bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒11‒29
twenty-four papers selected by
Maria Grazia Vizioli
Mayo Clinic
  1. Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence.
  2. Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts.
  3. A Single-Cell Transcriptomic Atlas of Human Skin Aging.
  4. Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model.
  5. MYSM1 Suppresses Cellular Senescence and the Aging Process to Prolong Lifespan.
  6. Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches.
  7. G6PD overexpression protects from oxidative stress and age-related hearing loss.
  8. Understanding immunosenescence and its impact on vaccination of older adults.
  9. The combination of mitogenic stimulation and DNA damage induces chondrocyte senescence.
  10. Senescent cell accumulation mechanisms inferred from parabiosis.
  11. Effects of Caloric Restriction on the Antagonistic and Integrative Hallmarks of Aging.
  12. Extracellular vesicles as potential tools for regenerative therapy.
  13. Sestrin2 Attenuates Cellular Senescence by Inhibiting NADPH Oxidase 4 Expression.
  14. Antioxidants N-Acetylcysteine and Vitamin C Improve T Cell Commitment to Memory and Long-Term Maintenance of Immunological Memory in Old Mice.
  15. Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche.
  16. Small but mighty: the causes and consequences of micronucleus rupture.
  17. Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence.
  18. Metformin protects against myocardial ischemia-reperfusion injury and cell pyroptosis via AMPK/NLRP3 inflammasome pathway.
  19. Advances in transcriptome analysis of human brain aging.
  20. Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas.
  21. Signaling mechanisms underlying inhibition of neuroinflammation by resveratrol in neurodegenerative diseases.
  22. Resveratrol improves motor function in patients with muscular dystrophies: an open-label, single-arm, phase IIa study.
  23. Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis.
  24. Nicotinamide, a vitamin B3 ameliorates depressive behaviors independent of SIRT1 activity in mice.
  1. Nat Commun. 2020 Nov 27. 11(1): 6049
    Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence.
    Ioana Olan, Aled J Parry, Stefan Schoenfelder, Masako Narita, Yoko Ito, Adelyne S L Chan, Guy St C Slater, Dóra Bihary, Masashige Bando, Katsuhiko Shirahige, Hiroshi Kimura, Shamith A Samarajiwa, Peter Fraser, Masashi Narita.
      Senescence is a state of stable proliferative arrest, generally accompanied by the senescence-associated secretory phenotype, which modulates tissue homeostasis. Enhancer-promoter interactions, facilitated by chromatin loops, play a key role in gene regulation but their relevance in senescence remains elusive. Here, we use Hi-C to show that oncogenic RAS-induced senescence in human diploid fibroblasts is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks often at the 3' end of a subset of active genes. RAS-induced de novo cohesin peaks are transcription-dependent and enriched for senescence-associated genes, exemplified by IL1B, where de novo cohesin binding is involved in new loop formation. Similar IL1B induction with de novo cohesin appearance and new loop formation are observed in terminally differentiated macrophages, but not TNFα-treated cells. These results suggest that RAS-induced senescence represents a cell fate determination-like process characterised by a unique gene expression profile and 3D genome folding signature, mediated in part through cohesin redistribution on chromatin.
    DOI:  https://doi.org/10.1038/s41467-020-19878-4
  2. Proc Natl Acad Sci U S A. 2020 Nov 23. pii: 201920338. [Epub ahead of print]
    Inhibition of 3-phosphoinositide-dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts.
    Sugyun An, Si-Young Cho, Junsoo Kang, Soobeom Lee, Hyung-Su Kim, Dae-Jin Min, EuiDong Son, Kwang-Hyun Cho.
      Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.
    Keywords:  PDK1; cellular senescence; network modeling; skin aging; systems biology
    DOI:  https://doi.org/10.1073/pnas.1920338117
  3. Dev Cell. 2020 Nov 23. pii: S1534-5807(20)30877-7. [Epub ahead of print]
    A Single-Cell Transcriptomic Atlas of Human Skin Aging.
    Zhiran Zou, Xiao Long, Qian Zhao, Yandong Zheng, Moshi Song, Shuai Ma, Yaobin Jing, Si Wang, Yifang He, Concepcion Rodriguez Esteban, Nanze Yu, Jiuzuo Huang, Piu Chan, Ting Chen, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Guang-Hui Liu.
      Skin undergoes constant self-renewal, and its functional decline is a visible consequence of aging. Understanding human skin aging requires in-depth knowledge of the molecular and functional properties of various skin cell types. We performed single-cell RNA sequencing of human eyelid skin from healthy individuals across different ages and identified eleven canonical cell types, as well as six subpopulations of basal cells. Further analysis revealed progressive accumulation of photoaging-related changes and increased chronic inflammation with age. Transcriptional factors involved in the developmental process underwent early-onset decline during aging. Furthermore, inhibition of key transcription factors HES1 in fibroblasts and KLF6 in keratinocytes not only compromised cell proliferation, but also increased inflammation and cellular senescence during aging. Lastly, we found that genetic activation of HES1 or pharmacological treatment with quercetin alleviated cellular senescence of dermal fibroblasts. These findings provide a single-cell molecular framework of human skin aging, providing a rich resource for developing therapeutic strategies against aging-related skin disorders.
    Keywords:  HES1; KLF6; aging; fibroblast; keratinocyte; quercetin; senescence; single-cell RNA sequencing; skin
    DOI:  https://doi.org/10.1016/j.devcel.2020.11.002
  4. bioRxiv. 2020 Sep 12. pii: 2020.09.11.294363. [Epub ahead of print]
    Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model.
    Seungjin Ryu, Irina Shchukina, Yun-Hee Youm, Hua Qing, Brandon K Hilliard, Tamara Dlugos, Xinbo Zhang, Yuki Yasumoto, Carmen J Booth, Carlos Fernández-Hernando, Yajaira Suárez, Kamal M Khanna, Tamas L Horvath, Marcelo O Dietrich, Maxim N Artyomov, Andrew Wang, Vishwa Deep Dixit.
      Increasing age is the strongest predictor of risk of COVID-19 severity. Unregulated cytokine storm together with impaired immunometabolic response leads to highest mortality in elderly infected with SARS-CoV-2. To investigate how aging compromises defense against COVID-19, we developed a model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain MHV-A59 (mCoV-A59) that recapitulated majority of clinical hallmarks of COVID-19. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Ketogenic diet increases beta-hydroxybutyrate, expands tissue protective γδ T cells, deactivates the inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data underscore the value of mCoV-A59 model to test mechanism and establishes harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against COVID-19 in the elderly.Highlights: - Natural MHV-A59 mouse coronavirus infection mimics COVID-19 in elderly.- Aged infected mice have systemic inflammation and inflammasome activation.- Murine beta coronavirus (mCoV) infection results in loss of pulmonary γδ T cells.- Ketones protect aged mice from infection by reducing inflammation.
    eTOC Blurb: Elderly have the greatest risk of death from COVID-19. Here, Ryu et al report an aging mouse model of coronavirus infection that recapitulates clinical hallmarks of COVID-19 seen in elderly. The increased severity of infection in aged animals involved increased inflammasome activation and loss of γδ T cells that was corrected by ketogenic diet.
    DOI:  https://doi.org/10.1101/2020.09.11.294363
  5. Adv Sci (Weinh). 2020 Nov;7(22): 2001950
    MYSM1 Suppresses Cellular Senescence and the Aging Process to Prolong Lifespan.
    Mingfu Tian, Yuqing Huang, Yunting Song, Wen Li, Peiyi Zhao, Weiyong Liu, Kailang Wu, Jianguo Wu.
      Aging is a universal feature of life that is a major focus of scientific research and a risk factor in many diseases. A comprehensive understanding of the cellular and molecular mechanisms of aging are critical to the prevention of diseases associated with the aging process. Here, it is shown that MYSM1 is a key suppressor of aging and aging-related pathologies. MYSM1 functionally represses cellular senescence and the aging process in human and mice primary cells and in mice organs. MYSM1 mechanistically attenuates the aging process by promoting DNA repair processes. Remarkably, MYSM1 deficiency facilitates the aging process and reduces lifespan, whereas MYSM1 over-expression attenuates the aging process and increases lifespan in mice. The functional role of MYSM1 is demonstrated in suppressing the aging process and prolonging lifespan. MYSM1 is a key suppressor of aging and may act as a potential agent for the prevention of aging and aging-associated diseases.
    Keywords:  DNA repair; Myb‐like, SWIRM, and MPN domains‐containing protein 1 (MYSM1); aging; senescence; senescence‐associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.1002/advs.202001950
  6. J Hematol Oncol. 2020 Nov 23. 13(1): 157
    Molecular and cellular mechanisms of aging in hematopoietic stem cells and their niches.
    Lei Zhang, Ryan Mack, Peter Breslin, Jiwang Zhang.
      Aging drives the genetic and epigenetic changes that result in a decline in hematopoietic stem cell (HSC) functioning. Such changes lead to aging-related hematopoietic/immune impairments and hematopoietic disorders. Understanding how such changes are initiated and how they progress will help in the development of medications that could improve the quality life for the elderly and to treat and possibly prevent aging-related hematopoietic diseases. Here, we review the most recent advances in research into HSC aging and discuss the role of HSC-intrinsic events, as well as those that relate to the aging bone marrow niche microenvironment in the overall processes of HSC aging. In addition, we discuss the potential mechanisms by which HSC aging is regulated.
    Keywords:  Aging; HSCs; Replication stress
    DOI:  https://doi.org/10.1186/s13045-020-00994-z
  7. Aging Cell. 2020 Nov 22. e13275
    G6PD overexpression protects from oxidative stress and age-related hearing loss.
    Jose M Bermúdez-Muñoz, Adelaida M Celaya, Sara Hijazo-Pechero, Jing Wang, Manuel Serrano, Isabel Varela-Nieto.
      Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises cell viability, and, ultimately, leads to functional decline. Cellular detoxification relies in part on the production of NADPH, which is an important cofactor for major cellular antioxidant systems. NADPH is produced principally by the housekeeping enzyme glucose-6-phosphate dehydrogenase (G6PD), which catalyzes the rate-limiting step in the pentose phosphate pathway. We show here that G6PD transgenic mice (G6PD-Tg), which show enhanced constitutive G6PD activity and NADPH production along life, have lower auditory thresholds than wild-type mice during aging, together with preserved inner hair cell (IHC) and outer hair cell (OHC), OHC innervation, and a conserved number of synapses per IHC. Gene expression of antioxidant enzymes was higher in 3-month-old G6PD-Tg mice than in wild-type counterparts, whereas the levels of pro-apoptotic proteins were lower. Consequently, nitration of proteins, mitochondrial damage, and TUNEL+ apoptotic cells were all lower in 9-month-old G6PD-Tg than in wild-type counterparts. Unexpectedly, G6PD overexpression triggered low-grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophage infiltration. Our results lead us to propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the production of ROS and cellular detoxification power along aging and thus prevents hearing loss progression.
    Keywords:  ARHL; NADPH; TrxR; aging; glutathione
    DOI:  https://doi.org/10.1111/acel.13275
  8. Vaccine. 2020 Nov 20. pii: S0264-410X(20)31426-2. [Epub ahead of print]
    Understanding immunosenescence and its impact on vaccination of older adults.
    Jessica C Allen, Franklin R Toapanta, Wilbur Chen, Sharon M Tennant.
      Older adults are more susceptible to viral and bacterial infection, and experience higher incidence and severity of infectious diseases. Although vaccination is the most logical solution in preventing infectious diseases, primary vaccine responses in individuals aged ≥65 years-old fail to generate complete protection. This is presumably attributed to immunosenescence, a term that describes functional differences associated with the immune system and natural age advancement. Both the innate and adaptive immune systems experience age-related impairments that contribute to insufficient protection following vaccination. This review addresses current knowledge of age-related changes that affect vaccine responsiveness; including the deficits in innate cell functions, dampened humoral and cell-mediated immune responses, current vaccination schedules for older adults, and concludes with potential strategies for improving vaccine efficacy specifically for this age group. Due to an age-related decline in immunity and poor vaccine responses, infectious diseases remain a burden among the aged population.
    Keywords:  Immune; Older adults; Senescence; Vaccine
    DOI:  https://doi.org/10.1016/j.vaccine.2020.11.002
  9. Osteoarthritis Cartilage. 2020 Nov 20. pii: S1063-4584(20)31172-9. [Epub ahead of print]
    The combination of mitogenic stimulation and DNA damage induces chondrocyte senescence.
    Michaela E Copp, Margaret C Flanders, Rachel Gagliardi, Jessica M Gilbertie, Garrett A Sessions, Susanna Chubinskaya, Richard F Loeser, Lauren V Schnabel, Brian O Diekman.
      OBJECTIVE: Cellular senescence is a phenotypic state characterized by stable cell-cycle arrest, enhanced lysosomal activity, and the secretion of inflammatory molecules and matrix degrading enzymes. Senescence has been implicated in osteoarthritis (OA) pathophysiology; however, the mechanisms that drive senescence induction in cartilage and other joint tissues are unknown. While numerous physiological signals are capable of initiating senescence, one emerging theme is that damaged cells convert to senescence in response to sustained mitogenic stimulation. The goal of this study was to develop an in vitro articular cartilage explant model to investigate the mechanisms of senescence induction.DESIGN: This study utilized healthy cartilage derived from cadaveric equine stifles and human ankles. Explants were irradiated to initiate DNA damage, and mitogenic stimulation was provided through serum-containing medium and treatment with transforming growth factor β1 and basic fibroblastic growth factor. Readouts of senescence were a quantitative flow cytometry assay to detect senescence-associated ꞵ galactosidase activity (SA-ꞵ-gal), immunofluorescence for p16 and γH2AX, and qPCR for the expression of inflammatory genes.
    RESULTS: Human cartilage explants required both irradiation and mitogenic stimulation to induce senescence as compared to baseline control conditions (7.16% vs. 2.34% SA-β-gal high, p=0.0007). These conditions also resulted in chondrocyte clusters within explants, a persistent DNA damage response, increased p16, and gene expression changes.
    CONCLUSIONS: Treatment of cartilage explants with mitogenic stimuli in the context of cellular damage reliably induces high levels of SA-β-gal activity and other senescence markers, which provides a physiologically relevant model system to investigate the mechanisms of senescence induction.
    Keywords:  DNA damage; SA-β-gal; TGF- β1; aging; bFGF; osteoarthritis
    DOI:  https://doi.org/10.1016/j.joca.2020.11.004
  10. Geroscience. 2020 Nov 25.
    Senescent cell accumulation mechanisms inferred from parabiosis.
    Omer Karin, Uri Alon.
      Senescent cells are growth-arrested cells that cause inflammation and play a causal role in aging. They accumulate with age, and preventing this accumulation delays age-related diseases. However, the mechanism for senescent cell accumulation is not fully understood. Accumulation can result from increasing production or decreasing removal of senescent cells with age, or both. To distinguish between these possibilities, we analyze data from parabiosis, the surgical conjoining of two mice so that they share circulation. Parabiosis between a young and old mouse, called heterochronic parabiosis, reduces senescent cell levels in the old mouse, while raising senescent cell levels in the young mouse. We show that parabiosis data can reject mechanisms for senescent cell accumulation in which only production rises with age or only removal decreases with age; both must vary with age. Since removal drops with age, senescent cell half-life rises with age. This matches a recent model for senescent cell accumulation developed from independent data on senescent cell dynamics, called the SR model, in which production rises linearly with age and senescent cells inhibit their own removal. The SR model further explains the timescales and mechanism of rejuvenation in parabiosis, based on transfer of spare removal capacity from the young mouse to the old. The present quantitative understanding can help design optimal treatments that remove senescent cells, by matching the time between treatments to the time it takes senescent cells to re-accumulate.
    Keywords:  Aging; Mathematical modeling; Parabiosis; Senescent cells; Systems biology
    DOI:  https://doi.org/10.1007/s11357-020-00286-x
  11. Ageing Res Rev. 2020 Nov 24. pii: S1568-1637(20)30363-9. [Epub ahead of print] 101228
    Effects of Caloric Restriction on the Antagonistic and Integrative Hallmarks of Aging.
    Begun Erbaba, Ayca Arslan-Ergul, Michelle M Adams.
      Aging is a significant risk factor for cognitive decline associated with neurodegenerative diseases, which makes understanding what promotes 'healthy brain aging' very important. Studies suggest that caloric restriction (CR) is a non-genetic intervention that reliably extends life- and healthspan. Here, we review the CR literature related to both the subject of aging and alterations in cell cycle machinery, especially surrounding the regulation of the E2F/DP1 complex, to elucidate the cellular protection mechanisms in the brain induced via dietary applications. The alterations extending lifespan via CR appear to exert their effects by promoting survival of individual cells, downregulating cell proliferation, and inducing stem cell quiescence, which results in keeping the stem cell reserve for extreme needs. This survival instinct of cells is believed to cause some molecular adaptations for their maintenance of the system. Avoiding energy waste of proliferation machinery promotes the long term survival of the individual cells and this is due to adaptations to the limited nutrient supply in the environment. Such a protective mechanism induced by diet could be promoted via the downregulation of crucial cell cycle-related transcription activators. This review article aims to bring attention to the importance of molecular adaptations induced by diet that promote healthy brain aging. It will provide insights into alternative targets for new treatments or neuroprotective approaches against neurodegenerative pathophysiologies.
    Keywords:  Aging; Brain; Calorie Restriction; Cell Cycle; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.arr.2020.101228
  12. Mol Cell Oncol. 2020 Sep 08. 7(6): 1809958
    Extracellular vesicles as potential tools for regenerative therapy.
    Jose Antonio Rodriguez-Navarro, Jorge Pascual-Guerra, Silvia Sacristan, Maria Del Carmen Nogales, Juan Antonio Fafián-Labora, Ana O'Loghlen.
      Small extracellular vesicles released by fibroblasts from young human donors diminish lipid peroxidation in senescent cells and in different old mice organs due to their enrichment in Glutathione-S-transferase Mu lipid antioxidant activity.
    Keywords:  Small extracellular vesicles; aging; glutathione-S-transferase M; lipid peroxidation; senescence
    DOI:  https://doi.org/10.1080/23723556.2020.1809958
  13. Ann Geriatr Med Res. 2020 Nov 24.
    Sestrin2 Attenuates Cellular Senescence by Inhibiting NADPH Oxidase 4 Expression.
    Chae Young Hwang, Ying-Hao Han, Seung-Min Lee, Sang-Mi Cho, Dae-Yeul Yu, Ki-Sun Kwon.
      Background: Sestrin2 (Sesn2) is involved in the maintenance of metabolic homeostasis and aging via modulation of the 5' AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) pathway.Methods: Wild-type and Sesn2 knockout (KO) mice of the 129/SvJ background were maintained in a pathogen-free authorized facility under a 12-hour dark/light cycle at 20°C-22°C and 50%-60% humidity. Mouse embryonic fibroblasts (MEFs) were prepared from 13.5-day-old embryos derived from Sesn2-KO mice mated with each other.
    Results: The MEFs from Sesn2-KO mice showed enlarged and flattened morphologies and senescence-associated β-galactosidase activity, accompanied by an elevated level of reactive oxygen species. These senescence phenotypes recovered following treatment with N-acetyl-cysteine. Notably, the mRNA levels of NADPH oxidase 4 (NOX4) and transforming growth factor (TGF)-β were markedly increased in Sesn2-KO MEFs. Treatment of Sesn2-KO MEFs with the NOX inhibitor diphenyleneiodonium and the TGF-β inhibitor SB431542 restored cell growth inhibited by Sesn2-KO.
    Conclusion: Sesn2 attenuates cellular senescence via suppression of TGF-β- and NOX4-induced reactive oxygen species generation and subsequent inhibition of AMPK.
    Keywords:  NOX4; Reactive oxygen species; Senescence; Sestrin2
    DOI:  https://doi.org/10.4235/agmr.20.0051
  14. Antioxidants (Basel). 2020 Nov 19. pii: E1152. [Epub ahead of print]9(11):
    Antioxidants N-Acetylcysteine and Vitamin C Improve T Cell Commitment to Memory and Long-Term Maintenance of Immunological Memory in Old Mice.
    Andreas Meryk, Marco Grasse, Luigi Balasco, Werner Kapferer, Beatrix Grubeck-Loebenstein, Luca Pangrazzi.
      Aging is characterized by reduced immune responses, a process known as immunosenescence. Shortly after their generation, antigen-experienced adaptive immune cells, such as CD8+ and CD4+ T cells, migrate into the bone marrow (BM), in which they can be maintained for long periods of time within survival niches. Interestingly, we recently observed how oxidative stress may negatively support the maintenance of immunological memory in the BM in old age. To assess whether the generation and maintenance of immunological memory could be improved by scavenging oxygen radicals, we vaccinated 18-months (old) and 3-weeks (young) mice with alum-OVA, in the presence/absence of antioxidants vitamin C (Vc) and/or N-acetylcysteine (NAC). To monitor the phenotype of the immune cell population, blood was withdrawn at several time-points, and BM and spleen were harvested 91 days after the first alum-OVA dose. Only in old mice, memory T cell commitment was boosted with some antioxidant treatments. In addition, oxidative stress and the expression of pro-inflammatory molecules decreased in old mice. Finally, changes in the phenotype of dendritic cells, important regulators of T cell activation, were additionally observed. Taken together, our data show that the generation and maintenance of memory T cells in old age may be improved by targeting oxidative stress.
    Keywords:  NAC; T cells; aging; antioxidants; immunosenescence; vaccination; vitamin C
    DOI:  https://doi.org/10.3390/antiox9111152
  15. J Exp Med. 2021 Mar 01. pii: e20192283. [Epub ahead of print]218(3):
    Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche.
    Wakako Kuribayashi, Motohiko Oshima, Naoki Itokawa, Shuhei Koide, Yaeko Nakajima-Takagi, Masayuki Yamashita, Satoshi Yamazaki, Bahityar Rahmutulla, Fumihito Miura, Takashi Ito, Atsushi Kaneda, Atsushi Iwama.
      Hematopoietic stem cells (HSCs) exhibit functional alterations, such as reduced regenerative capacity and myeloid-biased differentiation, with age. The HSC niche, which is essential for the maintenance of HSCs, also undergoes marked changes with aging. However, it has been technically challenging to directly evaluate the contribution of niche aging to age-associated HSC alterations without niche-damaging myeloablation in HSC transplantation assays. We herein transplanted an excess of aged HSCs into young mice without preconditioning. Although aged HSCs successfully engrafted in the intact young bone marrow niche, they poorly regenerated downstream progenitors and exhibited persistent myeloid-biased differentiation, resulting in no significant functional rejuvenation. Transcriptome and methylome analyses revealed that the young niche largely restored the transcriptional profile of aged HSCs, but not their DNA methylation profiles. Therefore, the restoration of the young niche is insufficient for rejuvenating HSC functions, highlighting a key role for age-associated cell-intrinsic defects in HSC aging.
    DOI:  https://doi.org/10.1084/jem.20192283
  16. Exp Mol Med. 2020 Nov 24.
    Small but mighty: the causes and consequences of micronucleus rupture.
    Mijung Kwon, Mitchell L Leibowitz, Jae-Ho Lee.
      Micronuclei are small DNA-containing nuclear structures that are spatially isolated from the main nucleus. They are frequently found in pathologies, including cancer. It was recently shown that these nuclear structures are not only biomarkers of disease but also play an active role in tumor biology. Many consequences of micronucleus formation on tumor biology are dependent on the frequent and irreversible rupture of their nuclear envelopes, which results in the exposure of their DNA contents to the cytoplasm. In this review, we discuss models of defective nuclear envelope deposition on missegregated chromosomes that lead to nuclear envelope rupture. Furthermore, we expound upon the various downstream consequences of micronucleus nuclear envelope rupture on cells. These consequences include a massive DNA rearrangement phenomenon called chromothripsis and activation of the cGAS-STING innate immune signaling pathway, which can be a double-edged sword with tumorigenesis and tumor prevention functions. Although micronuclei are small structures, the impact they have on cells and their microenvironment is quite large.
    DOI:  https://doi.org/10.1038/s12276-020-00529-z
  17. Signal Transduct Target Ther. 2019 Nov 29. 4(1): 50
    Seryl tRNA synthetase cooperates with POT1 to regulate telomere length and cellular senescence.
    Yingxi Li, Xiyang Li, Mei Cao, Yuke Jiang, Jie Yan, Ze Liu, Rongcun Yang, Xu Chen, Peiqing Sun, Rong Xiang, Longlong Wang, Yi Shi.
      Deregulated telomere length is a causative factor in many physiological and pathological processes, including aging and cancer. Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length. However, it remains largely unknown whether and how aging-related stresses, such as deregulated protein homeostasis, impact telomere length. Here, we explored the possible roles of aminoacyl tRNA synthetases (AARSs), key enzymes catalyzing the first reactions in protein synthesis, in regulating telomere length and aging. We selected seryl tRNA synthetase (SerRS) since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis. In this study, we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells. In the nucleus, SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1. We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres, resulting in progressive telomere shortening. Our data suggested a possible molecular link between protein synthesis and telomere length control, the deregulation of which may be associated with aging and cancer.
    DOI:  https://doi.org/10.1038/s41392-019-0078-1
  18. Aging (Albany NY). 2020 Nov 24. 12
    Metformin protects against myocardial ischemia-reperfusion injury and cell pyroptosis via AMPK/NLRP3 inflammasome pathway.
    Jing Zhang, Lelin Huang, Xing Shi, Liu Yang, Fuzhou Hua, Jianyong Ma, Wengen Zhu, Xiao Liu, Rui Xuan, Yunfeng Shen, Jianping Liu, Xiaoyang Lai, Peng Yu.
      Ischemia/reperfusion (I/R) injury is a life-threatening vascular emergency following myocardial infarction. Our previous study showed cardioprotective effects of metformin against myocardial I/R injury. In this study, we further examined the involvement of AMPK mediated activation of NLRP3 inflammasome in this cardioprotective effect of metformin. Myocardial I/R injury was simulated in a rat heart Langendorff model and neonatal rat ventricle myocytes (NRVMs) were subjected to hypoxi/reoxygenation (H/R) to establish an in vitro model. Outcome measures included myocardial infarct size, hemodynamic monitoring, myocardial tissue injury, myocardial apoptotic index and the inflammatory response. myocardial infarct size and cardiac enzyme activities. First, we found that metformin postconditioning can not only significantly alleviated myocardial infarct size, attenuated cell apoptosis, and inhibited myocardial fibrosis. Furthermore, metformin activated phosphorylated AMPK, decreased pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, and decreased NLRP3 inflammasome activation. In isolated NRVMs metformin increased cellular viability, decreased LDH activity and inhibited cellular apoptosis and inflammation. Importantly, inhibition of AMPK phosphorylation by Compound C (CC) resulted in decreased survival of cardiomyocytes mainly by inducing the release of inflammatory cytokines and increasing NLRP3 inflammasome activation. Finally, in vitro studies revealed that the NLRP3 activator nigericin abolished the anti-inflammatory effects of metformin in NRVMs, but it had little effect on AMPK phosphorylation. Collectively, our study confirmed that metformin exerts cardioprotective effects by regulating myocardial I/R injury-induced inflammatory response, which was largely dependent on the enhancement of the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.
    Keywords:  APMK; NLRP3; metformin; myocardial ischemia reperfusion injury; pyroptosis
    DOI:  https://doi.org/10.18632/aging.202143
  19. Exp Mol Med. 2020 Nov 26.
    Advances in transcriptome analysis of human brain aging.
    Seokjin Ham, Seung-Jae V Lee.
      Aging is associated with gradual deterioration of physiological and biochemical functions, including cognitive decline. Transcriptome profiling of brain samples from individuals of varying ages has identified the whole-transcriptome changes that underlie age-associated cognitive declines. In this review, we discuss transcriptome-based research on human brain aging performed by using microarray and RNA sequencing analyses. Overall, decreased synaptic function and increased immune function are prevalent in most regions of the aged brain. Age-associated gene expression changes are also cell dependent and region dependent and are affected by genotype. In addition, the transcriptome changes that occur during brain aging include different splicing events, intersample heterogeneity, and altered levels of various types of noncoding RNAs. Establishing transcriptome-based hallmarks of human brain aging will improve the understanding of cognitive aging and neurodegenerative diseases and eventually lead to interventions that delay or prevent brain aging.
    DOI:  https://doi.org/10.1038/s12276-020-00522-6
  20. Blood. 2020 Nov 24. pii: blood.2020005244. [Epub ahead of print]
    Adaptive T-cell immunity controls senescence-prone MyD88- or CARD11-mutant B-cell lymphomas.
    Maurice Reimann, Jens F Schrezenmeier, Paulina Richter-Pechanska, Anna Dolnik, Timon Pablo Hick, Kolja Schleich, Xiurong Cai, Dorothy N Y Fan, Philipp Lohneis, Sven Masswig, Sophy Denker, Antonia Busse, Gero Knittel, Ruth Flümann, Dorothee Childs, Liam Childs, Ana Maria Gätjens-Sanchez, Lars Bullinger, Andreas Rosenwald, Hans Christian Reinhardt, Clemens A Schmitt.
      Aberrant B-cell receptor (BCR)/NF-kB signaling is a hallmark feature of B-cell non-Hodgkin lymphomas (B-NHL), especially in diffuse large B-cell lymphoma (DLBCL). Recurrent mutations in this cascade, e.g. in CD79B, CARD11, or NFKBIZ, and also in the Toll-like receptor pathway transducer MyD88, all deregulate NF-kB, but their differential impact on lymphoma development and biology remains to be determined. We functionally investigate here primary mouse lymphomas that formed in recipient mice of Eµ-myc transgenic hematopoietic stem cells (HSC) stably transduced with naturally occurring NF-kB mutants. While most mutants supported Myc-driven lymphoma formation through repressed apoptosis, CARD11- or MyD88-mutant lymphoma cells selectively presented with a macrophage-activating secretion profile, which, in turn, strongly enforced TGF-b-mediated senescence in the lymphoma cell compartment. However, MyD88- or CARD11-mutant Eµ-myc lymphomas exhibited high-level expression of the immune checkpoint mediator PD-L1, thus preventing their efficient clearance by adaptive host immunity. Conversely, these mutant-specific dependencies were therapeutically exploitable by anti-PD1 checkpoint blockade, leading to direct T-cell-mediated lysis of predominantly but not exclusively senescent lymphoma cells. Importantly, mouse-based mutant MyD88- and CARD11-derived signatures marked DLBCL subgroups exhibiting mirroring phenotypes with respect to the triad of senescence induction, macrophage attraction, and evasion of cytotoxic T-cell immunity. Complementing genomic subclassification approaches, our functional, cross-species investigation unveils pathogenic principles and therapeutic vulnerabilities applicable to and testable in human DLBCL subsets that may inform future personalized treatment strategies.
    DOI:  https://doi.org/10.1182/blood.2020005244
  21. J Nutr Biochem. 2020 Nov 18. pii: S0955-2863(20)30584-2. [Epub ahead of print] 108552
    Signaling mechanisms underlying inhibition of neuroinflammation by resveratrol in neurodegenerative diseases.
    Juan Huang, Nanqu Huang, Shangfu Xu, Yong Luo, Yan Li, Hai Jin, Changyin Yu, Jingshan Shi, Feng Jin.
      Neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the progressive loss of the structure and function of neurons and most commonly occur in the elderly population. Microglia are resident macrophages of the central nervous system (CNS). The neuroinflammation caused by excessive microglial activation is closely related to the onset and progression of many NDs. Therefore, inhibiting excessive microglial activation is a potential drug target for controlling neuroinflammation. In recent years, natural products as modulators of microglial polarization have attracted considerable attention in the field of NDs therapy. Furthermore, resveratrol (RES) has been found to have a protective effect in NDs through the inhibition of microglial activation and the regulation of neuroinflammation. In this review, we mainly summarize the therapeutic potential of RES and its various molecular mechanisms in the treatment of NDs through the modulation of microglial activation.
    Keywords:  microglia; neurodegenerative diseases; neuroinflammation; resveratrol
    DOI:  https://doi.org/10.1016/j.jnutbio.2020.108552
  22. Sci Rep. 2020 Nov 25. 10(1): 20585
    Resveratrol improves motor function in patients with muscular dystrophies: an open-label, single-arm, phase IIa study.
    Kentaro Kawamura, Shinobu Fukumura, Koki Nikaido, Nobutada Tachi, Naoki Kozuka, Tsugumi Seino, Kingya Hatakeyama, Mitsuru Mori, Yoichi M Ito, Akiyoshi Takami, Shiro Hinotsu, Atsushi Kuno, Yukihiko Kawasaki, Yoshiyuki Horio, Hiroyuki Tsutsumi.
      Muscular dystrophies (MDs) are inherited disorders characterized by progressive muscle weakness. Previously, we have shown that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant and an activator of the protein deacetylase SIRT1, decreases muscular and cardiac oxidative damage and improves pathophysiological conditions in animal MD models. To determine whether resveratrol provides therapeutic benefits to patients with MDs, an open-label, single-arm, phase IIa trial of resveratrol was conducted in 11 patients with Duchenne, Becker or Fukuyama MD. The daily dose of resveratrol was 500 mg/day, which was increased every 8 weeks to 1000 and then 1500 mg/day. Primary outcomes were motor function, evaluated by a motor function measure (MFM) scale, muscular strength, monitored with quantitative muscle testing (QMT), and serum creatine kinase (CK) levels. Adverse effects and tolerability were evaluated as secondary outcomes. Despite the advanced medical conditions of the patients, the mean MFM scores increased significantly from 34.6 to 38.4 after 24 weeks of medication. A twofold increase was found in the mean QMT scores of scapula elevation and shoulder abduction. Mean CK levels decreased considerably by 34%. Diarrhoea and abdominal pain was noted in six and three patients, respectively. Resveratrol may provide some benefit to MD patients.
    DOI:  https://doi.org/10.1038/s41598-020-77197-6
  23. Osteoarthritis Cartilage. 2020 Nov 23. pii: S1063-4584(20)31182-1. [Epub ahead of print]
    Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis.
    Zhenxuan Shao, Ben Wang, Yifeng Shi, Chenglong Xie, Chongan Huang, Boda Chen, Huawei Zhang, Guoling Zeng, Haibo Liang, Yaosen Wu, Yifei Zhou, Naifeng Tian, Aimin Wu, Weiyang Gao, Xiangyang Wang, Xiaolei Zhang.
      OBJECTIVE: Intervertebral disc degeneration (IDD) represents major cause of low back pain. Quercetin (QUE) is one of the approved senolytic agents. In this study, we evaluated the protective effects of QUE on IDD development and its underlying mechanism.METHODS: Effects of senolytic agent QUE on the viability of nucleus pulposus cells (NPCs) were measured by CCK-8 assays and EdU staining. The senescence associated secreted phenotype (SASP) factors expressions were measured by qPCR, western blot, and ELISA; and NF-κB pathway was detected by immunofluorescence and western blot. Molecular docking was applied to predict the interacting protein of QUE; while Nrf2 was knocked down by siRNAs to confirm its role in QUE regulated senescence phenotype. X-ray, MRI, Hematoxylin-Eosin and Safranin O-Fast green staining were performed to evaluate the therapeutic effects of QUE on IDD in the puncture-induced rat model.
    RESULTS: In in vitro experiments, QUE inhibited SASP factors expression and senescence phenotype in IL-1β-treated NPCs. Mechanistically, QUE suppressed IL-1β induced activation of the NF-κB pathway cascades; it was also demonstrated in molecular docking and knock down studies that QUE might bind to Keap1-Nrf2 complex to suppress NF-κB pathway. In vivo, QUE ameliorated the IDD process in the puncture-induced rat model.
    CONCLUSIONS: Together the present work suggests that QUE inhibits SASP factors expression and senescence phenotype in NPCs and ameliorates the progression of IDD via the Nrf2/NF-κB axis, which supports senolytic agent QUE as a potential therapeutic agent for the treatment of IDD.
    Keywords:  NF-κB pathway; Nrf2; Quercetin; intervertebral disc degeneration; senescence
    DOI:  https://doi.org/10.1016/j.joca.2020.11.006
  24. Mol Brain. 2020 Nov 23. 13(1): 162
    Nicotinamide, a vitamin B3 ameliorates depressive behaviors independent of SIRT1 activity in mice.
    Zhuxi Liu, Caiqin Li, Xuelian Fan, Yifang Kuang, Xu Zhang, Lei Chen, Jinjing Song, Ying Zhou, Eiki Takahashi, Guang He, Weidong Li.
      Sirtuin 1 (SIRT1), is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase and a candidate gene for depression. Nicotinamide (NAM), a form of vitamin B3, is reported as a potential inhibitor of SIRT1. Our previous study found that the 24-h-restraint stress could induce long-term depressive-like phenotypes in mice. These mice displayed increased SIRT1 activity. Here, we studied whether NAM was capable of attenuating depressive behaviors through inhibiting SIRT1 activity. Surprisingly, the application of NAM significantly reversed the depressive behaviors but increased SIRT1 activity further. In contrast, the level of adenosine triphosphate (ATP) was reduced in the restraint model for depression, and recovered by the administration of NAM. Furthermore, the Sirt1flox/flox; Nestin-Cre mice exhibited antidepressant behaviors and increased ATP levels. These data suggest that ATP plays an important role in depression pathogenesis, and NAM could be a potential treatment method for depression by regulating ATP independent of SIRT1 activity.
    Keywords:  ATP; Depression; Nicotinamide; Restraint animal model; SIRT1
    DOI:  https://doi.org/10.1186/s13041-020-00703-4
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