1. The Role of EPC in Old Age and Atherosclerosis Dr.Boenjamin Setiawan, Ph.D. 25 October 2008

3. TEN LEADING CAUSES OF DEATH IN THE U.S.A., 2004 Heart disease is the leading cause of death of Americans 24 years of age and older, 30.3% or 724,269 annual deaths are due to heart disease. Sixteen percent of those deaths, 115,883, occur in smokers. Cancer is the second leading cause of death causing 23% or 538,947 deaths. Twenty-three percent of those are lung cancer, 83% of lung cancers occur in smokers and exsmokers (101, 724).

4. Ten leading causes of death, all WHO member states, 2000 TEN LEADING CAUSES OF DEATH, ALL WHO MEMBER STATES, 2000 2.2% (10) Trachea, Bronchus, Lung Cancers 2.3% (9) Road Traffic Injuries 3.0% (8) Tuberculosis 3.8% (7) Diarrhoeal Diseases 4.4% (6) Perinatal conditions 4.5% (5) Chronic Obstructive Pulmonary Disease 5.3% (4) HIV/AIDS 6.9% (3) Lower Respiratory Infections 9.2% (2) Cerebrovascular Disease 12.4% (1) Ischemic Heart Disease PERCENT OF TOTAL CAUSE

6. Embryonic stem cells are derived from the Inner Cell Mass

7. Multiple embryos are produced in vitro for clinical purposes. Donated surplus embryos are used as a source of ES cells. These surplus embryos would otherwise be discarded or remain unused How are ES Cells Generated?

8. Fertilized Embryos Are Allowed to Divide Several Times in Culture

9. Harvesting ES Cells The blastocyst is the stage of development (~1,000 cells) at which the embryos inner cell mass (ICM) forms. It is the ICM that harbors ES cells. Stem cells exist only fleetingly at this stage of development

10. Generating an ES Cell Line The trophoblast is removed from the embryo, the inner cell mass is isolated and, using a micropipette, ES cells are extracted and placed in tissue culture. These cells are passaged for many generations until some spontaneously form “immortal” lines

11. Stem Cells are taken from the Inner Cell Mass at the blastocyst stage and cultured in a Petri disk

15. Structure of Animal Cell

16. seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.

19. seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.

20. seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.

21. World’s oldest person celebrates 129 th birthday, died March 2007 According to national records, Hernandez was born on May 3, 1878, in one of the country's central provinces, where she gave birth to 13 children. She now has 60 grandchildren, 80 great-grandchildren and 25 great-great grandchildren.

22. FIGURE 1. Tissue heterogeneity and stem-cell functionality for homeostasis and repair

23. FIGURE 2. Variation of maximal lifespan across species. From the following article: Stem cells, ageing and the quest for immortality Thomas A. Rando Nature 441, 1080-1086 (29 June 2006) doi:10.1038/nature04958

24. Stem cells, ageing and the quest for immortality Thomas A. Rando Influence on Stem Cell Functionality

25. FIGURE 4. Ageing of stem-cell functionality

28. Figure 1. Origin and differentiation of endothelial progenitor cells . Scheme depicts the potential origin and differentiation of endothelial progenitor

29. ( Circulation. 2007;115:1285-1295.) © 2007 American Heart Association, Inc. Endothelial Function and Dysfunction Testing and Clinical Relevance John E. Deanfield, MB, BCh, FRCP; Julian P. Halcox, MD, MA, MRCP; Ton J. Rabelink, MD, PhD From the Vascular Physiology Unit (J.E.D., J.P.H.), UCL Institute of Child Health, London, UK; and the Department of Nephrology (T.R.), Leiden University Medical Center, Leiden, The Netherlands. Contemporary Reviews in Cardiovascular Medicine

33. Figure 2. Sustained ROS signaling induces senescence of endothelial cells. Left, This is reflected in detachment of endothelial cells or parts of the endothelial cell membrane (endothelial microparticles). Right, With increasing age and persisting ROS signaling, the capacity of neighboring endothelial cells to repair the endothelial injury is limited, and vascular integrity becomes dependent on the incorporation of circulating PC

39. seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D.

42. Spinal Cord Injuries seminar Active Aging 17 Juli 2008 dr.Boenjamin Setiawan, Ph.D. Hwang Mi-Soon: South Korea Paralyzed 19 years Multipotent adult stem cells injected into her spinal cord Currently: debilitating pain Published in 2005 ( Cytotherapy )

43. J Am Coll Cardiol, 2003; 42:2081-2082, doi:10.1016/j.jacc.2003.09.016 © 2003 by the American College of Cardiology Foundation EDITORIAL COMMENT Aging of progenitor cells: limitation for regenerative capacity? Stefanie Dimmeler, PhD ,* and Mariuca Vasa-Nicotera, MD Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany Department of Cardiovascular Science, Division of Cardiology, University of Leicester, Leicester, United Kingdom

45. Figure 1 Possible influences of age on endothelial progenitor levels. VEGF = vascular endothelial growth factor.

46. Fig. 1 Regeneration of the endothelial monolayer after injury. After induction of endothelial injury ( 1 ) two possibilities exist to regenerate the injured endothelial monolayer ( 2 , 3 ). 2 Regeneration by mature endothelial cells which migrate and proliferate to regenerate the endothelial layer. 3 Regeneration by bone marrow derived endothelial progenitor cells

48. Fig. 3 Possible targets of risk factors for coronary artery disease to reduce circulating endothelial progenitor cells ( 1 – 4 ). Risk factors for coronary artery disease may interfere with hematopoietic stem cells in the bone marrow, reducing mobilization or affecting survival and differentiation of circulating progenitor cells. Additionally, risk factors such as age may also reduce homing by reducing stimulatory factors such as VEGF and the block receptor independent kinases

50. Competent Marrow compared to Senescent Marrow

52. Fig. 2 Different effects of physical exercise on redox status of the cell. Abbreviations: ROS, reactive oxygen species.

54. Figure 1 EPC origins. EPCs could be released from bone marrow, fat tissues, vessel wall, especially adventitia and spleen, liver, and intestine, where they form a circulating EPC pool. They can then contribute to the repair of damaged vessels in pathological conditions.

55. Figure 3 EPC mobilization and differentiation. Schematic graphics summarize cytokines, growth factors, and other mediators inducing EPC release from tissues and homing to the surface of arteries where endothelial cells are damaged. After attachment to the vessel wall, EPCs differentiate into endothelial cells induced by the micro-environment.

66. Thank You