1. AGING ……. What is it, why does it happen, what's to be done about it (if anything)?

2. What IS Aging?

3. Scientifically …. Aging is a biological process Aging not disease, per se Aging is a PROCESS that converts an optimally healthy, fit organism (for its environment) into a less healthy, less fit organism

4. Practically …. Aging = reduced tissue/physiological function Aging = increased susceptibility to disease (age-related diseases) Aging = decreased resistance to stress (physical and psychological)

5. Why does this happen? (Why do we age? If we don't understand this, we haven't hope of doing something about it! ) What can we do about it? (How can we postpone aging)

6. WHY do we age? Genes + Environment

7. Why do we age --- GENES Genes determine species-specific life span (LAGs) (e.g., mice, monkeys, humans, tortoises) Genes determine differences among individuals within a species (e.g., big/small noses) (genetic polymorphisms)

8. Species-specific longevity genes Flies ( Drosophila melanogaster ) Nematodes ( Caenorhabditis elegans ) Mice ( Mus musculus ) Humans ( Homo sapiens ) Galapagos turtles ( Geochelone elephantopus) Life spans ranging from 2-3 weeks to 100-200 years!

9. AGE (log) Fitness Disease (Cancer, osteoporosis, diabetes, etc.) AGING in MICE AND MEN 18 Months 50 Years MICE HUMANS Mice and Humans are 97% genetically similar!

10. Species-specific longevity genes Potentially big pay-off, but complicated by development/evolution What are the genes that determine why mice live <4 years, whereas humans live >100 years?

11. Individual longevity genes (polymorphisms) Smaller pay-off, but possibly amenable to intervention (environment, life style, drugs??)

12. Individual longevity genes Most identified so far are disease-susceptibility genes (e.g., ApoE4) Healthy centenarian studies are underway! Solution = preventive drugs Solution = ??????

13. Why do we age --- ENVIRONMENT Present environment (including life style) Past environment (evolutionary history)

14. Why do we age --- PRESENT ENVIRONMENT DIET (a brief discourse about calorie restriction) EXERCISE THINK GOOD THOUGHTS! (a brief discourse about stress/hormesis)

15. DIET Eat well, but not too much! FOOD ---> ENERGY Food ----> simple molecules + oxygen (mitochondria) ----> energy Oxygen metabolism ----> damaging byproducts (ROS, oxidative stress) OPTIMAL food = less ROS, less damage, more defenses longer lifespans! Anti-oxidant defenses good, but not perfect (differ among species)

16. DIET CALORIC RESTRICTION GOOD NEWS! 30-40% calorie restriction without malnutrition extends HEALTHY lifespan 40-50% (worms, flies, mice, rats -- maybe monkeys) BAD NEWS! Life SEEMS longer!! (let's develop that CR pill)

17. EXERCISE Yes, yes, yes ….. (but not too much) Exercise ---> healthier muscles, greater fitness Greater protection from oxidative stress! (not such a paradox, anti-oxidant defenses)

18. Think good thoughts! Avoid undue stress Physiological stress: Stress hormones, a double edged sword Physical stress: Overwhelm cellular defense mechanisms The peculiar phenomenon of hormesis

19. HORMESIS --- (a little stress is good for you!) Low level stress + high stress ---> Less damage by high stress Low level stress ---> Longer life span Temperature stress, chemicals, radiation, etc

20. Why do we age --- PAST ENVIRONMENT Genes evolve in response to environment This is REALLY why we age!

21. Aging before cell phones …….. 100% SURVIVORS AGE "Natural" Environment (hazards, predators, infection, etc.) 80 yrs 3-4 yrs "Protected" Environment (climate control, biomedical intervention etc.) 40 yrsHUMANS: 4 mosMICE:

22. Aging before cell phones …….. 100% SURVIVORS AGE "Natural" Environment (hazards, predators, infection, etc.) "Protected" Environment (climate control, biomedical intervention etc.) Mutation Accumulation ("bad" genes can persist) Antagonistic Pleiotropy (what's good when you're young can be bad when you're old)

23. GOOD NEWS! If we keep our "protected" environment, we WILL evolve longer life spans! BAD NEWS! It's going to take a LONG time!

24. Sooo…. What's to be done about aging now? Optimize present environment Support basic research in aging! New therapies on the horizon! Cell based therapies Drug based therapies

25. Cell based therapies Stem cells! embryonic adult nuclear transplant (cloning) Telomerase! increase cell divisions anti-cancer therapy

26. Drug-based therapies Anti-oxidants, mitochondrial protectors, etc. Hormones! growth hormone insulin/IGF (lessons from worms and flies) estrogen CR mimetics!

27. AGING ….. Long, healthy life spans (it's already happening) Treatments for age-related diseases (it's already happening) Limits -- not yet reached (we've still a long way to go)