bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒12‒13
nine papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Adv Sci (Weinh). 2020 Dec;7(23): 2002611
    Song S, Tchkonia T, Jiang J, Kirkland JL, Sun Y.
      Aging is a physiological decline in both structural homeostasis and functional integrity, progressively affecting organismal health. A major hallmark of aging is the accumulation of senescent cells, which have entered a state of irreversible cell cycle arrest after experiencing inherent or environmental stresses. Although cellular senescence is essential in several physiological events, it plays a detrimental role in a large array of age-related pathologies. Recent biomedical advances in specifically targeting senescent cells to improve healthy aging, or alternatively, postpone natural aging and age-related diseases, a strategy termed senotherapy, have attracted substantial interest in both scientific and medical communities. Challenges for aging research are highlighted and potential avenues that can be leveraged for therapeutic interventions to control aging and age-related disorders in the current era of precision medicine.
    Keywords:  aging; clinical trials; healthspan; senescent cells; senolytics; senotherapy
  2. Autophagy. 2020 Dec 08.
    Wang L, Xu C, Johansen T, Berger SL, Dou Z.
      Macroautophagic/autophagic degradation of nuclear components (or nuclear autophagy) is a poorly understood area in autophagy research. We previously reported the nuclear lamina protein LMNB1 (lamin B1) as a nuclear autophagy substrate in primary human cells, stimulating the investigation of nuclear autophagy in the mammalian system. We recently reported the sirtuin protein SIRT1 as a new selective substrate of nuclear autophagy in senescence and aging. Upon senescence of primary human cells, SIRT1 degradation is mediated by a direct nuclear SIRT1-LC3 interaction, followed by nucleus-to-cytoplasm shuttling of SIRT1 and autophagosome-lysosome degradation. In vivo, SIRT1 is downregulated by lysosomes in hematopoietic and immune organs upon natural aging in mice and in aged human T cells. Our study identified another substrate of nuclear autophagy and suggests a new strategy to promote SIRT1-mediated health benefits by suppressing its autophagic degradation.
    Keywords:  Aging; SIRT1; nuclear autophagy; senescence; sirtuin
  3. Front Med (Lausanne). 2020 ;7 606462
    Venosa A.
      To date, chronic pulmonary pathologies represent the third leading cause of death in the elderly population. Evidence-based projections suggest that >65 (years old) individuals will account for approximately a quarter of the world population before the turn of the century. Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, are described as the nine "hallmarks" that govern cellular fitness. Any deviation from the normal pattern initiates a complex cascade of events culminating to a disease state. This blueprint, originally employed to describe aberrant changes in cancer cells, can be also used to describe aging and fibrosis. Pulmonary fibrosis (PF) is the result of a progressive decline in injury resolution processes stemming from endogenous (physiological decline or somatic mutations) or exogenous stress. Environmental, dietary or occupational exposure accelerates the pathogenesis of a senescent phenotype based on (1) window of exposure; (2) dose, duration, recurrence; and (3) cells type being targeted. As the lung ages, the threshold to generate an irreversibly senescent phenotype is lowered. However, we do not have sufficient knowledge to make accurate predictions. In this review, we provide an assessment of the literature that interrogates lung epithelial, mesenchymal, and immune senescence at the intersection of aging, environmental exposure and pulmonary fibrosis.
    Keywords:  aging; epithelial cells; immune-senescence; inflamm-aging; lung fibrosis; mesenchymal senescence; senescence
  4. Mol Cell Endocrinol. 2020 Dec 07. pii: S0303-7207(20)30416-0. [Epub ahead of print] 111114
    Lee J, Yoo JH, Kim HS, Cho YK, La Lee Y, Lee WJ, Park JY, Jung CH.
      Autophagy is an important process in the pathogenesis of atherosclerosis. C1q/tumor necrosis factor-related protein 9 (CTRP9) is the closest adiponectin paralog. CTRP9 has anti-aging and anti-atherogenic effects, but its roles in autophagy and endothelial senescence are currently unknown. This study aimed to evaluate whether CTRP9 prevents palmitic acid (PA)-induced endothelial senescence by promoting autophagy. After no treatment or pre-treatment of human umbilical vein endothelial cells with CTRP9 prior to PA treatment, the level of senescence was measured by senescence associated acidic β-galactosidase staining and the level of hyperphosphorylated pRB protein. Autophagy was evaluated by LC3 conversion and the level of p62/SQSTM1, a protein degraded during autophagy. Autophagosome-lysosome fusion was detected by fluorescence microscopy. Pre-treatment with CTRP9 attenuated PA-induced endothelial senescence. CTRP9 increased the conversion of LC3-I to LC3-II and decreased p62 levels in a time- and dose-dependent manner. Although both CTRP9 and PA treatment increased LC3 conversion, treatment with PA increased the expression level of p62 and decreased the fusion of autophagosomes and lysosomes, which represented decreased autophagic flux. However, pre-treatment with CTRP9 recovered the autophagic flux inhibited by PA. AMP-activated kinase (AMPK) activation was involved in LC3 conversion and decreased p62 levels induced by CTRP9. CTRP9 inhibits PA-induced endothelial senescence by recovering autophagy and autophagic flux through AMPK activation.
    Keywords:  C1q/TNF-related protein-9; aging; atherosclerosis; autophagy; endothelial senescence
  5. Semin Cancer Biol. 2020 Dec 05. pii: S1044-579X(20)30260-1. [Epub ahead of print]
    Książek K.
      Although ovarian cancer is the leading cause of death from gynecological malignancies, there are still some issues that hamper accurate interpretation of the complexity of cellular and molecular events underlying the pathophysiology of this disease. One of these is cellular senescence, which is the process whereby cells irreversibly lose their ability to divide and develop a phenotype that fuels a variety of age-related diseases, including cancer. In this review, various aspects of cellular senescence associated with intraperitoneal ovarian cancer metastasis are presented and discussed, including mechanisms of senescence in normal peritoneal mesothelial cells; the role of senescent mesothelium in ovarian cancer progression; the effect of drugs commonly used as first-line therapy in ovarian cancer patients on senescence of normal cells; mechanisms of spontaneous senescence in ovarian cancer cells; and, last but not least, other pharmacologic strategies to induce senescence in ovarian malignancies. Collectively, this study shows that cellular senescence is involved in several aspects of ovarian cancer pathobiology. Proper understanding of this phenomenon, particularly its clinical relevance, seems to be critical for oncology patients from both therapeutic and prognostic perspectives.
    Keywords:  cancer metastasis; cellular senescence; ovarian cancer; peritoneal mesothelial cells; tumor microenvironment
  6. EMBO J. 2020 Dec 10. e105819
    Bedrosian TA, Houtman J, Eguiguren JS, Ghassemzadeh S, Rund N, Novaresi NM, Hu L, Parylak SL, Denli AM, Randolph-Moore L, Namba T, Gage FH, Toda T.
      Neurogenesis in the adult hippocampus declines with age, a process that has been implicated in cognitive and emotional impairments. However, the mechanisms underlying this decline have remained elusive. Here, we show that the age-dependent downregulation of lamin B1, one of the nuclear lamins in adult neural stem/progenitor cells (ANSPCs), underlies age-related alterations in adult hippocampal neurogenesis. Our results indicate that higher levels of lamin B1 in ANSPCs safeguard against premature differentiation and regulate the maintenance of ANSPCs. However, the level of lamin B1 in ANSPCs declines during aging. Precocious loss of lamin B1 in ANSPCs transiently promotes neurogenesis but eventually depletes it. Furthermore, the reduction of lamin B1 in ANSPCs recapitulates age-related anxiety-like behavior in mice. Our results indicate that the decline in lamin B1 underlies stem cell aging and impacts the homeostasis of adult neurogenesis and mood regulation.
    Keywords:  adult hippocampal neurogenesis; lamin B1; mood regulation; stem cell aging
  7. Antioxidants (Basel). 2020 Dec 08. pii: E1248. [Epub ahead of print]9(12):
    Piszczatowska K, Przybylska D, Sikora E, Mosieniak G.
      NADPH oxidases (NOX) are commonly expressed ROS-producing enzymes that participate in the regulation of many signaling pathways, which influence cell metabolism, survival, and proliferation. Due to their high expression in several different types of cancer it was postulated that NOX promote tumor progression, growth, and survival. Thus, the inhibition of NOX activity was considered to have therapeutic potential. One of the possible outcomes of anticancer therapy, which has recently gained much interest, is cancer cell senescence. The induction of senescence leads to prolonged inhibition of proliferation and contributes to tumor growth restriction. The aim of our studies was to investigate the influence of low, non-toxic doses of diphenyleneiodonium chloride (DPI), a potent inhibitor of flavoenzymes including NADPH oxidases, on p53-proficient and p53-deficient HCT116 human colon cancer cells and MCF-7 breast cancer cells. We demonstrated that the temporal treatment of HCT116 and MCF-7 cancer cells (both p53 wild-type) with DPI caused induction of senescence, that was correlated with decreased level of ROS and upregulation of p53/p21 proteins. On the contrary, in the case of p53-/- HCT116 cells, apoptosis was shown to be the prevailing effect of DPI treatment. Thus, our studies provided a proof that inhibiting ROS production, and by this means influencing ROS sensitive pathways, remains an alternative strategy to facilitate so called therapy-induced senescence in cancers.
    Keywords:  DPI; NADPH oxidases; ROS; apoptosis; cancer; senescence
  8. Sci Rep. 2020 Dec 10. 10(1): 21752
    El-Nimri NW, Moore SM, Zangwill LM, Proudfoot JA, Weinreb RN, Skowronska-Krawczyk D, Baxter SL.
      Glaucoma, a chronic neurodegenerative disease of retinal ganglion cells (RGCs), is a leading cause of irreversible blindness worldwide. Its management currently focuses on lowering intraocular pressure to slow disease progression. However, disease-modifying, neuroprotective treatments for glaucoma remain a major unmet need. Recently, senescent cells have been observed in glaucomatous eyes, exposing a potential pathway for alternative glaucoma therapies. Prior studies demonstrated that targeting senescent RGCs for removal (i.e., a senolytic approach) protected healthy RGCs and preserved visual function in a mouse ocular hypertension model. However, the effects of senolytic drugs on vision in human patients are unknown. Here, we used existing clinical data to conduct a retrospective cohort study in 28 human glaucoma patients who had been exposed to senolytics. Senolytic exposure was not associated with decreased visual acuity, elevated intraocular pressure, or documentation of senolytic-related adverse ocular effects by treating ophthalmologists. Additionally, patients exposed to senolytics (n = 9) did not exhibit faster progression of glaucomatous visual field damage compared to matched glaucoma patients (n = 26) without senolytic exposure. These results suggest that senolytic drugs do not carry significant ocular toxicity and provide further support for additional evaluation of the potential neuroprotective effects of senolytics on glaucoma and other neurodegenerative diseases.
  9. Cell Cycle. 2020 Dec 11. 1-13
    Giam M, Wong CK, Low JS, Sinelli M, Dreesen O, Rancati G.
      Aneuploidy is the condition of having an imbalanced karyotype, which is associated with tumor initiation, evolution, and acquisition of drug-resistant features, possibly by generating heterogeneous populations of cells with distinct genotypes and phenotypes. Multicellular eukaryotes have therefore evolved a range of extrinsic and cell-autonomous mechanisms for restraining proliferation of aneuploid cells, including activation of the tumor suppressor protein p53. However, accumulating evidence indicates that a subset of aneuploid cells can escape p53-mediated growth restriction and continue proliferating in vitro. Here we show that such aneuploid cell lines display a robust modal karyotype and low frequency of chromosomal aberrations despite ongoing chromosome instability. Indeed, while these aneuploid cells are able to survive for extended periods in vitro, their chromosomally unstable progeny remain subject to p53-induced senescence and growth restriction, leading to subsequent elimination from the aneuploid pool. This mechanism helps maintain low levels of heterogeneity in aneuploid populations and may prevent detrimental evolutionary processes such as cancer progression and development of drug resistance.
    Keywords:  P53; aneuploidy; genome instability; senescence