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Prospects for defeating aging altogether Aubrey D.N.J. de Grey, Ph.D. Chairman and CSO, Methuselah Foundation Lorton, VA

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/. Semi-technical book. Out now: $17.79 at Amazon. Structure of this talk

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Prospects for defeating aging altogether Aubrey D.N.J. de Grey, Ph.D. Chairman and CSO, Methuselah Foundation Lorton, VA

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  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/

  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 • 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

  8. Problem 2: this is metabolism

  9. If VW Bugs were built to last

  10. Maintained to last

  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 • Specifics: the seven types of damage • Intracellular junk/medical bioremediation • Longevity escape velocity: concept • Some evidence that LEV is realistic • 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”) • damage is simpler than metabolism or pathology

  15. 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!

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

  17. 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

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

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

  20. Endothelial Cells Lipid-engorged Lysosome Foam Cell

  21. 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…

  22. 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

  23. Environmental decontamination in vivo

  24. 7-ketocholesterol degradation - a promising start

  25. First MF-funded paper published

  26. Stable isotope labeling and LC/MS reveal 7-ketocholesterol metabolites in the culture supernatant Hydroxylated dione ? M = 414 M13C = 415 7-ketocholesterol M = 400 M13C = 401 Dione metabolite ? M = 398 M13C = 399 Culture growing on 7-ketocholesterol: Culture growing on 13C-labeled 7-ketocholesterol:

  27. 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

  28. 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

  29. Only 30 years?! Hardly “defeating aging”…

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

  31. Progress avoids diminishing returns 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

  32. 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

  33. 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

  34. What rate of progress is realistic? Data 1903 1927 1949 1969

  35. 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

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

  37. Data

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

  39. 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

  40. 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!

  41. Why I am doing this

  42. Fun Not fun Why I am doing this

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

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