A hallmark trait of cellular senescence is the acquisition of a senescence-associated secretory phenotype (SASP). SASP factors include cytokines and their receptors (IL-6, IL-8, osteoprotegerin, GM-CSF), chemokines and their ligands (MCP-1, HCC4), and oncogenes (Gro1 and Gro2), many of them encoded by mRNAs whose stability and translation are tightly regulated. Using two models of human fibroblast senescence (WI-38 and IDH4 cells), we report the identification of RNA-binding protein NF90 as a post-transcriptional repressor of several SASP factors. In ‘young', proliferating fibroblasts, NF90 was highly abundant, associated with numerous SASP mRNAs, and inhibited their expression. By contrast, senescent cells expressed low levels of NF90, thus allowing SASP factor expression to increase. NF90 elicited these effects mainly by repressing the translation of target SASP mRNAs, since silencing NF90 did not increase the steady-state levels of SASP mRNAs but elevated key SASP factors including MCP-1, GROa, IL-6, and IL-8. Our findings indicate that NF90 contributes to maintaining low levels of SASP factors in non-senescent cells, while NF90 reduction in senescent cells allows SASP factor expression to rise.
Targeted Cargo Delivery in Senescent Cells Using Capped Mesoporous Silica Nanoparticles
Abstract
Intracellular controlled release of molecules within senescent cells was achieved using mesoporous silica nanoparticles(MSNs) capped with a galacto-oligosaccharide (GOS) to contain the cargo molecules (magenta spheres; see scheme). The GOS is a substrate of the senescent biomarker, senescence-associated β-galactosidase (SA-β-gal), and releases the cargo upon entry into SA-β-gal expressing cells.
Link: http://1.usa.gov/TFDGVS
Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells
Abstract
Background
Human dental pulp stem cells (DPSCs) have potential applications in tissue regeneration because of their convenient cell harvesting procedures and multipotent capacity. However, the tissue regenerative potential of DPSCs is known to be negatively regulated by aging in long-term culture and under oxidative stress. With an aim of reducing cellular senescence and oxidative stress in DPSCs, an intracellular delivery system for superoxide dismutase 1 (SOD1) was developed. We conjugated SOD1 with a cell-penetrating peptide known as low-molecular weight protamine (LMWP), and investigated the effect of LMWP-SOD1 conjugates on hydrogen peroxide-induced cellular senescence and osteoblastic differentiation.
Results
LMWP-SOD1 significantly attenuated enlarged and flattened cell morphology and increased senescence-associated β-galactosidase activity. Under the same conditions, LMWP-SOD1 abolished activation of the cell cycle regulator proteins, p53 and p21Cip1, induced by hydrogen peroxide. In addition, LMWP-SOD1 reversed the inhibition of osteoblastic differentiation and downregulation of osteogenic gene markers induced by hydrogen peroxide. However, LMWP-SOD1 could not reverse the decrease in odontogenesis caused by hydrogen peroxide.
Conclusion
Overall, cell-penetrating LMWP-SOD1 conjugates are effective for attenuation of cellular senescence and reversal of osteoblastic differentiation of DPSCs caused by oxidative stress inhibition. This result suggests potential application in the field of antiaging and tissue engineering to overcome the limitations of senescent stem cells.
Picture: Ras-induced senescent IMR90
RED: Ras-induced senescent IMR90 (mCherry)
GREEN: Growing IMR90 (GFP)
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
ABSTRACT
Tae-Won Kang, Tetyana Yevsa, Norman Woller, Lisa Hoenicke, Torsten Wuestefeld, Daniel Dauch, Anja Hohmeyer, Marcus Gereke, Ramona Rudalska, Anna Potapova, Marcus Iken, Mihael Vucur, Siegfried Weiss, Mathias Heikenwalder, Sadaf Khan, Jesus Gil, Dunja Bruder, Michael Manns, Peter Schirmacher, Frank Tacke, Michael Ott, Tom Luedde, Thomas Longerich, Stefan Kubicka & Lars Zender
Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo1. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this ‘secretory phenotype’ can have pro- as well as anti-tumorigenic effects2, 3, 4, 5. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as ‘senescence surveillance’), which depends on an intact CD4+ T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of NrasG12V. We also found that CD4+ T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.
Link: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10599.html
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
A paper worth reading. Excellent work.
ABSTRACT
Darren J. Baker, Tobias Wijshake, Tamar Tchkonia, Nathan K. LeBrasseur, Bennett G. Childs, Bart van de Sluis, James L. Kirkland & Jan M. van Deursen
Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells1, 2. Senescent cells accumulate in various tissues and organs with ageing3 and have been hypothesized to disrupt tissue structure and function because of the components they secrete4, 5. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16Ink4a, to design a novel transgene, INK-ATTAC, for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-positive senescent cells upon drug treatment. In tissues—such as adipose tissue, skeletal muscle and eye—in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
Link: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10600.html
Cellular Senescence and COPD
Chronic obstructive pulmonary disease (COPD) is characterized by progressively reduced airflow within the lungs, making it difficult to breath. During normal breathing, air sacs (alveoli) (which are elastic) fill up with air and oxygen passes through the air sac walls into the blood. With COPD the air sacs can lose elasticity, the walls between air sacs are destroyed, the walls become thick and inflamed and the airways make more mucus than normal leading to clogging. All these changes contribute to reduced airflow in COPD.
COPD is predominately associated with tobacco smoking and previous studies investigating the pathophysiology of emphysema have demonstrated that cigarette smoke can cause cells to enter cellular senescence (Tsuji et al, 2004, Nyunoya et al 2006). As such, a number of studies have investigated the role of cellular senescence in the development and progression of COPD. Cigarette smoke may trigger cells to senesce directly due to DNA damage or indirectly (if apoptosis is occurring) through increasing cell turnover leading to accelerated telomere shortening.
Senescent cells secrete pro-inflammatory cytokines, growth factors and proteases (most likely for immune clearance) that can cause tissue damage, leading to loss of function of the tissue in which they reside. In the case off COPD the secretion of proteases by senescent cells could result in loss of elasticity of air sacs and destruction of air sac walls. The secretion of cytokines and chemokines by senescent cells would lead to persistent inflammation.
Tsuji et al (2009) has shown that lung tissue of COPD patients contained higher percentages of senescent alveolar cells displaying a pro-inflammatory phenotype compared with tissue from asymptomatic smokers and non-smokers. Noureddine et al (2011) has demonstrated that pulmonary artery smooth muscle cell (PA-SMC) senescence is an important contributor in the process of pulmonary vessel remodeling in COPD patients. Senescent PA-SMC were shown to stimulate cell growth and migration of normal PA-SMC through the release of paracrine soluble and insoluble factors. Dogauassat et al (2011) have shown that lung fibroblasts in smokers and ex-smokers with moderate COPD display a senescent phenotype. This study suggests that even after stopping smoking, the persistence of senescent cells may still contribute to COPD. Amsellem et al (2011) have recently showed that premature senescence in pulmonary vascular endothelial cells may contribute to inflammation in COPD.
Research also suggests that patients with COPD have a two to six times more chance of developing lung cancer compared with people of normal lung function (COPD Foundation). It could be speculated that the presence of senescent cells in COPD patients may increase the chances of lung cancer. It has been shown that the secretory phenotype of senescent cells can play a role in cancer development by stimulating growth and angiogenic activity of pre-malignant cells (reviewed in Campisi and d'Adda di Fagagna, 2007). Additionally, stochastic epigenetic/genetic alterations within senescent cells may allow them to escape the senescence growth arrest, thus becoming cancerous.
Publications
Tsuji T, Aoshiba K, Nagai A. Alveolar cell senescence exacerbates pulmonary inflammation in patients with chronic obstructive pulmonary disease. Respiration. 2010;80(1):59-70. Epub 2009 Dec 17.
Noureddine H, Gary-Bobo G, Alifano M, Marcos E, Saker M, Vienney N, Amsellem V, Maitre B, Chaouat A, Chouaid C, Dubois-Rande JL, Damotte D, Adnot S. Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease. Circ Res. 2011 Aug 19;109(5):543-53. Epub 2011 Jun 30.
Amsellem V, Gary-Bobo G, Marcos E, Maitre B, Chaar V, Validire P, Stern JB, Noureddine H, Sapin E, Rideau D, Hue S, Le Corvoisier P, Le Gouvello S, Dubois-Randé JL, Boczkowski J, Adnot S. Telomere Dysfunction Causes Sustained Inflammation in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2011 Sep 8. [Epub ahead of print]
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