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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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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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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
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
Aging in a nutshell Product of evolutionary nelect, not intent Metabolism ongoingly causes “damage” Damage eventually causes pathology Pathology causes more pathology
Strategies for intervention Gerontology Geriatrics Metabolism Damage Pathology
How to make a car last 50 years -- plan A
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
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
Reasons for the engineering approach • it targets initially inert intermediates (“damage”)
Reasons for the engineering approach • it targets initially inert intermediates (“damage”) • repairing damage buys time
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%
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
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
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…
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
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
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
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
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)
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
Results: defeat of damage Therapies doubling in efficacy every 42 y 0 50 100 150 200 250 300 350
Results: LEV in practice Therapies doubling in efficacy every 42 y 0 50 100 150 200 250 300 350
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
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
Reasons for the engineering approach • it targets initially inert intermediates (“damage”) • repairing damage buys time • damage is simpler than metabolism or pathology
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
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!
Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation
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
Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation
Aggregates: major examples - Proteins in neurodegeneration - Oxysterols in atherosclerosis
Autophagy in Alzheimer’s Disease Dystrophic Neurites IEM Calnexin Cat D
Endothelial Cells Lipid-engorged Lysosome Foam Cell
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…
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
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
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
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