bims-senagi 2020-10-11 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2020‒10‒11
23 papers selected by
Maria Grazia Vizioli
Mayo Clinic

The eroding chromatin landscape of aging stem cells.
Isoparvifuran isolated from Dalbergia odorifera attenuates H2O2-induced senescence of BJ cells through SIRT1 activation and AKT/mTOR pathway inhibition.
B Cell Immunosenescence.
Age-Dependent Assessment of Genes Involved in Cellular Senescence, Telomere, and Mitochondrial Pathways in Human Lung Tissue of Smokers, COPD, and IPF: Associations With SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 Axis.
G3BP1 controls the senescence-associated secretome and its impact on cancer progression.
Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response.
Effect of rapamycin on aging and age-related diseases-past and future.
Cellular Senescence: Friend or Foe to Respiratory Viral Infections?
In vivo clonal analysis of aging hematopoietic stem cells.
Senescence-accelerated mouse prone 8 mice exhibit specific morphological changes in the small intestine during senescence and after pectin supplemented diet.
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.
miR-195 reduces age-related blood-brain barrier leakage caused by thrombospondin-1-mediated selective autophagy.
Autophagy displays divergent roles during intermittent amino acid starvation and toxic stress-induced senescence in cultured skeletal muscle cells.
ASPH Regulates Osteogenic Differentiation and Cellular Senescence of BMSCs.
Silencing p53 inhibits interleukin 10-induced activated hepatic stellate cell senescence and fibrotic degradation in vivo.
The Significance of 8-oxoGsn in Aging-Related Diseases.
Obesity Impairs Short-Term and Working Memory through Gut Microbial Metabolism of Aromatic Amino Acids.
Stress-induced premature senescence activated by the SENEX gene mediates apoptosis resistance of diffuse large B-cell lymphoma via promoting immunosuppressive cells and cytokines.
Defective Mitophagy in Alzheimer's Disease.
The cross-talk of NLRP3 inflammasome activation and necroptotic hepatocyte death in acetaminophen-induced mice acute liver injury.
Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria.
Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors.
Blood extracellular vesicles from healthy individuals regulate hematopoietic stem cells as humans age.

Transl Med Aging. 2020 ;4 121-131

The eroding chromatin landscape of aging stem cells.

Changyou Shi, Lin Wang, Payel Sen.

  Adult stem cells undergo both replicative and chronological aging in their niches, with catastrophic declines in regenerative potential with age. Due to repeated environmental insults during aging, the chromatin landscape of stem cells erodes, with changes in both DNA and histone modifications, accumulation of damage, and altered transcriptional response. A body of work has shown that altered chromatin is a driver of cell fate changes and a regulator of self-renewal in stem cells and therefore a prime target for juvenescence therapeutics. This review focuses on chromatin changes in stem cell aging and provides a composite view of both common and unique epigenetic themes apparent from the studies of multiple stem cell types.

Keywords:  Aging; Differentiation; Epigenetics/chromatin; Self-renewal; Stem cell

DOI:  https://doi.org/10.1016/j.tma.2020.08.002
Biochem Biophys Res Commun. 2020 Sep 30. pii: S0006-291X(20)31849-0. [Epub ahead of print]

Isoparvifuran isolated from Dalbergia odorifera attenuates H2O2-induced senescence of BJ cells through SIRT1 activation and AKT/mTOR pathway inhibition.

Zengsheng Yin, Raekil Park, Byung-Min Choi.

  Isoparvifuran is a benzofuran compound isolated from the heartwood of Dalbergia odorifera. Related research reported that isoparvifuran has antioxidant property. However, it is unclear whether isoparvifuran has anti-aging effects. In this research, we established an aging model, hydrogen peroxide (H2O2)-induced BJ cell senescence, to explore the protective effect of isoparvifuran on cell senescence and its related mechanisms. Our results revealed that isoparvifuran obviously attenuated H2O2-induced cell senescence, increased the cell proliferation rate,and reversed senescence-associated molecular markers expression such as cyclin D1, pRb, caveolin-1, ace-p53, p21 and p16. Moreover, isoparvifuran dose and time dependently increased the expression level of Sirtuin 1 (SIRT1) in BJ cells. The inhibition of SIRT1 obviously reversed the reduction of SA-β-gal activity and the alteration of senescence-associated molecular markers induced by isoparvifuran. Additionally, isoparvifuran also inhibited H2O2-induced AKT and S6 phosphorylation and increase of SA-β-gal activity. In summary, isoparvifuran protects BJ cells from H2O2-induced premature senescence, the anti-senescence effect of isoparvifuran is associated with the activation of SIRT1 and the suppression of AKT/mTOR signaling pathway.

Keywords:  AKT/mTOR signaling pathway; Antioxidant: SIRT1; Cellular senescence; Isoparvifuran

DOI:  https://doi.org/10.1016/j.bbrc.2020.09.096
Annu Rev Cell Dev Biol. 2020 Oct 06. 36 551-574

B Cell Immunosenescence.

Daniela Frasca, Alain Diaz, Maria Romero, Denisse Garcia, Bonnie B Blomberg.

  Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more severe in old than in young individuals and have a greater impact on health outcomes such as morbidity, disability, and mortality. Aging is characterized by increased low-grade chronic inflammation, so-called inflammaging, that represents a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we summarize current knowledge on age-associated changes in immune cells with special emphasis on B cells, which are more inflammatory and less responsive to infections and vaccines in the elderly. We highlight recent findings on factors and pathways contributing to inflammaging and how these lead to dysfunctional immune responses. We summarize recent published studies showing that adipose tissue, which increases in size with aging, contributes to inflammaging and dysregulated B cell function.

Keywords:  B cells; aging; inflammation; obesity; vaccine responses

DOI:  https://doi.org/10.1146/annurev-cellbio-011620-034148
Front Pharmacol. 2020 ;11 584637

Age-Dependent Assessment of Genes Involved in Cellular Senescence, Telomere, and Mitochondrial Pathways in Human Lung Tissue of Smokers, COPD, and IPF: Associations With SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-DPP4 Axis.

Krishna P Maremanda, Isaac K Sundar, Dongmei Li, Irfan Rahman.

  Background: Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of COPD and idiopathic pulmonary fibrosis (IPF).Methods: Total RNA from the human lung tissues of non-smokers, smokers, and patients with COPD and IPF were processed and analyzed using a Nanostring platform based on their ages (younger: <55 years and older: >55 years).
Results: Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 & 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 & 2, GADD45A), and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases including the SARS-CoV-2 infection. Lung immunoblot analysis of smokers, COPD and IPF subjects revealed increased abundance of proteases and receptor/spike protein like TMPRSS2, furin, and DPP4 in association with a slight increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor ACE2 levels.
Conclusions: Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition in the pathobiology of lung aging in COPD and IPF is associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis as pharmacological targets for COVID-19.

Keywords:  DNA damage; aging; cellular senescence; chronic obstructive pulmonary diseases; idiopathic pulmonary fibrosis; mitochondria; smokers; telomere

DOI:  https://doi.org/10.3389/fphar.2020.584637
Nat Commun. 2020 10 05. 11(1): 4979

G3BP1 controls the senescence-associated secretome and its impact on cancer progression.

Amr Omer, Monica Cruz Barrera, Julian L Moran, Xian J Lian, Sergio Di Marco, Christian Beausejour, Imed-Eddine Gallouzi.

Cellular senescence is a known driver of carcinogenesis and age-related diseases, yet senescence is required for various physiological processes. However, the mechanisms and factors that control the negative effects of senescence while retaining its benefits are still elusive. Here, we show that the rasGAP SH3-binding protein 1 (G3BP1) is required for the activation of the senescent-associated secretory phenotype (SASP). During senescence, G3BP1 achieves this effect by promoting the association of the cyclic GMP-AMP synthase (cGAS) with cytosolic chromatin fragments. In turn, G3BP1, through cGAS, activates the NF-κB and STAT3 pathways, promoting SASP expression and secretion. G3BP1 depletion or pharmacological inhibition impairs the cGAS-pathway preventing the expression of SASP factors without affecting cell commitment to senescence. These SASPless senescent cells impair senescence-mediated growth of cancer cells in vitro and tumor growth in vivo. Our data reveal that G3BP1 is required for SASP expression and that SASP secretion is a primary mediator of senescence-associated tumor growth.

DOI: https://doi.org/10.1038/s41467-020-18734-9
Mol Cell. 2020 Sep 29. pii: S1097-2765(20)30647-X. [Epub ahead of print]

Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response.

Franziska Walser, Monique P C Mulder, Benoît Bragantini, Sibylle Burger, Tatiana Gubser, Marco Gatti, Maria Victoria Botuyan, Alessandra Villa, Matthias Altmeyer, Dario Neri, Huib Ovaa, Georges Mer, Lorenza Penengo.

  The ubiquitin system regulates the DNA damage response (DDR) by modifying histone H2A at Lys15 (H2AK15ub) and triggering downstream signaling events. Here, we find that phosphorylation of ubiquitin at Thr12 (pUbT12) controls the DDR by inhibiting the function of 53BP1, a key factor for DNA double-strand break repair by non-homologous end joining (NHEJ). Detectable as a chromatin modification on H2AK15ub, pUbT12 accumulates in nuclear foci and is increased upon DNA damage. Mutating Thr12 prevents the removal of ubiquitin from H2AK15ub by USP51 deubiquitinating enzyme, leading to a pronounced accumulation of ubiquitinated chromatin. Chromatin modified by pUbT12 is inaccessible to 53BP1 but permissive to the homologous recombination (HR) proteins RNF169, RAD51, and the BRCA1/BARD1 complex. Phosphorylation of ubiquitin at Thr12 in the chromatin context is a new histone mark, H2AK15pUbT12, that regulates the DDR by hampering the activity of 53BP1 at damaged chromosomes.

Keywords:  53BP1; BRCA1/BARD1; DDR; DNA damage response; DNA repair; H2AK15pUbT12; RAD51; RNF168; RNF169; RNF8; USP51; chromatin ubiquitination; genome stability; histone mark H2AK15ub; pUbT12; phospho-ubiquitin Thr12; ubiquitin phosphorylation

DOI:  https://doi.org/10.1016/j.molcel.2020.09.017
Geroscience. 2020 Oct 10.

Effect of rapamycin on aging and age-related diseases-past and future.

Ramasamy Selvarani, Sabira Mohammed, Arlan Richardson.

  In 2009, rapamycin was reported to increase the lifespan of mice when implemented later in life. This observation resulted in a sea-change in how researchers viewed aging. This was the first evidence that a pharmacological agent could have an impact on aging when administered later in life, i.e., an intervention that did not have to be implemented early in life before the negative impact of aging. Over the past decade, there has been an explosion in the number of reports studying the effect of rapamycin on various diseases, physiological functions, and biochemical processes in mice. In this review, we focus on those areas in which there is strong evidence for rapamycin's effect on aging and age-related diseases in mice, e.g., lifespan, cardiac disease/function, central nervous system, immune system, and cell senescence. We conclude that it is time that pre-clinical studies be focused on taking rapamycin to the clinic, e.g., as a potential treatment for Alzheimer's disease.

Keywords:  Aging; Cancer; Heart; Lifespan; Neurodegeneration; Rapamycin

DOI:  https://doi.org/10.1007/s11357-020-00274-1
Eur Respir J. 2020 Oct 08. pii: 2002708. [Epub ahead of print]

Cellular Senescence: Friend or Foe to Respiratory Viral Infections?

William J Kelley, Rachel L Zemans, Daniel R Goldstein.

Cellular senescence permanently arrests the replication of various cell types and contributes to age-associated diseases. In particular, cellular senescence may enhance chronic lung diseases including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. However, the role cellular senescence plays in the pathophysiology of acute inflammatory diseases, especially viral infections, is less well-understood. There is evidence that cellular senescence prevents viral replication by increasing antiviral cytokines, but other evidence shows that senescence may enhance viral replication by downregulating antiviral signalling. Furthermore, cellular senescence leads to the secretion of inflammatory mediators, which may either promote host defense or exacerbate immune pathology during viral infections. In this perspective, we summarise how senescence contributes to physiology and disease, the role of senescence in chronic lung diseases, and how senescence impacts acute respiratory viral infections. Finally, we develop a potential framework of how senescence may contribute, both positively and negatively, to the pathophysiology of viral respiratory infections, including SARS-CoV-2.

DOI: https://doi.org/10.1183/13993003.02708-2020
Mech Ageing Dev. 2020 Oct 03. pii: S0047-6374(20)30174-3. [Epub ahead of print] 111378

In vivo clonal analysis of aging hematopoietic stem cells.

Ryo Yamamoto, Hiromitsu Nakauchi.

  Hematopoietic stem cells (HSCs) are characterized by two key features: Self-renewal ability and multilineage differentiation potential (multipotentiality). With aging, these key features gradually change. This is thought to be related to hematological diseases. However, clonal in vivo analysis assessing the potential of HSCs to differentiate along erythroid and platelet lineages ("five-lineage tracing") has not been performed in the aged bone marrow. By contrast, in young HSCs clonal in vivo analysis combined with five-lineage tracing has provided us with novel insights into HSC biology. Understanding HSC aging at the clonal level will help us to elucidate aging mechanisms and disease progression. We review recent progress towards understanding HSC aging at the clonal cell level in the transplantation setting.

Keywords:  five-lineage tracing; hematopoietic stem cell aging; latent hematopoietic stem cell; myeloid-restricted repopulating progenitor; myeloid-restricted stem cell

DOI:  https://doi.org/10.1016/j.mad.2020.111378
Exp Gerontol. 2020 Oct 01. pii: S0531-5565(20)30447-2. [Epub ahead of print] 111099

Senescence-accelerated mouse prone 8 mice exhibit specific morphological changes in the small intestine during senescence and after pectin supplemented diet.

Sana Ben Othman, Kenji Ido, Ryoya Masuda, Saki Gotoh, Ritsuko Hosoda-Yabe, Kohji Kitaguchi, Tomio Yabe.

  Impairment of gastrointestinal function and reduction of nutrient absorption associated with aging contribute to increased risk of malnutrition in the elderly population, resulting in physical weakness and vulnerability to disease. The present study was performed to examine the relationships between aging-associated morphological changes of the small intestine and nutrient malabsorption using senescence-accelerated mouse prone 8 (SAMP8) mice. Comparison of the morphology of the small intestine of young (22-week-old) and senescent (43-week-old) SAMP8 mice showed no significant changes in villus length, while the mRNA expression levels of secretory cell marker genes were significantly reduced in senescent mice. In addition, crypts recovered from the small intestine of senescent mice showed a good capacity to form intestinal organoids ex vivo, suggesting that the regenerative capacity of intestinal stem cells (ISCs) was unaffected by accelerated senescence. These results indicated that changes induced by accelerated senescence in the small intestine of SAMP8 mice are different from changes reported previously in normal aging mouse models. Biochemical analyses of serum before and during senescence also indicated that senescent SAMP8 mice are not in a malabsorption state. Furthermore, a diet supplemented with persimmon pectin had a mild effect on the small intestine of senescent SAMP8 mice. Intestinal villus length was slightly increased in the medial part of the small intestine of pectin-fed mice. In contrast, intestinal crypt formation capacity was enhanced by the pectin diet. Organoid culture derived from the small intestine of mice fed pectin exhibited a greater number of lobes per organoid compared with those from mice fed a control diet, and Lyz1 and Olfm4 mRNA levels were significantly increased. In conclusion, accelerated senescence induced exclusive changes in the small intestine, which were not related to nutrient malabsorption. Therefore, the SAMP8 strain may not be a suitable model to evaluate the effects of aging on intestinal homeostasis and nutrient absorption impairment.

Keywords:  Gastrointestinal function; Intestinal organoid; Pectin; SAMP8; Senescent mouse

DOI:  https://doi.org/10.1016/j.exger.2020.111099
Cell. 2020 Oct 03. pii: S0092-8674(20)31161-2. [Epub ahead of print]

TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.

Chien-Hsiung Yu, Sophia Davidson, Cassandra R Harapas, James B Hilton, Michael J Mlodzianoski, Pawat Laohamonthonkul, Cynthia Louis, Ronnie Ren Jie Low, Jonas Moecking, Dominic De Nardo, Katherine R Balka, Dale J Calleja, Fiona Moghaddas, Erya Ni, Catriona A McLean, Andre L Samson, Shiraz Tyebji, Christopher J Tonkin, Christopher R Bye, Bradley J Turner, Genevieve Pepin, Michael P Gantier, Kelly L Rogers, Kate McArthur, Peter J Crouch, Seth L Masters.

  Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.

Keywords:  ALS; IFN; NF-κB; STING; TDP-43; cGAMP; cGAS; mPTP; mitochondria; neurodegeneration

DOI:  https://doi.org/10.1016/j.cell.2020.09.020
Aging Cell. 2020 Oct 07. e13236

miR-195 reduces age-related blood-brain barrier leakage caused by thrombospondin-1-mediated selective autophagy.

Chien-Yuan Chen, Yung-Mei Chao, Hsiu-Fen Lin, Chao-Jung Chen, Cheng-Sheng Chen, Jenq-Lin Yang, Julie Y H Chan, Suh-Hang H Juo.

Blood-brain barrier (BBB) disruption contributes to neurodegenerative diseases. Loss of tight junction (TJ) proteins in cerebral endothelial cells (ECs) is a leading cause of BBB breakdown. We recently reported that miR-195 provides vasoprotection, which urges us to explore the role of miR-195 in BBB integrity. Here, we found cerebral miR-195 levels decreased with age, and BBB leakage was significantly increased in miR-195 knockout mice. Furthermore, exosomes from miR-195-enriched astrocytes increased endothelial TJ proteins and improved BBB integrity. To decipher how miR-195 promoted BBB integrity, we first demonstrated that TJ proteins were metabolized via autophagic-lysosomal pathway and the autophagic adaptor p62 was necessary to promote TJ protein degradation in cerebral ECs. Next, proteomic analysis of exosomes revealed miR-195-suppressed thrombospondin-1 (TSP1) as a major contributor to BBB disruption. Moreover, TSP1 was demonstrated to activate selective autophagy of TJ proteins by increasing the formation of claudin-5-p62 and ZO1-p62 complexes in cerebral ECs while TSP1 impaired general autophagy. Delivering TSP1 antibody into the circulation showed dose-dependent reduction of BBB leakage by 20%-40% in 25-month-old mice. Intravenous or intracerebroventricular injection of miR-195 rescued TSP1-induced BBB leakage. Dementia patients with BBB damage had higher levels of serum TSP1 compared to those without BBB damage (p = 0.0015), while the normal subjects had the lowest TSP1 (p < 0.0001). Taken together, the study implies that TSP1-regulated selective autophagy facilitates the degradation of TJ proteins and weakens BBB integrity. An adequate level of miR-195 can suppress the autophagy-lysosome pathway via a reduction of TSP1, which may be important for maintaining BBB function.

DOI: https://doi.org/10.1111/acel.13236
J Cell Physiol. 2020 Oct 06.

Autophagy displays divergent roles during intermittent amino acid starvation and toxic stress-induced senescence in cultured skeletal muscle cells.

Darin Bloemberg, Joe Quadrilatero.

  Due to the ever-expanding functions attributed to autophagy, there is widespread interest in understanding its contribution to human physiology; however, its specific cellular role as a stress-response mechanism is still poorly defined. To investigate autophagy's role in this regard, we repeatedly subjected cultured mouse myoblasts to two stresses with diverse impacts on autophagic flux: amino acid and serum withdrawal (Hank's balanced salt solution [HBSS]), which robustly induces autophagy, or low-level toxic stress (staurosporine, STS). We found that intermittent STS (int-STS) administration caused cell cycle arrest, development of enlarged and misshapen cells/nuclei, increased senescence-associated heterochromatic foci and senescence-associated β-galactosidase activity, and prevented myogenic differentiation. These features were not observed in cells intermittently incubated in HBSS (int-HB). While int-STS cells displayed less DNA damage (phosphorylated H2A histone family, member X content) and caspase activity when administered cisplatin, int-HB cells were protected from STS-induced cell death. Interestingly, STS-induced senescence was attenuated in autophagy related 7-deficient cells. Therefore, while repeated nutrient withdrawal did not cause senescence, autophagy was required for senescence caused by toxic stress. These results illustrate the context-dependent effects of different stressors, potentially highlighting autophagy as a distinguishing factor.

Keywords:  autophagy; caspase; cell death; remodeling; senescence

DOI:  https://doi.org/10.1002/jcp.30079
Front Cell Dev Biol. 2020 ;8 872

ASPH Regulates Osteogenic Differentiation and Cellular Senescence of BMSCs.

Hui Peng, Qi Guo, Ye Xiao, Tian Su, Tie-Jian Jiang, Li-Juan Guo, Min Wang.

  Osteogenesis and senescence of BMSCs play great roles in age-related bone loss. However, the causes of these dysfunctions remain unclear. In this study, we identified a differentially expressed ASPH gene in middle-aged and elderly aged groups which were obtained from GSE35955. Subsequent analysis in various databases, such as TCGA, GTEx, and CCLE, revealed that ASPH had positive correlations with several osteogenic markers. The depletion of mouse Asph suppressed the capacity of osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs). Notably, the expression of ASPH in vitro decreased during aging and senescence. The deficiency of Asph accelerated cellular senescence in BMSCs. Conversely, the overexpression of Asph enhanced the capacity of osteogenic differentiation and inhibited cellular senescence. Mechanistically, ASPH regulated Wnt signaling mediated by Gsk3β. Taken together, our data established that ASPH was potentially involved in the pathogenesis of age-related bone loss through regulating cellular senescence and osteogenic differentiation, which provides some new insights to treat age-related bone loss.

Keywords:  ASPH; BMSCs; aging; cellular senescence; osteogenesis

DOI:  https://doi.org/10.3389/fcell.2020.00872
Exp Biol Med (Maywood). 2020 Oct 07. 1535370220960391

Silencing p53 inhibits interleukin 10-induced activated hepatic stellate cell senescence and fibrotic degradation in vivo.

Qilan Guo, Minghua Chen, Qingduo Chen, Guitao Xiao, Zhixin Chen, Xiaozhong Wang, Yuehong Huang.

  IMPACT STATEMENT: This work further expanded the knowledge of the molecular mechanisms underlying IL-10 anti-fibrogenic effect by exploring the function of p53 in IL-10-induced activated HSCs senescence and fibrotic degradation in vivo. Our data showed that IL-10 gene intervention could lighten hepatic fibrosis induced by CCL4 and induce the senescence of activated HSCs accompanied by up-regulating the expression of senescence-related proteins. In addition, depletion of p53 could abrogate up-regulation of IL-10 on the expression of aging-related proteins in vivo and vitro. Moreover, p53 knockout in fibrotic mice could block the senescence of activated HSCs and the degradation of fibrosis induced by IL-10 gene treatment. In summary, our results suggested that IL-10 gene intervention could attenuate CCL4-induced hepatic fibrosis by inducing senescence of activated HSCs in vivo, and this induction was closely related to p53 signaling pathway. Our study sheds important light into the anti-fibrogenic therapy of IL-10.

Keywords:  Interleukin 10; gene therapy; hepatic stellate cells; liver fibrosis; p53; senescence

DOI:  https://doi.org/10.1177/1535370220960391
Aging Dis. 2020 Oct;11(5): 1329-1338

The Significance of 8-oxoGsn in Aging-Related Diseases.

Xinmu Zhang, Lin Li.

  Aging is a common risk factor for the occurrence and development of many diseases, such as Parkinson's disease, Alzheimer's disease, diabetes, hypertension, atherosclerosis and coronary heart disease, and cancer, among others, and is a key problem threatening the health and life expectancy of the elderly. Oxidative damage is an important mechanism involved in aging. The latest discovery pertaining to oxidative damage is that 8-oxoGsn (8-oxo-7,8-dihydroguanosine), an oxidative damage product of RNA, can represent the level of oxidative stress. The significance of RNA oxidative damage to aging has not been fully explained, but the relationship between the accumulation of 8-oxoGsn, a marker of RNA oxidative damage, and the occurrence of diseases has been confirmed in many aging-related diseases. Studying the aging mechanism, monitoring the aging level of the body and exploring the corresponding countermeasures are of great significance for achieving healthy aging and promoting public health and social development. This article reviews the progress of research on 8-oxoGsn in aging-related diseases.

Keywords:  8-oxoGsn; RNA oxidative damage; aging-related diseases

DOI:  https://doi.org/10.14336/AD.2019.1021
Cell Metab. 2020 Oct 06. pii: S1550-4131(20)30480-0. [Epub ahead of print]32(4): 548-560.e7

Obesity Impairs Short-Term and Working Memory through Gut Microbial Metabolism of Aromatic Amino Acids.

María Arnoriaga-Rodríguez, Jordi Mayneris-Perxachs, Aurelijus Burokas, Oren Contreras-Rodríguez, Gerard Blasco, Clàudia Coll, Carles Biarnés, Romina Miranda-Olivos, Jèssica Latorre, José-Maria Moreno-Navarrete, Anna Castells-Nobau, Mònica Sabater, María Encarnación Palomo-Buitrago, Josep Puig, Salvador Pedraza, Jordi Gich, Vicente Pérez-Brocal, Wifredo Ricart, Andrés Moya, Xavier Fernández-Real, Lluís Ramió-Torrentà, Reinald Pamplona, Joaquim Sol, Mariona Jové, Manuel Portero-Otin, Rafael Maldonado, José Manuel Fernández-Real.

  The gut microbiome has been linked to fear extinction learning in animal models. Here, we aimed to explore the gut microbiome and memory domains according to obesity status. A specific microbiome profile associated with short-term memory, working memory, and the volume of the hippocampus and frontal regions of the brain differentially in human subjects with and without obesity. Plasma and fecal levels of aromatic amino acids, their catabolites, and vegetable-derived compounds were longitudinally associated with short-term and working memory. Functionally, microbiota transplantation from human subjects with obesity led to decreased memory scores in mice, aligning this trait from humans with that of recipient mice. RNA sequencing of the medial prefrontal cortex of mice revealed that short-term memory associated with aromatic amino acid pathways, inflammatory genes, and clusters of bacterial species. These results highlight the potential therapeutic value of targeting the gut microbiota for memory impairment, specifically in subjects with obesity.

Keywords:  B vitamins; brain structure; cognition; memory; metabolomics; metagenomics; microbiome; obesity; one-carbon metabolism; tryptophan metabolites

DOI:  https://doi.org/10.1016/j.cmet.2020.09.002
Immun Inflamm Dis. 2020 Oct 04.

Stress-induced premature senescence activated by the SENEX gene mediates apoptosis resistance of diffuse large B-cell lymphoma via promoting immunosuppressive cells and cytokines.

Jiyu Wang, Qianshan Tao, Ying Pan, Zhixiang Wanyan, Fengfeng Zhu, Xuanxuan Xu, Huiping Wang, Liuying Yi, Mei Zhou, Zhimin Zhai.

  BACKGROUND: The underlying cause of relapsed and refractory (r/r) diffuse large B-cell lymphoma (DLBCL) is usually related to apoptosis resistance to antitumor drugs. The recent years have provided lots of evidence that tumor cells may undergo stress-induced premature senescence (SIPS) in response to chemotherapy, but how SIPS affects lymphoma cells remains inconclusive.METHODS: Fifty-two DLBCL patients, including 6 newly diagnosed (ND), 17 complete remissions (CR), and 29 (r/r), were enrolled in this study. We used a senescence-associated-β-galactosidase (SA-β-Gal) staining kit for senescence staining. Suppressive immune cells including regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) were detected by flow cytometry (FCM). Secreted cytokines were measured by ELISA Kit and SENEX gene expression was detected by a quantitative real-time polymerase chain reaction. We used 40 nM doxorubicin to induce the SIPS model of DLBCL in vitro. Apoptosis and proliferation activity of senescent LY8 cells were respectively detected by FCM and CCK8. SENEX gene was silenced by RNA interference.
RESULTS: The proportion of senescent lymphoma cells was significantly increased in r/r DLBCL patients, concomitant with increased Treg, MDSC, and various secreted cytokines with proinflammatory and immunosuppressive effects. The SENEX gene was significantly elevated in the SIPS model. Senescent DLBCL cells had good antiapoptotic ability and proliferative activity accompanied by increased immunosuppressive cytokines. Interestingly, when we silenced the SENEX gene in the DLBCL cell line, the results were the opposite to the above.
CONCLUSION: SIPS activated by the SENEX gene mediates apoptosis resistance of r/r DLBCL via promoting immunosuppressive cells and cytokines.

Keywords:  DLBCL; SASP; SENEX gene; immunosuppressive cells; stress-induced premature senescence

DOI:  https://doi.org/10.1002/iid3.356
Ageing Res Rev. 2020 Oct 03. pii: S1568-1637(20)30326-3. [Epub ahead of print] 101191

Defective Mitophagy in Alzheimer's Disease.

Jangampalli Adi Pradeepkiran, P Hemachandra Reddy.

  Alzheimer's disease (AD) is a progressive, mental illness without cure. Several years of intense research on postmortem AD brains using cell and mouse models of AD have revealed that multiple cellular changes are involved in the disease process, including mitochondrial abnormalities, synaptic damage, and glial/astrocytic activation, in addition to age-dependent accumulation of amyloid beta (Aβ) and hyperphosphorylated tau (p-tau). Synaptic damage and mitochondrial dysfunction are early cellular changes in the disease process. Healthy and functionally active mitochondria are essential for cellular functioning. Dysfunctional mitochondria play a central role in aging and AD. Mitophagy is a cellular process whereby damaged mitochondria are selectively removed from cell and mitochondrial quality and biogenesis. Mitophagy impairments cause the progressive accumulation of defective organelle and damaged mitochondria in cells. In AD, increased levels of Aβ and p-tau can induce reactive oxygen species (ROS) production, causing excessive fragmentation of mitochondria and promoting defective mitophagy. The current article discusses the latest developments of mitochondrial research and also highlights multiple types of mitophagy, including Aβ and p-tau-induced mitophagy, stress-induced mitophagy, receptor-mediated mitophagy, ubiquitin mediated mitophagy and basal mitophagy. This article also discusses the physiological states of mitochondria, including fission-fusion balance, Ca2+ transport, and mitochondrial transport in normal and diseased conditions. Our article summarizes current therapeutic interventions, like chemical or natural mitophagy enhancers, that influence mitophagy in AD. Our article discusses whether a partial reduction of Drp1 can be a mitophagy enhancer and a therapeutic target for mitophagy in AD and other neurological diseases.

Keywords:  Alzheimer’s disease; amyloid beta; mitochondrial dysfunction; mitophagy; phosphorylated tau

DOI:  https://doi.org/10.1016/j.arr.2020.101191
Hum Exp Toxicol. 2020 Oct 06. 960327120961158

The cross-talk of NLRP3 inflammasome activation and necroptotic hepatocyte death in acetaminophen-induced mice acute liver injury.

L Li, S Shan, K Kang, C Zhang, R Kou, F Song.

  Overdose acetaminophen (APAP) can result in severe liver injury, which is responsible for nearly half of drug-induced liver injury in western countries. Previous studies have found that there existed massive hepatocellular necrosis and severe inflammatory response in APAP-induced liver injury. However, the mechanistic linkage between necroptosis and NLRP3 inflammasome pathway in APAP-induced hepatotoxicity remains poorly understood. In order to investigate the relationship between inflammation and hepatocytes death in APAP hepatotoxicity, a time-course model for APAP hepatotoxicity in C57/BL6 mice was established by intraperitoneal (i.p) injection of 300 mg/kg APAP in this study. The activity of serum enzymes and pathological changes of APAP-treated mice were evaluated, and the critical molecules in necroptosis and NF-κB-NLRP3 inflammasome signaling pathway were determined by immunoblot and immunofluorescence analysis. The results demonstrated that APAP overdose resulted in a severe liver injury. Furthermore, the expression of critical molecules in NLRP3 inflammasome and necroptosis pathways peaked at 12-24 h, and then was decreased gradually, which is consistent with the pattern of pathological injury induced by APAP. Our further investigation found that the level of IL-1β in mouse liver was closely correlated with the level of phosphorylated MLKL following exposure to APAP. Furthermore, inhibition of necroptosis with necrostatin-1 significantly suppressed the activation of NLRP3 inflammasome signaling. Taken together, our results highlighted that the cross-talk between necroptosis and NLRP3 inflammasome played a critical role for promoting APAP-induced liver injury. Inhibition of the interaction of inflammation and necroptosis by pharmaceutical methods may represent a promising therapeutic strategy for APAP-induced liver injury.

Keywords:  Acetaminophen; NLRP3 inflammasome; acute liver injury; necroptosis

DOI:  https://doi.org/10.1177/0960327120961158
Proc Natl Acad Sci U S A. 2020 Oct 06. pii: 202009838. [Epub ahead of print]

Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria.

Danielle E Mor, Salman Sohrabi, Rachel Kaletsky, William Keyes, Alp Tartici, Vrinda Kalia, Gary W Miller, Coleen T Murphy.

  Metabolic dysfunction occurs in many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood. We recently discovered a potential causal link between the branched-chain amino acid transferase BCAT-1 and the neurodegenerative movement disorder Parkinson's disease (PD). RNAi-mediated knockdown of Caenorhabditis elegans bcat-1 is known to recapitulate PD-like features, including progressive motor deficits and neurodegeneration with age, yet the underlying mechanisms have remained unknown. Using transcriptomic, metabolomic, and imaging approaches, we show here that bcat-1 knockdown increases mitochondrial respiration and induces oxidative damage in neurons through mammalian target of rapamycin-independent mechanisms. Increased mitochondrial respiration, or "mitochondrial hyperactivity," is required for bcat-1(RNAi) neurotoxicity. Moreover, we show that post-disease-onset administration of the type 2 diabetes medication metformin reduces mitochondrial respiration to control levels and significantly improves both motor function and neuronal viability. Taken together, our findings suggest that mitochondrial hyperactivity may be an early event in the pathogenesis of PD, and that strategies aimed at reducing mitochondrial respiration may constitute a surprising new avenue for PD treatment.

Keywords:  Caenorhabditis elegans; Parkinson’s disease; branched-chain amino acid metabolism; metformin; mitochondria

DOI:  https://doi.org/10.1073/pnas.2009838117
J Clin Invest. 2020 Oct 05. pii: 130445. [Epub ahead of print]

Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors.

Lulu Wang, Lin Yang, Chen Wang, Wei Zhao, Zhenlin Ju, Wei Zhang, Jianfeng Shen, Yang Peng, Clemens An, Yen T Luu, Shumei Song, Timothy A Yap, Jaffer A Ajani, Gordon B Mills, Xuetong Shen, Guang Peng.

  ARID1A, a component of the chromatin-remodeling complex SWI/SNF, is one of the most frequently mutated genes in human cancer. We sought to develop rational combination therapy to potentiate the efficacy of immune checkpoint blockade in ARID1A-deficient tumors. In a proteomic analysis of a data set from The Cancer Genomic Atlas, we found enhanced expression of Chk2, a DNA damage checkpoint kinase, in ARID1A-mutated/deficient tumors. Surprisingly, we found that ARID1A targets the nonchromatin substrate Chk2 for ubiquitination. Loss of ARID1A increased the Chk2 level through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation. Inhibition of the ATM/Chk2 DNA damage checkpoint axis led to replication stress and accumulation of cytosolic DNA, which subsequently activated the DNA sensor STING-mediated innate immune response in ARID1A-deficient tumors. As expected, tumors with mutation or low expression of both ARID1A and ATM/Chk2 exhibited increased tumor-infiltrating lymphocytes and were associated with longer patient survival. Notably, an ATM inhibitor selectively potentiated the efficacy of immune checkpoint blockade in ARID1A-depleted tumors but not in WT tumors. Together, these results suggest that ARID1A's targeting of the nonchromatin substrate Chk2 for ubiquitination makes it possible to selectively modulate cancer cell-intrinsic innate immunity to enhance the antitumor activity of immune checkpoint blockade.

Keywords:  Cancer; Cancer immunotherapy; Cell Biology; Immunology

DOI:  https://doi.org/10.1172/JCI130445
Aging Cell. 2020 Oct 07. e13245

Blood extracellular vesicles from healthy individuals regulate hematopoietic stem cells as humans age.

Isabelle Grenier-Pleau, Kathrin Tyryshkin, Tri Dung Le, John Rudan, Eric Bonneil, Pierre Thibault, Karen Zeng, Cecilia Lässer, David Mallinson, Dimitrios Lamprou, Jialui Hui, Lynne-Marie Postovit, Edmond Y W Chan, Sheela A Abraham.

  Hematopoietic stem cells (HSCs) maintain balanced blood cell production in a process called hematopoiesis. As humans age, their HSCs acquire mutations that allow some HSCs to disproportionately contribute to normal blood production. This process, known as age-related clonal hematopoiesis, predisposes certain individuals to cancer, cardiovascular and pulmonary pathologies. There is a growing body of evidence suggesting that factors outside cells, such as extracellular vesicles (EVs), contribute to the disruption of stem cell homeostasis during aging. We have characterized blood EVs from humans and determined that they are remarkably consistent with respect to size, concentration, and total protein content, across healthy subjects aged 20-85 years. When analyzing EV protein composition from mass spectroscopy data, our machine-learning-based algorithms are able to distinguish EV proteins based on age and suggest that different cell types dominantly produce EVs released into the blood, which change over time. Importantly, our data show blood EVs from middle and older age groups (>40 years) significantly stimulate HSCs in contrast to untreated and EVs sourced from young subjects. Our study establishes for the first time that although EV particle size, concentration, and total protein content remain relatively consistent over an adult lifespan in humans, EV content evolves during aging and potentially influences HSC regulation.

Keywords:  aging; clonal hematopoiesis; exosomes; extracellular vesicles; hematopoiesis; hematopoietic stem cells

DOI:  https://doi.org/10.1111/acel.13245