bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒09‒27
fifty-one papers selected by
Maria Grazia Vizioli
Mayo Clinic
  1. Cellular senescence as a potential mediator of COVID-19 severity in the elderly.
  2. CXCL5-CXCR2 signaling is a senescence-associated secretory phenotype in preimplantation embryos.
  3. Single-cell analyses of aging, inflammation and senescence.
  4. IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis.
  5. Cellular Senescence Variation by Metabolic and Epigenomic Remodeling.
  6. Caloric restriction alleviates aging-related fibrosis of kidney through downregulation of miR-21 in extracellular vesicles.
  7. Therapeutic Potential of Senolytics in Cardiovascular Disease.
  8. ATP-dependent chromatin remodelers in ageing and age-related disorders.
  9. Autophagy-Sirt3 axis decelerates hematopoietic aging.
  10. Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts.
  11. Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo.
  12. Rapamycin maintains NAD+/NADH redox homeostasis in muscle cells.
  13. A guide to assessing cellular senescence in vitro and in vivo.
  14. Contribution of Ferroptosis to Aging and Frailty.
  15. Nutrient metabolism and cancer in the in vivo context: a metabolic game of give and take.
  16. IGF-1 induces cellular senescence in rat articular chondrocytes via Akt pathway activation.
  17. Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis.
  18. Effects of long-term in vivo micro-CT imaging on hallmarks of osteopenia and frailty in aging mice.
  19. Resemblance and differences in dietary restriction nephroprotective mechanisms in young and old rats.
  20. Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction.
  21. Next steps in mechanisms of inflammaging.
  22. The conundrum of human immune system "senescence".
  23. Spermidine, a caloric restriction mimetic, provides neuroprotection against normal and D-galactose-induced oxidative stress and apoptosis through activation of autophagy in male rats during aging.
  24. Age-related differences in the translational landscape of mammalian oocytes.
  25. NLRP3 activation in endothelia promotes development of diabetes-associated atherosclerosis.
  26. Saturated Fatty Acids Promote Hepatocytic Senecence through Negative Regulation of miR-34a/Cyclin-dependent Kinase 6.
  27. Fight to the bitter end: DNA repair and aging.
  28. The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging.
  29. Targeting Aging Pathways in Chronic Obstructive Pulmonary Disease.
  30. Mitochondrial DNA deletion mutations increase exponentially with age in human skeletal muscle.
  31. The Epigenetic Link between Polyphenols, Aging and Age-Related Diseases.
  32. Flavonoids from dark chocolate and (-)-epicatechin ameliorate high-fat diet-induced decreases in mobility and muscle damage in aging mice.
  33. Unique signatures of stress-induced senescent human astrocytes.
  34. Metabolic regulation of aging and age-related disease.
  35. Senescence and castration resistance in prostate cancer: A review of experimental evidence and clinical implications.
  36. ATM mediated-p53 signaling pathway forms a novel axis for senescence control.
  37. Telomere dysfunction activates YAP1 to drive tissue inflammation.
  38. Epigenetic Regulation in Mesenchymal Stem Cell Aging and Differentiation and Osteoporosis.
  39. Mitochondria as Therapeutic Targets in Transplantation.
  40. Mitochondrial Dysfunction and Alzheimer's Disease: Role of Microglia.
  41. Epigenetic Mechanisms of Learning and Memory: Implications for Aging.
  42. Cardiolipin, Perhydroxyl Radicals, and Lipid Peroxidation in Mitochondrial Dysfunctions and Aging.
  43. Programmed cell death in alcohol-associated liver disease.
  44. Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS).
  45. Combination of metformin and genistein alleviates non-alcoholic fatty liver disease in high-fat diet-fed mice.
  46. Oxidative Stress as a Therapeutic Target for the Prevention and Treatment of Early Age-related Macular Degeneration.
  47. Resveratrol Modulates the Gut Microbiota and Inflammation to Protect Against Diabetic Nephropathy in Mice.
  48. PIK3R3 inhibits cell senescence through p53/p21 signaling.
  49. Effects of caloric restriction on retinal aging and neurodegeneration.
  50. Ubiquitination in rheumatoid arthritis.
  51. Immunosenescence: the role of age in multiple sclerosis.
  1. Aging Cell. 2020 Sep 21. e13237
    Cellular senescence as a potential mediator of COVID-19 severity in the elderly.
    Jamil Nehme, Michela Borghesan, Sebastian Mackedenski, Thomas G Bird, Marco Demaria.
      SARS-CoV-2 is a novel betacoronavirus which infects the lower respiratory tract and can cause coronavirus disease 2019 (COVID-19), a complex respiratory distress syndrome. Epidemiological data show that COVID-19 has a rising mortality particularly in individuals with advanced age. Identifying a functional association between SARS-CoV-2 infection and the process of biological aging may provide a tractable avenue for therapy to prevent acute and long-term disease. Here, we discuss how cellular senescence-a state of stable growth arrest characterized by pro-inflammatory and pro-disease functions-can hypothetically be a contributor to COVID-19 pathogenesis, and a potential pharmaceutical target to alleviate disease severity. First, we define why older COVID-19 patients are more likely to accumulate high levels of cellular senescence. Second, we describe how senescent cells can contribute to an uncontrolled SARS-CoV-2-mediated cytokine storm and an excessive inflammatory reaction during the early phase of the disease. Third, we discuss the various mechanisms by which senescent cells promote tissue damage leading to lung failure and multi-tissue dysfunctions. Fourth, we argue that a high senescence burst might negatively impact on vaccine efficacy. Measuring the burst of cellular senescence could hypothetically serve as a predictor of COVID-19 severity, and targeting senescence-associated mechanisms prior and after SARS-CoV-2 infection might have the potential to limit a number of severe damages and to improve the efficacy of vaccinations.
    DOI:  https://doi.org/10.1111/acel.13237
  2. Aging Cell. 2020 Sep 22. e13240
    CXCL5-CXCR2 signaling is a senescence-associated secretory phenotype in preimplantation embryos.
    Yuta Kawagoe, Ikko Kawashima, Yorino Sato, Naoki Okamoto, Kazuei Matsubara, Kazuhiro Kawamura.
      Pregnancy rate of women decreases with age due to declining quality of oocytes and embryos. However, there is no established method to improve pregnancy rate in aging women. In this study, we identified a senescence-associated secretory phenotype (SASP) factor partially responsible for the decline in embryo implantation potential. Based on microarray analysis using young and aging human embryos at the same morphological grade, 702 genes showed >fivefold increases in aging human blastocysts. Among these genes, C-X-C motif chemokine 5 (CXCL5) showed 7.7-fold increases in aging human blastocysts. However, no-age-dependent changes in expression of the CXCR2, the cognate receptor for CXCL5, were found. In aging mice, Cxcl5 transcript levels were also increased in oocytes and embryos. Treatment of young mouse embryos with CXCL5 decreased implantation rates, together with increased expression of aging markers (P53, P21, Pai-1, and Il-6). Moreover, CXCL5 treatment suppressed trophoblast outgrowth in young mouse blastocysts. Conversely, suppression of CXCL5-CXCR2 signaling in aging mouse embryos using neutralizing antibodies and a receptor antagonist improved the implantation rate, leading to increases in pregnancy and delivery of normal pups. The gene expression pattern of these embryos was comparable to that in young mouse embryos showing enriched cell proliferation-related pathways. In conclusion, we identified CXCL5 as a SASP factor in human and mouse embryos and suppression of CXCL5-CXCR2 signaling during embryo culture improved pregnancy success in aging mice. Future analysis on CXCL5-CXCR2 signaling suppression in human embryos could be the basis to improve embryo development and pregnancy outcome in middle-aged infertile patients.
    Keywords:  CXCL5; CXCR2; SASP; aging; infertility; preimplantation embryo
    DOI:  https://doi.org/10.1111/acel.13240
  3. Ageing Res Rev. 2020 Sep 16. pii: S1568-1637(20)30291-9. [Epub ahead of print] 101156
    Single-cell analyses of aging, inflammation and senescence.
    Bora Uyar, Daniel Palmer, Axel Kowald, Hugo Murua Escobar, Israel Barrantes, Steffen Möller, Altuna Akalin, Georg Fuellen.
      Single-cell gene expression (transcriptomics) data are becoming robust and abundant, and are increasingly used to track organisms along their life-course. This allows investigation into how aging affects cellular transcriptomes, and how changes in transcriptomes may underlie aging, including chronic inflammation (inflammaging), immunosenescence and cellular senescence. We compiled and tabulated aging-related single-cell datasets published to date, collected and discussed relevant findings, and inspected some of these datasets ourselves. We specifically note insights that cannot (or not easily) be based on bulk data. For example, in some datasets, the fraction of cells expressing p16 (CDKN2A), one of the most prominent markers of cellular senescence, was reported to increase, in addition to its upregulated mean expression over all cells. Moreover, we found evidence for inflammatory processes in most datasets, some of these driven by specific cells of the immune system. Further, single-cell data are specifically useful to investigate whether transcriptional heterogeneity (also called noise or variability) increases with age, and many (but not all) studies in our review report an increase in such heterogeneity. Finally, we demonstrate some stability of marker gene expression patterns across closely similar studies and suggest that single-cell experiments may hold the key to provide detailed insights whenever interventions (countering aging, inflammation, senescence, disease, etc.) are affecting cells depending on cell type.
    Keywords:  Aging; Biomarkers; Cellular senescence; Inflammaging; Single-cell sequencing; Transcriptional heterogeneity
    DOI:  https://doi.org/10.1016/j.arr.2020.101156
  4. J Clin Invest. 2020 Sep 21. pii: 134091. [Epub ahead of print]
    IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis.
    Heather J Faust, Hong Zhang, Jin Han, Matthew T Wolf, Ok Hee Jeon, Kaitlyn Sadtler, Alexis N Peña, Liam Chung, David R Maestas, Ada J Tam, Drew M Pardoll, Judith Campisi, Franck Housseau, Daohong Zhou, Clifton O Bingham, Jennifer H Elisseeff.
      Senescent cells (SnCs) are implicated in the pathogenesis of age-related diseases including osteoarthritis (OA), in part via expression of a senescence-associated secretory phenotype (SASP) that includes immunologically relevant factors and cytokines. In a model of posttraumatic OA (PTOA), anterior cruciate ligament transection (ACLT) induced a type 17 immune response in the articular compartment and draining inguinal lymph nodes (LNs) that paralleled expression of the senescence marker p16INK4a (Cdkn2a) and p21 (Cdkn1a). Innate lymphoid cells, γδ+ T cells, and CD4+ T cells contributed to IL-17 expression. Intra-articular injection of IL-17-neutralizing antibody reduced joint degeneration and decreased expression of the senescence marker Cdkn1a. Local and systemic senolysis was required to attenuate tissue damage in aged animals and was associated with decreased IL-17 and increased IL-4 expression in the articular joint and draining LNs. In vitro, we found that Th17 cells induced senescence in fibroblasts and that SnCs skewed naive T cells toward Th17 or Th1, depending on the presence of TGF-β. The SASP profile of the inflammation-induced SnCs included altered Wnt signaling, tissue remodeling, and cell-cycle pathways not previously implicated in senescence. These findings provide molecular targets and mechanisms for senescence induction and therapeutic strategies to support tissue healing in an aged environment.
    Keywords:  Aging; Arthritis; Cellular immune response; Cellular senescence; Immunology
    DOI:  https://doi.org/10.1172/JCI134091
  5. Trends Cell Biol. 2020 Sep 23. pii: S0962-8924(20)30170-7. [Epub ahead of print]
    Cellular Senescence Variation by Metabolic and Epigenomic Remodeling.
    Mitsuyoshi Nakao, Hiroshi Tanaka, Tomoaki Koga.
      Cellular senescence is a state of permanent cell cycle arrest accompanied by unique secretory actions, which influences tissue formation, tumor suppression and aging in vivo. Recent evidences suggest that metabolic and epigenomic reprogram cooperatively creates phenotypic differences of senescent cells, which may provide new clues to control aging processes.
    Keywords:  cellular senescence; epigenome; gene regulation; metabolism; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.tcb.2020.08.009
  6. Aging (Albany NY). 2020 Aug 27. 12
    Caloric restriction alleviates aging-related fibrosis of kidney through downregulation of miR-21 in extracellular vesicles.
    Jin-Rui Liu, Guang-Yan Cai, Yi-Chun Ning, Jing-Chao Wang, Yang Lv, Ya-Nan Guo, Bo Fu, Quan Hong, Xue-Feng Sun, Xiang-Mei Chen.
      Glomerulosclerosis and renal interstitial fibrosis occur with the aging kidney. In this study, we examined the expression of miR-21, peroxisome proliferator-activated receptor(PPARα), hypoxia-inducible factor(HIF-1α) in the kidney of 3-month-old rats fed ad libitum (YAL), 24-month-old rats fed ad libitum (OAL) and 24-month-old rats subjected to a 70% calorie-restricted diet for 8 months (OCR). We found long-term caloric restriction (CR) ameliorated aging and aging-related fibrosis. CR ameliorated the increment of miR-21 and HIF-1α, as well as the decrement of PPARα in old ad libitum group. Human proximal tubular cells (HPTCs) presented phenotypes of senescence and epithelial to mesenchymal transition (EMT) under high-glucose conditions, in which senescence occurred earlier than EMT. Senescent cells secreted extracellular vesicles (EVs) which contained miR-21 into the recipient cells. Inhibiting miR-21 of donor cells prevented the occurrence of EMT in recipient cells. In addition, miR-21 induced EMT through targeting PPARα protein and consequently enhancing HIF-1α expression, although other pathways cannot be ruled out. These findings demonstrated that miR-21-containing EVs derived from the senescent cells could facilitate EMT of HPTCs via PPARα-HIF-1α signaling pathway. Long-term caloric restriction and caloric restriction mimetics alleviated aging-related-fibrosis of kidney through downregulation of miR-21.
    Keywords:  EMT; age; caloric restriction; extracellular vesicles; miR-21
    DOI:  https://doi.org/10.18632/aging.103591
  7. Cardiovasc Drugs Ther. 2020 Sep 26.
    Therapeutic Potential of Senolytics in Cardiovascular Disease.
    Emily Dookun, João F Passos, Helen M Arthur, Gavin D Richardson.
      Ageing is the biggest risk factor for impaired cardiovascular health, with cardiovascular disease being the leading cause of death in 40% of individuals over 65 years old. Ageing is associated with both an increased prevalence of cardiovascular disease including heart failure, coronary artery disease, and myocardial infarction. Furthermore, ageing is associated with a poorer prognosis to these diseases. Genetic models allowing the elimination of senescent cells revealed that an accumulation of senescence contributes to the pathophysiology of cardiovascular ageing and promotes the progression of cardiovascular disease through the expression of a proinflammatory and profibrotic senescence-associated secretory phenotype. These studies have resulted in an effort to identify pharmacological therapeutics that enable the specific elimination of senescent cells through apoptosis induction. These senescent cell apoptosis-inducing compounds are termed senolytics and their potential to ameliorate age-associated cardiovascular disease is the focus of this review.
    Keywords:  Atherosclerosis; Cardiovascular; Inflammation; Remodelling; Senescence; Senolytic
    DOI:  https://doi.org/10.1007/s10557-020-07075-w
  8. Biogerontology. 2020 Sep 23.
    ATP-dependent chromatin remodelers in ageing and age-related disorders.
    Pynskhem Bok Swer, Ramesh Sharma.
      Ageing is characterized by the perturbation in cellular homeostasis associated with genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intracellular communication. Changes in the epigenome represent one of the crucial mechanisms during ageing and in age-related disorders. The ATP-dependent chromatin remodelers are an evolutionarily conserved family of nucleosome remodelling factors and generally regulate DNA repair, replication, recombination, transcription and cell cycle. Here, we review the chromatin based epigenetic changes that occur in ageing and age-related disorders with a specific reference to chromatin remodelers. We also discuss the link between dietary restriction and chromatin remodelers in regulating age-related processes with a view for consideration in future intervention studies.
    Keywords:  Ageing; Chromatin remodelers; Dietary restriction; Epigenetics
    DOI:  https://doi.org/10.1007/s10522-020-09899-3
  9. Aging Cell. 2020 Sep 20. e13232
    Autophagy-Sirt3 axis decelerates hematopoietic aging.
    Yixuan Fang, Ni An, Lingjiang Zhu, Yue Gu, Jiawei Qian, Gaoyue Jiang, Ruijin Zhao, Wen Wei, Li Xu, Gaochuan Zhang, Xingyun Yao, Na Yuan, Suping Zhang, Yun Zhao, Jianrong Wang.
      Autophagy suppresses mitochondrial metabolism to preserve hematopoietic stem cells (HSCs) in mice. However, the mechanism by which autophagy regulates hematopoietic aging, in particular in humans, has largely been unexplored. Here, we demonstrate that reduction of autophagy in both hematopoietic cells and their stem cells is associated with aged hematopoiesis in human population. Mechanistically, autophagy delays hematopoietic aging by activating the downstream expression of Sirt3, a key mitochondrial protein capable of rejuvenating blood. Sirt3 is the most abundant Sirtuin family member in HSC-enriched population, though it declines as the capacity for autophagy deteriorates with aging. Activation of autophagy upregulates Sirt3 in wild-type mice, whereas in autophagy-defective mice, Sirt3 expression is crippled in the entire hematopoietic hierarchy, but forced expression of Sirt3 in HSC-enriched cells reduces oxidative stress and prevents accelerated hematopoietic aging from autophagy defect. Importantly, the upregulation of Sirt3 by manipulation of autophagy is validated in human HSC-enriched cells. Thus, our results identify an autophagy-Sirt3 axis in regulating hematopoietic aging and suggest a possible interventional solution to human blood rejuvenation via activation of the axis.
    DOI:  https://doi.org/10.1111/acel.13232
  10. Mech Ageing Dev. 2020 Sep 22. pii: S0047-6374(20)30156-1. [Epub ahead of print] 111360
    Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch Syndrome fibroblasts.
    Cindy Tatiana Báez-Becerra, Estefania Valencia-Rincón, Karen Velásquez-Méndez, Nelson J Ramírez-Suárez, Claudia Guevara, Adrian Sandoval-Hernandez, Carlos E Arboleda-Bustos, Leonora Olivos-Cisneros, Gabriel Gutiérrez-Ospina, Humberto Arboleda, Gonzalo Arboleda.
      Recently, mutations in the RNA polymerase III subunit A (POLR3A) have been described as the cause of the neonatal progeria or Wiedemann-Rautenstrauch syndrome (WRS). POLR3A has important roles in transcription regulation of small RNAs, including tRNA, 5S rRNA, and 7SK rRNA. We aim to describe the cellular and molecular features of WRS fibroblasts. Cultures of primary fibroblasts from one WRS patient [monoallelic POLR3A variant c.3772_3773delCT (p.Leu1258Glyfs*12)] and one control patient were cultured in vitro. The mutation caused a decrease in the expression of wildtype POLR3A mRNA and POLR3A protein and a sharp increase in mutant protein expression. In addition, there was an increase in the nuclear localization of the mutant protein. These changes were associated with an increase in the number and area of nucleoli and to a high increase in the expression of pP53 and pH2AX. All these changes were associated with premature senescence. The present observations add to our understanding of the differences between Hutchinson-Gilford progeria syndrome and WRS and opens new alternatives to study cell senesce and human aging.
    Keywords:  DNA damage; Nucleolus; Nucleus; RNA polymerase III subunit A (POLR3A); Wiedemann-Rautenstrauch syndrome; cell senescence
    DOI:  https://doi.org/10.1016/j.mad.2020.111360
  11. Cell Metab. 2020 Sep 11. pii: S1550-4131(20)30484-8. [Epub ahead of print]
    Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo.
    Satotaka Omori, Teh-Wei Wang, Yoshikazu Johmura, Tomomi Kanai, Yasuhiro Nakano, Taketomo Kido, Etsuo A Susaki, Takuya Nakajima, Shigeyuki Shichino, Satoshi Ueha, Manabu Ozawa, Kisho Yokote, Soichiro Kumamoto, Atsuya Nishiyama, Takeharu Sakamoto, Kiyoshi Yamaguchi, Seira Hatakeyama, Eigo Shimizu, Kotoe Katayama, Yasuhiro Yamada, Satoshi Yamazaki, Kanako Iwasaki, Chika Miyoshi, Hiromasa Funato, Masashi Yanagisawa, Hiroo Ueno, Seiya Imoto, Yoichi Furukawa, Nobuaki Yoshida, Kouji Matsushima, Hiroki R Ueda, Atsushi Miyajima, Makoto Nakanishi.
      Cell senescence plays a key role in age-associated organ dysfunction, but the in vivo pathogenesis is largely unclear. Here, we generated a p16-CreERT2-tdTomato mouse model to analyze the in vivo characteristics of p16high cells at a single-cell level. We found tdTomato-positive p16high cells detectable in all organs, which were enriched with age. We also found that these cells failed to proliferate and had half-lives ranging from 2.6 to 4.2 months, depending on the tissue examined. Single-cell transcriptomics in the liver and kidneys revealed that p16high cells were present in various cell types, though most dominant in hepatic endothelium and in renal proximal and distal tubule epithelia, and that these cells exhibited heterogeneous senescence-associated phenotypes. Further, elimination of p16high cells ameliorated nonalcoholic steatohepatitis-related hepatic lipidosis and immune cell infiltration. Our new mouse model and single-cell analysis provide a powerful resource to enable the discovery of previously unidentified senescence functions in vivo.
    Keywords:  NASH; aging; p16Ink4a; senescence; single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.cmet.2020.09.006
  12. Aging (Albany NY). 2020 Sep 22. 12
    Rapamycin maintains NAD+/NADH redox homeostasis in muscle cells.
    Zhigang Zhang, He N Xu, Siyu Li, Antonio Davila Jr, Karthikeyani Chellappa, James G Davis, Yuxia Guan, David W Frederick, Weiqing Chu, Huaqing Zhao, Lin Z Li, Joseph A Baur.
      Rapamycin delays multiple age-related conditions and extends lifespan in organisms ranging from yeast to mice. However, the mechanisms by which rapamycin influences longevity are incompletely understood. The objective of this study was to investigate the effect of rapamycin on NAD+/NADH redox balance. We report that the NAD+/NADH ratio of C2C12 myoblasts or differentiated myotubes significantly decreases over time in culture, and that rapamycin prevents this effect. Despite lowering the NADH available to support ATP generation, rapamycin increases ATP availability, consistent with lowering energetic demand. Although rapamycin did not change the NAD+/NADH ratio or steady-state ATP concentration in the livers, kidneys, or muscles of young mice, optical redox imaging revealed that rapamycin caused a substantial decline in the NADH content and an increase in the optical redox ratio (a surrogate of NAD+/NADH redox ratio) in muscles from aged mice. Collectively, these data suggest that rapamycin favors a more oxidized NAD+/NADH ratio in aged muscle, which may influence metabolism and the activity of NAD+-dependent enzymes. This study provides new insight into the mechanisms by which rapamycin might influence the aging process to improve health and longevity among the aging population.
    Keywords:  NAD/NADH ratio +; aging; optical redox imaging; rapamycin; redox state
    DOI:  https://doi.org/10.18632/aging.103954
  13. FEBS J. 2020 Sep 22.
    A guide to assessing cellular senescence in vitro and in vivo.
    Estela González-Gualda, Andrew G Baker, Ljiljana Fruk, Daniel Muñoz-Espín.
      Cellular senescence is a physiological mechanism whereby a proliferating cell undergoes a stable cell cycle arrest upon damage or stress and elicits a secretory phenotype. This highly dynamic and regulated cellular state plays beneficial roles in physiology, such as during embryonic development and wound healing, but it can also result in antagonistic effects in age-related pathologies, degenerative disorders, aging and cancer. In an effort to better identify this complex state, and given that a universal marker has yet to be identified, a general set of hallmarks describing senescence has been established. However, as the senescent programme becomes more defined, further complexities, including phenotype heterogeneity, have emerged. This significantly complicates the recognition and evaluation of cellular senescence, especially within complex tissues and living organisms. To address these challenges, substantial efforts are currently being made towards the discovery of novel and more specific biomarkers, optimised combinatorial strategies, and the development of emerging detection techniques. Here, we compile such advances and present a multi-factorial guide to identify and assess cellular senescence in cell cultures, tissues and living organisms. The reliable assessment and identification of senescence is not only crucial for better understanding its underlying biology, but also imperative for the development of diagnostic and therapeutic strategies aimed at targeting senescence in the clinic.
    Keywords:  Cellular senescence; ageing; assessment; biomarkers; detection
    DOI:  https://doi.org/10.1111/febs.15570
  14. Rejuvenation Res. 2020 Sep 25.
    Contribution of Ferroptosis to Aging and Frailty.
    James Larrick, Jasmine W Larrick, Andrew R Mendelsohn.
      Ferroptosis is a recently characterized cell death phenotype resulting from iron catalyzed peroxidation of polyunsaturated fatty acid (PUFA) phospholipids. Increased dysfunctional iron metabolism is thought to lead to increased levels of iron and ferroptosis which in turn leads to cell and organismal death at least in the nematode C. elegans. Drugs that block lipid peroxidation or scavenge intracellular iron extend healthspan and lifespan in C. elegans independently of other mechanisms such as the daf-1/daf-16 (insulin/IGF-1) pathway, but unlike many aging mechanisms do not alter temporal scaling across the life cycle of C. elegans, but rather act at specific late points in the organism's life history, temporarily blocking execution of critical dysfunction that results in listless worms. As such, inhibition of ferroptosis may be a means to extend healthspan and treat frailty and possibly neurodegenerative diseases that have a reported role for iron dyshomeostasis. However, a significant effort to understand ferroptosis in the context of mammalian and human biology is necessary. For example, some tumors block ferroptosis in order to survive. The constraints of balancing iron metabolism are significant and will require careful consideration in any drug development program.
    DOI:  https://doi.org/10.1089/rej.2020.2390
  15. EMBO Rep. 2020 Sep 23. e50635
    Nutrient metabolism and cancer in the in vivo context: a metabolic game of give and take.
    Patricia Altea-Manzano, Alejandro M Cuadros, Lindsay A Broadfield, Sarah-Maria Fendt.
      Nutrients are indispensable resources that provide the macromolecular building blocks and energy requirements for sustaining cell growth and survival. Cancer cells require several key nutrients to fulfill their changing metabolic needs as they progress through stages of development. Moreover, both cell-intrinsic and microenvironment-influenced factors determine nutrient dependencies throughout cancer progression-for which a comprehensive characterization remains incomplete. In addition to the widely studied role of genetic alterations driving cancer metabolism, nutrient use in cancer tissue may be affected by several factors including the following: (i) diet, the primary source of bodily nutrients which influences circulating metabolite levels; (ii) tissue of origin, which can influence the tumor's reliance on specific nutrients to support cell metabolism and growth; (iii) local microenvironment, which dictates the accessibility of nutrients to tumor cells; (iv) tumor heterogeneity, which promotes metabolic plasticity and adaptation to nutrient demands; and (v) functional demand, which intensifies metabolic reprogramming to fuel the phenotypic changes required for invasion, growth, or survival. Here, we discuss the influence of these factors on nutrient metabolism and dependence during various steps of tumor development and progression.
    Keywords:  cancer metabolism; diet; microenvironment; nutrients; tumor heterogeneity
    DOI:  https://doi.org/10.15252/embr.202050635
  16. Exp Ther Med. 2020 Nov;20(5): 49
    IGF-1 induces cellular senescence in rat articular chondrocytes via Akt pathway activation.
    Li-Dong Zhao, Lian-Yu Bie, Lan Hu, Zi-Han Zhu, Xing-Hua Meng, Lin-Lin Cong, Shai Zhang, Ning Ma, Jian-Hua Xiao.
      Cellular senescence decreases cell proliferation over time and is characterized by typical markers, including larger cell volume, a flattened morphology, irreversible cell cycle arrest, augmentation of senescence-associated β-galactosidase (SA-β-gal) activity and senescence-associated secretory phenotype. A variety of factors are implicated in the process of cellular aging, which mediates an organisms' lifespan. Insulin-like growth factor-1 (IGF-1) serves an essential role in regulating cell growth, division, proliferation and senescence. In the present study, the role of IGF-1 and the downstream Akt signaling pathway in rat articular chondrocyte senescence was assessed. The results of the current study demonstrated that IGF-1 promoted cellular senescence in rat articular chondrocytes via activation of SA-β-gal and the upregulation of p53 and p21 mRNA and protein levels. IGF-1 enhanced Akt phosphorylation and treatment with Akt inhibitor, MK-2206, significantly suppressed the induction of these markers. Overall, the results indicated the involvement of IGF-1 and Akt in senescence exhibited by rat articular chondrocytes.
    Keywords:  Akt; insulin-like growth factor-1; rat articular chondrocytes; senescence
    DOI:  https://doi.org/10.3892/etm.2020.9177
  17. Cells. 2020 Sep 23. pii: E2146. [Epub ahead of print]9(10):
    Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis.
    Gisela Machado-Oliveira, Cristiano Ramos, André R A Marques, Otília V Vieira.
      Atherosclerosis is an age-related disorder associated with long-term exposure to cardiovascular risk factors. The asymptomatic progression of atherosclerotic plaques leads to major cardiovascular diseases (CVD), including acute myocardial infarctions or cerebral ischemic strokes in some cases. Senescence, a biological process associated with progressive structural and functional deterioration of cells, tissues and organs, is intricately linked to age-related diseases. Cell senescence involves coordinated modifications in cellular compartments and has been demonstrated to contribute to different stages of atheroma development. Senescence-based therapeutic strategies are currently being pursued to treat and prevent CVD in humans in the near-future. In addition, distinct experimental settings allowed researchers to unravel potential approaches to regulate anti-apoptotic pathways, facilitate excessive senescent cell clearance and eventually reverse atherogenesis to improve cardiovascular function. However, a deeper knowledge is required to fully understand cellular senescence, to clarify senescence and atherogenesis intertwining, allowing researchers to establish more effective treatments and to reduce the cardiovascular disorders' burden. Here, we present an objective review of the key senescence-related alterations of the major intracellular organelles and analyze the role of relevant cell types for senescence and atherogenesis. In this context, we provide an updated analysis of therapeutic approaches, including clinically relevant experiments using senolytic drugs to counteract atherosclerosis.
    Keywords:  atherosclerosis; cardiovascular diseases; senescence; senescent organelles
    DOI:  https://doi.org/10.3390/cells9102146
  18. PLoS One. 2020 ;15(9): e0239534
    Effects of long-term in vivo micro-CT imaging on hallmarks of osteopenia and frailty in aging mice.
    Ariane C Scheuren, Gisela A Kuhn, Ralph Müller.
      In vivo micro-CT has already been used to monitor microstructural changes of bone in mice of different ages and in models of age-related diseases such as osteoporosis. However, as aging is accompanied by frailty and subsequent increased sensitivity to external stimuli such as handling and anesthesia, the extent to which longitudinal imaging can be applied in aging studies remains unclear. Consequently, the potential of monitoring individual mice during the entire aging process-from healthy to frail status-has not yet been exploited. In this study, we assessed the effects of long-term in vivo micro-CT imaging-consisting of 11 imaging sessions over 20 weeks-on hallmarks of aging both on a local (i.e., static and dynamic bone morphometry) and systemic (i.e., frailty index (FI) and body weight) level at various stages of the aging process. Furthermore, using a premature aging model (PolgA(D257A/D257A)), we assessed whether these effects differ between genotypes. The 6th caudal vertebrae of 4 groups of mice (PolgA(D257A/D257A) and PolgA(+/+)) were monitored by in vivo micro-CT every 2 weeks. One group was subjected to 11 scans between weeks 20 and 40 of age, whereas the other groups were subjected to 5 scans between weeks 26-34, 32-40 and 40-46, respectively. The long-term monitoring approach showed small but significant changes in the static bone morphometric parameters compared to the other groups. However, no interaction effect between groups and genotype was found, suggesting that PolgA mutation does not render bone more or less susceptible to long-term micro-CT imaging. The differences between groups observed in the static morphometric parameters were less pronounced in the dynamic morphometric parameters. Moreover, the body weight and FI were not affected by more frequent imaging sessions. Finally, we observed that longitudinal designs including baseline measurements at young adult age are more powerful at detecting effects of in vivo micro-CT imaging on hallmarks of aging than cross-sectional comparisons between multiple groups of aged mice subjected to fewer imaging sessions.
    DOI:  https://doi.org/10.1371/journal.pone.0239534
  19. Aging (Albany NY). 2020 Sep 24. 12
    Resemblance and differences in dietary restriction nephroprotective mechanisms in young and old rats.
    Nadezda V Andrianova, Ljubava D Zorova, Irina B Pevzner, Vasily A Popkov, Valery P Chernikov, Denis N Silachev, Egor Y Plotnikov, Dmitry B Zorov.
      Dietary restriction (DR) is the strategy ameliorating the morbidity of various pathologies, including age-associated diseases. Acute kidney injury (AKI) remains a problem for the elderly with DR being a promising approach for diminishing its consequences. We evaluated the possible nephroprotective potential of short-term DR in young and old rats. DR in young rats resulted in pronounced beneficial effects normalizing lipid metabolism (triglycerides concentration, adiponectin level) activating autophagic-lysosomal system evaluated by LC3II/LC3I ratio, LAMP1, p62/SQSTM1 levels, and LysoTracker Green staining. DR had a remarkable recovering effect on mitochondrial structure and functions including regaining of mitochondrial membrane potential, the elevation of SIRT-3, PGC-1α, Bcl-XL levels and partial restoration of ultrastructure. The beneficial effects of DR resulted in the mitigation of oxidative stress including a decrease in levels of protein carbonylation and lipid peroxidation. Aging led to decreased activity of autophagy, elevated oxidative stress and impaired kidney regenerative capacity. Eventually, in old rats, even 8-week DR was not able to ameliorate AKI, but it caused some rejuvenating effects including elevation of mitochondrial membrane potential and Bcl-XL levels, as well as lowered severity of the oxidative stress. Thus, the age-associated decline of protective signaling demands extended DR to achieve nephroprotective potential in old animals.
    Keywords:  aging; caloric restriction; ischemia/reperfusion; kidney injury; mitochondria
    DOI:  https://doi.org/10.18632/aging.103960
  20. Nat Commun. 2020 Sep 25. 11(1): 4865
    Polyunsaturated fatty acids and p38-MAPK link metabolic reprogramming to cytoprotective gene expression during dietary restriction.
    Manish Chamoli, Anita Goyala, Syed Shamsh Tabrez, Atif Ahmed Siddiqui, Anupama Singh, Adam Antebi, Gordon J Lithgow, Jennifer L Watts, Arnab Mukhopadhyay.
      The metabolic state of an organism instructs gene expression modalities, leading to changes in complex life history traits, such as longevity. Dietary restriction (DR), which positively affects health and life span across species, leads to metabolic reprogramming that enhances utilisation of fatty acids for energy generation. One direct consequence of this metabolic shift is the upregulation of cytoprotective (CyTP) genes categorized in the Gene Ontology (GO) term of "Xenobiotic Detoxification Program" (XDP). How an organism senses metabolic changes during nutritional stress to alter gene expression programs is less known. Here, using a genetic model of DR, we show that the levels of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA) and eicosapentaenoic acid (EPA), are increased following DR and these PUFAs are able to activate the CyTP genes. This activation of CyTP genes is mediated by the conserved p38 mitogen-activated protein kinase (p38-MAPK) pathway. Consequently, genes of the PUFA biosynthesis and p38-MAPK pathway are required for multiple paradigms of DR-mediated longevity, suggesting conservation of mechanism. Thus, our study shows that PUFAs and p38-MAPK pathway function downstream of DR to help communicate the metabolic state of an organism to regulate expression of CyTP genes, ensuring extended life span.
    DOI:  https://doi.org/10.1038/s41467-020-18690-4
  21. Autophagy. 2020 Sep 22. 1-2
    Next steps in mechanisms of inflammaging.
    Leena P Bharath, Barbara S Nikolajczyk.
      Striking age-related changes occur in the human immune system, beginning in the sixth decade of life. Age is a non-modifiable, universal risk factor that results in the dysregulation of many cellular homeostatic processes. The decline in immune cell macroautophagy/autophagy and the increased generation of proinflammatory cytokines during agingfuels the development of diseases in the elderly. We reported that higher Th17 inflammation during aging was secondary to dysregulation in T cell autophagy. However, the mechanism underlying lower anti-CD3 and anti-CD28 activation-induced T cell autophagy during aging remain unknown. Our data fuel the speculation that dysregulation of the glutathione (GSH) system might cause the decline in T cell autophagy in aging, additionally provoked by reactive oxygen species signaling emanating from the mitochondria.
    Keywords:  Aging; autophagy; glutathione; membrane potential; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1080/15548627.2020.1822089
  22. Mech Ageing Dev. 2020 Sep 16. pii: S0047-6374(20)30153-6. [Epub ahead of print] 111357
    The conundrum of human immune system "senescence".
    Graham Pawelec, Anne Bronikowski, Stephen C Cunnane, Luigi Ferrucci, Claudio Franceschi, Tamas Fülöp, Pierrette Gaudreau, Vadim N Gladyshev, Efstathios S Gonos, Vera Gorbunova, Brian K Kennedy, Anis Larbi, Jean-François Lemaître, Guang-Hui Liu, Andrea B Maier, José A Morais, Otávio T Nóbrega, Alexey Moskalev, Marcel Olde Rikkert, Andrei Seluanov, Alistair M Senior, Svetlana Ukraintseva, Quentin Van Haelen, Jacek Witkowski, Alan A Cohen.
      There is a great deal of debate on the question of whether or not we know what ageing is (Ref. Cohen et al). Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as "immunosenescence". But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity. Such biomarkers of immunosenescence may nonetheless indicate beneficial effects in other contexts, consistent with the notion of antagonistic pleiotropy. Identifying what could be true immunosenescence in this respect requires examining: (1) what appears to correlate with age, though generality across human populations is not yet confirmed; (2) what clearly is part of a suite of canonical changes in the immune system that happen with age; (3) which subset of those changes accelerates rather than slows aging; and (4) all changes, potentially population-specific, that accelerate agig. This remains an immense challenge. These questions acquire an added urgency in the current SARS-CoV-2 pandemic, given the clearly greater susceptibility of older adults to COVID-19.
    Keywords:  Cytomegalovirus; Human immunosenescence; inflammageing; longitudinal study; vaccination
    DOI:  https://doi.org/10.1016/j.mad.2020.111357
  23. Biogerontology. 2020 Sep 26.
    Spermidine, a caloric restriction mimetic, provides neuroprotection against normal and D-galactose-induced oxidative stress and apoptosis through activation of autophagy in male rats during aging.
    Sandeep Singh, Raushan Kumar, Geetika Garg, Abhishek Kumar Singh, Avnish Kumar Verma, Akalabya Bissoyi, Syed Ibrahim Rizvi.
      Spermidine (SPD) is a natural polyamine present in all living organisms and is involved in the maintenance of cellular homeostasis by inducing autophagy in different model organisms. Its role as a caloric restriction mimetic (CRM) is still being investigated. We have undertaken this study to investigate whether SPD, acting as a CRM, can confer neuroprotection in D-galactose induced accelerated senescence model rat and naturally aged rats through modulation of autophagy and inflammation. Young male rats (4 months), D-gal induced (500 mg/kg b.w., subcutaneously) aging and naturally aged (22 months) male rats were supplemented with SPD (10 mg/kg b.w., orally) for 6 weeks. Standard protocols were employed to measure prooxidants, antioxidants, apoptotic cell death and electron transport chain complexes in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy and inflammatory marker genes. Our data demonstrate that SPD significantly (p ≤ 0.05) decreased the level of pro-oxidants and increased the level of antioxidants. SPD supplementation also augmented the activities of electron transport chain complexes in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. RT-PCR data revealed that SPD up-regulated the expression of autophagy genes (ATG-3, Beclin-1, ULK-1 and LC3B) and down-regulated the expression of the inflammatory gene (IL-6) in aging brain. Our results provide first line of evidence that SPD provides neuroprotection against aging-induced oxidative stress by regulating autophagy, antioxidants level and also reduces neuroinflammation. These results suggest that SPD may be beneficial for neuroprotection during aging and age-related disorders.
    Keywords:  Aging; Apoptosis; Autophagy; Caloric restriction mimetics; Spermidine
    DOI:  https://doi.org/10.1007/s10522-020-09900-z
  24. Aging Cell. 2020 Sep 20. e13231
    Age-related differences in the translational landscape of mammalian oocytes.
    Edgar Del Llano, Tomas Masek, Lenka Gahurova, Martin Pospisek, Marketa Koncicka, Anna Jindrova, Denisa Jansova, Rajan Iyyappan, Kristina Roucova, Alexander W Bruce, Michal Kubelka, Andrej Susor.
      Increasing maternal age in mammals is associated with poorer oocyte quality, involving higher aneuploidy rates and decreased developmental competence. Prior to resumption of meiosis, fully developed mammalian oocytes become transcriptionally silent until the onset of zygotic genome activation. Therefore, meiotic progression and early embryogenesis are driven largely by translational utilization of previously synthesized mRNAs. We report that genome-wide translatome profiling reveals considerable numbers of transcripts that are differentially translated in oocytes obtained from aged compared to young females. Additionally, we show that a number of aberrantly translated mRNAs in oocytes from aged females are associated with cell cycle. Indeed, we demonstrate that four specific maternal age-related transcripts (Sgk1, Castor1, Aire and Eg5) with differential translation rates encode factors that are associated with the newly forming meiotic spindle. Moreover, we report substantial defects in chromosome alignment and cytokinesis in the oocytes of young females, in which candidate CASTOR1 and SGK1 protein levels or activity are experimentally altered. Our findings indicate that improper translation of specific proteins at the onset of meiosis contributes to increased chromosome segregation problems associated with female ageing.
    DOI:  https://doi.org/10.1111/acel.13231
  25. Aging (Albany NY). 2020 Sep 23. 12
    NLRP3 activation in endothelia promotes development of diabetes-associated atherosclerosis.
    Dong Huang, Wei Gao, Xin Zhong, Junbo Ge.
      Inflammatory damage to endothelial cells plays a pivotal role in the diabetes-provoked atherosclerosis (AS). PYD domains-containing protein 3 (NLRP3) induces formation of inflammasome activates caspase-1, which subsequently cleaves the precursor form of IL-1β (pro-IL-1β) into the processed, secreted form IL-1β to promote the immune responses in AS. However, it is not known whether NLRP3 activation specifically in endothelial cells causes AS. Here, in an in vitro model for AS, we showed that NLRP3-depleted human aortic endothelial cells (HAECs) became resistant to apoptotic cell death, maintained proliferative potential and reduced reactive oxygen species (ROS) production upon treatment with oxidized low-density lipoprotein (ox-LDL). Next, the role of NLRP3 in endothelial cells in the development of diabetes-associated AS was assessed in endothelial cell-specific NLRP3 mutant, ApoE (-/-) mice (APOEKO/Tie2p-Cre/NLRP3MKO), compared to control ApoE (-/-) mice (APOEKO), supplied with either high-fat diet (HFD), or normal diet (ND). We found that endothelia-specific NLRP3-depletion significantly attenuated AS severity in mice treated with HFD, likely through reduced apoptotic death of endothelial cells and production of ROS. Together, our data suggest that NLRP3 activation in endothelial cells promotes development of diabetes-associated AS.
    Keywords:  NLRP3; atherosclerosis; diabetes; endothelial cells
    DOI:  https://doi.org/10.18632/aging.103666
  26. Mol Nutr Food Res. 2020 Sep 24. e2000383
    Saturated Fatty Acids Promote Hepatocytic Senecence through Negative Regulation of miR-34a/Cyclin-dependent Kinase 6.
    Yu-E Qin, Li Duan, Yumin He, Chengfu Yuan, Ting Wang, Ding Yuan, Changcheng Zhang, Chaoqi Liu.
      SCOPE: Obesity increases intracellular lipid accumulation in hepatocytes, which can induce non-alcoholic fatty liver disease (NAFLD). With progression of NAFLD, a sizable fraction of patients develop non-alcoholic steatohepatitis (NASH), eventually leading to cirrhosis and hepatocellular carcinoma (HCC). The mechanism involved in obesity-induced NAFLD remains unclear. Free fatty acids and high-fat diets, which induce hepatocyte senescence, are major risk factors for NAFLD. Therefore in this study, we investigated the mechanism of lipotoxicity-induced hepatocyte senescence.METHODS AND RESULTS: We fed mice a high-fat diet (HFD) and treated BNL CL.2 cells with palmitate acid (PA) to establish in vivo and in vitro models of lipotoxicity, respectively. SA-β-gal staining was used to analyze the positively stained senescent hepatocytes. The results showed that both PA and HFD induced cellular senescence. Real-time-PCR quantitative analysis revealed that miR-34a was significantly upregulated in the liver tissues of the HFD mice and in the PA-treated BNL CL.2 cells. Western blotting analysis showed that cyclin-dependent kinase inhibitor 1 (CDKN1, also known as p21) was upregulated, while cyclin-dependent kinase 6 (CDK6) was downregulated. Further investigation of the mechanism revealed that CDK6 was a target of miR-34a, which bound to the 3' UTR of CDK6 and inhibited its expression.
    CONCLUSION: Our findings revealed that miR-34a was upregulated in a high-fat environment in the liver, and induced hepatocyte senescence by targeting CDK6. The miR-34a-CDK6 signaling axis may promote NAFLD development in a high-fat environment and therefore represents a potential target for NAFLD therapy. This article is protected by copyright. All rights reserved.
    Keywords:  CDK6; HFD; PA; miR-34a; senescence
    DOI:  https://doi.org/10.1002/mnfr.202000383
  27. Ageing Res Rev. 2020 Sep 22. pii: S1568-1637(20)30289-0. [Epub ahead of print] 101154
    Fight to the bitter end: DNA repair and aging.
    Yu Chen, Anke Geng, Weina Zhang, Zhen Qian, Xiaoping Wan, Ying Jiang, Zhiyong Mao.
      DNA carries the genetic information that directs complex biological processes; thus, maintaining a stable genome is critical for individual growth and development and for human health. DNA repair is a fundamental and conserved mechanism responsible for mending damaged DNA and restoring genomic stability, while its deficiency is closely related to multiple human disorders. In recent years, remarkable progress has been made in the field of DNA repair and aging. Here, we will extensively discuss the relationship among DNA damage, DNA repair, aging and aging-associated diseases based on the latest research. In addition, the possible role of DNA repair in several potential rejuvenation strategies will be discussed. Finally, we will also review the emerging methods that may facilitate future research on DNA repair.
    Keywords:  Aging; DNA repair; DNA repair reporter cassette; Inflammation; Rejuvenation; Senescence
    DOI:  https://doi.org/10.1016/j.arr.2020.101154
  28. Cells. 2020 Sep 23. pii: E2148. [Epub ahead of print]9(10):
    The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging.
    Paloma Gallego, Beatriz Castejón-Vega, José A Del Campo, Mario D Cordero.
      Aging is associated with metabolic changes and low-grade inflammation in several organs, which may be due to NLRP3 inflammasome activation. Methods: Here, we asked whether age-related liver changes such as lipid metabolism and fibrosis are reduced in aged mice lacking the NLRP3 inflammasome. We report reduced protein levels of lipid markers (MTP, FASN, DGAT1), SOD activity, oxidative stress marker PTPRG, and the fibrotic markers TPM2β, COL1-α1 associated with increased GATA4, in NLRP3 deficient mice. Fibrotic, lipid, and oxidative reduction in liver tissues of mice was more pronounced in those old KO NLRP3 mice than in the younger ones, despite their greater liver damage. These results suggest that absence of the NLRP3 inflammasome attenuates age-related liver fibrotic pathology in mice, suggesting that pharmacological targeting may be beneficial.
    Keywords:  NLRP3-inflammasome complex; inflammation; liver damage; non-alcoholic fatty liver disease; oxidative stress
    DOI:  https://doi.org/10.3390/cells9102148
  29. Int J Mol Sci. 2020 Sep 21. pii: E6924. [Epub ahead of print]21(18):
    Targeting Aging Pathways in Chronic Obstructive Pulmonary Disease.
    Molly Easter, Seth Bollenbecker, Jarrod W Barnes, Stefanie Krick.
      Chronic obstructive pulmonary disease (COPD) has become a global epidemic and is the third leading cause of death worldwide. COPD is characterized by chronic airway inflammation, loss of alveolar-capillary units, and progressive decline in lung function. Major risk factors for COPD are cigarette smoking and aging. COPD-associated pathomechanisms include multiple aging pathways such as telomere attrition, epigenetic alterations, altered nutrient sensing, mitochondrial dysfunction, cell senescence, stem cell exhaustion and chronic inflammation. In this review, we will highlight the current literature that focuses on the role of age and aging-associated signaling pathways as well as their impact on current treatment strategies in the pathogenesis of COPD. Furthermore, we will discuss established and experimental COPD treatments including senolytic and anti-aging therapies and their potential use as novel treatment strategies in COPD.
    Keywords:  COPD; aging; cigarette smoke; inflammation; senescence; senolytics
    DOI:  https://doi.org/10.3390/ijms21186924
  30. Aging Clin Exp Res. 2020 Sep 23.
    Mitochondrial DNA deletion mutations increase exponentially with age in human skeletal muscle.
    Allen Herbst, Cathy C Lee, Amy R Vandiver, Judd M Aiken, Debbie McKenzie, Austin Hoang, David Allison, Nianjun Liu, Jonathan Wanagat.
      BACKGROUND: Mitochondrial DNA (mtDNA) deletion mutations lead to electron transport chain-deficient cells and age-induced cell loss in multiple tissues and mammalian species. Accurate quantitation of somatic mtDNA deletion mutations could serve as an index of age-induced cell loss. Quantitation of mtDNA deletion molecules is confounded by their low abundance in tissue homogenates, the diversity of deletion breakpoints, stochastic accumulation in single cells, and mosaic distribution between cells.AIMS: Translate a pre-clinical assay to quantitate mtDNA deletions for use in human DNA samples, with technical and biological validation, and test this assay on human subjects of different ages.
    METHODS: We developed and validated a high-throughput droplet digital PCR assay that quantitates human mtDNA deletion frequency.
    RESULTS: Analysis of human quadriceps muscle samples from 14 male subjects demonstrated that mtDNA deletion frequency increases exponentially with age-on average, a 98-fold increase from age 20-80. Sequence analysis of amplification products confirmed the specificity of the assay for human mtDNA deletion breakpoints. Titration of synthetic mutation mixtures found a lower limit of detection of at least 0.6 parts per million. Using muscle DNA from 6-month-old mtDNA mutator mice, we measured a 6.4-fold increase in mtDNA deletion frequency (i.e., compared to wild-type mice), biologically validating the approach.
    DISCUSSION/CONCLUSIONS: The exponential increase in mtDNA deletion frequency is concomitant with the known muscle fiber loss and accelerating mortality that occurs with age. The improved assay permits the accurate and sensitive quantification of deletion mutations from DNA samples and is sufficient to measure changes in mtDNA deletion mutation frequency in healthy individuals across the lifespan and, therefore, patients with suspected mitochondrial diseases.
    Keywords:  Biomarker; Deletion; Mitochondria; MtDNA; Mutation; Sarcopenia
    DOI:  https://doi.org/10.1007/s40520-020-01698-7
  31. Genes (Basel). 2020 Sep 18. pii: E1094. [Epub ahead of print]11(9):
    The Epigenetic Link between Polyphenols, Aging and Age-Related Diseases.
    Itika Arora, Manvi Sharma, Liou Y Sun, Trygve O Tollefsbol.
      Aging is a complex process mainly categorized by a decline in tissue, cells and organ function and an increased risk of mortality. Recent studies have provided evidence that suggests a strong association between epigenetic mechanisms throughout an organism's lifespan and age-related disease progression. Epigenetics is considered an evolving field and regulates the genetic code at several levels. Among these are DNA changes, which include modifications to DNA methylation state, histone changes, which include modifications of methylation, acetylation, ubiquitination and phosphorylation of histones, and non-coding RNA changes. As a result, these epigenetic modifications are vital targets for potential therapeutic interventions against age-related deterioration and disease progression. Dietary polyphenols play a key role in modulating these modifications thereby delaying aging and extending longevity. In this review, we summarize recent advancements linking epigenetics, polyphenols and aging as well as critical findings related to the various dietary polyphenols in different fruits and vegetables. In addition, we cover studies that relate polyphenols and their epigenetic effects to various aging-related diseases such as cardiovascular diseases, neurodegenerative diseases, autoimmune disorders, diabetes, osteoporosis and cancer.
    Keywords:  DNA methylation; aging; histone modifications; non-coding RNAs and polyphenols
    DOI:  https://doi.org/10.3390/genes11091094
  32. Food Biosci. 2020 Oct;pii: 100710. [Epub ahead of print]37
    Flavonoids from dark chocolate and (-)-epicatechin ameliorate high-fat diet-induced decreases in mobility and muscle damage in aging mice.
    Levy Munguia, Israel Ramirez-Sanchez, Eduardo Meaney, Francisco Villarreal, Guillermo Ceballos, Nayelli Najera.
      Age-related muscle decline, when associated with obesity, leads to adverse outcomes with increased risks for falling, loss of independence, disability and risk of premature mortality. The aim of this study was to assess the potential beneficial effects of flavonoids in improving the age-/high-fat-diet-induced decrease in physical activity/capacity related to the onset of skeletal muscle decline. The effects of the administration of a cocoa beverage enriched with flavanols or pure (-)-epicatechin for 5 wk in a model of physical activity decline induced by the ingestion of a high-fat diet (60% fat) in middle-age mice were evaluated. The results showed that both products, the cocoa beverage enriched with flavanols and pure (-)-epicatechin, improved physical performance evaluated with the hang-wire, inverted-screen, and weight-lifting tests and dynamometry compared with the performance of the controls. The beverage and (-)-epicatechin increased the follistatin/myostatin ratio and increased the expression of myocyte enhancer factor 2A (MEF2A), suggesting an effect on molecular modulators of growth differentiation. Furthermore, the beverage and (-)-epicatechin decreased the expression of O-type fork-head transcription factor (FOXO1A) and muscle ring finger 1 (MURF1) markers of the skeletal muscle ubiquitin-proteasome degradation pathway.
    Keywords:  (−)-epicatechin; Aging; cocoa; dark chocolate; sarcopenia
    DOI:  https://doi.org/10.1016/j.fbio.2020.100710
  33. Exp Neurol. 2020 Sep 16. pii: S0014-4886(20)30297-1. [Epub ahead of print] 113466
    Unique signatures of stress-induced senescent human astrocytes.
    Katrin Simmnacher, Florian Krach, Yanni Schneider, Julian E Alecu, Lena Mautner, Paulina Klein, Laurent Roybon, Iryna Prots, Wei Xiang, Beate Winner.
      Senescence was recently linked to neurodegeneration and astrocytes are one of the major cell types to turn senescent under neurodegenerative conditions. Senescent astrocytes were detected in Parkinson's disease (PD) patients' brains besides reactive astrocytes, yet the difference between senescent and reactive astrocytes is unclear. We aimed to characterize senescent astrocytes in comparison to reactive astrocytes and investigate differences and similarities. In a cell culture model of human fetal astrocytes, we determined a unique senescent transcriptome distinct from reactive astrocytes which comprises dysregulated pathways. Both, senescent and reactive human astrocytes activated a pro-inflammatory pattern. Astrocyte senescence was at least partially depending on active mechanistic-target-of-rapamycin (mTOR) and DNA-damage-response signaling, both drivers of senescence. To further investigate how PD and senescence connect to each other, we asked if a PD-linked environmental factor induces senescence and if senescence impairs midbrain neurons. We could show that the PD-linked pesticide rotenone causes astrocyte senescence. We further delineate, that the senescent secretome exaggerates rotenone-induced neurodegeneration in midbrain neurons differentiated from human induced pluripotent stem cells (hiPSC) of PD patients with alpha-synuclein gene (SNCA) locus duplication.
    Keywords:  Alpha synuclein aggregation; Astrocyte neuron interplay; Parkinson's disease; Reactive astrocyte; Rotenone; Senescence; iPSC derived neurons
    DOI:  https://doi.org/10.1016/j.expneurol.2020.113466
  34. Ageing Res Rev. 2020 Sep 21. pii: S1568-1637(20)30310-X. [Epub ahead of print] 101175
    Metabolic regulation of aging and age-related disease.
    Mark W Hamrick, Alexis M Stranahan.
      Inquiry into relationships between energy metabolism and brain function requires a uniquely interdisciplinary mindset, and implementation of anti-aging lifestyle strategies based on this work also involves consistent mental and physical discipline. Dr. Mark P. Mattson embodies both of these qualities, based on the breadth and depth of his work on neurobiological responses to energetic stress, and on his own diligent practice of regular exercise and caloric restriction. Dr. Mattson created a neurotrophic niche in his own laboratory, allowing trainees to grow their skills, form new connections, and eventually migrate, forming their own labs while remaining part of the extended lab family. In this historical review, we highlight Dr. Mattson's many contributions to understanding neurobiological responses to physical exercise and dietary restriction, with an emphasis on the mechanisms that may underlie neuroprotection in ageing and age-related disease. On the occasion of Dr. Mattson's retirement from the National Institute on Aging, we highlight his foundational work on metabolism and neuroplasticity by reviewing the context for these findings and considering their impact on future research on the neuroscience of aging.
    Keywords:  Aging; Caloric restriction; Exercise; Hippocampus; Intermittent fasting; Mitochondria
    DOI:  https://doi.org/10.1016/j.arr.2020.101175
  35. Biochim Biophys Acta Rev Cancer. 2020 Sep 18. pii: S0304-419X(20)30143-8. [Epub ahead of print] 188424
    Senescence and castration resistance in prostate cancer: A review of experimental evidence and clinical implications.
    Valerie J Carpenter, Bhaumik B Patel, Riccardo Autorino, Steven C Smith, David A Gewirtz, Tareq Saleh.
      The development of the Castration-Resistant Prostate Cancer (CRPC) remains a major challenge in the treatment of this disease. While Androgen Deprivation Therapy (ADT) can result in tumor shrinkage, a primary response of Prostate Cancer (PCa) cells to ADT is a senescent growth arrest. As a response to cancer therapies, senescence has been considered as a beneficial outcome due to its association with stable growth abrogation, as well as the potential of immune system activation via the Senescence-Associated Secretory Phenotype (SASP). However, there is increasing evidence that not only can senescent cells regain proliferative capacity, but that senescence contributes to deleterious effects of cancer chemotherapy, including disease recurrence. Notably, the majority of work investigating the consequences of therapy-induced senescence on tumor progression has been performed in non-PCa models. Here, we summarize the evidence that ADT promotes a senescent response in PCa and postulate mechanisms by which senescence may contribute to the development of castration-resistance. Primarily, we suggest that ADT-induced senescence may support CRPC development via escape from senescence, by cell autonomous-reprogramming, and by the formation of a pro-tumorigenic SASP. However, due to the scarcity of direct evidence from PCa models, the consequences of ADT-induced senescence outlined here are speculative until the relationship between senescence and CRPC can be experimentally defined.
    Keywords:  Androgen deprivation; Castration resistance; Prostate cancer; Senescence; Senolytic; Senomorphic
    DOI:  https://doi.org/10.1016/j.bbcan.2020.188424
  36. Mitochondrion. 2020 Sep 17. pii: S1567-7249(20)30180-X. [Epub ahead of print]55 54-63
    ATM mediated-p53 signaling pathway forms a novel axis for senescence control.
    Su Young Hwang, Myeong Uk Kuk, Jae Won Kim, Yun Haeng Lee, Young-Sam Lee, Hyon E Choy, Sang Chul Park, Joon Tae Park.
      Previously, we uncovered a novel mechanism in which senescence is controlled by mitochondrial functional recovery upon Ataxia-telangiectasia mutated (ATM) inhibition. However, it remains elusive how ATM controls signaling pathways to achieve restorative effect. In this study, we performed microarray and found that p53 pathway was differentially expressed upon ATM inhibition. We found that ATM inhibition yields senescence amelioration through p53-dependent manner. The restorative effect was also afforded by direct p53 inhibition. Furthermore, mitochondrial metabolic reprogramming via p53 inhibition was a prerequisite for senescence amelioration. Taken together, our data indicated that p53 pathway functions as potential target for ATM-mediated senescence amelioration.
    Keywords:  ATM inhibition; Metabolic reprogrammer; Mitochondria; P53; Senescence alleviation
    DOI:  https://doi.org/10.1016/j.mito.2020.09.002
  37. Nat Commun. 2020 09 21. 11(1): 4766
    Telomere dysfunction activates YAP1 to drive tissue inflammation.
    Deepavali Chakravarti, Baoli Hu, Xizeng Mao, Asif Rashid, Jiexi Li, Jun Li, Wen-Ting Liao, Elizabeth M Whitley, Prasenjit Dey, Pingping Hou, Kyle A LaBella, Andrew Chang, Guocan Wang, Denise J Spring, Pingna Deng, Di Zhao, Xin Liang, Zhengdao Lan, Yiyun Lin, Sharmistha Sarkar, Christopher Terranova, Yonathan Lissanu Deribe, Sarah E Blutt, Pablo Okhuysen, Jianhua Zhang, Eduardo Vilar, Ole Haagen Nielsen, Andrew Dupont, Mamoun Younes, Kalyani R Patel, Noah F Shroyer, Kunal Rai, Mary K Estes, Y Alan Wang, Alison A Bertuch, Ronald A DePinho.
      Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.
    DOI:  https://doi.org/10.1038/s41467-020-18420-w
  38. Stem Cells Int. 2020 ;2020 8836258
    Epigenetic Regulation in Mesenchymal Stem Cell Aging and Differentiation and Osteoporosis.
    Ruoxi Wang, Yu Wang, Lisha Zhu, Yan Liu, Weiran Li.
      Mesenchymal stem cells (MSCs) are a reliable source for cell-based regenerative medicine owing to their multipotency and biological functions. However, aging-induced systemic homeostasis disorders in vivo and cell culture passaging in vitro induce a functional decline of MSCs, switching MSCs to a senescent status with impaired self-renewal capacity and biased differentiation tendency. MSC functional decline accounts for the pathogenesis of many diseases and, more importantly, limits the large-scale applications of MSCs in regenerative medicine. Growing evidence implies that epigenetic mechanisms are a critical regulator of the differentiation programs for cell fate and are subject to changes during aging. Thus, we here review epigenetic dysregulations that contribute to MSC aging and osteoporosis. Comprehending detailed epigenetic mechanisms could provide us with a novel horizon for dissecting MSC-related pathogenesis and further optimizing MSC-mediated regenerative therapies.
    DOI:  https://doi.org/10.1155/2020/8836258
  39. Trends Mol Med. 2020 Sep 17. pii: S1471-4914(20)30190-8. [Epub ahead of print]
    Mitochondria as Therapeutic Targets in Transplantation.
    Kourosh Saeb-Parsy, Jack L Martin, Dominic M Summers, Christopher J E Watson, Thomas Krieg, Michael P Murphy.
      Advances in surgical procedures, technology, and immune suppression have transformed organ transplantation. However, the metabolic changes that occur during organ retrieval, storage, and implantation have been relatively neglected since the developments many decades ago of cold storage organ preservation solutions. In this review we discuss how the metabolic changes that occur within the organ during transplantation, particularly those associated with mitochondria, may contribute to the outcome. We show how a better understanding of these processes can lead to changes in surgical practice and the development of new drug classes to improve the function and longevity of transplanted grafts, while increasing the pool of organs available for transplantation.
    Keywords:  ischemia–reperfusion injury; metabolism.; mitochondria; transplantation
    DOI:  https://doi.org/10.1016/j.molmed.2020.08.001
  40. Front Aging Neurosci. 2020 ;12 252
    Mitochondrial Dysfunction and Alzheimer's Disease: Role of Microglia.
    Ishan Agrawal, Sushmita Jha.
      In 1907, Alois Alzheimer observed, as he quoted, development of "numerous fibers" and "adipose saccules" in the brain of his diseased patient Auguste Deter. The neurodegenerative disease became known as Alzheimer's disease (AD) and is the most common cause of dementia worldwide. AD normally develops with aging and is mostly initiated because of the imbalance between the formation and clearance of amyloid-β (Aβ). Formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau is another hallmark of AD. Neuroinflammation plays a significant role in the development and pathology of AD. This chapter explores the role of mitochondrial dysfunction in microglia in case of AD. Mitochondrial oxidative stress in microglia has been linked to the development of AD. Elevated generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential through various mechanisms have been observed in AD. Aβ interacts with microglial receptors, such as triggering receptor expressed in myeloid cells 2 (TREM2), activating downstream pathways causing mitochondrial damage and aggravating inflammation and cytotoxicity. Fibrillar Aβ activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in microglia leading to elevated induction of mitochondrial ROS which further causes neurotoxicity. Elevated ROS in microglia causes activation of inflammatory and cell death pathways. Production of ATP, regulation of mitochondrial health, autophagy, and mitophagy in microglia play significant roles in the AD pathology. Understanding microglial physiology and mitochondrial dysfunction will enable better therapeutic interventions.
    Keywords:  ROS; amyloid-β; microglia; mitochondria; neurodegeneration
    DOI:  https://doi.org/10.3389/fnagi.2020.00252
  41. Int J Mol Sci. 2020 Sep 21. pii: E6918. [Epub ahead of print]21(18):
    Epigenetic Mechanisms of Learning and Memory: Implications for Aging.
    Samantha D Creighton, Gilda Stefanelli, Anas Reda, Iva B Zovkic.
      The neuronal epigenome is highly sensitive to external events and its function is vital for producing stable behavioral outcomes, such as the formation of long-lasting memories. The importance of epigenetic regulation in memory is now well established and growing evidence points to altered epigenome function in the aging brain as a contributing factor to age-related memory decline. In this review, we first summarize the typical role of epigenetic factors in memory processing in a healthy young brain, then discuss the aspects of this system that are altered with aging. There is general agreement that many epigenetic marks are modified with aging, but there are still substantial inconsistencies in the precise nature of these changes and their link with memory decline. Here, we discuss the potential source of age-related changes in the epigenome and their implications for therapeutic intervention in age-related cognitive decline.
    Keywords:  aging; brain; epigenetics; memory
    DOI:  https://doi.org/10.3390/ijms21186918
  42. Oxid Med Cell Longev. 2020 ;2020 1323028
    Cardiolipin, Perhydroxyl Radicals, and Lipid Peroxidation in Mitochondrial Dysfunctions and Aging.
    Alexander V Panov, Sergey I Dikalov.
      Mitochondrial dysfunctions caused by oxidative stress are currently regarded as the main cause of aging. Accumulation of mutations and deletions of mtDNA is a hallmark of aging. So far, however, there is no evidence that most studied oxygen radicals are directly responsible for mutations of mtDNA. Oxidative damages to cardiolipin (CL) and phosphatidylethanolamine (PEA) are also hallmarks of oxidative stress, but the mechanisms of their damage remain obscure. CL is the only phospholipid present almost exclusively in the inner mitochondrial membrane (IMM) where it is responsible, together with PEA, for the maintenance of the superstructures of oxidative phosphorylation enzymes. CL has negative charges at the headgroups and due to specific localization at the negative curves of the IMM, it creates areas with the strong negative charge where local pH may be several units lower than in the surrounding bulk phases. At these sites with the higher acidity, the chance of protonation of the superoxide radical (O2 •), generated by the respiratory chain, is much higher with the formation of the highly reactive hydrophobic perhydroxyl radical (HO2 •). HO2 • specifically reacts with the double bonds of polyunsaturated fatty acids (PUFA) initiating the isoprostane pathway of lipid peroxidation. Because HO2 • is formed close to CL aggregates and PEA, it causes peroxidation of the linoleic acid in CL and also damages PEA. This causes disruption of the structural and functional integrity of the respirosomes and ATP synthase. We provide evidence that in elderly individuals with metabolic syndrome (MetS), fatty acids become the major substrates for production of ATP and this may increase several-fold generation of O2 • and thus HO2 •. We conclude that MetS accelerates aging and the mitochondrial dysfunctions are caused by the HO2 •-induced direct oxidation of CL and the isoprostane pathway of lipid peroxidation (IPLP). The toxic products of IPLP damage not only PEA, but also mtDNA and OXPHOS proteins. This results in gradual disruption of the structural and functional integrity of mitochondria and cells.
    DOI:  https://doi.org/10.1155/2020/1323028
  43. Clin Mol Hepatol. 2020 Sep 21.
    Programmed cell death in alcohol-associated liver disease.
    Tatsunori Miyata, Laura E Nagy.
      Alcohol-associated liver disease (ALD), which ranges from mild disease to alcohol-associated hepatitis and cirrhosis, is the most prevalent type of chronic liver disease and a leading cause of morbidity and mortality worldwide. Accumulating evidence reveals that programmed cell death (PCD) plays a crucial role in progression of ALD involving crosstalk between hepatocytes and immune cells. Multiple pathways of PCD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis, are reported in ALD. Interestingly, PCD pathways are intimately linked and interdependent, making it difficult to therapeutically target a single pathway. This review clarifies the multiple types of PCD occurring in liver and focuses on crosstalk between hepatocytes and innate immune cells in ALD.
    Keywords:   Autophagy; Cell death; Necroptosis; Pyroptosis and ferroptosis; Liver diseases, Alcoholic
    DOI:  https://doi.org/10.3350/cmh.2020.0142
  44. Sci Rep. 2020 Sep 21. 10(1): 15385
    Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS).
    Huawei Wang, Chuanlong Zang, Mengtian Ren, Mengdi Shang, Zhenghua Wang, Xuemei Peng, Qiangzhe Zhang, Xin Wen, Zhen Xi, Chuanzheng Zhou.
      The nucleosome is the basic structural repeating unit of chromatin. DNA damage and cell apoptosis release nucleosomes into the blood circulatory system, and increased levels of circulating nucleosomes have been observed to be related to inflammation and autoimmune diseases. However, how circulating nucleosomes trigger immune responses has not been fully elucidated. cGAS (cGMP-AMP synthase) is a recently discovered pattern recognition receptor that senses cytoplasmic double-stranded DNA (dsDNA). In this study, we employed in vitro reconstituted nucleosomes to examine whether extracellular nucleosomes can gain access to the cytoplasm of mammalian cells to induce immune responses by activating cGAS. We showed that nucleosomes can be taken up by various mammalian cells. Additionally, we found that in vitro reconstituted mononucleosomes and oligonucleosomes can be recognized by cGAS. Compared to dsDNA, nucleosomes exhibit higher binding affinities to cGAS but considerably lower potency in cGAS activation. Incubation of monocytic cells with reconstituted nucleosomes leads to limited production of type I interferons and proinflammatory cytokines via a cGAS-dependent mechanism. This proof-of-concept study reveals the cGAS-dependent immunogenicity of nucleosomes and highlights the potential roles of circulating nucleosomes in autoimmune diseases, inflammation, and antitumour immunity.
    DOI:  https://doi.org/10.1038/s41598-020-72393-w
  45. J Nutr Biochem. 2020 Sep 18. pii: S0955-2863(20)30537-4. [Epub ahead of print] 108505
    Combination of metformin and genistein alleviates non-alcoholic fatty liver disease in high-fat diet-fed mice.
    Fahimeh Zamani-Garmsiri, Seyyed Mohammad Reza Hashemnia, Maryam Shabani, Molood Bagherieh, Solaleh Emamgholipour, Reza Meshkani.
      Metformin (MET) and genistein (GEN) have beneficial role in alleviating non-alcoholic fatty liver disease (NAFLD), but their combined effect on this disease has not yet been studied. The present study aimed to investigate the potential protective effects of combined MET and GEN on NAFLD in high-fat diet (HFD) fed mice. C57BL/6 male mice were fed on an HFD for 10 weeks. Animals were then divided into different groups and treated with MET (0.23%), GEN (0.2%) and MET+ GEN (0.23%+0.2%) for 3 months. Treatment with MET and GEN, alone or in combination significantly lowered body and liver weights and fasting blood glucose (FBG) in HFD mice. Combination therapy reduced liver triglyceride (TG) level and this effect was correlated with increased expression of carnitine palmitoyl transferase 1 (CPT1) gene reduced expression of fatty-acid synthase (FAS) and sterol regulatory element-binding protein-1c (SREBP-1c) genes. Combination therapy also affects gluconeogenesis pathway through decreasing expression of Glucose 6-phosphatase (G6Pase) and increasing phosphorylation of Glycogen synthase kinase 3β (GSK-3β). Furthermore, combination of MET and GEN ameliorates liver inflammation by switching macrophage into M2 phenotype, decreasing macrophage infiltration, reducing expression of pro-inflammatory cytokines and decreasing Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activity. In addition, combination therapy enhances phosphorylation of 5' Adenosine monophosphate-activated protein kinase (AMPK). Taken together, these findings suggest that the combination of MET and GEN have beneficial effects against NAFLD in HFD-fed model.
    Keywords:  AMPK; Combination; Genistein; High Fat Diet; Liver Inflammation; Macrophage Polarization; Metformin; Non-alcoholic Fatty Liver Disease
    DOI:  https://doi.org/10.1016/j.jnutbio.2020.108505
  46. Surv Ophthalmol. 2020 Sep 19. pii: S0039-6257(20)30132-6. [Epub ahead of print]
    Oxidative Stress as a Therapeutic Target for the Prevention and Treatment of Early Age-related Macular Degeneration.
    Sayena Jabbehdari, James T Handa.
      Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss among older adults in developed countries. It is a chronic, multifactorial, and progressive disease with the development of painless, central vision loss. Retinal pigment epithelial cell dysfunction is a core change in AMD that results from aging and the accumulated effects of genetic and environmental factors that, in part, is both caused by and leads to oxidative stress. In this review, we describe the role of oxidative stress, the cytoprotective oxidative stress pathways, and the impact of oxidative stress on critical cellular processes involved in AMD pathobiology. We also offer targeted therapy that may define how antioxidant therapy can either prevent or improve specific stages of AMD.
    Keywords:  Age-related macular degeneration; Aging; Oxidative stress; antioxidant therapy
    DOI:  https://doi.org/10.1016/j.survophthal.2020.09.002
  47. Front Pharmacol. 2020 ;11 1249
    Resveratrol Modulates the Gut Microbiota and Inflammation to Protect Against Diabetic Nephropathy in Mice.
    Ting-Ting Cai, Xiao-Long Ye, Ru-Run Li, Hui Chen, Ya-Yun Wang, Hui-Juan Yong, Ming-Lin Pan, Wei Lu, Ying Tang, Heng Miao, Antoine M Snijders, Jian-Hua Mao, Xing-Yin Liu, Yi-Bing Lu, Da-Fa Ding.
      Oral administration of resveratrol is able to ameliorate the progression of diabetic nephropathy (DN); however, its mechanisms of action remain unclear. Recent evidence suggested that the gut microbiota is involved in the metabolism therapeutics. In the current study, we sought to determine whether the anti-DN effects of resveratrol are mediated through modulation of the gut microbiota using the genetic db/db mouse model of DN. We demonstrate that resveratrol treatment of db/db mice relieves a series of clinical indicators of DN. We then show that resveratrol improves intestinal barrier function and ameliorates intestinal permeability and inflammation. The composition of the gut microbiome was significantly altered in db/db mice compared to control db/m mice. Dysbiosis in db/db mice characterized by low abundance levels of Bacteroides, Alistipes, Rikenella, Odoribacter, Parabacteroides, and Alloprevotella genera were reversed by resveratrol treatment, suggesting a potential role for the microbiome in DN progression. Furthermore, fecal microbiota transplantation, derived from healthy resveratrol-treated db/m mice, was sufficient to antagonize the renal dysfunction, rebalance the gut microbiome and improve intestinal permeability and inflammation in recipient db/db mice. These results indicate that resveratrol-mediated changes in the gut microbiome may play an important role in the mechanism of action of resveratrol, which provides supporting evidence for the gut-kidney axis in DN.
    Keywords:  diabetic nephropathy; gut microbiome; gut–kidney axis; inflammation; resveratrol
    DOI:  https://doi.org/10.3389/fphar.2020.01249
  48. Cell Death Dis. 2020 Sep 24. 11(9): 798
    PIK3R3 inhibits cell senescence through p53/p21 signaling.
    Qianzhi Chen, Xuling Sun, Xuelai Luo, Jing Wang, Junbo Hu, Yongdong Feng.
      Cellular senescence is a stress response of human cells that removes potentially harmful cells by initiating cell cycle arrest. Inducing senescence of tumor cells may be an effective tumor-inhibiting strategy. In this study we found that PIK3R3 could inhibit the cell senescence of colorectal cancer cells and promote cell proliferation through the p53/p21 signal pathway. PIK3R3 could bind to p53 and inhibit the binding of p53 to the p21 gene promoter region, and thus affecting the transcriptional activity of p21 gene. Our study has provided new evidence of the role of PIK3R3 in p53 regulation and inhibition of PIK3R3 may be one of the potential targets of tumor therapy.
    DOI:  https://doi.org/10.1038/s41419-020-02921-z
  49. Prog Brain Res. 2020 ;pii: S0079-6123(20)30103-5. [Epub ahead of print]256(1): 189-207
    Effects of caloric restriction on retinal aging and neurodegeneration.
    Annagrazia Adornetto, Luigi Antonio Morrone, Andrea Satriano, Maria Luisa Laganà, Ester Licastro, Carlo Nucci, Maria Tiziana Corasaniti, Paolo Tonin, Giacinto Bagetta, Rossella Russo.
      Glaucoma is the most common neurodegenerative cause of irreversible blindness worldwide. Restricted caloric regimens are an attractive approach for delaying the progression of neurodegenerative diseases. Here we review the current literature on the effects of caloric restriction on retinal neurons, under physiological and pathological conditions. We focused on autophagy as one of the mechanisms modulated by restricted caloric regimens and involved in the death of retinal ganglion cells (RGCs) over the course of glaucoma.
    Keywords:  AMPK; Aging; Autophagy; Caloric restriction; Glaucoma; Neurodegeneration; Retina; SIRT1
    DOI:  https://doi.org/10.1016/bs.pbr.2020.07.005
  50. Life Sci. 2020 Sep 19. pii: S0024-3205(20)31212-1. [Epub ahead of print]261 118459
    Ubiquitination in rheumatoid arthritis.
    Tapan Behl, Swati Chadha, Monika Sachdeva, Arun Kumar, Abdul Hafeez, Vineet Mehta, Simona Bungau.
      Rheumatoid arthritis is a chronic, inflammatory joint disease leading to inflammation of synovial membrane that lines the joints. This inflammation further progresses and results in destruction of joints and surrounding cartilages. The underlying factors can be oxidative stress, pro-inflammatory mediators, imbalance and attenuation between various enzymes and proteins (like nuclear factor erythroid 2 related factor 2/Nrf2 and ubiquitin). Protein degradation pathways comprises of lysosomal, proteasomal pathway, and autophagosome (that are carried out in mammalian cells) are regulated through ubiquitin. Ubiquitin proteasomal system is dominating pathway for carrying out non-lysosomal proteolysis of intracellularly proteins. Fundamental processes including cell cycle progression, process of division, apoptosis, modulation of immune responses and cell trafficking are regulated by process of ubiquitination. Ubiquitin proteasomal pathway (UPP) includes ubiquitin moieties which are covalently attached to proteins and guides them proteasome for degradation. Misfolded, oxidized and damaged proteins which are responsible for critical processes, are major targets of degradation process. Any alteration in this system leads to dysregulated cellular homeostasis; progressively leading to numerous diseases including rheumatoid arthritis. Factors including TAK1, TRAF6 undergo are required for the progression of disease and thus contributes towards pathology of inflammatory disorders such as rheumatoid arthritis. This review will include all linked aspects which contribute its major role in rheumatoid arthritis.
    Keywords:  Inflammation; Proteasome; Proteins; Rheumatoid arthritis; Ubiquitin
    DOI:  https://doi.org/10.1016/j.lfs.2020.118459
  51. Neurologia. 2020 Sep 19. pii: S0213-4853(20)30226-7. [Epub ahead of print]
    Immunosenescence: the role of age in multiple sclerosis.
    A Ostolaza Ibáñez, J Corroza Laviñeta, T Ayuso Blanco.
      INTRODUCTION: The number of elderly people with multiple sclerosis (MS) has increased in line with population ageing. As the immune system presents profound changes over an individual's lifetime, it is important to understand the differences between these patients and younger patients.DEVELOPMENT: Immunosenescence, defined as age-related alterations naturally occurring in the immune system, particularly influences tolerance, response, and adverse effects of disease-modifying treatments for MS. Thymic involution is the most noteworthy characteristic of this phenomenon. This process leads to a reduction in the number of virgin T cells. Other effects include an inverted CD4 + /CD8 + cell ratio, severe alterations in NK cell functioning, and reduced tissue repair capacity in the brain.
    CONCLUSIONS: The number of older people with MS is increasing due to population ageing, advances in disease-modifying treatments, and improved health and social care of these patients. Ageing of the immune system increases the risk of infections, tumours, and autoimmune diseases in elderly individuals. Furthermore, neurodegeneration is accelerated in patients with MS due to the nervous system's loss of remyelination capacity. Understanding of the changes affecting the immune system in the elderly population is essential to improving the care provided to this ever-growing patient group.
    Keywords:  Ageing; Envejecimiento; Esclerosis múltiple; Esclerosis múltiple de comienzo tardío; Immunosenescence; Inmunosenescencia; Late-onset multiple sclerosis; Multiple sclerosis
    DOI:  https://doi.org/10.1016/j.nrl.2020.05.016
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