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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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slide1
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/

slide2
Shameless plug

Out now: $17.79 at Amazon

slide4
Fun Not fun

Why I am doing this

slide5
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
slide6
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
slide7
Aging in a nutshell

Product of evolutionary nelect, not intent

Metabolism ongoingly causes “damage”

Damage eventually causes pathology

Pathology causes more pathology

slide8
Strategies for intervention

Gerontology Geriatrics

Metabolism Damage Pathology

slide11
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

slide12
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
slide13
Reasons for the engineering approach
  • it targets initially inert intermediates (“damage”)
slide14
Reasons for the engineering approach
  • it targets initially inert intermediates (“damage”)
  • repairing damage buys time
slide15
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%

slide16
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

slide17
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

slide18
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…

slide19
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

slide20
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

slide21
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
slide22
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

slide23
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)
slide24
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

slide27
Results: defeat of damage

Therapies doubling in efficacy every 42 y

0 50 100 150 200 250 300 350

slide28
Results: LEV in practice

Therapies doubling in efficacy every 42 y

0 50 100 150 200 250 300 350

slide29
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

slide31
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
slide32
Reasons for the engineering approach
  • it targets initially inert intermediates (“damage”)
  • repairing damage buys time
  • damage is simpler than metabolism or pathology
slide34
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
slide35
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!

slide36
Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation
slide37
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
slide38
Giving the middle-aged 30 years of extra healthy life: Robust Human Rejuvenation
slide39
Aggregates: major examples

- Proteins in neurodegeneration

- Oxysterols in atherosclerosis

slide40
Autophagy in Alzheimer’s Disease

Dystrophic Neurites

IEM

Calnexin

Cat D

slide41
Endothelial

Cells

Lipid-engorged

Lysosome

Foam

Cell

slide42
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…
slide43
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

slide44
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

slide49
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

slide50
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
slide51
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)
slide52
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
slide53
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)

slide54
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)

slide57
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

slide58
Shameless plug

Out now: $17.79 at Amazon

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