bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒10‒25
thirty-five papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Cell Metab. 2020 Oct 14. pii: S1550-4131(20)30537-4. [Epub ahead of print]
    Wang L, Chen R, Li G, Wang Z, Liu J, Liang Y, Liu JP.
      Tissue stem cells undergo premature senescence under stress, promoting age-related diseases; however, the associated mechanisms remain unclear. Here, we report that in response to radiation, oxidative stress, or bleomycin, the E3 ubiquitin ligase FBW7 mediates cell senescence and tissue fibrosis through telomere uncapping. FBW7 binding to telomere protection protein 1 (TPP1) facilitates TPP1 multisite polyubiquitination and accelerates degradation, triggering telomere uncapping and DNA damage response. Overexpressing TPP1 or inhibiting FBW7 by genetic ablation, epigenetic interference, or peptidomimetic telomere dysfunction inhibitor (TELODIN) reduces telomere uncapping and shortening, expanding the pulmonary alveolar AEC2 stem cell population in mice. TELODIN, synthesized from the seventh β strand blade of FBW7 WD40 propeller domain, increases TPP1 stability, lung respiratory function, and resistance to senescence and fibrosis in animals chronically exposed to environmental stress. Our findings elucidate a pivotal mechanism underlying stress-induced pulmonary epithelial stem cell senescence and fibrosis, providing a framework for aging-related disorder interventions.
    Keywords:  DNA damage response; FBXW7; TPP1; cellular senescence; chronic stress; idiopathic pulmonary fibrosis; premature aging; proteostasis; stem cells; telomere; telomere uncapping
  2. J Dent Res. 2020 Oct 17. 22034520962463
    Shi HZ, Zeng JC, Shi SH, Giannakopoulos H, Zhang QZ, Le AD.
      Healthy aging is a complex biological process with progressive accumulation of senescent cells characterized by stable cell cycle arrest, resulting in impaired homeostasis, regenerative potential, and gradual functional decline in multiple tissues and organs, whereby the aberrant activation of mammalian target of rapamycin (mTOR) signaling networks plays a central role. Herein, we explored the effects of extracellular vesicles (EVs) released by gingiva-derived mesenchymal stem cells (GMSC-EVs) on oxidative stress-induced cellular senescence in human endothelial cells and skin fibroblasts and their antiaging potentials. Our results showed that GMSC-EVs robustly abrogated oxidative stress-induced upregulation in the expression of cellular senescence-related genes, such as β-galactosidase, p21, p53, and γH2AX, and mTOR/pS6 signaling pathway, in human umbilical vein endothelial cells (HUVECs) and skin fibroblasts. Meanwhile, GMSC-EVs restored oxidative stress-induced impairment in proliferation and tube formation by HUVECs. Systemic administration of GMSC-EVs attenuated aging-associated elevation in the expression levels of p21, mTOR/pS6, interleukin 6, and tumor necrosis factor α in skin and heart tissues of aged mice. These findings suggest that GMSC-EVs could be a potential alternative source of cell-free product for attenuation of aging-related skin and vascular dysfunctions due to their potent inhibitory effects on oxidative stress-induced cellular senescence in endothelial cells and skin fibroblasts.
    Keywords:  endothelial cells; fibroblasts; mTOR; mesenchymal stem cells; oxidative stress; skin aging
  3. Mol Cell Biol. 2020 Oct 19. pii: MCB.00512-20. [Epub ahead of print]
    Payea MJ, Anerillas C, Tharakan R, Gorospe M.
      Senescence is a state of long-term cell-cycle arrest that arises in cells that have incurred sub-lethal damage. While senescent cells no longer replicate, they remain metabolically active and further develop unique and stable phenotypes that are not present in proliferating cells. On one hand, senescent cells increase in size, maintain an active mTORC1 complex, and produce and secrete a substantial amount of inflammatory proteins as part of the senescence associated secretory phenotype (SASP). On the other hand, these pro-growth phenotypes contrast with the p53-mediated growth arrest typical of senescent cells that is associated with nucleolar stress and an inhibition of rRNA processing and ribosome biogenesis. In sum, translation in senescent cells paradoxically comprises both a global repression of translation triggered by DNA damage and a select increase in the translation of specific proteins, including SASP factors.
  4. Exp Gerontol. 2020 Oct 15. pii: S0531-5565(20)30457-5. [Epub ahead of print] 111109
    Ito N, Takemoto H, Hasegawa A, Sugiyama C, Honma K, Nagai T, Kobayashi Y, Odaguchi H.
      Aging causes psychological dysfunction and neurodegeneration, and can lead to cognitive impairments. Although numerous studies have reported that neurodegeneration and subsequent cognitive impairments are involved in neuroinflammation, relationship between psychological disturbance and neuroinflammation with aging (neuroinflammaging) remains unclear. Here, to clarify the relationship, we examined whether neuroinflammaging affects emotional behaviors in senescence-accelerated mouse prone 8 (SAMP8) mice. Microglial inflammatory responses to a subsequent lipopolysaccharide (LPS) challenge were significantly enhanced in male SAMP8 mice relative to normal aging senescence-accelerated mouse resistant 1 (SAMR1) mice at 17 weeks, but not 8 weeks of age. LPS injection also significantly increased brain and systemic inflammation in SAMP8 mice at 17 weeks. In a battery of behavioral tests, SAMP8 mice at 17 weeks, but not 8 weeks, exhibited anxiety- and depression-like behaviors and circadian rhythm disruption. Taken together, SAMP8 mice at 17 weeks possess a brain microenvironment in which it is easier to trigger neuroinflammatory priming; this may lead to an emergence of anxiety- and depression-like behaviors and circadian rhythm disruption. These findings provide new insights into the temporal relationship between neuroinflammaging and emotion.
    Keywords:  Aging; Circadian rhythm; Depression; Microglia; Neuroinflammation; Senescence-accelerated mouse
  5. Aging Cell. 2020 Aug;19(8): e13192
    Smith LK, Verovskaya E, Bieri G, Horowitz AM, von Ungern-Sternberg SNI, Lin K, Seizer P, Passegué E, Villeda SA.
      The aged systemic milieu promotes cellular and cognitive impairments in the hippocampus. Here, we report that aging of the hematopoietic system directly contributes to the pro-aging effects of old blood on cognition. Using a heterochronic hematopoietic stem cell (HSC) transplantation model (in which the blood of young mice is reconstituted with old HSCs), we find that exposure to an old hematopoietic system inhibits hippocampal neurogenesis, decreases synaptic marker expression, and impairs cognition. We identify a number of factors elevated in the blood of young mice reconstituted with old HSCs, of which cyclophilin A (CyPA) acts as a pro-aging factor. Increased systemic levels of CyPA impair cognition in young mice, while inhibition of CyPA in aged mice improves cognition. Together, these data identify age-related changes in the hematopoietic system as drivers of hippocampal aging.
    Keywords:  aging; cognition; cyclophilin A; hematopoietic system; hippocampus
  6. Eur J Pharmacol. 2020 Oct 15. pii: S0014-2999(20)30745-7. [Epub ahead of print] 173653
    Dong R, Wang X, Wang L, Wang C, Huang K, Fu T, Liu K, Wu J, Sun H, Meng Q.
      Chronic alcohol assumption has been recognized as a major cause of alcoholic liver disease (ALD), which ranges from alcoholic steatohepatitis to fibrosis and hepatocellular carcinoma. Alcoholic liver disease has become the leading cause of liver-related health problem in the world. Herewith, effective therapeutic strategy for alcoholic liver disease is necessary. Yangonin (Yan), a bioactive compound extract from Kava, has been reported to exert hepatoprotective effects via Farnesoid X receptor (FXR) activation. The present study aims to investigate whether Yan ameliorated the ethanol-stimulated liver injury and further to elucidate the mechanisms in vivo and in vitro. Yan improved cell viabilities via cell count kit-8 (CCK-8) methods and obviously reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC) and total triglyceride (TG) levels. We detected miR-194 levels in ethanol-induced LO2 cells and male C57BL/6 mice by quantitative real-time PCR. Also, the effects of miR-194 on modulating cellular senescence via targeting FXR were further verified. The cellular senescence markers p16, p21, telomerase activity and senescence-related β-galactosidase (SA-β-gal) were evaluated by quantitative real-time PCR and Western blot. Also, LO2 cells or liver tissues were stained with special primary antibodies and 4',6'-Diamidino-2-phenylindole (DAPI). The cell cycle was detected by flow cytometry. We observed that Yan significantly inhibited ethanol-induced cellular senescence via FXR activation (P < 0.05). Our results demonstrate that Yan significantly reduced the cellular markers p16, p21 and Hmga1 expression and inhibited the cell cycle arrest (P < 0.05). MiR-194 was upregulated in the alcoholic liver disease, which was significantly suppressed by Yan (P < 0.05). Moreover, miR-194 mimic inhibited FXR expression in vitro. In summary, these aggregated data demonstrate that Yan alleviates chronic ethanol-induced liver injury through inhibition of cellular senescence via regulating miR-194/FXR axis.
    Keywords:  Alcoholic liver disease; Cellular senescence; FXR; Yangonin; miR-194
  7. Clin Sci (Lond). 2020 Oct 30. 134(20): 2681-2706
    Blokland KEC, Pouwels SD, Schuliga M, Knight DA, Burgess JK.
      The extracellular matrix (ECM) is a complex network of macromolecules surrounding cells providing structural support and stability to tissues. The understanding of the ECM and the diverse roles it plays in development, homoeostasis and injury have greatly advanced in the last three decades. The ECM is crucial for maintaining tissue homoeostasis but also many pathological conditions arise from aberrant matrix remodelling during ageing. Ageing is characterised as functional decline of tissue over time ultimately leading to tissue dysfunction, and is a risk factor in many diseases including cardiovascular disease, diabetes, cancer, dementia, glaucoma, chronic obstructive pulmonary disease (COPD) and fibrosis. ECM changes are recognised as a major driver of aberrant cell responses. Mesenchymal cells in aged tissue show signs of growth arrest and resistance to apoptosis, which are indicative of cellular senescence. It was recently postulated that cellular senescence contributes to the pathogenesis of chronic fibrotic diseases in the heart, kidney, liver and lung. Senescent cells negatively impact tissue regeneration while creating a pro-inflammatory environment as part of the senescence-associated secretory phenotype (SASP) favouring disease progression. In this review, we explore and summarise the current knowledge around how aberrant ECM potentially influences the senescent phenotype in chronic fibrotic diseases. Lastly, we will explore the possibility for interventions in the ECM-senescence regulatory pathways for therapeutic potential in chronic fibrotic diseases.
    Keywords:  Antifibrotics; DAMPs; Senescence; Senolytics; extracellular matrix; fibrosis
  8. Aging (Albany NY). 2020 Oct 20. 12
    Coninx E, Chew YC, Yang X, Guo W, Coolkens A, Baatout S, Moons L, Verslegers M, Quintens R.
      Epigenetic clocks are based on age-associated changes in DNA methylation of CpG-sites, which can accurately measure chronological age in different species. Recently, several studies have indicated that the difference between chronological and epigenetic age, defined as the age acceleration, could reflect biological age indicating functional decline and age-associated diseases. In humans, an epigenetic clock associated Alzheimer's disease (AD) pathology with an acceleration of the epigenetic age. In this study, we developed and validated two mouse brain region-specific epigenetic clocks from the C57BL/6J hippocampus and cerebral cortex. Both clocks, which could successfully estimate chronological age, were further validated in a widely used mouse model for AD, the triple transgenic AD (3xTg-AD) mouse. We observed an epigenetic age acceleration indicating an increased biological age for the 3xTg-AD mice compared to non-pathological C57BL/6J mice, which was more pronounced in the cortex as compared to the hippocampus. Genomic region enrichment analysis revealed that age-dependent CpGs were enriched in genes related to developmental, aging-related, neuronal and neurodegenerative functions. Due to the limited access of human brain tissues, these epigenetic clocks specific for mouse cortex and hippocampus might be important in further unravelling the role of epigenetic mechanisms underlying AD pathology or brain aging in general.
    Keywords:  Alzheimer's disease; DNA methylation; cortex; epigenetic clock; hippocampus
  9. Life (Basel). 2020 Oct 17. pii: E246. [Epub ahead of print]10(10):
    Chen YJ, Liao YJ, Tram VTN, Lin CH, Liao KC, Liu CL.
      To investigate the association of immunosenescence with aged-related morbidity in the elderly, a clinical study was conducted to analyze and compare the alterations in peripheral blood (PB) T-cell subsets among young healthy (YH) controls, elderly healthy (EH) controls, and age-matched elderly patients with metabolic diseases (E-MDs), with cardiovascular diseases (E-CVDs) or with both (E-MDs/E-CVDs). The frequencies of CD3T, CD8T and invariant natural killer T (iNKT) cells were decreased in the EH, E-MD and E-CVD cohorts, indicating a decline in defense function. Although CD4T and regulatory T (Treg) cell frequencies tended to increase with aging, they were lower in patients with E-MDs and E-CVDs. Subset analyses of T-cells consistently showed the accumulation of senescent T-cell in aging and in patients with E-MDs and E-CVDs, compared with YH volunteers. These accumulated senescent T-cells were undergoing apoptosis upon stimulation due to the replicative senescence stage of T-cells. In addition, serum levels of cytokines, including interferon (IF)-γ, transforming growth factor (TGF)-β and growth differentiation factor (GDF)-15, consistently reflected alterations in T-cell subsets. This study demonstrated that T-cell subset changes with paralleled alterations in cytokines were associated with aging and age-related pathogenesis. These altered T-cell subsets and/or cytokines can potentially serve as biomarkers for the prevention, diagnosis and treatment of age-related morbidities.
    Keywords:  E-CVDs; E-MDs; TEM; TEMRA; aging; immunosenescence
  10. Ageing Res Rev. 2020 Oct 19. pii: S1568-1637(20)30329-9. [Epub ahead of print] 101194
    Vatner SF, Zhang J, Oydanich M, Berkman T, Naftalovich R, Vatner DE.
      The progressive increase in lifespan over the past century carries with it some adversity related to the accompanying burden of debilitating diseases prevalent in the older population. This review focuses on oxidative stress as a major mechanism limiting longevity in general, and healthful aging, in particular. Accordingly, the first goal of this review is to discuss the role of oxidative stress in limiting longevity, and compare healthful aging and its mechanisms in different longevity models. Secondly, we discuss common signaling pathways involved in protection against oxidative stress in aging and in the associated diseases of aging, e.g., neurological, cardiovascular and metabolic diseases, and cancer. Much of the literature has focused on murine models of longevity, which will be discussed first, followed by a comparison with human models of longevity and their relationship to oxidative stress protection. Finally, we discuss the extent to which the different longevity models exhibit the healthful aging features through physiological protective mechanisms related to exercise tolerance and increased β-adrenergic signaling and also protection against diabetes and other metabolic diseases, obesity, cancer, neurological diseases, aging-induced cardiomyopathy, cardiac stress and osteoporosis.
    Keywords:  Healthful Longevity; Oxidative Stress; Reactive Oxygen Species
  11. Antioxidants (Basel). 2020 Oct 16. pii: E1008. [Epub ahead of print]9(10):
    Cirilli I, Orlando P, Marcheggiani F, Dludla PV, Silvestri S, Damiani E, Tiano L.
      Endothelial dysfunction represents the initial stage in atherosclerotic lesion development which occurs physiologically during aging, but external factors like diet, sedentary lifestyle, smoking accelerate it. Since cigarette smoking promotes oxidative stress and cell damage, we developed an in vitro model of endothelial dysfunction using vascular cells exposed to chemicals present in cigarette smoke, to help elucidate the protective effects of anti-inflammatory and antioxidant agents, such as ubiquinol and vitamin K, that play a fundamental role in vascular health. Treatment of both young and senescent Human Umbilical Vein Endothelial Cells (HUVECs) for 24 h with cigarette smoke extract (CSE) decreased cellular viability, induced apoptosis via reactive oxygen species (ROS) imbalance and mitochondrial dysfunction and promoted an inflammatory response. Moreover, the senescence marker SA-β-galactosidase was observed in both young CSE-exposed and in senescent HUVECs suggesting that CSE exposure accelerates aging in endothelial cells. Supplementation with 10 µM ubiquinol and menaquinone-7 (MK7) counteracted oxidative stress and inflammation, resulting in improved viability, decreased apoptosis and reduced SA-β-galactosidase, but were ineffective against CSE-induced mitochondrial permeability transition pore opening. Other K vitamins tested like menaquinone-4 (MK4) and menaquinone-1 (K1) were less protective. In conclusion, CSE exposure was able to promote a stress-induced senescent phenotype in young endothelial cells likely contributing to endothelial dysfunction in vivo. Furthermore, the molecular changes encountered could be offset by ubiquinol and menaquinone-7 supplementation, the latter resulting the most bioactive K vitamin in counteracting CSE-induced damage.
    Keywords:  aging; cigarette smoke; endothelial dysfunction; menaquinone; mitochondrial dysfunction; oxidative stress; ubiquinol; vitamin K
  12. Front Cell Dev Biol. 2020 ;8 565970
    Shimoni C, Goldstein M, Ribarski-Chorev I, Schauten I, Nir D, Strauss C, Schlesinger S.
      Heat stress can have a serious impact on the health of both humans and animals. A major question is how heat stress affects normal development and differentiation at both the cellular and the organism levels. Here we use an in vitro experimental system to address how heat shock treatment influences the properties of bovine mesenchymal stem cells (MSCs)-multipotent progenitor cells-which are found in most tissues. Because cattle are sensitive to harsh external temperatures, studying the effects of heat shock on MSCs provides a unique platform to address cellular stress in a physiologically relevant model organism. Following isolation and characterization of MSCs from the cow's umbilical cord, heat shock was induced either as a pulse (1 h) or continuously (3 days), and consequent effects on MSCs were characterized. Heat shock induced extensive phenotypic changes in MSCs and dramatically curtailed their capacity to proliferate and differentiate. These changes were associated with a partial arrest in the G1/S or G2/M checkpoints. Furthermore, MSCs lost their ability to resolve the inflammatory response of RAW macrophages in coculture. A possible explanation for this loss of function is the accumulation of reactive oxygen species and malfunction of the mitochondria in the treated cells. Heat shock treatments resulted in stress-induced premature senescence, affecting the MSCs' ability to proliferate properly for many cell passages to follow. Exposure to elevated external temperatures leads to mitochondrial damage and oxidative stress, which in turn conveys critical changes in the proliferation, differentiation, and immunomodulatory phenotype of heat-stressed MSCs. A better understanding of the effect of heat shock on humans and animals may result in important health and economic benefits.
    Keywords:  bovine; heat shock; immunomodulation; mesenchymal stem cells; oxidative stress; senescence
  13. J Food Biochem. 2020 Oct 19. e13525
    Chuang HL, Baskaran R, Hsuan Day C, Lin YM, Ho CC, Ho TJ, Chen RJ, Mahalakshmi BK, Kuo WW, Huang CY.
      Nonalcoholic fatty liver disease (NAFLD) is considered to be a serious clinical complication, which could cause significant liver dysfunction including fibrosis, cirrhosis, and cancer. Obesity could lead to NAFLD and contributes to liver disorder and related complicated liver diseases. Effect of exercise combined with alcalase treatment derived potato protein hydrolysate (APPH) on high-fat diet (HFD)-induced hepatic injury was investigated in senescence accelerated mouse-prone 8 (SAMP8) mice in the present study. Mice were divided into six groups (n = 6): Group I-Control, Group II-HFD, Group III-Exercise, Group IV-HFD + APPH, Group V-HFD + Exercise, and Group VI-HFD + Exercise + APPH. Combined APPH treatment and exercise offer better cytoprotection in HFD-induced histological changes than APPH treatment and exercise alone. Further, APPH and exercise activate the cell survival proteins PI3K/Akt and prevent FasL/FADD-mediated apoptosis in HFD fed SAMP8 mouse. APPH with swimming exercise effectively modulate HFD-induced liver damage and apoptosis in aged mice through activation of PI3K/Akt protein. PRACTICAL APPLICATIONS: Exercise training is proven to reduce the health problems associated with aging and obesity, however, intensity and duration of the exercise differs between individuals. We used integrated pharmacological and nonpharmacological approach as a therapeutic strategy for preventing HFD-induced hepatic injury in aged subjects.
    Keywords:  SAMP8; aging; apoptosis; high-fat diet; liver
  14. Arch Gerontol Geriatr. 2020 Sep 25. pii: S0167-4943(20)30263-6. [Epub ahead of print]92 104266
    Santos MA, Franco FN, Caldeira CA, de Araújo GR, Vieira A, Chaves MM, Lara RC.
      Aging is characterized by a progressive loss of physiological integrity. One common denominator is the increase of reactive oxygen species (ROS) caused by inhibition of important antioxidant pathways. Resveratrol is a polyphenol known for its potent antioxidant activity. However, antioxidant pathways activated by them change with aging. The objective of our study was to verify the antioxidant effect of resveratrol in an oxidative stress environment in Human Mononuclear Cells (PBMC) from donors with different ages. Resveratrol (5 μM), a stimulus with H2O2 (0,64 % v/v) in addition to inhibitors of PKA, AkT/PKB and MAPK signaling pathways were used in chemiluminescence assay. An incresed basal production of ROS was observed in the elderly than in the middle-aged group. Resveratrol was able to reduce ROS in both groups, but with greater efficiency in the middle-aged group. By inhibiting PKA, Akt/PKB and MAPK signaling pathways we observed that resveratrol presented an altered performance in the aging process, changing signaling pattern of MAPK pathway.
    Keywords:  Aging; AkT/PKB; MAPK; PKA; Resveratrol
  15. Geriatrics (Basel). 2020 Oct 19. pii: E80. [Epub ahead of print]5(4):
    Falkenstein M, Karthaus M, Brüne-Cohrs U.
      Due to demographic changes, the number of older drivers is steadily increasing. Mobility is highly relevant for leading an independent life in the elderly. It largely depends on car driving, which is a complex task requiring a multitude of cognitive and motor skills vulnerable to age- related functional deterioration. The almost inevitable effects of senescence may be potentiated by age-related diseases, such as stroke or diabetes mellitus. Respective pharmacological treatment may cause side effects, additionally affecting driving safety. The present article reviews the impact of age-related diseases and drug treatment of these conditions on driving fitness in elderly drivers. In essence, we focus on diseases of the visual and auditory systems, diseases of the central nervous system (i.e., stroke, depression, dementia and mild cognitive disorder, and Parkinson's disease), sleep disorders, as well as cardiovascular diseases, diabetes mellitus, musculoskeletal disorders, and frailty. We will outline the role of functional tests and the assessment of driving behavior (by a driving simulator or in real traffic), as well as the clinical interview including questions about frequency of (near) accidents, etc. in the evaluation of driving fitness of the elderly. We also address the impact of polypharmacy on driving fitness and end up with recommendations for physicians caring for older patients.
    Keywords:  age-related diseases; aging; cognitive assessment; cognitive functions; driving assessment; medication; mobility; motor functions; older drivers; sensory functions
  16. Cardiovasc Res. 2020 Oct 18. pii: cvaa300. [Epub ahead of print]
    Rouhi L, Cheedipudi SM, Chen SN, Fan S, Lombardi R, Chen X, Coarfa C, Robertson MJ, Gurha P, Marian AJ.
      AIMS: Arrhythmogenic cardiomyopathy (ACM) encompasses a genetically heterogeneous group of myocardial diseases whose manifestations are sudden cardiac death, cardiac arrhythmias, heart failure, and in a subset fibro-adipogenic infiltration of the myocardium. Mutations in the TMEM43 gene, encoding transmembrane protein 43 (TMEM43) are known to cause ACM. The purpose of the study was to gain insights into the molecular pathogenesis of ACM caused by TMEM43 haploinsufficiency.METHODS AND RESULTS: The Tmem43 gene was specifically deleted in cardiac myocytes by crossing the Myh6-Cre and floxed Tmem43 mice. Myh6-Cre: Tmem43W/F mice showed an age-dependent phenotype characterized by an increased mortality, cardiac dilatation and dysfunction, myocardial fibrosis, adipogenesis, and apoptosis. Sequencing of cardiac myocyte transcripts prior to and after the onset of cardiac phenotype predicted early activation of the TP53 pathway. Increased TP53 activity was associated with increased levels of markers of DNA damage response (DDR), and a subset of senescence-associated secretary phenotype (SASP). Activation of DDR, TP53, SASP and their selected downstream effectors, including phospho-SMAD2 and phospho-SMAD3 were validated by alternative methods, including immunoblotting. Expression of SASP was associated with epithelial-mesenchymal transition (EMT) and age-dependent expression of myocardial fibrosis and apoptosis in the Myh6-Cre: Tmem43W/F mice.
    CONCLUSIONS: TMEM43 haplo-insufficiency is associated with activation of the DDR and the TP53 pathways, which lead to increased expression of SASP and an age-dependent expression of a pro-fibrotic cardiomyopathy. Given that TMEM43 is a nuclear envelope protein and our previous data showing deficiency of another nuclear envelope protein, namely lamin A/C, activates the DDR/TP53 pathway, we surmise that DNA damage is a shared mechanism in the pathogenesis of cardiomyopathies caused by mutations involving nuclear envelope proteins.
    TRANSLATIONAL PERSPECTIVE: The data indicate that the DNA damage response (DDR) to double stranded DNA breaks (DSBs) is activated in a mouse model of cardiomyopathy caused by haplo-insufficiency of the Tmem43 gene. The TMEM43 gene is a known cause of arrhythmogenic cardiomyopathy in humans. The DDR activates the TP53 pathway and leads to expression of senescence associated secretary phenotype (SASP), such as TGFβ1, which induce a senescence-associated pro-fibrotic cardiomyopathy.These findings along with our previous data identify the DDR as a putative common mechanism in the pathogenesis of cardiomyopathies, and likely in the pathogenesis of over two dozen diseases, caused by mutations in the nuclear envelope proteins (envelopathies).
  17. Aging Cell. 2020 Aug;19(8): e13185
    Chen Y, Chen J, Sun X, Yu J, Qian Z, Wu L, Xu X, Wan X, Jiang Y, Zhang J, Gao S, Mao Z.
      Cellular reprogramming is an emerging strategy for delaying the aging processes. However, a number of challenges, including the impaired genome integrity and decreased pluripotency of induced pluripotent stem cells (iPSCs) derived from old donors, may hinder their potential clinical applications. The longevity gene, Sirtuin 6 (SIRT6), functions in multiple biological processes such as the maintenance of genome integrity and the regulation of somatic cell reprogramming. Here, for the first time, we demonstrate that MDL-800, a recently developed selective SIRT6 activator, improved genomic stability by activating two DNA repair pathways-nonhomologous end joining (NHEJ) and base excision repair (BER) in old murine-derived iPSCs. More interestingly, we found that pretreating old murine iPSCs, which normally exhibit a restricted differentiation potential, with MDL-800 promoted the formation of teratomas comprised of all three germ layers and robustly stimulated chimera generation. Our findings suggest that pharmacological activation of SIRT6 holds great promise in treating aging-associated diseases with iPSC-based cell therapy.
    Keywords:  DNA repair; MDL-800; SIRT6; aging; genome integrity; pluripotency
  18. Aging Cell. 2020 Oct 21. e13244
    Saferding V, Hofmann M, Brunner JS, Niederreiter B, Timmen M, Magilnick N, Hayer S, Heller G, Steiner G, Stange R, Boldin M, Schabbauer G, Weigl M, Hackl M, Grillari J, Smolen JS, Blüml S.
      Bone loss is one of the consequences of aging, leading to diseases such as osteoporosis and increased susceptibility to fragility fractures and therefore considerable morbidity and mortality in humans. Here, we identify microRNA-146a (miR-146a) as an essential epigenetic switch controlling bone loss with age. Mice deficient in miR-146a show regular development of their skeleton. However, while WT mice start to lose bone with age, animals deficient in miR-146a continue to accrue bone throughout their life span. Increased bone mass is due to increased generation and activity of osteoblasts in miR-146a-deficient mice as a result of sustained activation of bone anabolic Wnt signaling during aging. Deregulation of the miR-146a target genes Wnt1 and Wnt5a parallels bone accrual and osteoblast generation, which is accompanied by reduced development of bone marrow adiposity. Furthermore, miR-146a-deficient mice are protected from ovariectomy-induced bone loss. In humans, the levels of miR-146a are increased in patients suffering fragility fractures in comparison with those who do not. These data identify miR-146a as a crucial epigenetic temporal regulator which essentially controls bone homeostasis during aging by regulating bone anabolic Wnt signaling. Therefore, miR-146a might be a powerful therapeutic target to prevent age-related bone dysfunctions such as the development of bone marrow adiposity and osteoporosis.
    Keywords:  aging; bone metabolism; microRNA; osteopetrosis; osteoporosis
  19. Ageing Res Rev. 2020 Oct 15. pii: S1568-1637(20)30328-7. [Epub ahead of print]64 101193
    Gil-Hernández A, Silva-Palacios A.
      Although the elixir of youth remains in the darkness, medical and scientific advances have succeeded in increasing human longevity; however, the predisposition to disease and its high economic cost are raising. Different strategies (e.g., antioxidants) and signaling pathways (e.g., Nrf2) have been identified to help regulate disease progression, nevertheless, there are still missing links that we need to understand. Contact sites called mitochondria-associated membranes (MAM) allow bi-directional communication between organelles as part of the essential functions in the cell to maintain its homeostasis. Different groups have deeply studied the role of MAM in aging; however, it's necessary to analyze their involvement in the progression of age-related diseases. In this review, we highlight the role of contact sites in these conditions, as well as the morphological and functional changes of mitochondria and ER in aging. We emphasize the intimate relationship between both organelles as a reflection of the biological processes that take place in the cell to try to regulate the deterioration characteristic of the aging process; proposing MAM as a potential target to help limit the disease progression with age.
    Keywords:  Aging; MAM; contact site; longevity; membrane; mitochondria; sarco/endoplasmic reticulum
  20. FEBS Open Bio. 2020 Oct 23.
    Niklander S, Bandaru D, Lambert DW, Hunter KD.
      Senescent cells accumulate in different organs and develop a senescence-associated secretory phenotype (SASP), associated with the development of age-related pathologies. The constitution of the SASP varies among cell types and with the method of senescence induction; nevertheless, there is substantial overlap among SASPs, especially the presence of pro-inflammatory cytokines such as IL-1β, IL-1α, IL-6 and IL-8. These cytokines are highly conserved among SASPs and are implicated in the development of several cancers. Here, we report that ROCK inhibition by Y-27632 reduces levels of IL-1α, IL-1β, IL-6 and IL-8 secreted by senescent normal and dysplastic oral keratinocytes without affecting the permanent cell growth arrest. The data indicate some inflammatory genes downregulated by Y-27632 remain downregulated even after repeated passage in the absence of Y-27632. We propose ROCK kinase inhibition as a novel alternative to current strategies to modulate the inflammatory components of the SASP, without compromising the permanent cell growth arrest. This observation potentially has wide clinical applications, given the involvement of senescence in cancer and a wide range of age-related disease. It also suggests care should be exercised when using Y-27632 to facilitate cell expansion of primary cells, as its effects on gene expression are not entirely reversible.
    Keywords:  ROCK inhibitors; Rho-kinase; SASP; Y-27632; senescence
  21. Aging Cell. 2020 Oct 20. e13262
    Lanfermeijer J, Borghans JAM, van Baarle D.
      Older adults often show signs of impaired CD8+ T-cell immunity, reflected by weaker responses against new infections and vaccinations, and decreased protection against reinfection. This immune impairment is in part thought to be the consequence of a decrease in both T-cell numbers and repertoire diversity. If this is indeed the case, a strategy to prevent infectious diseases in older adults could be the induction of protective memory responses through vaccination at a younger age. However, this requires that the induced immune responses are maintained until old age. It is therefore important to obtain insights into the long-term maintenance of the antigen-specific T-cell repertoire. Here, we review the literature on the maintenance of antigen-experienced CD8+ T-cell repertoires against acute and chronic infections. We describe the complex interactions that play a role in shaping the memory T-cell repertoire, and the effects of age, infection history, and T-cell avidity. We discuss the implications of these findings for the development of new vaccination strategies to protect older adults.
    Keywords:  CD8+ T-cell; T-cell receptor; aging; infection history; repertoire; vaccination
  22. Placenta. 2020 Oct 15. pii: S0143-4004(20)30396-9. [Epub ahead of print]103 64-71
    Jiang J, Hu H, Chen Q, Zhang Y, Chen W, Huang Q, Chen X, Li J, Zhong M.
      INTRODUCTION: Spontaneous preterm birth affects>5-18% of pregnancies and causes infant morbidity and mortality. Long non-coding RNAs can regulate gene expression and have been associated with preterm birth. In this study, we investigated whether the long non-coding RNA SNHG29 was associated with spontaneous preterm birth.METHODS: We collected the placentas from women who underwent preterm/full-term birth with/without labor. We determined the levels of expression of SNHG29 in the placental tissues using quantitative real-time polymerase chain reaction. We generated a senescence model by treating HTR8/SVneo cells with 200 μM H2O2 for 2 h. The degree of senescence induced in cells depleted of or overexpressing SNHG29 was determined by measuring senescence-associated gene expression and β-galactosidase activity.
    RESULTS: SNHG29 was overexpressed in the placentas of women who delivered preterm with labor and in HTR8/SVneo cells treated with H2O2 (p < 0.05). The levels of mRNA of p53 and p21, protein levels of p53, phospho-p53, p21and phospho-p21, and β-galactosidase activity was decreased in HTR8/SVneo cells depleted of SNHG29, while the opposite trend was observed in HTR8/SVneo cells overexpressing SNHG29 (p < 0.05). We observed an increase in the expression of IL-8 and TNF-α in senescent HTR8/SVneo cells (p < 0.05).
    DISCUSSION: SNHG29 was overexpressed in placentas from women who delivered preterm with labor compared to those in women who underwent preterm birth without labor and full-term birth with/without labor. High levels of SNHG29 enhanced senescence in vivo. The increase in pro-inflammatory cytokine expression and release by senescent cells may be pivotal to the pathophysiology of spontaneous preterm birth.
    Keywords:  Cellular senescence; Oxidative stress; SASP; SNHG29; Spontaneous preterm birth; p53/p21
  23. Aging Cell. 2020 Oct 17. e13235
    Bao WD, Zhou XT, Zhou LT, Wang F, Yin X, Lu Y, Zhu LQ, Liu D.
      Incidence of intracerebral hemorrhage (ICH) and brain iron accumulation increases with age. Excess iron accumulation in brain tissues post-ICH induces oxidative stress and neuronal damage. However, the mechanisms underlying iron deregulation in ICH, especially in the aged ICH model have not been well elucidated. Ferroportin1 (Fpn) is the only identified nonheme iron exporter in mammals to date. In our study, we reported that Fpn was significantly upregulated in perihematomal brain tissues of both aged ICH patients and mouse model. Fpn deficiency induced by injecting an adeno-associated virus (AAV) overexpressing cre recombinase into aged Fpn-floxed mice significantly worsened the symptoms post-ICH, including hematoma volume, cell apoptosis, iron accumulation, and neurologic dysfunction. Meanwhile, aged mice pretreated with a virus overexpressing Fpn showed significant improvement of these symptoms. Additionally, based on prediction of website tools, expression level of potential miRNAs in ICH tissues and results of luciferase reporter assays, miR-124 was identified to regulate Fpn expression post-ICH. Higher serum miR-124 levels were correlated with poor neurologic scores of aged ICH patients. Administration of miR-124 antagomir enhanced Fpn expression and attenuated iron accumulation in aged mice model. Both apoptosis and ferroptosis, but not necroptosis, were regulated by miR-124/Fpn signaling manipulation. Our study demonstrated the critical role of miR-124/Fpn signaling in iron metabolism and neuronal death post-ICH in aged murine model. Thus, Fpn upregulation or miR-124 inhibition might be promising therapeutic approachs for this disease.
  24. Cell Stem Cell. 2020 Oct 10. pii: S1934-5909(20)30493-8. [Epub ahead of print]
    Mansell E, Sigurdsson V, Deltcheva E, Brown J, James C, Miharada K, Soneji S, Larsson J, Enver T.
      Aging is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia, and malignancy. We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programs. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age, and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs in vivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. Our results demonstrate that MMP is a source of heterogeneity in old HSCs, and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.
    Keywords:  Aging; Hematopoietc Stem Cell; Lineage bias; Mitochondria; Mitochondrial Membrane Potential; Mitoquinol; Transcription Rate
  25. J Clin Invest. 2020 Oct 21. pii: 144115. [Epub ahead of print]
    Channappanavar R, Perlman S.
      Human coronaviruses (hCoVs) cause severe respiratory illness in the elderly. Age-related impairments in innate immunity and sub-optimal virus-specific T cell and antibody responses are believed to cause severe disease upon respiratory virus infections. However, the basis for age-related fatal pneumonia following pathogenic hCoVs is not well understood. In this review article, we provide an overview of our current understanding of hCoV-induced fatal pneumonia in the elderly. We describe host immune response to hCoV infections derived from studies of young and aged animal models, and discuss the potential role of age-associated increases in sterile inflammation (inflammaging) and virus-induced dysregulated inflammation in causing age-related severe disease. We also highlight the existing gaps in our knowledge about virus replication and host immune responses to hCoV infection in young and aged individuals.
  26. Front Pharmacol. 2020 ;11 01187
    Zhang X, Guo L, Zhang X, Xu L, Tian Y, Fan Z, Wei H, Zhang J, Ren F.
      Acetaminophen (APAP) overdose induces hepatocyte necrosis and causes liver hepatotoxicity. Currently, the role of galactosyltransferase in APAP-induced liver injury is still unclear. This study assessed the contribution of the GLT25D2 gene, a kind of collagen galactosyltransferase, to the development of APAP-induced liver injury. This study found that the expression of GLT25D2 markedly increased first and then decreased in the liver of mice treated with APAP, however, it downregulated in the liver of APAP overdose-patients compared with normal controls. Knockout of GLT25D2 significantly ameliorated the liver injury, meanwhile, it downregulated the proinflammatory cytokines (IL-6, TNF-α) and chemokines (CXCL-10, MIG and CXCL-1) levels, however, and upregulated the anti-inflammatory cytokines (IL-22, IL-10) levels. Mechanistic explorations showed that (1) GLT25D2 knockout promoted autophagy pathway; and (2) the GLT25D2 knockout-induced autophagy selected to clear damaged mitochondria in APAP-induced liver injury by mitophagy; and (3) the autophagy intervention by Atg 7 siRNA cancelled liver protection by knockout of GLT25D2 through regulating liver inflammation. In conclusion, our study proves that the upregulated expression of GLT25D2 decreased autophagy contributing to APAP-induced hepatotoxicity by mediating the inflammatory immune regulatory mechanism.
    Keywords:  GLT25D2; acetaminophen; acute liver injury; autophagy; liver inflammation
  27. Aging Cell. 2020 Oct 20. e13259
    Amargant F, Manuel SL, Tu Q, Parkes WS, Rivas F, Zhou LT, Rowley JE, Villanueva CE, Hornick JE, Shekhawat GS, Wei JJ, Pavone ME, Hall AR, Pritchard MT, Duncan FE.
      Fibrosis is a hallmark of aging tissues which often leads to altered architecture and function. The ovary is the first organ to show overt signs of aging, including increased fibrosis in the ovarian stroma. How this fibrosis affects ovarian biomechanics and the underlying mechanisms are unknown. Using instrumental indentation, we demonstrated a quantitative increase in ovarian stiffness, as evidenced by an increase in Young's modulus, when comparing ovaries from reproductively young (6-12 weeks) and old (14-17 months) mice. This ovarian stiffness was dependent on collagen because ex vivo enzyme-mediated collagen depletion in ovaries from reproductively old mice restored their collagen content and biomechanical properties to those of young controls. In addition to collagen, we also investigated the role of hyaluronan (HA) in regulating ovarian stiffness. HA is an extracellular matrix glycosaminoglycan that maintains tissue homeostasis, and its loss can change the biomechanical properties of tissues. The total HA content in the ovarian stroma decreased with age, and this was associated with increased hyaluronidase (Hyal1) and decreased hyaluronan synthase (Has3) expression. These gene expression differences were not accompanied by changes in ovarian HA molecular mass distribution. Furthermore, ovaries from mice deficient in HAS3 were stiffer compared to age-matched WT mice. Our results demonstrate that the ovary becomes stiffer with age and that both collagen and HA matrices are contributing mechanisms regulating ovarian biomechanics. Importantly, the age-associated increase in collagen and decrease in HA are conserved in the human ovary and may impact follicle development and oocyte quality.
    Keywords:  Biomechanics; extracellular matrix; fibrosis; hyaluronan synthase; hyaluronidase; reproduction
  28. Elife. 2020 Oct 20. pii: e58815. [Epub ahead of print]9
    Littlejohn NK, Seban N, Liu CC, Srinivasan S.
      The relationship between lipid metabolism and longevity remains unclear. Although fat oxidation is essential for weight loss, whether it remains beneficial when sustained for long periods, and the extent to which it may attenuate or augment lifespan remain important unanswered questions. Here, we develop an experimental handle in the Caenorhabditis elegans model system, in which we uncover the mechanisms that connect long-term fat oxidation with longevity. We find that sustained β-oxidation via activation of the conserved triglyceride lipase ATGL-1, triggers a feedback transcriptional loop that involves the mito-nuclear transcription factor ATFS-1, and a previously unknown and highly conserved repressor of ATGL-1 called HLH-11/AP4. This feedback loop orchestrates the dual control of fat oxidation and lifespan, and shields the organism from life-shortening mitochondrial stress in the face of continuous fat oxidation. Thus, we uncover one mechanism by which fat oxidation can be sustained for long periods without deleterious effects on longevity.
    Keywords:  C. elegans; cell biology; lifespan; lipid oxidation; mitochondrial stress; neuroscience
  29. Aging Cell. 2020 Oct 22. e13250
    Sathyan S, Ayers E, Gao T, Weiss EF, Milman S, Verghese J, Barzilai N.
      Aging is a complex trait characterized by a diverse spectrum of endophenotypes. By utilizing the SomaScan® proteomic platform in 1,025 participants of the LonGenity cohort (age range: 65-95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN; β[SE] = 0.0262 [0.0012]; p = 3.21 × 10-86 ), WNT1-inducible-signaling pathway protein 2 (WISP-2; β[SE] = 0.0189 [0.0009]; p = 4.60 × 10-82 ), chordin-like protein 1 (CRDL1; β[SE] = 0.0203[0.0010]; p = 1.45 × 10-77 ), transgelin (TAGL; β[SE] = 0.0215 [0.0011]; p = 9.70 × 10-71 ), and R-spondin-1(RSPO1; β[SE] = 0.0208 [0.0011]; p = 1.09 × 10-70 ), were the proteins most significantly associated with age. Weighted gene co-expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age-associated diseases and other age-related traits. The correlation between proteomic age prediction based on elastic net regression and chronological age was 0.8 (p < 2.2E-16). Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging. The present study made novel associations between a number of proteins and aging, constructed a proteomic age model that predicted mortality, and suggested possible proteomic signatures possessed by a cohort enriched for familial exceptional longevity.
    Keywords:  SomaScan® assay; aging; proteomics; weighted gene co-expression network analysis
  30. DNA Repair (Amst). 2020 Sep;pii: S1568-7864(20)30167-1. [Epub ahead of print]93 102919
    Harrod A, Lane KA, Downs JA.
      Mammalian cells possess multiple closely related SWI/SNF chromatin remodelling complexes. These complexes have been implicated in the cellular response to DNA double strand breaks (DSBs). Evidence suggests that SWI/SNF complexes contribute to successful repair via both the homologous recombination and non-homologous end joining pathways. In addition, repressing transcription near DSBs is dependent on SWI/SNF activity. Understanding these roles is important because SWI/SNF complexes are frequently dysregulated in cancer, and DNA DSB repair defects have the potential to be therapeutically exploited. In this graphical review, we summarise what is known about SWI/SNF contribution to DNA DSB responses in mammalian cells and provide an overview of the SWI/SNF-encoding gene alteration spectrum in human cancers.
    Keywords:  BAF; BRG1; Cancer; Chromatin remodeling; DNA repair; Double strand breaks; SMARCA4; SWI/SNF
  31. Am J Transplant. 2020 Oct 14.
    Pesce F, Stea ED, Divella C, Accetturo M, Laghetti P, Gallo P, Rossini M, Cianciotta F, Crispino L, Granata A, Battaglia M, Lucarelli G, de Cordoba SR, Stallone G, Gesualdo L, Castellano G.
      IgA Nephropathy (IgAN) is a frequent cause of chronic kidney disease (CKD) and progressive renal impairment. A native renal biopsy diagnosis of IgAN is a predictor of graft loss, with a relative risk of 47% but it is difficult to predict graft survival and progressive allograft dysfunction in these patients. Deletion of Complement factor H-related genes 1 and 3 (delCFHR3-1) has been associated with a decreased risk of developing IgAN on native kidneys, but the impact on the graft in IgAN transplanted patients is unknown. We hypothesized that delCFHR3-1 is also associated to the processes that influence graft survival in transplant recipients with IgAN and tested whether cellular senescence is involved in mediating graft damage. We found that patients carrying two copies of CFHR1-3 had a worse outcome (p=0.000321) and presented increased FHR1 deposits at glomerular and tubulo-interstitial level associated with higher expression of the senescence marker p16INK4a (p=0.001) and tubulointerstitial fibrosis (p=0.005). Interestingly, FHR1 deposits were associated with increased Complement activation as demonstrated by C5b-9 deposits. These data support both the role of FHR1 in mediating Complement activation and tubular senescence, and suggest the possibility of genotyping delCFHR3-1 to predict graft survival in IgAN transplanted patients.
  32. Mol Cell Biochem. 2020 Oct 19.
    de Oliveira CM, Martins LAM, de Sousa AC, Moraes KDS, Costa BP, Vieira MQ, Coelho BP, Borojevic R, de Oliveira JR, Guma FCR.
      The phytoalexin Resveratrol (3,5,4'-trihydroxystilbene; RSV) has been related to numerous beneficial effects on health by its cytoprotection and chemoprevention activities. Liver fibrosis is characterized by the extracellular matrix accumulation after hepatic injury and can lead to cirrhosis. Hepatic stellate cells (HSC) play a crucial role during fibrogenesis and liver wound healing by changing their quiescent phenotype to an activated phenotype for protecting healthy areas from damaged areas. Strategies on promoting the activated HSC death, the quiescence return or the cellular activation stimuli decrease play an important role on reducing liver fibrosis. Here, we evaluated the RSV effects on some markers of activation in GRX, an HSC model. We further evaluated the RSV influence in the ability of GRX on releasing inflammatory mediators. RSV at 1 and 10 µM did not alter the protein content of α-SMA, collagen I and GFAP; but 50 µM increased the content of these activation-related proteins. Also, RSV did not change the myofibroblast-like morphology of GRX. Interestingly, RSV at 10 and 50 µM decreased the GRX migration and collagen-I gel contraction. Finally, we showed that RSV triggered the increase in the TNF-α and IL-10 content in culture media of GRX while the opposite occurred for the IL-6 content. Altogether, these results suggested that RSV did not decrease the activation state of GRX and oppositely, triggered a pro-activation effect at the 50 µM concentration. However, despite the increase of TNF- α in culture media, these results on IL-6 and IL-10 secretion were in accordance with the anti-inflammatory role of RSV in our model.
    Keywords:  Hepatic stellate cells; Liver fibrosis; Liver wound healing; Resveratrol
  33. Cell Rep. 2020 Oct 20. pii: S2211-1247(20)31275-4. [Epub ahead of print]33(3): 108286
    Balakrishnan I, Danis E, Pierce A, Madhavan K, Wang D, Dahl N, Sanford B, Birks DK, Davidson N, Metselaar DS, Meel MH, Lemma R, Donson A, Vijmasi T, Katagi H, Sola I, Fosmire S, Alimova I, Steiner J, Gilani A, Hulleman E, Serkova NJ, Hashizume R, Hawkins C, Carcaboso AM, Gupta N, Monje M, Jabado N, Jones K, Foreman N, Green A, Vibhakar R, Venkataraman S.
      Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.
    Keywords:  BH3 mimetics; BMI1; DIPG; H3K27M mutant; H3WT; PTC 028; RNAi screen; SASP; senescence
  34. Immun Ageing. 2020 ;17 31
    Chiu YL, Tsai WC, Hung RW, Chen IY, Shu KH, Pan SY, Yang FJ, Ting TT, Jiang JY, Peng YS, Chuang YF.
      Background: Type 2 diabetes is an important challenge given the worldwide epidemic and is the most important cause of end-stage renal disease (ESRD) in developed countries. It is known that patients with ESRD and advanced renal failure suffer from immunosenescence and premature T cell aging, but whether such changes develop in patients with less severe chronic kidney disease (CKD) is unclear.Method: 523 adult patients with type 2 diabetes were recruited for this study. Demographic data and clinical information were obtained from medical chart review. Immunosenescence, or aging of the immune system was assessed by staining freshly-obtained peripheral blood with immunophenotyping panels and analyzing cells using multicolor flow cytometry.
    Result: Consistent with previously observed in the general population, both T and monocyte immunosenescence in diabetic patients positively correlate with age. When compared to diabetic patients with preserved renal function (estimated glomerular filtration rate > 60 ml/min), patients with impaired renal function exhibit a significant decrease of total CD3+ and CD4+ T cells, but not CD8+ T cell and monocyte numbers. Immunosenescence was observed in patients with CKD stage 3 and in patients with more severe renal failure, especially of CD8+ T cells. However, immunosenescence was not associated with level of proteinuria level or glucose control. In age, sex and glucose level-adjusted regression models, stage 3 CKD patients exhibited significantly elevated percentages of CD28-, CD127-, and CD57+ cells among CD8+ T cells when compared to patients with preserved renal function. In contrast, no change was detected in monocyte subpopulations as renal function declined. In addition, higher body mass index (BMI) is associated with enhanced immunosenescence irrespective of CKD status.
    Conclusion: The extent of immunosenescence is not significantly associated with proteinuria or glucose control in type 2 diabetic patients. T cells, especially the CD8+ subsets, exhibit aggravated characteristics of immunosenescence during renal function decline as early as stage 3 CKD. In addition, inflammation increases since stage 3 CKD and higher BMI drives the accumulation of CD8+CD57+ T cells. Our study indicates that therapeutic approaches such as weight loss may be used to prevent the emergence of immunosenescence in diabetes before stage 3 CKD.
    Keywords:  BMI; CKD; Diabetes; Immunosenescence; T cell