Prospects for defeating aging altogether

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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 aubrey_at_sens.org Website
http//www.mfoundation.org/
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Semi-technical book
Out now 17.79 at Amazon
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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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What is aging? Metabolism always causes
damage Damage eventually causes pathology
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Strategies for intervention Gerontology
Geriatrics Metabolism
Damage Pathology
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Problem 1this is the pathology

• Alzheimers
• Stroke
• Sarcopenia
• Osteoarthritis
• Hormonal Imbalance
• Kidney Failure

• Cancer
• Heart Disease
• Diabetes
• Incontinence
• Osteoporosis
• Macular Degeneration

• Parkinsons
• Pneumonia
• Emphysema
• Sex Drive
• and LOTS more

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Problem 2 this is metabolism
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(No Transcript)
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If VW Bugs were built to last
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Maintained to last
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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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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!
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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 hydrolases
Nuclear epimutations (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 hydrolases
Nuclear epimutations (only cancer matters) Telomerase/ALT gene deletion plus periodic stem cell reseeding
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Autophagy in Alzheimers 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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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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7-ketocholesterol degradation - a promising start
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First MF-funded paper published
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Stable isotope labeling and LC/MS reveal
7-ketocholesterol metabolites in the culture
supernatant
Hydroxylated dione ? M 414 M13C 415
7-ketocholesterol M 400 M13C 401
Dione metabolite ? M 398 M13C 399
Culture growing on 7-ketocholesterol
Culture growing on 13C-labeled 7-ketocholesterol
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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
• 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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Only 30 years?! Hardly defeating aging
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 hydrolases
Nuclear epimutations (only cancer matters) Telomerase/ALT gene deletion plus periodic stem cell reseeding
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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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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
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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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What rate of progress is realistic? Data
1903 1927
1949 1969
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Simulating aging (Phoenix de Grey, AGE 2007
29133) Metabolism ongoingly causes
damage and Damage eventually causes
pathology So. Simulations of aging (and
intervention) should simulate damage accumulation
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Results LEV is very easy Therapies double
efficacy only every 42y
0 50 100 150
200 250 300 350
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Data
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What this means The first 1000-year-old
is probably less than 20 years younger
than the first 150-year-old
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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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• The Methuselah Foundation
• 4.5M in Mprize pot
• 7M donated/pledged for research
• Current research support 2M/year
• Growth gt2x/year since MFs formation
• Ideal budget 100M/year (500 scientists)
• Proof of concept (mice) probably lt10y away
• Bottom line
• Its going well, and its pretty cheap!

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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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Semi-technical book
Out now 17.79 at Amazon