Transcript Document

Prospects for defeating
aging altogether
Aubrey D.N.J. de Grey, Ph.D.
Chairman and CSO, Methuselah Foundation
Lorton, VA, USA and Cambridge, UK
Email: [email protected]
Website: http://www.mfoundation.org/
Semi-technical book
Out now:
$17.79 at
Amazon
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
What is aging?
Metabolism always causes “damage”
Damage eventually causes pathology
Strategies for intervention
Gerontology
Metabolism
Geriatrics
Damage
Pathology
Problem 1:
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
Problem 2: this is metabolism
If VW Bugs were built to last
Maintained to last
Strategies for intervention
Gerontology
Metabolism
Engineering
Damage
Geriatrics
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
This is the damage
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
No new type of damage identified since 1982!
Giving the middle-aged
30 years of extra healthy life:
Robust Human Rejuvenation
Damage rising with age
Cell loss, cell atrophy
Extracellular junk
Extracellular crosslinks
It or its effects reversible by
Cell therapy, mainly
Phagocytosis by immune stimulation
AGE-breaking molecules/enzymes
Death-resistant cells
Mitochondrial mutations
Intracellular junk
Nuclear [epi]mutations
(only cancer matters)
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 middle-aged
30 years of extra healthy life:
Robust Human Rejuvenation
Damage rising with age
Cell loss, cell atrophy
Extracellular junk
Extracellular crosslinks
It or its effects reversible by
Cell therapy, mainly
Phagocytosis by immune stimulation
AGE-breaking molecules/enzymes
Death-resistant cells
Mitochondrial mutations
Intracellular junk
Nuclear [epi]mutations
(only cancer matters)
Suicide genes, immune stimulation
Allotopic expression of 13 proteins
Transgenic microbial hydrolases
Telomerase/ALT gene deletion plus
periodic stem cell reseeding
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, 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
7-ketocholesterol degradation - a promising start
HPLC area [arbitrary
units]
7KC over time in enrichment cultures
500
450
400
350
300
250
200
150
100
50
0
0
2
4
6
day
8
10
First MF-funded paper published
Stable isotope labeling and LC/MS reveal 7-ketocholesterol metabolites in the culture supernatant
7-ketocholesterol
M = 400
M13C = 401
Hydroxylated dione ?
M = 414
M13C = 415
Dione metabolite ?
M = 398
M13C = 399
OH
HO
Culture growing on
7-ketocholesterol:
Culture growing on
13C-labeled
7-ketocholesterol:
O
O
O
O
O
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
Only 30 years?!
Hardly “defeating aging”…
Damage rising with age
Cell loss, cell atrophy
Extracellular junk
Extracellular crosslinks
It or its effects reversible by
Cell therapy, mainly
Phagocytosis by immune stimulation
AGE-breaking molecules/enzymes
Death-resistant cells
Mitochondrial mutations
Intracellular junk
Nuclear [epi]mutations
(only cancer matters)
Suicide genes, immune stimulation
Allotopic expression of 13 proteins
Transgenic microbial hydrolases
Telomerase/ALT gene deletion plus
periodic stem cell reseeding
Reasons for the
engineering approach
- it targets initially inert intermediates (“damage”)
- damage is simpler than metabolism or pathology
- repairing damage buys time
Progress avoids diminishing returns
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
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
What rate of progress is realistic?
1903
1949
Data
1927
1969
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
Results: LEV is very easy
Therapies double efficacy only every 42y
0
50
100
150
200
250
300
350
Data
What this means:
The first 1000-year-old
is probably less than
20 years younger than
the first 150-year-old
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
The Methuselah Foundation
- $4.5M in Mprize pot
- $7M donated/pledged for research
- Current research support ~$2M/year
- Growth >2x/year since MF’s formation
- Ideal budget $100M/year (500 scientists)
- Proof of concept (mice) probably <10y away
Bottom line:
It’s going well, and it’s pretty cheap!
Why I am doing this
Why I am doing this
Fun
Not fun
Semi-technical book
Out now:
$17.79 at
Amazon