Mutant mammals with normal lifespan:

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Mutant mammals with normal lifespan an
underappreciated resourse Aubrey D.N.J. de
Grey Department of Genetics, University of
Cambridge
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A self-evident truth
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A self-evident truth
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The tragedy of the negative result
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Biogerontologists abandon Popper at their
peril de Grey 2000, BioEssays 22206-207 Hypothes
is H the rate of process P limits (may
determine, but not necessarily -- call this
stronger version H) a given populations
maximum, mean lifespan Known fact process P
causes accumulation of marker M i.e. M is a
marker of a putative LS-limiting process,
MPLP) When and how can measurement of M falsify
H?
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One out of eight aint bad
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Successful shortening of LS uninformative

• M unchanged H not falsified (we harmed the
• organism, but so what? -- we failed to accelerate
  P, so we didn't even test H)
• M faster H not falsified (this was its
  prediction)

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Failed extension of LS uninformative

• M unchanged H not falsified (we didnt help the
• organism, but so what? -- we failed to retard P,
  so we didn't even test H)
• M slower H not falsified (though H is falsified)

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Successful extension of LS uninformative

• M unchanged H not falsified (we benefited the
• organism, but so what? -- we failed to retard P,
  so we didn't even test H we may have merely
  improved tolerance of M)
• M slower H not falsified (this was its
  prediction)

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Failed shortening of LS potentially informative!!

• M unchanged H not falsified (we didnt harm the
• organism, but so what? -- we failed to accelerate
  P, so we didn't even test H)
• M faster H falsified!! We accelerated P and the
• organism didnt care, so P does not limit its LS

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A seductively similar pair

• (A) Successful extension of lifespan, M unchanged
• (B) Failed shortening of lifespan, M accelerated
• In both cases, the organism survives a higher
  level of M than normal.
• Why does only (B) falsify H?
• In (A), M may still be key we may have just
  improved tolerance of M.
• In (B), for that to be true, our intervention
  must have been both good and bad for the
  organism speeding progression of M but improving
  tolerance of M! Occam would disapprove.

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Examples

• - TERC-/- several labs, all focusing on
  late-generation mice!
• - TERT-/- one Japanese lab
• - MnSOD/- a few US labs, but many things not
  reported
• - mtDNA deletions
• - lipofuscin accumulation
• - AGE, AGE precursor accumulation
• - telomere shortening
• - .......
• - CuZnSOD-/- one US lab
• - ECSOD-/- nobody
• masses of promising genetic alterations that
  have not been
• made, let alone tested, e.g. combinations of the
  above

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Conclusion Correlation does not imply
causation BUT non-correlation DOES imply
non-causation