aubrey de grey - sens
TRANSCRIPT
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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: [email protected]
MF site: http://www.methuselahfoundation.org/
Science site: http://www.sens.org/
Prize site: http://www.mprize.org/
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Shameless plug
Out now: $17.79 at Amazon
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Why I am doing this
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Fun Not fun
Why I am doing this
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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
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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
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Aging in a nutshell
Product of evolutionary neglect, not intent
Metabolism ongoingly causes “damage”
Damage eventually causes pathology
Pathology causes more pathology
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Strategies for intervention
Gerontology Geriatrics
Metabolism Damage Pathology
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How to make a car last 50 years-- plan A
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How to make a car last 50 years -- plan B
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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
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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
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Reasons for the engineering approach
- it targets initially inert intermediates (“damage”)
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Reasons for the engineering approach
- it targets initially inert intermediates (“damage”)
- damage is simpler than metabolism or pathology
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Problem 1: this is metabolism
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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
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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
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Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation
Damage rising with age It or its effects reversible by
Cell loss, cell atrophy Cell therapy, mainly
Extracellular junk Phagocytosis by immune stimulation
Extracellular crosslinks AGE-breaking molecules/enzymes
Death-resistant cells Suicide genes, immune stimulation
Mitochondrial mutations Allotopic expression of 13 proteins
Intracellular junk Transgenic microbial hydrolasesNuclear [epi]mutations (only cancer matters)
Telomerase/ALT gene deletion plus periodic stem cell reseeding
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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
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Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation
Damage rising with age It or its effects reversible by
Cell loss, cell atrophy Cell therapy, mainly
Extracellular junk Phagocytosis by immune stimulation
Extracellular crosslinks AGE-breaking molecules/enzymes
Death-resistant cells Suicide genes, immune stimulation
Mitochondrial mutations Allotopic expression of 13 proteins
Intracellular junk Transgenic microbial hydrolasesNuclear [epi]mutations (only cancer matters)
Telomerase/ALT gene deletion plus periodic stem cell reseeding
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Aggregates: major examples
- Proteins in neurodegeneration
- Oxysterols in atherosclerosis
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Autophagy in Alzheimer’s Disease
Calnexin
Dystrophic Neurites IEM
Cat D
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EndothelialCells
Lipid-engorgedLysosome
FoamCell
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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…
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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
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Environmental decontamination in vivo
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7KC over time in enrichment cultures
0
50
100
150
200
250
300
350
400
450
500
0 2 4 6 8 10
day
HPLC area [arbitrary units]
7-ketocholesterol degradation - a good start
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7-KC degradation - presented at meetings
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First MF-funded paper submitted
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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
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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
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Reasons for the engineering approach
- it targets initially inert intermediates (“damage”)
- damage is simpler than metabolism or pathology
- repairing damage buys time
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Age
Reserve
00
max
frail
Retarding aging: benefits modest
Halving rate of damage starting in middle age - doubles remaining healthspan
- raises total healthspan by maybe 20%
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Age
Reserve
00
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
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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
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Age
Reserve
00
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
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Age
Reserve
00
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
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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
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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
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Simulating aging(Phoenix & de Grey, AGE 2007; 29:133)
Metabolism ongoingly causes “damage”
and
Damage eventually causes pathologySo….
Simulations of aging (and intervention) should simulate damage accumulation
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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)
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Simulating damage: modelStructural 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
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Validation: age at death
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Results: how damage evolves
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Results: defeat of damageTherapies doubling in efficacy every 42 y
0 50 100 150 200 250 300 350
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Results: LEV in practiceTherapies doubling in efficacy every 42 y
0 50 100 150 200 250 300 350
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Age
Reserve
00
max
frail
LEV decreases with time
Fixing half the damage, then 2/3, then 3/4…. - still good enough…
- just like gravitational escape velocity
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Data
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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
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Funds: current status- $4.5M in Mprize pot
- Research pot being spent as fast as we fill it
- “LysoSENS” being funded (~$100k/yr) by 2005-2006 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)
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Eventual organisational structure
Medium-term goal: proof of concept in miceStrategy: 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
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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)
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Ramping up….
Level 3: funding of $3M-$20M per year guaranteed for at least five years. Grant applications solicited; 30-100 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 (50-150 FTEs); extramural research support as in Level 3 (100-350 FTEs)
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Why I am doing this
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Why I am doing this
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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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Shameless plug
Out now: $17.79 at Amazon