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:
[email protected] MF site: http://www.methuselahfoundation.org/ Science site: http://www.sens.org/
Prize site: http://www.mprize.org/
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Why I am doing this
Why I am doing this
Fun
Not fun
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
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
Aging in a nutshell Product of evolutionary neglect, 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 Specifics: the seven types of damage Intracellular junk/medical bioremediation Longevity escape velocity: concept Some evidence that LEV is realistic 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”) damage is simpler than metabolism or pathology
Problem 1: this is metabolism
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 middleaged 30 years of extra healthy life: Robust Human Rejuvenation Damage rising with age Cell loss, cell atrophy Extracellular junk Extracellular crosslinks Deathresistant cells Mitochondrial mutations Intracellular junk Nuclear [epi]mutations (only cancer matters)
It or its effects reversible by Cell therapy, mainly Phagocytosis by immune stimulation AGEbreaking molecules/enzymes Suicide genes, immune stimulation Allotopic expression of 13 proteins Transgenic microbial hydrolases Telomerase/ALT gene deletion plus periodic stem cell reseeding
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
Giving the middleaged 30 years of extra healthy life: Robust Human Rejuvenation Damage rising with age Cell loss, cell atrophy Extracellular junk Extracellular crosslinks Deathresistant cells Mitochondrial mutations Intracellular junk Nuclear [epi]mutations (only cancer matters)
It or its effects reversible by Cell therapy, mainly Phagocytosis by immune stimulation AGEbreaking molecules/enzymes Suicide genes, immune stimulation Allotopic expression of 13 proteins Transgenic microbial hydrolases Telomerase/ALT gene deletion plus periodic stem cell reseeding
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, energyrich 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…
Xenocatabolism: the concept
Graveyards: are abundant in human remains…
accumulate bones (which are not energyrich)… do not accumulate oxysterols, tau etc... so, should harbour microbes that degrade them whose catabolic enzymes could be therapeutic
Environmental decontamination in vivo
7ketocholesterol degradation a good start 7KC over time in enrichment cultures 500 450 400 350 300 250 200 150 100 50
HPLC area [arbitrary units] 0 0
2
4
6
day
8
10
7KC degradation presented at meetings
First MFfunded paper submitted
Steps to biomedical application 3) Isolate competent strains; select by starvation 4) Identify the enzymes (mutagenesis, chemistry, genomics) 5) Make lysosometargeted transgenes, assay cell toxicity 6) Assay competence in vitro (more mutagenesis/selection) 7) Construct transgenic mice, assay toxicity in vivo 8) Assay competence in disease mouse models 9) Test in humans as for lysosomal storage diseases
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
Reasons for the engineering approach it targets initially inert intermediates (“damage”) damage is simpler than metabolism or pathology 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
Reserve
hard easy
frail 0
0
Age
Fixing half the damage starting in middle age doubles total healthspan raises remaining healthspan maybe 5fold
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
Everimproving repair: better yet max
Reserve
very hard 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 sofarunfixable 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 sofarirreparable damage
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
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
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)*(1BASAL_H) + PB*BASAL_H
MEc,m: Exponential rate for each mechanism:
lognorm(EXP_M, EXP_SD)*(1EXP_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(t1)
Cumulative damage: D_Mc,m(t) = DI_Mc,m(t) + D_Mc,m(t1)
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_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
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
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
Funds: current status $4.5M in Mprize pot Research pot being spent as fast as we fill it “LysoSENS” being funded (~$100k/yr) by 20052006 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 Mediumterm 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 inhouse 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, 12 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 (13 projects/strand, 13 FTE/project)
Ramping up…. Level 3:
funding of $3M$20M per year guaranteed for at least five years. Grant applications solicited; 30100 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 (50150 FTEs); extramural research support as in Level 3 (100350 FTEs)
Why I am doing this
Why I am doing this
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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