Prospects for extending healthy life - a lot Aubrey D.N.J. de Grey, Ph.D. Chairman and CSO, Methuselah Foundation Lorton

1. Prospects for extending healthy life - a lot Aubrey D.N.J. de Grey, Ph.D. Chairman and CSO, Methuselah Foundation Lorton, VA, USA and Cambridge, UK Email: aubrey@sens.org MF site: http://www.methuselahfoundation.org/ Science site: http://www.sens.org/ Prize site: http://www.mprize.org/

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3. Why I am doing this

4. Fun Not fun Why I am doing this

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

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

7. Aging in a nutshell Product of evolutionary nelect, not intent Metabolism ongoingly causes “damage” Damage eventually causes pathology Pathology causes more pathology

8. Strategies for intervention Gerontology Geriatrics Metabolism Damage Pathology

9. How to make a car last 50 years -- plan A

10. How to make a car last 50 years -- plan B

11. 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

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

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

14. Reasons for the engineering approach • it targets initially inert intermediates (“damage”) • repairing damage buys time

15. Retarding aging: benefits modest max Reserve frail 0 0 Age Halving rate of damage starting in middle age - doubles remaining healthspan - raises total healthspan by maybe 20%

16. Comparable repair: far better max hard Reserve easy frail 0 0 Age Fixing half the damage starting in middle age - doubles total healthspan - raises remaining healthspan maybe 5-fold

17. Robust human rejuvenation (RHR) Addition of 30 extra years of healthy life (and total life) to people who are already in middle age when treatment is begun

18. Ever-improving repair: better yet max very hard Reserve hard easy frail 0 0 Age Fixing half the damage, then 3/4 - not as good as doing 3/4 first time… - but better than doing 1/2 first time…

19. Infinitely better, in fact max Reserve frail 0 0 Age Fixing half the damage, then 3/4, then 7/8…. - outpaces the so-far-unfixable damage… - maintains healthspan indefinitely

20. 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

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

22. Simulating aging (Phoenix & de Grey, AGE, in press) Metabolism ongoingly causes “damage” and Damage eventually causes pathology So…. Simulations of aging (and intervention) should simulate damage accumulation

23. Simulating damage: basis • damage of many types accumulates • any can kill us (i.e. they are not additive) • within each type, subtypes are additive • damage feeds back to hasten more damage • people differ in damage accumulation rates • death is from damage X challenge (e.g. flu)

24. Simulating damage: model Structural parameters N_CAT: The number of damage categories each person has N_MECH: The number of mechanisms in each category MECH_WEIGHTm: The contribution of a mechanism to a category Fitting parameters BASAL_M: The mean basal damage rate BASAL_SD: The standard deviation of the basal damage rate BASAL_H: The homogeneity of basal damage rate in a single person EXP_M: The mean exponential damage rate EXP_SD: The standard deviation of the exponential damage rate EXP_H: The homogeneity of exponential damage rate in a single person FATAL_M: The mean yearly challenge FATAL_SD: The standard deviation of the yearly challenge Values set for each person at initialisation: PB: Basal rate for the person: lognorm(BASAL_M, BASAL_SD) PE: Exponential rate for the person: lognorm(EXP_M, EXP_SD) MBc,m:Basal rate for each mechanism: lognorm(BASAL_M, BASAL_SD)*(1-BASAL_H) + PB*BASAL_H MEc,m: Exponential rate for each mechanism: lognorm(EXP_M, EXP_SD)*(1-EXP_H) + PE*EXP_H D_Mc,m : Cumulative damage for each mechanism: 0 D_Cc : Cumulative damage for each category: 0 Variables updated for each person at each time step (year): Total damage: PD(t) = [SUM c=1..N_CAT] D_Cc(t) Damage increment: DI_Mc,m(t) = MBc,m + MEc,m*PD(t-1) Cumulative damage: D_Mc,m(t) = DI_Mc,m(t) + D_Mc,m(t-1) Cumulative category damage: D_Cc(t) = [SUM m=1..N_MECH] DI_Mc,m(t) Fatality challenge: FATAL(t) = |norm(FATAL_M, FATAL_SD)| If D_Cc(t) > FATAL(t) for any c, the person dies at age t

25. Validation: age at death

26. Results: how damage evolves

27. Results: defeat of damage Therapies doubling in efficacy every 42 y 0 50 100 150 200 250 300 350

28. Results: LEV in practice Therapies doubling in efficacy every 42 y 0 50 100 150 200 250 300 350

29. LEV decreases with time max Reserve frail 0 0 Age Fixing half the damage, then 2/3, then 3/4…. - still good enough… - just like gravitational escape velocity

30. Data

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

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

33. Problem 1: this is metabolism

34. Problem 2:this is the pathology • Cancer • Heart Disease • Diabetes • Incontinence • Osteoporosis • Macular Degeneration • Alzheimer’s • Stroke • Sarcopenia • Osteoarthritis • Hormonal Imbalance • Kidney Failure • Parkinson’s • Pneumonia • Emphysema • Sex Drive • … and LOTS more

35. This is the damage Seven Deadly Things • Junk - Inside Cells • Junk - Outside Cells • Cells - Too Few • Cells - Too Many • Mutations - Chromosomes • Mutations - Mitochondria • Protein Crosslinks No new type of damage identified since 1982!

36. Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation

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

38. Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation

39. Aggregates: major examples - Proteins in neurodegeneration - Oxysterols in atherosclerosis

40. Autophagy in Alzheimer’s Disease Dystrophic Neurites IEM Calnexin Cat D

41. Endothelial Cells Lipid-engorged Lysosome Foam Cell

42. 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…

43. R1 day 20 R5 day 71 R4 day 71 R1 day 71 R1 day 36 R2 day 71 R5 day 20 R2 day 36 R5 day 36 R3 day 71 R3 day 36 R4 day 36 1 2 5 7 9 11 12 15 Example: DGGE Results from Perchlorate-Reducing, Membrane Biofilm Reactors

44. 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

45. Environmental decontamination in vivo

46. 7-ketocholesterol degradation - a good start

47. 7-KC degradation - presented at meetings

48. First MF-funded paper submitted

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

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