Cipher: 2311
Nomenclature: Molecular genetics of aging and carcinogenesis
Study programme: Molecular biosciences
Module: Biology
Case holder:

Title prof.dr. Sc. Ivica Rubelj, zn. permanent advisor
Institution of the case holder:

Rudjer Boskovic Institute, Department of Molecular Biology
Contributors - Contractors:
Subject status: Electoral College
The year in which the case is submitted: Year I
The semester in which the case is submitted: Semester II
Subject objective:

To know the latest research ideas and methodology in the field of molecular mechanisms of aging and carcinogenesis and their interconnection.
Case contents:

Introduction to molecular biology of aging. Beginnings of research of the basic mechanisms of cellular aging, an overview of modern ideas and methodological approaches to aging research from cell to organism. Cellular aging. Model of human and mouse fibroblasts, endothelial and epithelial cells, M1/M2 mechanism, entry into crisis and imortalization, effect sv40 large T antigen (Tg), role p53 and pRb. Molecular basics (patho)physiology of cellular aging. Mechanisms of genetic control of cellular aging: the role of telomeresa and telomerase (telomeresa structure, proteins that interact with telomeresa, the role of telomerase and recombination mechanisms in controlling telomeresa length in normal and imortal cells), the ALT mechanism, the role of cell cycle control in aging and the interaction of it with telomeres. Oxidative stress in cellular aging: hyper/hypooxia, telomeres and oxidative stress, the role of mitochondria in the formation of cellular damage and cellular aging, the role of antioxidants and stress-response mechanisms in cellular aging. Molecular basis (patho)physiology of tissue and organ aging. Skin as a model object: aging fibroblasts, melanocytes, keratinocytes, endothelial cells, skin matrix and microvasculature. Aging of inert organs and tissues (nervous system, myocardium) and their resistance to stress. Genetic and epigenetic mechanisms of aging control in laboratory mice (knock out experiments, microarray analyses, oxidative stress and caloric diet) and nematodes C. elegans and their similarities and differences with aging in humans. Molecular mechanisms of some degenerative diseases associated with aging. Alzheimer's, Werner syndrome, Hutchinson-Gilford syndrome (Progeria). Evolutionary theories of the mechanisms of aging and their reciprocity with carcinogenesis.
Learning outcomes: competences, knowledge, skills that the subject develops:

1. To analyze the molecular mechanism of aging and carcinogenesis.
2. Compare molecular mechanisms of cellular aging with aging at the level of the organism.
3. Predict how changes in molecular mechanisms lead to immortality and how various environmental influences change the dynamics of the aging process and carcinogenesis.
4. Examine the interrelationship between telomere metabolism, mitochondria metabolism and free radicals in carcinogenesis, aging and the development of various age-related diseases.
5. To conclude that the same molecular mechanisms in one case provide limited cellular growth, and in imortalization they allow infinite cellular divisions.
6. Critically judge about today's very widespread use of antioxidants and various diets that try to slow down aging.
ECTS Credits 6
Lectures 5
Seminars (IS) 0
Exercises (E) 25
Altogether 30
The way of teaching and acquiring knowledge:

Attending lectures and exercises.
Ways of teaching and acquiring knowledge: (notes)
Monitoring and evaluating students (mark in fat printing only relevant categories) Attendance, Exercise or case study
Rating method: Viva voce
Mandatory literature:

1. Handbook of the Biology of Aging. Third edition. Editors: Schneider, E. L. and Rowe, J. W., Academic Press, Inc. San Diego, California, 1990.

Kim, S., Jiang, J.C., Kirchman, P. A., Rublelj, I., Helm, E. G. and Jazwinski, S.M.: Cellular and molecular aging. in Comprehensive Geriatric Oncology, second edition, (L. Balducci, W.B. Ershler, G. H. Lyman, eds.) Harwood Academic Publishers, Amsterdam, 1998 pp. 123-155.

Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rublelj, I., Pereira-Smith, O.M., Peacocke, M. and Campisi, J.: A biomarker that identifies senescent human cells in culture and in aging skinaging in vivo, Proc. Natl. The Acad. Sci. USA, 1995; 92: 9363-9367.

Blasco M. A. mouse models to study the role of telomeres in cancer, aging and dna repair [Review]. European Journal of Cancer. 38(17): 2222-2228, 2002 Nov.

Rublelj, I., Brdar, B. and Pereira-Smith, O.M.: Replicative senescence in vitro and in vivo, Croatian Med. J. 1997; 38: 190-198.

Rublelj, I. and Pereira-Smith, O.M.: sv40-transformed human cells in crisis exhibit changes that occur in normal cellular senescence. Exp. Cell Res. 1994; 211: 82-89.

Rubelj, I. and Vondraček, Z.: Stochastic mechanism of cellular aging – abrupt telomere shortening as a model for stochastic nature of cellular aging, J. theor. Biol. 1999; 197: 425-438.

Rublelj, I., Huzak, M., Brdar, B. and Pereira-Smith, O.M.: A single-stage mechanism controls replicative senescence through sudden senescence syndrome, Biogerontology 2002; 3 (4): 213-222.
Supplementary (recommended) literature:

Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB. 1992. Telomere length predicts replicative capacity of human fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 89: 10114–10118.
Allsopp RC, Harley CB. 1995. Evidence for a critical telomere length in senescent human fibroblasts. Experimental cell research 219: 130–136.
Bisoffi M, Heaphy CM, Griffith JK. 2006. Telomeres: prognostic markers for solid tumors. International journal of cancer. Journal international du cancer 119: 2255–2260.
Blackburn EH. 1991. Structure and function of telomeres. Nature 350: 569–573.
Colavitti R, Finkel T. 2005. Reactive oxygen species as mediators of cellular senescence. IUBMB life 57: 277–281.
Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S. 1992. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. The EMBO journal 11: 1921–1929.
Ducray C, Pommier JP, Martins L, Boussin FD, Sabatier L. 1999. Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process. Oncogene 18: 4211–4223.
Finkel T. 2011. Signal transduction by reactive oxygen species. The Journal of cell biology 194: 7–15.
Fordyce CA, Heaphy CM, Bisoffi M, Wyaco JL, Joste NE, Mangalik A, Baumgartner KB, Baumgartner RN, Hunt WC, Griffith JK. 2006. Telomere content correlates with stage and prognosis in breast cancer. Breast cancer research and treatment 99: 193–202.
Harley CB, Futcher AB, Greider CW. 1990. Telomeres shorten during ageing of human fibroblasts. Nature 345: 458–460.
Kirkinezos IG, Moraes CT. 2001. Reactive oxygen species and mitochondrial diseases. Seminars in Cell & Developmental Biology 12: 449–457.
Lindsey J, McGill NI, Lindsey LA, Green DK, Cooke HJ. 1991. In vivo loss of telomeric repeats with age in humans. Mutation research 256: 45–48.
Ornish D. 2008. The Spectrum: A Scientifically Proven Program to Feel Better, Live Longer, Lose Weight, and Gain Health. Ballantine Books.
Ornish D, Lin J, Daubenmier J, Weidner G, Epel E, Kemp C, Magbanua MJM, Marlin R, Yglecias L, Carroll PR, et al. 2008. Increased telomerase activity and comprehensive lifestyle changes: a pilot study. The lancet oncology 9: 1048–1057.
Ornish D, Lin J, Chan JM, Epel E, Kemp C, Weidner G, Marlin R, Frenda SJ, Magbanua MJM, Daubenmier J, et al. 2013. Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. The Lancet Oncology 14: 1112–1120.
Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birket MJ, Harold G, Schaeuble K, et al. 2007. Mitochondrial Dysfunction Accounts for the Stochastic Heterogeneity in Telomere-Dependent Senescence. PLoS Biol 5: e110.
Passos JF, Von Zglinicki T. 2006. Oxygen free radicals in cell senescence: are they signal transducers? Free radical research 40: 1277–1283.
Plentz RR, Schlegelberger B, Flemming P, Gebel M, Kreipe H, Manns MP, Rudolph KL, Wilkens L. 2005. Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma. Hepatology (Baltimore, Md.) 42:522–526.
Shay JW, Wright WE. 2011. Role of telomeres and telomerase in cancer. Seminars in cancer biology 21: 349–353.
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. 2006. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chemico-biological interactions 160: 1–40.
Weng NP, Palmer LD, Levine BL, Lane HC, June CH, Hodes RJ. 1997. Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging. Immunological reviews 160: 43–54.
Von Zglinicki T, Pilger R, Sitte N. 2000. Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radical Biology and Medicine 28: 64–74.
How to monitor the quality and performance performance (evaluation):

Discussions with students and colleagues, monitoring of the progress of each student, evaluation of performance by the study leadership and joint expert committee of the holders of the study. The success of the course will be evaluated annually by the joint expert committee of the Rudjer Boskovic Institute, the University of Dubrovnik and the University of Osijek