Geoffrey C. Wall, Pharm.D ., FCCP, BCPS, CGP Professor of Clinical Sciences

1. Geoffrey C. Wall, Pharm.D., FCCP, BCPS, CGP Professor of Clinical Sciences College of Pharmacy and Health Sciences Drake University, Des Moines, IA

2. Review projections of human lifespan in the late 20th Century • Possible medical breakthrough that will significantly extend lifespan • Current projections of lifespan in the 21st Century

3. http://www.census.gov/population/www/pop-profile/natproj.html. Accessed 2/5/12

4. Fertility in the middle series was assumed to remain almost constant, near the current fertility level of about 2.1 births per woman. • Life expectancy is projected in the middle series to increase from 76.0 years in 1993 to 82.6 years in 2050. In 2050, life expectancy in the low assumption would be 75.3 years and in the high assumption would be 87.5 years • Net immigration for the middle series remains constant at 880,000 per year

5. https://www.cia.gov/library/publications/the-world-factbook/rankorder/2102rank.htmlhttps://www.cia.gov/library/publications/the-world-factbook/rankorder/2102rank.html

6. Fries Hypothesis • Proposed a maximum theoretical age limit • 85 years +/- SD 7 years • “biological warranty” period • If upper limit is unknown why is there functional decline in middle and late-middle ages? • Built in plateau to average human lifespan • Notes it would take an 85% relative decrease in 1985 mortality levels for average human lifespan to reach 100 years Am J Public Health. 2008; 98: 1163–1166.

7. Vaupel and colleagues • Note that every published estimate of life-expectancy has been broken within several years of its publication date • Has looked at trends in mortality among the “oldest old” • Found that death rates actually DECREASE after age 80 until age 110 when they level off • Note that centegenarians are the fastest growing segment of the developed world’s population (over 60,000 in the US in 2010) • Census bureau estimates that 1 in 9 baby boomers will live to at least their mid-90s! Science 2002; 296: 1029-31

8. Decreased smoking rates • Improvements in indentifying and treating coronary artery disease risk factors • Improved immunization schedule in baby boomers and up • Advancing technologies

9. Term coined by Robert Fogel • “Synergy between technological and physiological improvements that have given human beings an unprecedented degree of control over their environment and the factors that affect mortality” • Nutrition • Improved diagnostic techniques • Improved surgical techniques • Prosthetic implants/technology

13. Exactly HOW do some people live so long compared to others? • Telomere length • Oxidative damage • Caloric restriction • Gene expression

14. Telomere Length • Nucleotide sequences at the end of a chromosome, which protects the end of the chromosome from deterioration • These sequences shorten in length as cell age and make them vulnerable to mutation and death • Expanding the length of telomeres with drugs or by gene therapy may be a way of extending lifespan Am J Hum Biol 2011;23:149-67

15. Oxidative Damage • Theory holds that reactive oxygen species (ROS) which can damage cell DNA accumulate as humans age, leading to the degeneration of organ systems and susceptibility to disease characteristic of aging • Could drugs reverse process? Am J Physiol Regul Integr Comp Physiol 2007; 292: R18–R36

16. Caloric Restriction • Currently a vibrant area of research • Numerous studies at the cellular and animal level have suggested a 20% decrease in caloric intake can extend life • Data in numerous animal models including primates • The big question is WHY? • More chronic disease? • Genetic adaptability (i.e. a “leaner, meaner” organism? Eur J Clin Invest. 2010;40: 440–450

17. Science. 2009;325: 201–204.

18. Science. 2009;325: 201–204.

19. Gene Expression • Some data suggest that 25% of human lifespan is heritable (found in twin studies) • Studies to find the “long-life” gene have been inconclusive • Maybe more than one gene? • Responsible for different regulatory assignments • Cytokine production—Responsible for immunogenic responses • NK receptor genes—Responsible for cancer surveillance • Etc Int J Immunogenet. 2011;38:373-81

20. mTOR • Mammalian Target of rapamycin (mTOR) is a gene derived kinase that is a central controller of cell growth, metabolism and aging • Implicated in a wide variety of human disease • Rapamycin administration may inhibitor amount of mTOR in tissues, PERHAPS decreasing development of disease • Animal and human studies underway Curr Opin Cell Biol. 2011;23:744-55.

21. Other Theoretical Prospects • Therapeutic cloning • Technology available, but how to turn cellular machinery off?? • Stem-Cells • Use in diseased organs? Data to date has been disappointing • Nanotechnology • Molecular sized “machines” to target cancer cells or remove atherosclerosis?

25. Conclusion • Although difficult to project, the increase in American lifespan is predicted to continue into the 21st Century • New Technologies MAY dramatically cause a shift in these numbers, but no indications at this time strongly suggest this • Stay tuned for research in this area

26. Thank you! Geoff.wall@drake.edu