- Email: [email protected]
The role of macroautophagy in senescent cells and aged tissue
S. Gargiulo et al. / Free Radical Biology and Medicine 108 (2017) S4–S13
inhibition triggers an irreversible p53-dependent premature senescence phenotype, its activation through genetic means or compound treatment confers cellular lifespan extension and extended maintenance of youthful morphological features. Using the nematode Caenorhabditis elegans, we have achieved proteasome activation at the organismal level thus promoting beneficial effects on the lifespan of the nematode. Moreover, proteasome activation seems to be a potential strategy to minimize protein homeostasis deficiencies underlying aggregation-related diseases such as Alzheimer’s or Huntington’s. Consequently, compounds with proteasome activating properties might be used in preventive or therapeutic approaches against such diseases. In conclusion, our results show the dynamic interconnection between the proteasome, the proteostatic mechanisms and the progression of ageing and age-related diseases. E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.050
OP-12
Thiol- and heme-dependent peroxide detoxification enzymes in pathogens: role in infectivity and virulence Rafael Radi 1,2 1
Departamento de Bioquímica, Facultad de Medicina, Universidad de la República Montevideo, Uruguay 2 Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Pathogenic bacteria and unicellular parasites are typically exposed to a large flux of cytotoxic oxidants generated during the cellular immune response mediated by macrophages and neutrophils. Invading pathogens cope with mammalian-cell derived oxidants (including superoxide radicals, hydrogen peroxide, peroxynitrite, hypochlorous acid) and secondary species (e.g. lipid hydroperoxides) through an array of enzymatic antioxidant systems, which are being progressively revealed as virulence factors. In this presentation, I will provide some general view on how pathogen antioxidant detoxification systems can impact on infectivity and virulence and report recent findings (1, 2) on the kinetic characterization, oxidant selectivity and biological relevance of thiol- and heme-dependent peroxidatic sytems in bacteria (Ohr) and T. cruzi (APx-CcP). E-mail address: [email protected] References 1. Alegria et al. Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):E132-E141. 2. Hugo, Martinez et al. Proc Natl Acad Sci U S A. 2017 Feb 21;114(8): E1326-E1335.
http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.051
S7
2
German Center for Cardiovascular Research (DZHK), Berlin, Germany
Keywords: Proteolysis; Macroautophagy; Senescence; Ageing; mTOR
Due to the steady increase in life expectancy, the prevalence of age-associated diseases such as Diabetes mellitus, Alzheimer’s disease and cardiovascular diseases as well as the syndrome of "frailty" is also rising. The progressive loss of cellular functionality and the elevated presence of protein aggregates play a decisive role. These aggregates and the age-dependent loss of proteasomal activity are common features of the aging process. Besides the proteasomal system, cells possess another protein quality control system, the Autophagy-Lysosomal-Pathway. Knock-down studies and the use of inhibitors have shown that the loss of proteasomal function can be compensated by the upregulation of lysosomal activity. Our aim was to examine whether these compensatory mechanisms also occur in senescent cells. Using a replicative senescence model of human fibroblasts and aged murine tissue our results reveal a decline in both, proteasomal activity and autophagy. Using the autophagy stimulant rapamycin, we were able to induce protein turnover by autophagy in senescent cells and aged tissue, suggesting an additional role of mTOR in the age-dependent decreased in autophagy and in age-related diseases. Since mTOR also possess several protective functions, understanding how mTOR regulates autophagy may open up new opportunities for maintaining cellular homeostasis and life quality in aging. E-mail address: [email protected] Acknowledgements German Research Foundation (DFG) and a scholarship of the University of Jena, funded by the state of Thuringia http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.052
OP-14
Ferroptotic Cell Death: Does the Iron Go "Wild" or Stay Enzymatically Controlled? Valerian Kagan Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA No abstract was supplied by the speaker.
http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.053
OP-15
Tocotrienols induce the expression of specific miRNA in breast cancer cells Raffaella Comitato, Roberto Ambra, Guido Leoni, Fabio Virgili Council of Agricultural Research and Economics - Food and Nutrition Research Centre (CREA - NUT), via Ardeatina 546 - 00178 Rome, Italy
OP-13
The role of macroautophagy in senescent cells and aged tissue Christiane Ott 1,2 1
German Institute of Human Nutrition, Germany
We have demonstrated that γ-and δ-tocotrienol (γ-and δ-T3) induce apoptosis in human breast cancer cells (MDA-MB-231 and MCF-7) at least in part, by the binding and activation of the estrogen receptor-β (ERβ). Further experiments conducted in HeLa cells, a line of human cervical cancer cells void of any canonical ER, demonstrated that γ-and δ-T3 induce Ca2 þ release. This event is eventually followed by the induction of specific Ca-dependent signals leading to the expression and activation of IRE1-α and, in
inhibition triggers an irreversible p53-dependent premature senescence phenotype, its activation through genetic means or compound treatment confers cellular lifespan extension and extended maintenance of youthful morphological features. Using the nematode Caenorhabditis elegans, we have achieved proteasome activation at the organismal level thus promoting beneficial effects on the lifespan of the nematode. Moreover, proteasome activation seems to be a potential strategy to minimize protein homeostasis deficiencies underlying aggregation-related diseases such as Alzheimer’s or Huntington’s. Consequently, compounds with proteasome activating properties might be used in preventive or therapeutic approaches against such diseases. In conclusion, our results show the dynamic interconnection between the proteasome, the proteostatic mechanisms and the progression of ageing and age-related diseases. E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.050
OP-12
Thiol- and heme-dependent peroxide detoxification enzymes in pathogens: role in infectivity and virulence Rafael Radi 1,2 1
Departamento de Bioquímica, Facultad de Medicina, Universidad de la República Montevideo, Uruguay 2 Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay Pathogenic bacteria and unicellular parasites are typically exposed to a large flux of cytotoxic oxidants generated during the cellular immune response mediated by macrophages and neutrophils. Invading pathogens cope with mammalian-cell derived oxidants (including superoxide radicals, hydrogen peroxide, peroxynitrite, hypochlorous acid) and secondary species (e.g. lipid hydroperoxides) through an array of enzymatic antioxidant systems, which are being progressively revealed as virulence factors. In this presentation, I will provide some general view on how pathogen antioxidant detoxification systems can impact on infectivity and virulence and report recent findings (1, 2) on the kinetic characterization, oxidant selectivity and biological relevance of thiol- and heme-dependent peroxidatic sytems in bacteria (Ohr) and T. cruzi (APx-CcP). E-mail address: [email protected] References 1. Alegria et al. Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):E132-E141. 2. Hugo, Martinez et al. Proc Natl Acad Sci U S A. 2017 Feb 21;114(8): E1326-E1335.
http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.051
S7
2
German Center for Cardiovascular Research (DZHK), Berlin, Germany
Keywords: Proteolysis; Macroautophagy; Senescence; Ageing; mTOR
Due to the steady increase in life expectancy, the prevalence of age-associated diseases such as Diabetes mellitus, Alzheimer’s disease and cardiovascular diseases as well as the syndrome of "frailty" is also rising. The progressive loss of cellular functionality and the elevated presence of protein aggregates play a decisive role. These aggregates and the age-dependent loss of proteasomal activity are common features of the aging process. Besides the proteasomal system, cells possess another protein quality control system, the Autophagy-Lysosomal-Pathway. Knock-down studies and the use of inhibitors have shown that the loss of proteasomal function can be compensated by the upregulation of lysosomal activity. Our aim was to examine whether these compensatory mechanisms also occur in senescent cells. Using a replicative senescence model of human fibroblasts and aged murine tissue our results reveal a decline in both, proteasomal activity and autophagy. Using the autophagy stimulant rapamycin, we were able to induce protein turnover by autophagy in senescent cells and aged tissue, suggesting an additional role of mTOR in the age-dependent decreased in autophagy and in age-related diseases. Since mTOR also possess several protective functions, understanding how mTOR regulates autophagy may open up new opportunities for maintaining cellular homeostasis and life quality in aging. E-mail address: [email protected] Acknowledgements German Research Foundation (DFG) and a scholarship of the University of Jena, funded by the state of Thuringia http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.052
OP-14
Ferroptotic Cell Death: Does the Iron Go "Wild" or Stay Enzymatically Controlled? Valerian Kagan Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA No abstract was supplied by the speaker.
http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.053
OP-15
Tocotrienols induce the expression of specific miRNA in breast cancer cells Raffaella Comitato, Roberto Ambra, Guido Leoni, Fabio Virgili Council of Agricultural Research and Economics - Food and Nutrition Research Centre (CREA - NUT), via Ardeatina 546 - 00178 Rome, Italy
OP-13
The role of macroautophagy in senescent cells and aged tissue Christiane Ott 1,2 1
German Institute of Human Nutrition, Germany
We have demonstrated that γ-and δ-tocotrienol (γ-and δ-T3) induce apoptosis in human breast cancer cells (MDA-MB-231 and MCF-7) at least in part, by the binding and activation of the estrogen receptor-β (ERβ). Further experiments conducted in HeLa cells, a line of human cervical cancer cells void of any canonical ER, demonstrated that γ-and δ-T3 induce Ca2 þ release. This event is eventually followed by the induction of specific Ca-dependent signals leading to the expression and activation of IRE1-α and, in