prospects for defeating aging altogether aubrey d.n.j. de grey, ph.d. chairman and cso, methuselah...
TRANSCRIPT
![Page 1: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/1.jpg)
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/
![Page 2: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/2.jpg)
Semi-technical book
Out now: $17.79 at Amazon
![Page 3: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/3.jpg)
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
![Page 4: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/4.jpg)
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
![Page 5: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/5.jpg)
What is aging?
Metabolism always causes “damage”
Damage eventually causes pathology
![Page 6: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/6.jpg)
Strategies for intervention
Gerontology Geriatrics
Metabolism Damage Pathology
![Page 7: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/7.jpg)
Problem 1: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
![Page 8: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/8.jpg)
Problem 2: this is metabolism
![Page 9: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/9.jpg)
![Page 10: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/10.jpg)
If VW Bugs were built to last
![Page 11: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/11.jpg)
Maintained to last
![Page 12: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/12.jpg)
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
![Page 13: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/13.jpg)
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
![Page 14: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/14.jpg)
Reasons for the engineering approach
- it targets initially inert intermediates (“damage”)
![Page 15: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/15.jpg)
Reasons for the engineering approach
- it targets initially inert intermediates (“damage”)
- damage is simpler than metabolism or pathology
![Page 16: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/16.jpg)
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
![Page 17: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/17.jpg)
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
![Page 18: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/18.jpg)
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
![Page 19: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/19.jpg)
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
![Page 20: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/20.jpg)
Autophagy in Alzheimer’s Disease
Calnexin
Dystrophic Neurites IEM
Cat D
![Page 21: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/21.jpg)
EndothelialCells
Lipid-engorgedLysosome
FoamCell
![Page 22: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/22.jpg)
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…
![Page 23: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/23.jpg)
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
![Page 24: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/24.jpg)
Environmental decontamination in vivo
![Page 25: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/25.jpg)
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 promising start
![Page 26: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/26.jpg)
First MF-funded paper published
![Page 27: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/27.jpg)
O O
OH
O OOH O
7-ketocholesterolM = 400M13C = 401
Dione metabolite ?M = 398M13C = 399
Hydroxylated dione ?M = 414M13C = 415
Culture growing on7-ketocholesterol:
Culture growing on13C-labeled7-ketocholesterol:
Stable isotope labeling and LC/MS reveal 7-ketocholesterol metabolites in the culture supernatant
![Page 28: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/28.jpg)
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
![Page 29: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/29.jpg)
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
![Page 30: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/30.jpg)
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 hydrolasesNuclear [epi]mutations (only cancer matters)
Telomerase/ALT gene deletion plus periodic stem cell reseeding
![Page 31: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/31.jpg)
Reasons for the engineering approach
- it targets initially inert intermediates (“damage”)
- damage is simpler than metabolism or pathology
- repairing damage buys time
![Page 32: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/32.jpg)
Age
Reserve
00
max
frail
Progress avoids diminishing returns
Fixing half the damage, then 3/4, then 7/8…. - outpaces the so-far-unfixable damage…
- maintains healthspan indefinitely
![Page 33: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/33.jpg)
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
![Page 34: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/34.jpg)
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
![Page 35: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/35.jpg)
What rate of progress is realistic?
Data1903 1927
1949 1969
![Page 36: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/36.jpg)
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
![Page 37: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/37.jpg)
Results: LEV is very easyTherapies double efficacy only every 42y
0 50 100 150 200 250 300 350
![Page 38: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/38.jpg)
Data
![Page 39: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/39.jpg)
What this means:
The first 1000-year-old is probably less than 20 years younger than the first 150-
year-old
![Page 40: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/40.jpg)
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
![Page 41: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/41.jpg)
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!
![Page 42: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/42.jpg)
Why I am doing this
![Page 43: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/43.jpg)
Fun Not fun
Why I am doing this
![Page 44: 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:](https://reader036.vdocuments.us/reader036/viewer/2022062421/56649d0c5503460f949e03f2/html5/thumbnails/44.jpg)
Semi-technical book
Out now: $17.79 at Amazon