1. The Buck Institute for Research on Aging • Brian Kennedy, President & CEO • Presented by JosephAntoun, Pr. of Health Policy Almaty 03|12| 2012

2. The Buck Institute • Best-in-class R&D institution that is solely focused on Aging and Chronic Diseases • Mission: to increase the healthy years of life through aging research and education on the aging process • Unique Assets: 20 Head Investigators, 140 PhDs, >100 supporting staff • Focusing on biogerentology, Aging & aging disorders, Genetics, Epigenetics, Animal models of aging • Age-related disease: Neurodegenerative disease, Cancer, Cardiovascular disease, Metabolic disease

3. CDs: Heart, Stroke, Hypertension, Lung, Mental, Diabetes & Cancer December 13th, 2003 The shape of things that are here! December, 2011

4. Prevention and Treatment- Current Options Risk Factor The Buck Institute Metabolism ‘Primordial’ Smoking, Body Weight, exercise Prevention Primary Damage Intervention Statins, aspirin + primary prevention Secondary Prevention Pathology Treatment Control cholesterol, hypertension, glycemia, etc. Tertiary Prevention Morbid Complications Treatment Death

5. Compression & Expansion of Morbidity An important metric is the relative rate of increase/decrease in morbidity compared to changes in life expectancy: goal is relative compression of morbidity Compression of Morbidity 1980–2011: A Focused Review of Paradigms and Progress. Journal of Aging Research, 2011

6. Is Aging a correlate or a Catalyst of Chronic Diseases? CANCER NEURODEGENERATIVE DISEASE Cellular Senescence CARDIOVASCULAR DISEASE Inflammation Cardiac Hypertrophy AGING AUTOIMMUNE DISEASE Protein Aggregation METABOLIC SYNDROME Metabolic Syndrome Sarcopenia ARTHRITIS Mitochondrial Dysfunction TYPE II DIABETES FRAILTY Kohn 1978 STROKE

7. Aged Related Chronic Diseases Could be Deferred • Diet & exercise, processes known to inhibit key pathways of interest (such as mTOR) have clearly shown ability to extend healthy lifespan (healthspan) • Stanford runners study • Intermittent caloric restriction DIET – Caloric Restriction AEROBIC EXERCISE

8. Aging Can Be Slowed: Dietary Restriction Control Control Control Control DR DR DR DR 1 1 0.8 0.8 0.6 0.6 Fraction Viable Fraction Viable 0.4 0.4 0.2 0.2 0 0 10 20 30 40 0 0 20 40 60 80 Age (days) Age (Cell Divisions)

9. DR also “works” in primates Science July 10, 2009 CONTROL CR

10. How Diet & Exercise Work? Growth Factors Nutrients Energy Stress Healthy State or Chronic Disease? Chronic Disease mTOR mTORC2 mTORC1 Insulin sensitivity Metabolism Aging Neoplastic tendencies

11. The TOR Pathway Pankaj Kapahi Current Biology, 2004 RAPAMYCIN Science 2005 Genes Dev. 2006

12. Rapamycin – The First mTORInhibitor • The first, non-specific mTOR inhibitor • Approved in the US & worldwide as • Adjunctive agent for prevention of acute renal allograft failure (Rapamune – Wyeth) • Improving coronary luminal diameter in patients with symptomatic ischemic disease (Cypher Stent – Cordis Corporation) • Has shown efficacy in many other disease states in mice BRAIN DISEASES (eg. HD/AD/PD) METABOLIC DISEASE AGING Extends Healthspanin Mice STROKE CANCER CARDIOVASCULAR DISEASE NIA Intervention testing program Nature 460:392 Biochim. Biophys. Acta(2009) 1790: 1067-1074

13. The Mice are Healthier! Randy Strong, UTHSCSA; NIA Intervention testing program Nature 460:392

14. Rapamycin and Age-Related Disease Neuro-degeneration Frailty Cancer Stroke Wrinkles ? Type II Diabetes Heart Disease Arthritis Biochim. Biophys. Acta (2009) 1790: 1067-1074.

15. A Tale of Two “Anti-Aging” Compounds

16. Thioflavin T Alavez et al. Nature 2011

17. Therapeutic Approaches • Targeted approaches to age-related diseases • - Andersen / Zeng Parkinson’s • - Ellerby / Hughes / Others Huntington’s • - Dale Bredesen Alzheimer’s • - Chris Benz Breast Cancer • - David Greenberg Stroke • - Kapahi/ BrandDiabetes • - Brian Kennedy CVD, Progeria • - Deepak Lamba Macular Degener. • - Simon Melov Sarcopenia

18. Economics of Increasing Healthy Life Expectancy or ’Slowing’ CDs • 1 QALY (Quality Adjusted Life Year) and VSLY (Value of Statistical Life Year) in US: • 50k to 500k depending on methodology (VSLY) • 100k hospitals; 50k pharmaceuticals (QALY) • GDP per capita in US is $47K • If we consider $100,000, a medicine that increases life by 5%, at full health and across the US population, increases life expectancy by • ~4 years; and the corresponding dollar benefit would be: • 4 years*300 million Americans*$100,000= 120,000,000,000,000 or 120 trillion dollars! • If we consider CDs and non-CDs independent and uncorrelated: a medicine that delays CDs (70% of morbidity/mortality rates in US) has an economic value of: 120 trillion * 0.7= $ 84 trillion

19. Conclusion: The Framework of the Buck Institute Prevention of Treatments for Chronic Disease State-of-the-Art Basic Science Extend Healthspan!

20. Thank you. • www.buckinstitute.org Almaty 03|12| 2012

21. Burden of CDs-Example of Diabetes in US • 25.8 million people in the United States (8.3% of the population) have diabetes. • In 2010, about 1.9 million new cases of diabetes were diagnosed in people aged 20 years or older. • If current trends continue, 1 of 3 U.S. adults will have diabetes by 2050 • Total costs (direct and indirect) of diabetes in 2007: $174 billion ~8% of total healthcare costs • Available treatments: decrease disease evolution… http://www.cdc.gov/chronicdisease/resources/publications/AAG/ddt.htm