). Our findings supported the idea of a possible correlation between the TL and biomarkers of oxidative stress in aging. The study has remarkable scope in medical science as the findings on correlation of TL with biomarkers of oxidative stress in aging are novel and they will help in further research against oxidative stress.
    DOI:  https://doi.org/10.1089/rej.2021.0045
  48. Glia. 2022 Jan 21.
    Astrocyte immunosenescence and deficits in interleukin 10 signaling in the aged brain disrupt the regulation of microglia following innate immune activation.
    Shane M O'Neil, Emma E Hans, Starr Jiang, Lynde M Wangler, Jonathan P Godbout.
      Microglia, the innate immune cells of the brain, develops a pro-inflammatory, "primed" profile with age. Using single-cell RNA-sequencing, we confirmed hippocampal microglia of aged mice (18 m.o.) had an amplified (4 h) and prolonged (24 h) neuroinflammatory response to peripheral lipopolysaccharide (LPS) challenge compared to adults (2 m.o.). Overall, there were several unique cell-, age-, and time-dependent differences in the clusters of microglia identified. Analysis of upstream regulators and canonical pathways revealed impaired regulation of an activated, neuroinflammatory state within microglia. Moreover, microglia in the aged hippocampus failed to turn over during the resolving phase of neuroinflammation. Concomitantly, astrocytes in the aged hippocampus were "immunosenescent" both 4 and 24 h after LPS challenge. For example, aged astrocytes had reduced anti-inflammatory signaling and cholesterol biosynthesis, two pathways by which astrocytes regulate the inflammatory profile of microglia. One of the pathways reduced in the aged hippocampus was interleukin (IL)-10 signaling. This pathway increases astrocytic expression of transforming growth factor (TGF)-β, an anti-inflammatory cytokine with abundant receptor expression on microglia. Therefore, transgenic astrocytic Il10raKO mice were generated to determine if impaired IL-10R/TGFβ signaling within astrocytes caused an amplified microglial neuroinflammatory response. Astrocytic Il10raKO caused exaggerated sickness behavior and a prolonged neuroinflammatory response to peripheral LPS, including increased social avoidance with amplified microglial Il1b and Tnf mRNA expression. In summary, astrocytes had an immunosenescent profile with age and, in response to peripheral LPS, had IL-10R signaling deficits and a lack of cholesterol biosynthesis, both leading to the inability to resolve microglial activation.
    Keywords:  aging; astrocytes; immunosenescence; microglia; neuroimmunology; neuroinflammation
    DOI:  https://doi.org/10.1002/glia.24147
  49. Front Immunol. 2021 ;12 795401
    The cGAS/STING Pathway: A Novel Target for Cancer Therapy.
    Yu Gan, Xiaoying Li, Shuangze Han, Qi Liang, Xiaoqian Ma, Pengfei Rong, Wei Wang, Wei Li.
      As a DNA receptor, cyclic GMP-AMP synthase (cGAS) plays a crucial role in the immune system by recognizing abnormal DNA in the cytoplasm and activating the stimulator of interferon genes (STING) signaling pathway. This signaling cascade reaction leads to an immune response produced by type I interferon and other immune mediators. Recent advances in research have enhanced our current understanding of the potential role of the cGAS/STING pathway in anticancer therapy; however, in some cases, chronic STING activation may promote tumorigenesis. The present review article discusses the biological mechanisms of the cGAS/STING pathway, its dichotomous role in tumors, and the latest advances with respect to STING agonists and antagonists.
    Keywords:  STING agonists; cGAS-STING; cancer; combined therapy; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2021.795401
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