Download AGING Dr Aubrey de Grey Chief Science Officer

Regenerative medicine for aging:
are we reaching the knee of the
exponential curve?
Aubrey D.N.J. de Grey, Ph.D.
Chief Science Officer, SENS Foundation
[email protected]
http://www.sens.org/
Dr Aubrey de Grey
Chief Science Officer
SENS Foundation
SENS Foundation is a US-registered
charity that works to develop, promote
and enable widespread access to
regenerative medicine solutions to the
disabilities and diseases of…
AGING
Dr Aubrey de Grey
Chief Science Officer
But surely <insert favourite
knee-jerk reaction>?
-
Treating aging is just preventative geriatrics
-
Old people are people too, deserve health
-
Is medicine good only so long as it doesn’t
work very well?
-
Was the Industrial Revolution a bad thing?
-
How much did Jenner/Pasteur understand?
Dr Aubrey de Grey
Chief Science Officer
What is…
- Regenerative medicine?
- Aging?
Dr Aubrey de Grey
Chief Science Officer
What is regen med?
Any intervention that seeks
to restore the structure of a
tissue/organ to its state
before it suffered damage
Dr Aubrey de Grey
Chief Science Officer
What is aging?
Metabolism
ongoingly causes “damage”.
Damage
eventually causes pathology.
Dr Aubrey de Grey
Chief Science Officer
Options for intervention
Gerontology
Metabolism
Geriatrics
Damage
Pathology
Dr Aubrey de Grey
Chief Science Officer
Problem: this is metabolism
Dr Aubrey de Grey
Chief Science Officer
Options for intervention
Gerontology
Maintenance
Geriatrics
Metabolism
Damage
Pathology
Claim: unlike the others, the maintenance approach may
achieve a big extension of human healthy lifespan quite soon.
Dr Aubrey de Grey
Chief Science Officer
This is the damage
Seven
Deadly
Things
Cell loss, cell atrophy
Division-obsessed cells (cancer)
Death-resistant cells
Mitochondrial mutations
Intracellular junk
Extracellular junk
Extracellular crosslinks
No new type of damage confirmed since 1982!
Dr Aubrey de Grey
Chief Science Officer
Giving the middle-aged 30 years of extra healthy life:
Robust Human Rejuvenation
Damage rising with age
Cell loss, cell atrophy
Division-obsessed cells
(i.e. cancer)
Death-resistant cells
It or its effects reversible by
Cell therapy, mainly
Telomerase/ALT gene deletion plus
periodic stem cell reseeding
Suicide genes, immune stimulation
Mitochondrial mutations Allotopic expression of 13 proteins
Intracellular junk
Extracellular junk
Extracellular crosslinks
Transgenic microbial hydrolases
Phagocytosis by immune stimulation
AGE-breaking molecules/enzymes
Dr Aubrey de Grey
Chief Science Officer
Giving the middle-aged 30 years of extra healthy life:
Robust Human Rejuvenation
Some parts are in clinical trials
Damage rising with age
Cell loss, cell atrophy
Division-obsessed cells
(i.e. cancer)
Death-resistant cells
It or its effects reversible by
Cell therapy, mainly
Telomerase/ALT gene deletion plus
periodic stem cell reseeding
Suicide genes, immune stimulation
Mitochondrial mutations Allotopic expression of 13 proteins
Intracellular junk
Extracellular junk
Extracellular crosslinks
Transgenic microbial hydrolases
Phagocytosis by immune stimulation
AGE-breaking molecules/enzymes
Dr Aubrey de Grey
Chief Science Officer
About those amyloid trials…
- Clinical endpoints not achieved
- Amyloid is removed
- Tau is not
- No one knows what causes what in AD
- Combination therapies = wings + engine
Dr Aubrey de Grey
Chief Science Officer
Giving the middle-aged 30 years of extra healthy life:
Robust Human Rejuvenation
Other parts are making headlines
Damage rising with age
Cell loss, cell atrophy
Division-obsessed cells
(i.e. cancer)
Death-resistant cells
It or its effects reversible by
Cell therapy, mainly
Telomerase/ALT gene deletion plus
periodic stem cell reseeding
Suicide genes, immune stimulation
Mitochondrial mutations Allotopic expression of 13 proteins
Intracellular junk
Extracellular junk
Extracellular crosslinks
Transgenic microbial hydrolases
Phagocytosis by immune stimulation
AGE-breaking molecules/enzymes
Dr Aubrey de Grey
Chief Science Officer
Dr Aubrey de Grey
Chief Science Officer
Giving the middle-aged 30 years of extra healthy life:
Robust Human Rejuvenation
Others are early but exciting
Damage rising with age
Cell loss, cell atrophy
Division-obsessed cells
(i.e. cancer)
Death-resistant cells
It or its effects reversible by
Cell therapy, mainly
Telomerase/ALT gene deletion plus
periodic stem cell reseeding
Suicide genes, immune stimulation
Mitochondrial mutations Allotopic expression of 13 proteins
Intracellular junk
Extracellular junk
Extracellular crosslinks
Transgenic microbial hydrolases
Phagocytosis by immune stimulation
AGE-breaking molecules/enzymes
Dr Aubrey de Grey
Chief Science Officer
Intracellular junk in the artery
Endothelial Cells
Lipidengorged
Lysosome
Foam
Cell
Dr Aubrey de Grey
Chief Science Officer
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 that 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…
Dr Aubrey de Grey
Chief Science Officer
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
Dr Aubrey de Grey
Chief Science Officer
Environmental decontamination
in vivo
Dr Aubrey de Grey
Chief Science Officer
7-ketocholesterol degradation
a promising start
7KC over time
in enrichment
7KC
over time in cultures
enrichment
cultures
units]
500
450
400
350
300
250
200
150
100
50
0
0
2
4
6
day
8
days
10
Biodegradation 2008; 19(6):807-813
Dr Aubrey de Grey
Chief Science Officer
Stable isotope labelling and LC/MS reveal 7-ketocholesterol
metabolites in the culture supernatant
7-ketocholesterol
M = 400, M13C = 401
Dione metabolite ?
M = 398, M13C = 399
Hydroxylated dione ?
M = 414, M13C = 415
OH
HO
O
O
O
O
O
Culture growing on
7-ketocholesterol
Culture growing on
13C-labeled
7-ketocholesterol
Dr Aubrey de Grey
Chief Science Officer
COX/LAMP1 co-localizes with AO
Acridine Orange
EGFP
Merge
Dr Aubrey de Grey
Chief Science Officer
pEGFP-COXL1 transfected cells are
protected from 7KC-induced toxicity
Mathieu et al., Biotechnol. Bioeng. 2012; 109(9):2409-2415
Dr Aubrey de Grey
Chief Science Officer
neural retina
RPE
Age-related accumulation of
fluorescent compounds in
retinal pigment epithelium
Dr Aubrey de Grey
Chief Science Officer
Fundus autofluorescence (= RPE lipofuscin) increases with age
Exc.: 550 nm
Individually corrected for lens absorption
Delori et al., IOVS 42:1855. 2001
Dr Aubrey de Grey
Chief Science Officer
MOD FA
A major constitutent of RPE lipofuscin is the
fluorescent pigment A2E
Eldred and Lasky, 1993
Sakai et al., 1996
Parish et al., 1998
Dr Aubrey de Grey
Chief Science Officer
A2E
pyridinium bisretinoid
Sakai, Decatur, Nakanishi and Eldred, 1996
Dr Aubrey de Grey
Chief Science Officer
Amphiphilic compound
2 hydrophobic
side-arms
cationic
polar head
Cl -
Cl -
A2E
iso-A2E
Dr Aubrey de Grey
Chief Science Officer
Dr Aubrey de Grey
Chief Science Officer
Dr Aubrey de Grey
Chief Science Officer
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.
Dr Aubrey de Grey
Chief Science Officer
A word about “MetaSENS”
-
SENSF does research to implement SENS
-
But is that enough? Three reasons why not:
-
Is SENS complete? (Vijg lab): “prot pleio”
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Is SENS needed? (Reis lab): “weather”
<cue interminable digression re primate CR>
-
What will SENS cause? (Hughes group)
Dr Aubrey de Grey
Chief Science Officer
Learn more
Read the (semi-technical) book.
Available at Amazon and all good book stores.
Paperback is cheaper, and has an extra chapter!
Visit us on the web at
http://www.sens.org/
Drop us a line at
[email protected]
Dr Aubrey de Grey
Chief Science Officer
SENS Foundation
SENS Foundation works to develop, promote and ensure
widespread access to regenerative medicine solutions to the
disabilities and diseases of aging.
www.sens.org
[email protected]
Dr Aubrey de Grey
Chief Science Officer