Prospects for extending healthy life - a lot
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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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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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Fun Not fun

Why I am doing this


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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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  • 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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Aging in a nutshell

Product of evolutionary nelect, 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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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

  • 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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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%


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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


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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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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…


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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


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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

  • 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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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


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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: 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




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Results: defeat of damage

Therapies doubling in efficacy every 42 y

0 50 100 150 200 250 300 350


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Results: LEV in practice

Therapies doubling in efficacy every 42 y

0 50 100 150 200 250 300 350


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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



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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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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


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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!


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


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


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Aggregates: major examples

- Proteins in neurodegeneration

- Oxysterols in atherosclerosis


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Autophagy in Alzheimer’s Disease

Dystrophic Neurites

IEM

Calnexin

Cat D


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Endothelial

Cells

Lipid-engorged

Lysosome

Foam

Cell


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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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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


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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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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


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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 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


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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

    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


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