bims-senagi Biomed News
on Senescence and aging
Issue of 2021–11–21
twenty-one papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization.
  2. Inhibition of ERK5 elicits cellular senescence in melanoma via the cyclin-dependent kinase inhibitor p21.
  3. Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies.
  4. Epigenetic dysregulation in cardiovascular aging and disease.
  5. DRG2 Accelerates Senescence via Negative Regulation of SIRT1 in Human Diploid Fibroblasts.
  6. Autophagy and Aging: Roles in Skeletal Muscle, Eye, Brain and Hepatic Tissue.
  7. GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy.
  8. mTORC1 Activation in Chx10-Specific Tsc1 Knockout Mice Accelerates Retina Aging and Degeneration.
  9. Cyclosporin A alleviates trophoblast apoptosis and senescence by promoting autophagy in preeclampsia.
  10. α-Synuclein antisense transcript SNCA-AS1 regulates synapses- and aging-related genes suggesting its implication in Parkinson's disease.
  11. Mitochondrial aconitase 1 regulates age-related memory impairment via autophagy/mitophagy-mediated neural plasticity in middle-aged flies.
  12. Nuclear pore complex maintenance and implications for age-related diseases.
  13. PD-L1 sustains chronic, cancer cell-intrinsic responses to type I interferon, enhancing resistance to DNA damage.
  14. The ups and downs of caloric restriction and fasting: from molecular effects to clinical application.
  15. AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice.
  16. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation.
  17. R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage.
  18. The autophagy protein ATG9A enables lipid mobilization from lipid droplets.
  19. Adiponectin alleviated Alzheimer-like pathologies via autophagy-lysosomal activation.
  20. The Role of RAD6B and PEDF in Retinal Degeneration.
  21. Sex-specific accelerated decay in time/activity-dependent plasticity and associative memory in an animal model of Alzheimer's disease.
  1. Mol Cell. 2021 Nov 12. pii: S1097-2765(21)00909-6. [Epub ahead of print]
    A recurrent chromosomal inversion suffices for driving escape from oncogene-induced senescence via subTAD reorganization.
    Christos P Zampetidis, Panagiotis Galanos, Andriani Angelopoulou, Yajie Zhu, Aikaterini Polyzou, Timokratis Karamitros, Athanassios Kotsinas, Nefeli Lagopati, Ioanna Mourkioti, Reza Mirzazadeh, Alexandros Polyzos, Silvano Garnerone, Athanasia Mizi, Eduardo G Gusmao, Konstantinos Sofiadis, Zita Gál, Dorthe H Larsen, Dafni-Eleftheria Pefani, Marco Demaria, Aristotelis Tsirigos, Nicola Crosetto, Apolinar Maya-Mendoza, Angelos Papaspyropoulos, Konstantinos Evangelou, Jiri Bartek, Argyris Papantonis, Vassilis G Gorgoulis.
      Oncogene-induced senescence (OIS) is an inherent and important tumor suppressor mechanism. However, if not removed timely via immune surveillance, senescent cells also have detrimental effects. Although this has mostly been attributed to the senescence-associated secretory phenotype (SASP) of these cells, we recently proposed that "escape" from the senescent state is another unfavorable outcome. The mechanism underlying this phenomenon remains elusive. Here, we exploit genomic and functional data from a prototypical human epithelial cell model carrying an inducible CDC6 oncogene to identify an early-acquired recurrent chromosomal inversion that harbors a locus encoding the circadian transcription factor BHLHE40. This inversion alone suffices for BHLHE40 activation upon CDC6 induction and driving cell cycle re-entry of senescent cells, and malignant transformation. Ectopic overexpression of BHLHE40 prevented induction of CDC6-triggered senescence. We provide strong evidence in support of replication stress-induced genomic instability being a causative factor underlying "escape" from oncogene-induced senescence.
    Keywords:  BHLHE40; DNA damage; DNA replication; Hi-C; cancer; chromatin loop; replication stress; senescence
    DOI:  https://doi.org/10.1016/j.molcel.2021.10.017
  2. Cancer Res. 2021 Nov 19. pii: canres.0993.2021. [Epub ahead of print]
    Inhibition of ERK5 elicits cellular senescence in melanoma via the cyclin-dependent kinase inhibitor p21.
    Alessandro Tubita, Zoe Lombardi, Ignazia Tusa, Azzurra Lazzeretti, Giovanna Sgrignani, Dimitri Papini, Alessio Menconi, Sinforosa Gagliardi, Matteo Lulli, Persio Dello Sbarba, Azucena Esparís-Ogando, Atanasio Pandiella, Barbara Stecca, Elisabetta Rovida.
      Melanoma is the deadliest skin cancer with a very poor prognosis in advanced stages. Although targeted and immune therapies have improved survival, not all patients benefit from these treatments. The mitogen-activated protein kinase ERK5 supports the growth of melanoma cells in vitro and in vivo. However, ERK5 inhibition results in cell cycle arrest rather than appreciable apoptosis. To clarify the role of ERK5 in melanoma growth, we performed transcriptomic analyses following ERK5 knockdown in melanoma cells expressing BRAFV600E and found that cellular senescence was among the most affected processes. In melanoma cells expressing either wild type or mutant (V600E) BRAF, both genetic and pharmacological inhibition of ERK5 elicited cellular senescence, as observed by a marked increase in senescence associated β-galactosidase activity and p21 expression. Additionally, depletion of ERK5 from melanoma cells resulted in increased levels of CXCL1, CXCL8 and CCL20, proteins typically involved in the senescence-associated secretory phenotype. Knockdown of p21 suppressed the induction of cellular senescence by ERK5 blockade, pointing to p21 as a key mediator of this process. In vivo, ERK5 knockdown or inhibition with XMD8-92 in melanoma xenografts promoted cellular senescence. Based on these results, small-molecule compounds targeting ERK5 constitute a rational series of pro-senescence drugs that may be exploited for melanoma treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0993
  3. Semin Cancer Biol. 2021 Nov 16. pii: S1044-579X(21)00271-6. [Epub ahead of print]
    Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies.
    Hanxin Liu, Huifang Zhao, Yu Sun.
      The tumor microenvironment (TME) is a major contributor to cancer malignancy including development of therapeutic resistance, a process mediated in part through intercellular crosstalk. Besides diverse soluble factors responsible for pro-survival pathway activation, immune evasion and extracellular matrix (ECM) remodeling further promote cancer resistance. Importantly, therapy-induced senescence (TIS) of cells in the TME is frequently observed in anticancer regimens, an off-target effect that can generate profound impacts on disease progression. By conferring the resistance and fueling the repopulation of remaining cancerous cells, TIS is responsible for tumor relapse and distant metastasis in posttreatment stage. This pathological trajectory can be substantially driven by the pro-inflammatory feature of senescent cells, termed as the senescence-associated secretory phenotype (SASP). Targeting strategies to selectively and efficiently remove senescent cells before they exert non-autonomous but largely deleterious effects, are emerging as an effective solution to prevent drug resistance acquired from a treatment-remodeled TME. In this review, we summarize the TME composition and key activities that affect tissue homeostasis and support treatment resistance. Promising opportunities that allow TME-manipulation and senescent cell-targeting (senotherapy) are discussed, with translational pipelines to overcome therapeutic barriers in clinical oncology projected.
    Keywords:  Cancer resistance; Senescent cell; Senotherapy; Stromal cell; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.semcancer.2021.11.004
  4. J Cardiovasc Aging. 2021 ;pii: 10. [Epub ahead of print]1
    Epigenetic dysregulation in cardiovascular aging and disease.
    Allison B Herman, James R Occean, Payel Sen.
      Cardiovascular disease (CVD) is the leading cause of mortality and morbidity for all sexes, racial and ethnic groups. Age, and its associated physiological and pathological consequences, exacerbate CVD incidence and progression, while modulation of biological age with interventions track with cardiovascular health. Despite the strong link between aging and CVD, surprisingly few studies have directly investigated heart failure and vascular dysfunction in aged models and subjects. Nevertheless, strong correlations have been found between heart disease, atherosclerosis, hypertension, fibrosis, and regeneration efficiency with senescent cell burden and its proinflammatory sequelae. In agreement, senotherapeutics have had success in reducing the detrimental effects in experimental models of cardiovascular aging and disease. Aside from senotherapeutics, cellular reprogramming strategies targeting epigenetic enzymes remain an unexplored yet viable option for reversing or delaying CVD. Epigenetic alterations comprising local and global changes in DNA and histone modifications, transcription factor binding, disorganization of the nuclear lamina, and misfolding of the genome are hallmarks of aging. Limited studies in the aging cardiovascular system of murine models or human patient samples have identified strong correlations between the epigenome, age, and senescence. Here, we compile the findings in published studies linking epigenetic changes to CVD and identify clear themes of epigenetic deregulation during aging. Pending direct investigation of these general mechanisms in aged tissues, this review predicts that future work will establish epigenetic rejuvenation as a potent method to delay CVD.
    Keywords:  Epigenetics; aging; cardiovascular; chromatin; senescence
    DOI:  https://doi.org/10.20517/jca.2021.16
  5. Oxid Med Cell Longev. 2021 ;2021 7301373
    DRG2 Accelerates Senescence via Negative Regulation of SIRT1 in Human Diploid Fibroblasts.
    Bing Si Li, Ai Lin Jin, ZiQi Zhou, Jae Ho Seo, Byung-Min Choi.
      Accumulating evidence suggests that developmentally regulated GTP-binding protein 2 (DRG2), an evolutionarily conserved GTP-binding protein, plays an important role in regulating cell growth, inflammation, and mitochondria dynamics. However, the effect of DRG2 in aging remains unclear. In this study, we found that endogenous DRG2 protein expression is upregulated in oxidative stress-induced premature senescence models and tissues of aged mice. Ectopic expression of DRG2 significantly promoted senescence-associated β-galactosidase (SA-β-gal) activity and inhibited cell growth, concomitant with increase in levels of acetyl (ac)-p53 (Lys382), ac-nuclear factor-kB (NF-κB) p65 (Lys310), p21 Waf1/Cip1 , and p16 Ink4a and a decrease in cyclin D1. In this process, reactive oxygen species (ROS) and phosphorylation of H2A histone family member X (H2A.X), forming γ-H2A.X, were enhanced. Mechanistically, ectopic expression of DRG2 downregulated Sirtuin-1 (SIRT1), resulting in augmented acetylation of p53 and NF-κB p65. Additionally, DRG2 knockdown significantly abolished oxidative stress-induced premature senescence. Our results provide a possible molecular mechanism for investigation of cellular senescence and aging regulated by DRG2.
    DOI:  https://doi.org/10.1155/2021/7301373
  6. Front Cell Dev Biol. 2021 ;9 752962
    Autophagy and Aging: Roles in Skeletal Muscle, Eye, Brain and Hepatic Tissue.
    Ping Li, Yuanzheng Ma, Chengwei Yu, Shoutong Wu, Kai Wang, Hongyang Yi, Weizheng Liang.
      Autophagy is an evolutionary conserved degradative process contributing to cytoplasm quality control, metabolic recycling and cell defense. Aging is a universal phenomenon characterized by the progressive accumulation of impaired molecular and reduced turnover of cellular components. Recent evidence suggests a unique role for autophagy in aging and age-related disease. Indeed, autophagic activity declines with age and enhanced autophagy may prevent the progression of many age-related diseases and prolong life span. All tissues experience changes during aging, while the role of autophagy in different tissues varies. This review summarizes the links between autophagy and aging in the whole organism and discusses the physiological and pathological roles of autophagy in the aging process in tissues such as skeletal muscle, eye, brain, and liver.
    Keywords:  age-related diseases; aging; autophagy; brain; eye; liver; skeletal muscle
    DOI:  https://doi.org/10.3389/fcell.2021.752962
  7. Sci Rep. 2021 Nov 17. 11(1): 22448
    GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy.
    Zin Zin Ei, Kanuengnit Choochuay, Alisa Tubsuwan, Decha Pinkaew, Maneewan Suksomtip, Chanida Vinayanuwattikun, Pithi Chanvorachote, Preedakorn Chunhacha.
      Cisplatin (CDDP) induces senescence characterized by senescence-associated secretory phenotypes (SASP) and the unfolded protein response (UPR). In this study, we investigated the proteins related to the UPR during the senescence cell fate. Strikingly, we found that one of the critical ER-resident proteins, GRP78/BiP, was significantly altered. Here we show that GRP78 levels differentially expressed depending on non-small lung cancer subtypes. GRP78 indeed regulates the evasion of senescence in adenocarcinoma A549 cells, in which the increased GRP78 levels enable them to re-proliferate after CDDP removal. Conversely, GRP78 is downregulated in the senescence H460 cells, making them lacking senescence evasion capability. We observed that the translational regulation critically contributed to the GRP78 protein levels in CDDP-induces senescence. Furthermore, the increased GRP78 level during senescence confers resistance to senolytic drug, Bortezomib, as observed by a twofold increase in IC50 in A549 senescence cells compared to the wild-type. This observation is also consistent in the cells that have undergone genetic manipulation by transfection with pcDNA3.1(+)-GRP78/BiP plasmids and pSpCas9(BB)-2A-Puro containing guide RNA sequence targeting GRP78 exon 3 to induce the overexpression and downregulation of GRP78 in H460 cells, respectively. Our findings reveal a unique role of GRP78 on the senescence evasion cell fate and senolytic drug resistance after cisplatin-based chemotherapy.
    DOI:  https://doi.org/10.1038/s41598-021-01540-8
  8. Oxid Med Cell Longev. 2021 ;2021 6715758
    mTORC1 Activation in Chx10-Specific Tsc1 Knockout Mice Accelerates Retina Aging and Degeneration.
    Yu-Qing Rao, Yu-Tong Zhou, Wenchuan Zhou, Jia-Kai Li, Baojie Li, Jing Li.
      Age-associated decline in retina function is largely responsible for the irreversible vision deterioration in the elderly population. It is also an important risk factor for the development of degenerative and angiogenic diseases. However, the molecular mechanisms involved in the process of aging in the retina remain largely elusive. This study investigated the role of mTORC1 signaling in aging of the retina. We showed that mTORC1 was activated in old-aged retina, particularly in the ganglion cells. The role of mTORC1 activation was further investigated in Chx10-Cre;Tsc1fx/fx mouse (Tsc1-cKO). Activation of mTORC1 was found in bipolar and some of the ganglion and amacrine cells in the adult Tsc1-cKO retina. Bipolar cell hypertrophy and Müller gliosis were observed in Tsc1-cKO since 6 weeks of age. The abnormal endings of bipolar cell dendritic tips at the outer nuclear layer resembled that of the old-aged mice. Microglial cell activation became evident in 6-week-old Tsc1-cKO. At 5 months, the Tsc1-cKO mice exhibited advanced features of old-aged retina, including the expression of p16Ink4a and p21, expression of SA-β-gal in ganglion cells, decreased photoreceptor cell numbers, decreased electroretinogram responses, increased oxidative stress, microglial cell activation, and increased expression of immune and inflammatory genes. Inhibition of microglial cells by minocycline partially prevented photoreceptor cell loss and restored the electroretinogram responses. Collectively, our study showed that the activation of mTORC1 signaling accelerated aging of the retina by both cell autonomous and nonautonomous mechanisms. Our study also highlighted the role of microglia cells in driving the decline in retina function.
    DOI:  https://doi.org/10.1155/2021/6715758
  9. Placenta. 2021 Nov 12. pii: S0143-4004(21)00637-8. [Epub ahead of print]117 95-108
    Cyclosporin A alleviates trophoblast apoptosis and senescence by promoting autophagy in preeclampsia.
    Haoyue Hu, Wenqian Chen, Zixin Tao, Zhiju Li, Jiexing He, You Peng, Jing Ma, Huiting Wen, Jing Li, Xuefei Wang, Mei Zhong.
       INTRODUCTION: Abnormal extravillous trophoblast (EVT) function is closely related to preeclampsia (PE) and may be caused by inadequate autophagy, apoptosis, and senescence. Cyclosporin A (CsA) is an effective immunosuppressant that has been reported to stimulate autophagy and exert benign biological effects on EVTs. Therefore, we hypothesized that CsA may display therapeutic efficacy against PE by activating autophagy.
    METHODS: We established the nitro-l-arginine methyl ester (l-NAME)-induced preeclamptic mice model and a hypoxia-reoxygenation (H/R) model in vitro. The effects of CsA on autophagy were evaluated by western blotting (WB). The effects of CsA on apoptosis were analyzed by Hematoxylin-eosin (H&E) staining, cell apoptosis assay and WB. Senescence-associated β-galactosidase (SA-β-gal) staining, RT-qPCR and WB were used to examine the senescence level. RT-qPCR were used to detect the senescence-associated secretory phenotype (SASP) level. DCFH-DA fluorescent probe, dihydroethidium (DHE) staining and mitochondrial membrane potential (ΔΨm) were used to detect senescence-associated mitochondrial dysfunction (SAMD).
    RESULTS: CsA alleviated PE-like symptoms and reduced placental necrosis and senescence in mice injected with l-NAME. CsA ameliorated placental SASP and SAMD level induced by l-NAME. CsA also upregulated the expression of autophagic proteins in mouse placentas disrupted using l-NAME. In vitro, we found that CsA reversed H/R-induced apoptosis and senescence, as well as decreasing SASP and SAMD levels and upregulating autophagic proteins levels. Notably, 3-methyladenine (3-MA), an early phase inhibitor of autophagosome formation, abolished the protective effects of CsA against H/R.
    DISCUSSION: CsA may display some therapeutic effects against PE by activating autophagy in vivo and in vitro.
    Keywords:  Apoptosis; Autophagy; Cyclosporin A; Preeclampsia; Senescence; Trophoblast
    DOI:  https://doi.org/10.1016/j.placenta.2021.11.003
  10. Aging Cell. 2021 Nov 19. e13504
    α-Synuclein antisense transcript SNCA-AS1 regulates synapses- and aging-related genes suggesting its implication in Parkinson's disease.
    Federica Rey, Cecilia Pandini, Letizia Messa, Rossella Launi, Bianca Barzaghini, Roberta Zangaglia, Manuela Teresa Raimondi, Stella Gagliardi, Cristina Cereda, Gian Vincenzo Zuccotti, Stephana Carelli.
      SNCA protein product, α-synuclein, is widely renowned for its role in synaptogenesis and implication in both aging and Parkinson's disease (PD), but research efforts are still needed to elucidate its physiological functions and mechanisms of regulation. In this work, we aim to characterize SNCA-AS1, antisense transcript to the SNCA gene, and its implications in cellular processes. The overexpression of SNCA-AS1 upregulates both SNCA and α-synuclein and, through RNA-sequencing analysis, we investigated the transcriptomic changes of which both genes are responsible. We highlight how they impact neurites' extension and synapses' biology, through specific molecular signatures. We report a reduced expression of markers associated with synaptic plasticity, and we specifically focus on GABAergic and dopaminergic synapses, for their relevance in aging processes and PD, respectively. A reduction in SNCA-AS1 expression leads to the opposite effect. As part of this signature is co-regulated by the two genes, we discriminate between functions elicited by genes specifically altered by SNCA-AS1 or SNCA's overexpression, observing a relevant role for SNCA-AS1 in synaptogenesis through a shared molecular signature with SNCA. We also highlight how numerous deregulated pathways are implicated in aging-related processes, suggesting that SNCA-AS1 could be a key player in cellular senescence, with implications for aging-related diseases. Indeed, the upregulation of SNCA-AS1 leads to alterations in numerous PD-specific genes, with an impact highly comparable to that of SNCA's upregulation. Our results show that SNCA-AS1 elicits its cellular functions through the regulation of SNCA, with a specific modulation of synaptogenesis and senescence, presenting implications in PD.
    Keywords:  LncRNAs; Parkinson's disease; RNA-sequencing; SNCA; SNCA-AS1; aging; synapses; synuclein
    DOI:  https://doi.org/10.1111/acel.13504
  11. Aging Cell. 2021 Nov 19. e13520
    Mitochondrial aconitase 1 regulates age-related memory impairment via autophagy/mitophagy-mediated neural plasticity in middle-aged flies.
    Yun-Ho Cho, Gye-Hyeong Kim, Joong-Jean Park.
      Age-related memory impairment (AMI) occurs in many species, including humans. The underlying mechanisms are not fully understood. In wild-type Drosophila (w1118 ), AMI appears in the form of a decrease in learning (3-min memory) from middle age (30 days after eclosion [DAE]). We performed in vivo, DNA microarray, and behavioral screen studies to identify genes controlling both lifespan and AMI and selected mitochondrial Acon1 (mAcon1). mAcon1 expression in the head of w1118 decreased with age. Neuronal overexpression of mAcon1 extended its lifespan and improved AMI. Neuronal or mushroom body expression of mAcon1 regulated the learning of young (10 DAE) and middle-aged flies. Interestingly, acetyl-CoA and citrate levels increased in the heads of middle-aged and neuronal mAcon1 knockdown flies. Acetyl-CoA, as a cellular energy sensor, is related to autophagy. Autophagy activity and efficacy determined by the positive and negative changes in the expression levels of Atg8a-II and p62 were proportional to the expression level of mAcon1. Levels of the presynaptic active zone scaffold protein Bruchpilot were inversely proportional to neuronal mAcon1 levels in the whole brain. Furthermore, mAcon1 overexpression in Kenyon cells induced mitophagy labeled with mt-Keima and improved learning ability. Both processes were blocked by pink1 knockdown. Taken together, our results imply that the regulation of learning and AMI by mAcon1 occurs via autophagy/mitophagy-mediated neural plasticity.
    Keywords:  aconitase; age-related memory disorders; autophagy; mitochondria; mitophagy; neural plasticity
    DOI:  https://doi.org/10.1111/acel.13520
  12. Trends Cell Biol. 2021 Nov 12. pii: S0962-8924(21)00202-6. [Epub ahead of print]
    Nuclear pore complex maintenance and implications for age-related diseases.
    Jinqiang Liu, Martin W Hetzer.
      Nuclear pore complexes (NPCs) bridge the nucleus and the cytoplasm and are indispensable for crucial cellular activities, such as bidirectional molecular trafficking and gene transcription regulation. The discovery of long-lived proteins (LLPs) in NPCs from postmitotic cells raises the exciting possibility that the maintenance of NPC integrity might play an inherent role in lifelong cell function. Age-dependent deterioration of NPCs and loss of nuclear integrity have been linked to age-related decline in postmitotic cell function and degenerative diseases. In this review, we discuss our current understanding of NPC maintenance in proliferating and postmitotic cells, and how malfunction of nucleoporins (Nups) might contribute to the pathogenesis of various neurodegenerative and cardiovascular diseases.
    Keywords:  aging; neurodegenerative diseases; nuclear pore complex; protein turnover
    DOI:  https://doi.org/10.1016/j.tcb.2021.10.001
  13. Proc Natl Acad Sci U S A. 2021 Nov 23. pii: e2112258118. [Epub ahead of print]118(47):
    PD-L1 sustains chronic, cancer cell-intrinsic responses to type I interferon, enhancing resistance to DNA damage.
    HyeonJoo Cheon, Elise G Holvey-Bates, Daniel J McGrail, George R Stark.
      Programmed death ligand 1 (PD-L1), an immune-checkpoint protein expressed on cancer cells, also functions independently of the immune system. We found that PD-L1 inhibits the killing of cancer cells in response to DNA damage in an immune-independent manner by suppressing their acute response to type I interferon (IFN; IFN-I). In addition, PD-L1 plays a critical role in sustaining high levels of constitutive expression in cancer cells of a subset of IFN-induced genes, the IFN-related DNA damage resistance signature (IRDS) which, paradoxically, protects cancer cells. The cyclic GMP-AMP synthase-stimulator of the IFN genes (cGAS-STING) pathway is constitutively activated in a subset of cancer cells in the presence of high levels of PD-L1, thus leading to a constitutive, low level of IFN-β expression, which in turn increases IRDS expression. The constitutive low level of IFN-β expression is critical for the survival of cancer cells addicted to self-produced IFN-β. Our study reveals immune-independent functions of PD-L1 that inhibit cytotoxic acute responses to IFN-I and promote protective IRDS expression by supporting protective chronic IFN-I responses, both of which enhance the resistance of cancer cells to DNA damage.
    Keywords:  DNA damage resistance; cGAS-STING pathway; programmed death ligand 1 (PD-L1); type I interferon (IFN-I)
    DOI:  https://doi.org/10.1073/pnas.2112258118
  14. EMBO Mol Med. 2021 Nov 15. e14418
    The ups and downs of caloric restriction and fasting: from molecular effects to clinical application.
    Sebastian J Hofer, Didac Carmona-Gutierrez, Melanie I Mueller, Frank Madeo.
      Age-associated diseases are rising to pandemic proportions, exposing the need for efficient and low-cost methods to tackle these maladies at symptomatic, behavioral, metabolic, and physiological levels. While nutrition and health are closely intertwined, our limited understanding of how diet precisely influences disease often precludes the medical use of specific dietary interventions. Caloric restriction (CR) has approached clinical application as a powerful, yet simple, dietary modulation that extends both life- and healthspan in model organisms and ameliorates various diseases. However, due to psychological and social-behavioral limitations, CR may be challenging to implement into real life. Thus, CR-mimicking interventions have been developed, including intermittent fasting, time-restricted eating, and macronutrient modulation. Nonetheless, possible side effects of CR and alternatives thereof must be carefully considered. We summarize key concepts and differences in these dietary interventions in humans, discuss their molecular effects, and shed light on advantages and disadvantages.
    Keywords:  caloric restriction; fasting; healthspan; intermittent fasting; lifespan; time-restricted eating
    DOI:  https://doi.org/10.15252/emmm.202114418
  15. Commun Biol. 2021 Nov 18. 4(1): 1306
    AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice.
    Madelene Ericsson, Pär Steneberg, Rakel Nyrén, Helena Edlund.
      Age is associated with progressively impaired, metabolic, cardiac and vascular function, as well as reduced work/exercise capacity, mobility, and hence quality of life. Exercise exhibit positive effects on age-related dysfunctions and diseases. However, for a variety of reasons many aged individuals are unable to engage in regular physical activity, making the development of pharmacological treatments that mimics the beneficial effects of exercise highly desirable. Here we show that the pan-AMPK activator O304, which is well tolerated in humans, prevented and reverted age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity in aged mice. These results provide preclinical evidence that O304 mimics the beneficial effects of exercise. Thus, as an exercise mimetic in clinical development, AMPK activator O304 holds great potential to mitigate metabolic dysfunction, and to improve cardiac function and exercise capacity, and hence quality of life in aged individuals.
    DOI:  https://doi.org/10.1038/s42003-021-02837-0
  16. Nat Commun. 2021 Nov 15. 12(1): 6565
    Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation.
    Meihua Jin, Hiroki Shiwaku, Hikari Tanaka, Takayuki Obita, Sakurako Ohuchi, Yuki Yoshioka, Xiaocen Jin, Kanoh Kondo, Kyota Fujita, Hidenori Homma, Kazuyuki Nakajima, Mineyuki Mizuguchi, Hitoshi Okazawa.
      Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41467-021-26851-2
  17. Sci Adv. 2021 Nov 19. 7(47): eabj5769
    R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage.
    Ourania Chatzidoukaki, Kalliopi Stratigi, Evi Goulielmaki, George Niotis, Alexia Akalestou-Clocher, Katerina Gkirtzimanaki, Alexandros Zafeiropoulos, Janine Altmüller, Pantelis Topalis, George A Garinis.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abj5769
  18. Nat Commun. 2021 Nov 19. 12(1): 6750
    The autophagy protein ATG9A enables lipid mobilization from lipid droplets.
    Elodie Mailler, Carlos M Guardia, Xiaofei Bai, Michal Jarnik, Chad D Williamson, Yan Li, Nunziata Maio, Andy Golden, Juan S Bonifacino.
      The multispanning membrane protein ATG9A is a scramblase that flips phospholipids between the two membrane leaflets, thus contributing to the expansion of the phagophore membrane in the early stages of autophagy. Herein, we show that depletion of ATG9A does not only inhibit autophagy but also increases the size and/or number of lipid droplets in human cell lines and C. elegans. Moreover, ATG9A depletion blocks transfer of fatty acids from lipid droplets to mitochondria and, consequently, utilization of fatty acids in mitochondrial respiration. ATG9A localizes to vesicular-tubular clusters (VTCs) that are tightly associated with an ER subdomain enriched in another multispanning membrane scramblase, TMEM41B, and also in close proximity to phagophores, lipid droplets and mitochondria. These findings indicate that ATG9A plays a critical role in lipid mobilization from lipid droplets to autophagosomes and mitochondria, highlighting the importance of ATG9A in both autophagic and non-autophagic processes.
    DOI:  https://doi.org/10.1038/s41467-021-26999-x
  19. Aging Cell. 2021 Nov 14. e13514
    Adiponectin alleviated Alzheimer-like pathologies via autophagy-lysosomal activation.
    Kaiwu He, Lulin Nie, Tahir Ali, Shujin Wang, Xiao Chen, Zizhen Liu, Weifen Li, Kaiqin Zhang, Jia Xu, Jianjun Liu, Zhi-Jian Yu, Xifei Yang, Shupeng Li.
      Adiponectin (APN) deficiency has also been associated with Alzheimer-like pathologies. Recent studies have illuminated the importance of APN signaling in reducing Aβ accumulation, and the Aβ elimination mechanism remains rudimentary. Therefore, we aimed to elucidate the APN role in reducing Aβ accumulation and its associated abnormalities by targeting autophagy and lysosomal protein changes. To assess, we performed a combined pharmacological and genetic approach while using preclinical models and human samples. Our results demonstrated that the APN level significantly diminished in the plasma of patients with dementia and 5xFAD mice (6 months old), which positively correlated with Mini-Mental State Examination (MMSE), and negatively correlated with Clinical Dementia Rating (CDR), respectively. APN deficiency accelerated cognitive impairment, Aβ deposition, and neuroinflammation in 5xFAD mice (5xFAD*APN KO), which was significantly rescued by AdipoRon (AR) treatment. Furthermore, AR treatment also markedly reduced Aβ deposition and attenuated neuroinflammation in APP/PS1 mice without altering APP expression and processing. Interestingly, AR treatment triggered autophagy by mediating AMPK-mTOR pathway signaling. Most importantly, APN deficiency dysregulated lysosomal enzymes level, which was recovered by AR administration. We further validated these changes by proteomic analysis. These findings reveal that APN is the negative regulator of Aβ deposition and its associated pathophysiologies. To eliminate Aβ both extra- and intracellular deposition, APN contributes via the autophagic/lysosomal pathway. It presents a therapeutic avenue for AD therapy by targeting autophagic and lysosomal signaling.
    Keywords:  adiponectin; autophagy-lysosomal pathway; cognitive impairments; dementia; neuroinflammation
    DOI:  https://doi.org/10.1111/acel.13514
  20. Neuroscience. 2021 Nov 11. pii: S0306-4522(21)00559-5. [Epub ahead of print]
    The Role of RAD6B and PEDF in Retinal Degeneration.
    Qiang Ye, Jiaqi Wang, Xiangwen Liu, Zihua Liu, LuoSong BaZong, Jinhai Ma, Rong Shen, Weichun Ye, Wenfang Zhang, Degui Wang.
      RAD6B is an E2 ubiquitin-conjugating enzyme, playing an important role in DNA damage repair, gene expression, senescence, apoptosis and protein degradation. However, the specific mechanism between ubiquitin and retinal degeneration requires more investigation. Pigment epithelium-derived factor (PEDF) has a potent neurotrophic effect on the retina, protecting retinal neurons and photoreceptors from cell death caused by pathological damage. In this study, we found that loss of RAD6B leads to retinal degeneration in mice, especially in old age. Affymetrix microarray analysis showed that the PEDF signal was changed in RAD6B deficient groups. The expression of γ-H2AX, β-Gal, P53, Caspase-3, P21 and P16 was increased significantly in retinas of RAD6B knockout (KO) mice. Our studies suggest that RAD6B and PEDF play an important role in the health of retina, whereas the absence of RAD6B accelerates the degeneration.
    Keywords:  PEDF; RAD6B; apoptosis; degeneration; retina; senescence
    DOI:  https://doi.org/10.1016/j.neuroscience.2021.11.010
  21. Aging Cell. 2021 Nov 18. e13502
    Sex-specific accelerated decay in time/activity-dependent plasticity and associative memory in an animal model of Alzheimer's disease.
    Sheeja Navakkode, Jessica Ruth Gaunt, Maria Vazquez Pavon, Vibhavari Aysha Bansal, Riya Prasad Abraham, Yee Song Chong, Toh Hean Ch'ng, Sreedharan Sajikumar.
      Clinical studies have shown that female brains are more predisposed to neurodegenerative diseases such as Alzheimer's disease (AD), but the cellular and molecular mechanisms behind this disparity remain unknown. In several mouse models of AD, synaptic plasticity dysfunction is an early event and appears before significant accumulation of amyloid plaques and neuronal degeneration. However, it is unclear whether sexual dimorphism at the synaptic level contributes to the higher risk and prevalence of AD in females. Our studies on APP/PS1 (APPSwe/PS1dE9) mouse model show that AD impacts hippocampal long-term plasticity in a sex-specific manner. Long-term potentiation (LTP) induced by strong tetanic stimulation (STET), theta burst stimulation (TBS) and population spike timing-dependent plasticity (pSTDP) show a faster decay in AD females compared with age-matched AD males. In addition, behavioural tagging (BT), a model of associative memory, is specifically impaired in AD females with a faster decay in memory compared with males. Together with the plasticity and behavioural data, we also observed an upregulation of neuroinflammatory markers, along with downregulation of transcripts that regulate cellular processes associated with synaptic plasticity and memory in females. Immunohistochemistry of AD brains confirms that female APP/PS1 mice carry a higher amyloid plaque burden and have enhanced microglial activation compared with male APP/PS1 mice. Their presence in the diseased mice also suggests a link between the impairment of LTP and the upregulation of the inflammatory response. Overall, our data show that synaptic plasticity and associative memory impairments are more prominent in females and this might account for the faster progression of AD in females.
    Keywords:  Alzheimer's disease; LTP; STDP; behavioural tagging; sexual dimorphism; synaptic plasticity; synaptic tagging and capture; transcriptome profiling
    DOI:  https://doi.org/10.1111/acel.13502
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