The feasibility and desirability of
indefinite youth: recent advances
from unexpected quarters
Aubrey de Grey
Department of Genetics, University of Cambridge
Email: ag24@gen.cam.ac.uk
Website: http://www.gen.cam.ac.uk
Structure of this talk
Feasibility
- the “seven deadly things”
- help from organisms with no aging problem
Desirability
- a lifelong skeptic thinks for himself
- repugnance: pros and cons
- religion’s Achilles heel: lack of apathy
- and more…
FAQ #1:
What is your big idea?
Aging in a nutshell
Metabolism (the hugely messy network of
homeostatic processes that keep us alive)
causes
Pathology (the hugely messy network of
antihomeostatic processes that kill us)
This is not controversial -- indeed, it is
why most biogerontologists think there’s
little hope of curing aging for ages
A very simple observation
Aging is indisputably a side-effect of essential
biochemical and cellular processes
BUT
Its functional effect (loss of performance) is delayed
Putting it another way:
Being alive must have immediate side-effects, since
metabolically active molecules are short-lived
BUT
Those effects must accumulate, and have a
threshold level below which they are harmless
Aging in slightly less of a
nutshell
Metabolism ongoingly causes damage
whereas
Damage only eventually causes pathology
This turns out to be very useful
Three paradigms for intervention
Gerontology
Metabolism
Engineering
Damage
Geriatrics
Pathology
Claim: only the “engineering” approach
can achieve substantial extension of
human healthspan any time soon
FAQ #2:
That’s all a bit abstract
and theoretical, innit?
Engineer
Geriatrician
Gerontologist
FAQ #3:
Yes, but that’s just an
analogy: why believe it?
Metabolism
Damage
Pathology:
The seven deadly things
Respiration
(oxidation)
Carbohydrate
metabolism
(glycation)
Cell turnover
Cell loss/atrophy Neurodegeneration
Nuclear mutations
and epimutations Atherosclerosis
mtDNA mutations Cancer
Senescent cells
Diabetes
(mutations,
Hormone decline
AGE crosslinks
telomere
shortening,
Blindness
Extracellular
junk
dysregulation,
stem cell
Immune decline
Lysosomal junk
depletion)
Etc, etc, etc
Er.... that’s it! Etc, etc, etc
FAQ #4:
How do you know this
list is complete?
20 years is an instructively long
time to find nothing out
Damage rising w/ age
Cell loss, cell atrophy
Extracellular junk
Extracellular crosslinks
Senescent cells
Mitoch. mutations
Proposed as contributing to aging by
Brody (1955) or earlier
Alzheimer (1907)
Monnier and Cerami (1981)
Hayflick (1965)
Harman (1972)
Lysosomal junk
Strehler (1959) or earlier
Nuclear [epi]mutations
(only cancer matters) Szilard (1959) and Cutler (1982)
20 years is an instructively long
time to find nothing out
Damage rising w/ age
Cell loss, cell atrophy
Extracellular junk
Extracellular crosslinks
Senescent cells
Mitoch. mutations
Proposed as contributing to aging by
Brody (1955) or earlier
Alzheimer (1907)
Monnier and Cerami (1981)
Hayflick (1965)
Harman (1972)
Lysosomal junk
Strehler (1959) or earlier
Nuclear [epi]mutations
(only cancer matters) Szilard (1959) and Cutler (1982)
Mitochondrial biogenesis: ripe for tweaking
de Grey 2000, Trends in Biotechnology 18:394-399
13 genes
Mitochondrial DNA
Mitochondrion
Nucleus
Nuclear DNA
Messenger RNA
Protein
35
RNAs
13
genes
~1000 .
RNAs
13
proteins
Synthesis
Transport
~1000 .
proteins
(and a few
RNAs)
Mol. biology
Is it really that easy? No, but....
Gearing 1986: one small protein relocated in yeast
Nagley 1988: shown to be functional
Galanis 1991: a second small protein relocated in yeast
Lander/Lodish 1990: suggestion of therapeutic potential
Zullo 2000 (after 9 years): one big protein in rodent cells
Manfredi 2001 (after 6 years): same one in human cells
Guy 2002 (after 1 year): a different one in human cells
Clues from very unexpected quarters
1990: Chlamydomonas reinhardtii mito. genome sequenced
SIX of the “dirty baker’s dozen” missing!
Feb 1998: NONE cloned; AdG starts complaining about this
July 1998: King/Gonzalez-Halphen collaboration begins
~2001: C. reinhardtii COX2, COX3, ATP6, ND4L cloned
2002: C.r. ATP6 found to work unaltered in human cells
1991: Vigna radiata COX2 cloned
2002: importability found to depend on TWO a.a. changes
Steps to biomedical application
1) Derive 13 cell lines, each mutant for just one protein
2) Develop constructs that rescue respiration in these cells
3) Combine all 13, seek respiration without any mtDNA
4) Assay competence in mice using germline transformation
5) Assay competence in mice using somatic gene therapy
--- to get to here should take 6-8 years --6) Test in humans as for mitochondriopathies
A taster of tomorrow’s talk
- Lysosomal junk causes atherosclerosis, macular
degeneration and most -- if not all -- forms of
neurodegeneration
- It accumulates because we lack enzymes to break
it down
- Such enzymes seem to exist in some soil bacteria!
- As with plant mitochondrial genes, these can in
principle be exploited therapeutically
Desirability
Convincing the world that aging is bad:
futile until we really rejuvenate mice?
Desirability
breaking the global trance
Trance?
Consider some standard excuses for condemning
100,000 people to death, every day, forever:
“Wouldn’t it be crushingly boring?”
“How would we pay the pensions?”
“What about starving African children?”
“Dictators would rule forever!”
Claim: nobody is really that dumb
-- they MUST be in a trance
A heartening convert
Who's Afraid of Life Extension?
Harry R. Moody, Institute for Human Values in Aging International
Longevity Center-USA
When I began to prepare to write this article, I was clear
and confident about my direction. Anti-aging
technologies, I was sure, are a snare and a delusion … It
is a line of thought I have held for many years …
But the more I thought about my skepticism and hostility
to life-extension technology, the more uneasy I became.
Gradually, as I reflected on my uneasiness, I found it
more and more difficult to rationalize my strong rejection
of life extension.
Yes, Harry Moody said this
… within mainstream gerontology, anti-aging medicine
is widely viewed with hostility and skepticism (an
incipient form of “gerontological correctness”?). But we
are entitled to wonder: Are the arguments against antiaging medicine valid, or are the opponents of anti-aging
medicine (including me) simply gerontological Luddites?
If one lifelong opponent can wake HIMSELF up,
there is hope yet…
Another unexpected ally (eventually…):
the wisdom of repugnance
“Offensive.” “Grotesque.” “Revolting.” “Repugnant.” “Repulsive."
These are the words most commonly heard regarding the prospect of
human cloning. .... Even Dolly's creator has said he "would find it
offensive" to clone a human being.
Revulsion is not an argument; and some of yesterday's repugnances
are today calmly accepted -- though, one must add, not always for the
better. In crucial cases, however, repugnance is the emotional
expression of deep wisdom, beyond reason's power fully to articulate.
Would anybody's failure to give full rational justification for his or
her revulsion at these practices make that revulsion ethically suspect?
Not at all. On the contrary, we are suspicious of those who think that
they can rationalize away our horror
Leon Kass, 1997, “The Wisdom of Repugnance”
Why is this useful?
Traditional
Keeps the
numbers down
Fundamentally
barbaric
Fox
hunting
Human
aging






Why is this useful?
1) Leon Kass said it
2) Our wisdom about aging is precisely a
wisdom of repugnance -- well, mine is…
3) Repugnance can go down as well as up
Another unlikely ally in the making:
A4M
- Business: promoting “anti-aging” products
- Policy: “open-mindedness” -- anyone can buy
a stall at the expo right next to the meeting,
sell magnetic water or whatever, and they do
- Interpretation: profit first, efficacy second
- Resulting reputation: oiliest of the snakes
My abstract, intro at the A4M-funded
Singapore conference 6 weeks ago
“Anti-aging medicine does not currently exist, in
the sense in which the term ‘medicine’ is generally
used. Medicine is biomedical technology that, at
least for most recipients, effectively treats the
primary symptoms of the condition against which
it is claimed to act. The primary symptom of aging
is indisputably death, and no existing product
appreciably delays death from aging.”
And what happened?
- Bob Goldman cornered me for an hour to discuss
how we can work together
- I was asked to give a similar talk at A4M in Las
Vegas in December
- Ditto an A4M-sponsored conference in London
in September
One simple interpretation: I am in the
ascendancy, hence a good ally to have
Why did I accept (“academic suicide”)?
Why am I taking this risk?
1) The anti-A4M movement (Olshansky, Hayflick)
is backfiring, because everyone who sells
anything downplays its flaws - hence their
criticism is not considered fair
2) The “A4M community” are in much less of a
pro-aging trance than most people
3) They are numerous and their customers quite
affluent
4) They want their business to last long-term
The rational theist
Points to be carefully noted:
1) Fundamentalists (very numerous, very powerful)
do, in the end, follow the doctrine as it evolves
2) God deprecates hastening death, however good
the afterlife is claimed to be
3) God also deprecates apathy
The most invulnerable to the life-extension crusade is
“Yes, we should cure aging ASAP, but I don’t feel like it”
The hope that dare not speak its name
1) Little known fact: Len Hayflick looks after his health
2) Phenomena not to be ignored:
- Death penalty abolished throughout Europe
- Vietnam war rather less popular than WWII
- Britain banned gun ownership after one mass murder
- No war in Western Europe for 59 years - not seen
since Roman times
- Canada (and Norway, etc)
Let’s roll
ag24@gen.cam.ac.uk
http://www.gen.cam.ac.uk/sens/
http://www.methuselahmouse.org/