1. Prospects for defeating aging altogether Aubrey D.N.J. de Grey, Ph.D. Chairman and CSO, Methuselah Foundation Lorton, VA, USA and Cambridge, UK Email: aubrey@sens.org Website: http://www.mfoundation.org/http://www.mfoundation.org/

2. Semi-technical book Out now: $17.79 at Amazon

3. Structure of this talk -Repair versus retardation -Specifics: the seven types of damage -Intracellular junk/medical bioremediation -Longevity escape velocity: concept -Some evidence that LEV is realistic -The Methuselah Foundation

4. Structure of this talk -Repair versus retardation -Specifics: the seven types of damage -Intracellular junk/medical bioremediation -Longevity escape velocity: concept -Some evidence that LEV is realistic -The Methuselah Foundation

5. What is aging? Metabolism always causes “damage” Damage eventually causes pathology

6. Strategies for intervention Gerontology Geriatrics Metabolism Damage Pathology

7. Problem 1: this is the pathology Alzheimer’s Stroke Sarcopenia Osteoarthritis Hormonal Imbalance Kidney Failure Cancer Heart Disease Diabetes Incontinence Osteoporosis Macular Degeneration Parkinson’s Pneumonia Emphysema Sex Drive … and LOTS more

8. Problem 2: this is metabolism

10. If VW Bugs were built to last

11. Maintained to last

12. Strategies for intervention Gerontology Engineering Geriatrics Metabolism Damage Pathology Claim: unlike the others, the engineering approach may achieve a large extension of human healthy lifespan quite soon

13. Structure of this talk -Repair versus retardation -Specifics: the seven types of damage -Intracellular junk/medical bioremediation -Longevity escape velocity: concept -Some evidence that LEV is realistic -The Methuselah Foundation

14. Reasons for the engineering approach - it targets initially inert intermediates (“damage”)

15. Reasons for the engineering approach - it targets initially inert intermediates (“damage”) - damage is simpler than metabolism or pathology

16. This is the damage No new type of damage identified since 1982! Seven Deadly Things 1.Junk - Inside Cells 2.Junk - Outside Cells 3.Cells - Too Few 4.Cells - Too Many 5.Mutations - Chromosomes 6.Mutations - Mitochondria 7.Protein Crosslinks

17. Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Damage rising with ageIt or its effects reversible by Cell loss, cell atrophyCell therapy, mainly Extracellular junkPhagocytosis by immune stimulation Extracellular crosslinksAGE-breaking molecules/enzymes Death-resistant cellsSuicide genes, immune stimulation Mitochondrial mutationsAllotopic expression of 13 proteins Intracellular junkTransgenic microbial hydrolases Nuclear [epi]mutations (only cancer matters) Telomerase/ALT gene deletion plus periodic stem cell reseeding

18. Structure of this talk -Repair versus retardation -Specifics: the seven types of damage -Intracellular junk/medical bioremediation -Longevity escape velocity: concept -Some evidence that LEV is realistic -The Methuselah Foundation

19. Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation Damage rising with ageIt or its effects reversible by Cell loss, cell atrophyCell therapy, mainly Extracellular junkPhagocytosis by immune stimulation Extracellular crosslinksAGE-breaking molecules/enzymes Death-resistant cellsSuicide genes, immune stimulation Mitochondrial mutationsAllotopic expression of 13 proteins Intracellular junkTransgenic microbial hydrolases Nuclear [epi]mutations (only cancer matters) Telomerase/ALT gene deletion plus periodic stem cell reseeding

20. Autophagy in Alzheimer’s Disease Calnexin Dystrophic NeuritesIEM Cat D

21. Endothelial Cells Lipid-engorged Lysosome Foam Cell

22. Bioremediation: the concept - Microbes, like all life, need an ecological niche - Some get it by brawn (growing very fast) - Some by brain (living off material than others can't) - Any abundant, energy-rich organic material that is hard to degrade thus provides selective pressure to evolve the machinery to degrade it - That selective pressure works. Even TNT, PCBs…

23. Xenocatabolism: the concept Graveyards: - are abundant in human remains… - accumulate bones (which are not energy-rich)… - do not accumulate oxysterols, tau etc... - so, should harbour microbes that degrade them - whose catabolic enzymes could be therapeutic

24. Environmental decontamination in vivo

25. 7-ketocholesterol degradation - a promising start

26. First MF-funded paper published

27. 7-ketocholesterol M = 400 M 13C = 401 Dione metabolite ? M = 398 M 13C = 399 Hydroxylated dione ? M = 414 M 13C = 415 Culture growing on 7-ketocholesterol: Culture growing on 13 C-labeled 7-ketocholesterol: Stable isotope labeling and LC/MS reveal 7-ketocholesterol metabolites in the culture supernatant

28. Steps to biomedical application 1)Isolate competent strains; select by starvation 2)Identify the enzymes (mutagenesis, chemistry, genomics) 3)Make lysosome-targeted transgenes, assay cell toxicity 4)Assay competence in vitro (more mutagenesis/selection) 5)Construct transgenic mice, assay toxicity in vivo 6)Assay competence in disease mouse models 7)Test in humans as for lysosomal storage diseases

29. Structure of this talk -Repair versus retardation -Specifics: the seven types of damage -Intracellular junk/medical bioremediation -Longevity escape velocity: concept -Some evidence that LEV is realistic -The Methuselah Foundation

30. Only 30 years?! Hardly “defeating aging”… Damage rising with ageIt or its effects reversible by Cell loss, cell atrophyCell therapy, mainly Extracellular junkPhagocytosis by immune stimulation Extracellular crosslinksAGE-breaking molecules/enzymes Death-resistant cellsSuicide genes, immune stimulation Mitochondrial mutationsAllotopic expression of 13 proteins Intracellular junkTransgenic microbial hydrolases Nuclear [epi]mutations (only cancer matters) Telomerase/ALT gene deletion plus periodic stem cell reseeding

31. Reasons for the engineering approach - it targets initially inert intermediates (“damage”) - damage is simpler than metabolism or pathology - repairing damage buys time

32. Age Reserve 0 0 max frail Progress avoids diminishing returns Fixing half the damage, then 3/4, then 7/8…. - outpaces the so-far-unfixable damage… - maintains healthspan indefinitely

33. Longevity escape velocity (LEV) The rate at which rejuvenation therapies must improve (following the achievement of RHR) in order to outpace the accumulation of so-far-irreparable damage

34. Structure of this talk -Repair versus retardation -Specifics: the seven types of damage -Intracellular junk/medical bioremediation -Longevity escape velocity: concept -Some evidence that LEV is realistic -The Methuselah Foundation

35. What rate of progress is realistic? Data 19031927 19491969

36. Simulating aging (Phoenix & de Grey, AGE 2007; 29:133) Metabolism ongoingly causes “damage” and Damage eventually causes pathology So…. Simulations of aging (and intervention) should simulate damage accumulation

37. Results: LEV is very easy Therapies double efficacy only every 42y 0 50 100 150 200 250 300 350

38. Data

39. What this means: The first 1000-year-old is probably less than 20 years younger than the first 150-year-old

40. Structure of this talk -Repair versus retardation -Specifics: the seven types of damage -Intracellular junk/medical bioremediation -Longevity escape velocity: concept -Some evidence that LEV is realistic -The Methuselah Foundation

41. The Methuselah Foundation -$4.5M in Mprize pot -$7M donated/pledged for research -Current research support ~$2M/year -Growth >2x/year since MF’s formation -Ideal budget $100M/year (500 scientists) -Proof of concept (mice) probably <10y away Bottom line: It’s going well, and it’s pretty cheap!

42. Why I am doing this

43. Fun Not fun Why I am doing this

44. Semi-technical book Out now: $17.79 at Amazon