The plasma membrane redox system: proaging and antiaging roles

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The plasma membrane redox system pro-aging and
anti-aging roles Aubrey 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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• Breathing is bad for you
• Rubner, Loeb, Pearl longevity correlates with
  slow oxygen consumption (albeit modulatable by
  extrinsic mortality Kirkwood, Austad)
• Harman 1956 This is because oxygen can be
  converted to superoxide and other reactive oxygen
  species (ROS)
• Harman 1972 especially in mitochondria (source,
  hence target, of ROS)
• Sacher 1977 this may bear on why caloric
  restriction (CR) extends life
• Bandy/Davidson 1990 the vicious cycle theory

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The vicious cycle theory
Very faulty respiration Even more
free radicals Even more mtDNA damage

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Müller-Höcker 1990, J Neurol Sci 10014
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• Evidence against MiFRA
• Cortopassi 1990, others most tissues have lt0.1
  deleted (hence clear loss-of-function) mtDNA
• Methods questioned, but results later confirmed
  by safer methods (Müller-Höcker 1993, 1996)
• One exception substantia nigra (Corral-Debrinski
  1992, Itoh 1996) with 10 dysfunctional mtDNA
• Point mutations in non-coding mtDNA much more
  abundant (Attardi lab), but functional impairment
  not proven

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Clonal expansion, not vicious cycle
Brierley et al 1998, Ann Neurol 43217
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• Might the mtDNA be a decoy?
• - Comfort 1974 mitochondria are recycled about
  monthly, even in non-dividing cells. Hence,
  damage cannot accumulate
• - de Grey 1997 they accumulate because of mtDNA
  damage, which slows OXPHOS, so membrane damage.
  However, other damage (to lipids, proteins)
  indeed cannot accumulate
• - Brunk 1992, 1998 it cannot accumulate in
  mitochondria, but maybe in accumulates in
  lysosomes (the mitochondrial graveyard)

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• Does rarity prove harmlessness?
• - Aiken lab 1998 selective atrophy of mt-mutant
  muscle fibre segments. Whole fibre may die due
  to denervation!
• - de Grey 1998 Reductive Hotspot Hypothesis.
  Metabolic reorganisation for survival may cause
  extracellular free radical production,
  contaminating circulating lipoproteins and hence
  mt-normal cells.

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• 2004 An over-hasty about-turn?
• - Trifunovic 2004 accelerated mutation (mutant
  DNA polymerase) in mice causes faster aging!
• - Pro-MiFRA diverse symptoms of aging seen
• - Anti-MiFRA wrong order. Stem cells suffer
  first
• - Interpretation stem cells die when mt-mutant,
  and are depleted if division/selection cant
  balance this
• - My conclusion these mice say nothing about
  aging
• - However tissue-specific versions (Zassenhaus
  lab) will probably tell us plenty

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Müller-Höcker 1990, J Neurol Sci 10014
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Müller-Höcker 1990, J Neurol Sci 10014
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Rho-zero (?0) cells, classical view no TCA
activity!
? (normal) ?0
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RHH a model compatible with the observed COX-
SDH phenotype
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RHH mitochondrial import/export implications
? (normal) ?0
e-
MAS
e-
glucose
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RHH extracellular implications (the reason its
called RHH!)
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Plasma redox an age-related change in need of an
explanation
Age (years)
Jones et al 2002, Free Radic Biol Med
33(9)1290-1300
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A paradox In that case, what is the PMRS good
for?!
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The respiratory chain in CR
Complex I
Complex II (SDH)
Desai et al 1996, Arch Biochem Biophys 333145
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This seriously contradicts textbook biochemistry
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This seriously contradicts textbook biochemistry
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Varying TCA stoichiometry
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A paradox But if so, isnt CR very
energy-wasteful?!
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Oxidising NADH to NAD releases
30 kcal/mol
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PMRS proton-pumping and ROS production a model
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ATP thrift in CR a model
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How does CR extend rodent longevity? True
Believer Easy, it reduces damage in postmitotic
tissues Devils Advocate But how, if it doesnt
raise SOD (Luhtala 1994)? TB Easy, it reduces
superoxide production (Sohal 1994) DA But how,
if it doesnt slow metabolism there (McCarter
1985)? TB Easy, it reduces Complex I activity
(Desai 1996) DA But how, since it doesnt reduce
Complex II (Desai 1996)? TB Hm.. Ah, it
recycles NADH with the PMRS (de Grey 2001) DA
But wouldnt that make superoxide (de Grey
1998)? TB Not necessarily, since the PMRS is an
ETC (de Grey 2002) To be continued.