Genetic and biomedical influences on the rate of aging:

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Genetic and biomedical influences on the rate of
aging why eating less isnt enough to turn rats
into bats, and what will work better Aubrey
D.N.J. de Grey Department of Genetics, University
of Cambridge email ag24_at_gen.cam.ac.uk Website
http//www.gen.cam.ac.uk/sens/
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• Structure of this talk
• Dont believe what you hear in the media
• A detailed plan to cure aging properly
• One component in more detail
• A dose of contemporary social context

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High-profile anti-aging strategies What you
know - Growth hormone, melatonin, DHEA, deprenyl
and more have been reported to extend rodent
lifespan but not reproducibly charlatans are
noisy but wrong What you may not - The
respectable segment of biogerontology is
currently, albeit unwittingly, doing the same
thing
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Caloric Restriction (CR) good news or bad? Rats
3 years Bats 30 years -) Rats 3 years CR
rats 4 years -) Worms 4 wks CR worms 5
wks -) !! Worms 4 wks Dauers 3 (6) mths -(
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Caloric restriction and its emulation CR extends
lifespan of virtually all species
tested Irritatingly, CR supports all theories of
aging Recent realisation who cares?! Lets
just get on and emulate it, with drugs Better
yet we know what key genes CR affects
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Wheres the catch? The good news There are sound
scientific reasons to predict that drugs of
this sort may work nearly as well as CR itself
does -- though not better The bad news There
are sound scientific reasons to predict that CR
itself will not work anything like as well in
humans as in rodents
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CR is an evolved response it is useful to be
able to prioritise survival over reproduction
when reproduction is temporarily futile. This
implicates the weather!
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So, now for something completely different
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Some definitions -- broader than you might
assume Metabolism the entire collection of
biochemical and cellular processes that keep us
alive from one day to the next (as opposed to
just oxygen consumption, as in metabolic
rate) Damage the entire collection of
physiological differences between n-year-olds and
(n10)-year-olds that give the latter a shorter
remaining life expectancy (as opposed to just
wear-and-tear damage such as oxidation) Aging
(from an interventionist perspective) Metabolism
Damage
Pathology
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Three paradigms for intervention Gerontology
Engineering Geriatrics Metabolism
Damage
Pathology Claim only the engineering
approach can achieve substantial extension of
human healthspan any time soon
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Metabolism Damage Pathology The
seven deadly things
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FAQ 1 How do you know that list is exhaustive?
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20 years is a suspiciously long time to find
nothing out
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FAQ 2 How do you know theres a threshold?
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An idealised (but not very) graph of the rate of
change of human physiology with age
0
20
40
60
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An idealised (but not very) graph of the rate of
change of human physiology with age
Development
Pathology
0
20
40
60
AGING
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FAQ 3 How close are we to fixing these things?
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We know how to fix all of them (in mice, in
principle!)
c c c
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We know how to fix all of them (in mice, in
principle!)
c c c
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• Lysosomal junk
• a casualty of aging is not a disease
• Lipofuscin. Universal marker of postmitotic cell
  aging reaches 10 of total cell mass in heart,
  motor neurons. But.... no proof of pathogenicity
• A2E. Agreed to be pathogenic (causes macular
  degeneration). But.... MD isnt life-threatening.

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• Neglected lysosomal junk
• 3) Oxidised cholesterol causes arterial
  macrophages to become foam cells, leading to
  atherosclerotic plaques. If they could degrade
  it, nearly all cardiovascular disease would be
  prevented and cured. No kidding this is the
  scientific consensus
• 4) Hyperphosphorylated tau in neurons. Probably
  a major cause of Alzheimers disease. Similar
  aggregates are seen in other neurodegenerative
  diseases and in normal aging.

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• Why dont graveyards fluoresce?
• de Grey 2002, Trends in Biotechnology 20452-455
• Bacterial strains exist with extremely versatile
  catabolic activities, and are being used by many
  groups for bioremediation purposes. They degrade
  rubber, TNT, PCBs, dioxins... Some fungi are
  similarly versatile.
• Lysosomal aggregates do not accumulate in the
  environment, even in areas rich in the remains of
  animals that make them. Thus, something degrades
  them. They are highly energy-rich, so microbes
  could live off them.
• Can micro-organisms capable of degrading
  lysosomal junk be isolated from the soil??

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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 models (apoE-/- mice,
  etc)
• Test in humans as for lysosomal storage diseases

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We know how to fix all of them (in mice, in
principle!)
Claim this means that robust mouse
rejuvenation could be achieved in 10 years
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FAQ 4 If so, why arent other biogerontologists
saying all this?
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The curious case of the catatonic
biogerontologists Straw polls at IABG 10,
22/Sept/2003 - Most biogerontologists think we
might be able to treble the remaining lifespan
of 2-yo mice in 10 years ( RMR) given enough
funding - But, most biogerontologists think we
shouldnt discuss large human life extension
publicly Are these views compatible?
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Will WOA begin in one decade, or two?
Claim 1 RMR will trigger the War On Aging Claim
2 Lack of funds could delay RMR by 10 years
Biogerontologists
Peer review, short-termism
Media
Ballot box
Government, industry
Voters, shareholders
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• How can the triangular logjam be broken?
• Claim probably most easily at the
  biogerontologists corner (few, bright)
• What are promising strategies?
• Logic
• Bribery

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Strategy 1 break down the wall of comfortable
academic fallacies de Grey 2003, Exp. Gerontol.
38 927-934 Theres no evidence that aging can
be appreciably altered Theres so much in
biology that we dont remotely understand Its
more important to compress morbidity Tyrants
will reign forever treatments will only be for
the rich The overpopulation crisis would be
unmanageable Replacing brain cells would
endanger continuance of identity We must say
nothing to cause optimism until we succeed in
mice Well be seen as charlatans failure will
rebound as loss of funding
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Strategy 2 remember that scientists will do
anything interesting for food
Biogerontologists
Philanthropy and Vision
Peer review, short-termism
Media
Ballot box
Voters, shareholders
Government, industry
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Proposal an Institute of Biomedical
Gerontology Remit to promote, co-ordinate and
fund the focused development of solidly
science-based rejuvenation biotechnologies such
as those I have discussed Basis 100m/year of
purely philanthropic funding would have a 90
chance of making enough progress in already
long-lived mice (therapy starting at 2/3 of life
expectancy giving three-fold greater remaining
lifespan), within 10 years, to change public
attitudes and open the WOA floodgates
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The Methuselah Mouse Prize
Biogerontologists
Philanthropy and Vision
Peer review, short-termism
Media
Ballot box
Voters, shareholders
Government, industry
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The Methuselah Mouse Prize
FAME
Biogerontologists
Philanthropy and Vision
Peer review, short-termism
Media
Ballot box
Voters, shareholders
Government, industry
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http//www.methuselahmouse.org/
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A closing word to anyone who doesnt believe my
timescales
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Lets roll
Website http//www.gen.cam.ac.uk/sens/ Email
ag24_at_gen.cam.ac.uk