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 MF site: Science site: Prize site:

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Why I am doing this

Fun Not fun Why I am doing this

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

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

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

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

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

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

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

Age Reserve 0 0 max frail Infinitely better, in fact 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 hasN_MECH: The number of mechanisms in each category MECH_WEIGHT m : The contribution of a mechanism to a category Fitting parameters BASAL_M: The mean basal damage rateBASAL_SD: The standard deviation of the basal damage rate BASAL_H: The homogeneity of basal damage rate in a single personEXP_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 challengeFATAL_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) MB c,m :Basal rate for each mechanism: lognorm(BASAL_M, BASAL_SD)*(1-BASAL_H) + PB*BASAL_H ME c,m : Exponential rate for each mechanism: lognorm(EXP_M, EXP_SD)*(1-EXP_H) + PE*EXP_H D_M c,m : Cumulative damage for each mechanism: 0D_C c : 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_C c (t) Damage increment: DI_M c,m (t) = MB c,m + ME c,m *PD(t-1) Cumulative damage: D_M c,m (t) = DI_M c,m (t) + D_M c,m (t-1) Cumulative category damage: D_C c (t) = [SUM m=1..N_MECH] DI_M c,m (t) Fatality challenge: FATAL(t) = |norm(FATAL_M, FATAL_SD)| If D_C c (t) > FATAL(t) for any c, the person dies at age t

Validation: age at death

Results: how damage evolves

Results: defeat of damage Therapies doubling in efficacy every 42 y

Results: LEV in practice Therapies doubling in efficacy every 42 y

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

Data

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 1: this is metabolism

Problem 2: 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

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

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

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 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

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

Autophagy in Alzheimer’s Disease Calnexin Dystrophic NeuritesIEM 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…

R 1 da y 20 R 5 da y 20 R 1 da y 36 R 2 da y 36 R 3 da y 36 R 1 da y 71 R 2 da y 71 R 3 da y 71 R 4 da y 71 R 5 da y R 4 da y 36 R 5 da y 36 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

Environmental decontamination in vivo

7-ketocholesterol degradation - a good start

7-KC degradation - presented at meetings

First MF-funded paper submitted

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

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

Funds: current status -$4.5M in Mprize pot -Research pot being spent as fast as we fill it -“LysoSENS” being funded (~$100k/yr) by donations to the MF -“MitoSENS” being funded (~$150k/yr) by Peter Thiel’s donation of $500k -Thiel’s challenge pledge ($3M) is 1:2; our next goal is to match it in full (i.e. raise $6M)

Eventual organisational structure Medium-term goal: proof of concept in mice Strategy: solve/combine subgoals (SENS) Procedure: - implement subgoals: ~350 people - scientifically interesting and respected - best done extramurally by academics - combine in same mice: ~150 people - scientifically tedious and unrewarded - best done in-house by paid technicians

Ramping up…. Level 1: funding of up to $300k per year guaranteed for at least 3 years. (This is where we are now.) Selected SENS strands supported at entry level (1 project/strand, 1-2 FTEs/project) Level 2: funding of $300k-$3m per year, three years. (This is where we will be when the Thiel pledge is fully matched.) Six SENS strands supported at minimal level (1-3 projects/strand, 1-3 FTE/project)

Ramping up…. Level 3: funding of $3M-$20M per year guaranteed for at least five years. Grant applications solicited; FTEs funded, across up to 30 projects Level 4: funding of $20M-$100M per year, ten years. Physical facility (“Institute for Biomedical Gerontology”) set up ( FTEs); extramural research support as in Level 3 ( FTEs)

Why I am doing this

I offer no apology for using media interest in life extension to make the biology of ageing an exception to Planck’s observation that science advances funeral by funeral: lives, lots of them, are at stake. de Grey 2005, EMBO Reports 6(11):1000

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