Aubrey de Grey - SENS

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: aubrey@sens.org

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

Fun Not fun

Why I am doing this

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

• 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 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

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 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

Aggregates: major examples

- Proteins in neurodegeneration

- Oxysterols in atherosclerosis

Autophagy in Alzheimer’s Disease

Calnexin

Dystrophic Neurites IEM

Cat D

EndothelialCells

Lipid-engorgedLysosome

FoamCell

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…

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

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

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

- 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

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%

Age

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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

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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

Age

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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

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

- 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 pathologySo….

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: 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

Validation: age at death

Results: how damage evolves

Results: defeat of damageTherapies doubling in efficacy every 42 y

0 50 100 150 200 250 300 350

Results: LEV in practiceTherapies doubling in efficacy every 42 y

0 50 100 150 200 250 300 350

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

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 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)

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

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; 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)

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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