Mission Impossible?

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Tue Jul 29 17:27:06 EST 1997


Thank you for posting your very thought-provoking article on this newsgroup.
If that were to become a more popular habit, I think the gerontological
sophistication of the general (online) public would be sure to benefit.  Do
you think some journals would be unhappy with that?  Jay Olshansky asked
this on Longevity Digest in May, but no more was said.

I hold a sharply contrary view to yours, which I will take the opportunity
to lay out briefly in the context of your article.  My difficulty with your
argument involves three of your assertions, which I shall address in turn.

1. 'ageing is not controlled by a single mechanism.'

This is undoubtedly true, but is open to severe overinterpretation.  The
various mechanisms that contribute to aging are synergistic, such that the
effect of abolishing, or retarding, one of those mechanisms would be to
retard many, if not all, of the others (albeit by a lesser degree).  The
most extreme case of this is with regard to oxidative stress, whose effects
are widely held to dominate the aging process (e.g. [1]) but whose ultimate
causes are still a matter of debate.  To put this in concrete terms: let us
suppose that the root cause of 90% of the rise in oxidative stress with age
involves only a dozen easily identifiable genes.  I know of no evidence
that argues against this possibility.  Let us, then, further suppose that
these genes' role in oxidative stress could be completely abolished by gene
therapy (which, I will argue below, is highly plausible).  In that event,
it is also plausible -- some might even say likely -- that such therapy
would, single-handedly, double the maximum healthy human lifespan, by at
least halving the rates of all the other mechanisms that contribute to

2. 'gene therapy for ageing will require methods to improve upon the
   "genetic hand of cards" which determines the ageing and longevity
   of a "genetically normal" individual.'

This is only true if aging is not predominantly a result of spontaneous
somatic mutations (of either the nuclear or the mitochondrial DNA).  If
it is, then replacement of mutated genes will be the requirement; these
replacements need only restore, not improve on, what evolution has

Spontaneous somatic mutations in the mitochondrial genome may, possibly, be
the root cause of at least 90% of the rise in oxidative stress with age.
Experimental work (e.g. [2,3,4,5]) over the past decade, showing that
mtDNA mutations proliferate within non-dividing cells, has recently begun
to yield to theoretical interpretation (e.g. [6,7]); there are also hints
(e.g. [8]) of how cells which have thereby lost respiratory capacity impose
oxidative stress on their respirationally healthy neighbours.  Alternative
candidates for the root cause of rising oxidative stress are inconspicuous;
perhaps they do not exist.

3. <implicitly> gene therapy will be to improve nuclear coded, rather
   than mitochondrially-coded, genes.

Mitochondrial gene therapy has been considered in only a very few papers
during the past decade [9,10,7,11,12].  This is curious, since Lander's
summary in 1990 [9] identified highly realistic ways of directing both
proteins and RNAs into mitochondria, which could be used to "rescue"
mtDNA mutations with suitably modified duplicate copies transfected into
the nuclear genome.  Such therapies would essentially eliminate the effects
of mutations in those genes, since nuclear genes suffer somatic mutations
about 10,000 times more rarely than the effective rate in mtDNA [13].  In
yeast, import of a normally mtDNA-encoded gene has achieved phenotypic
rescue of a mutation in that gene [14].  Mitochondrial tRNAs are hot-spots
for mutation, and may be hard to import [11,12]; but clearly if all mt-coded
proteins are successfully imported, mitochondrial tRNAs are superfluous.
There are undoubtedly several hard problems to be solved before this system
could work [7], but none appears so hard that one would bet on its being
unsolved in twenty years.  Moreover, the hardest of all -- the transfection
of non-dividing somatic cells with engineered DNA -- need not stand in the
way of work on the others, since germ-line transformation of mice gives us
a versatile mammalian model which sidesteps it.

You close by stating that 'Immortality will remain unattainable'; other
prominent gerontologists have often stressed the same (e.g. [15]).  Let us
define "effective biological immortality" as a state where we are raising
the maximum healthy human lifespan by more than a decade per decade.  It is
hard to argue that we will never achieve this, since our understanding of
the human body is inexorably -- and not asymptotically -- improving while
the human body itself is not getting any more complex.  In view of the
arguments outlined above, I will make the stronger statement that there is
at least a 10% chance of our achieving it within 50 years.  Gerontologists
may soon be tempering their assertions to the contrary.

Aubrey de Grey

1.  Beckman, K.B. and B.N. Ames (1997). Oxidants, Antioxidants and Aging.
    In: "Oxidative Stress and the Molecular Biology of Antioxidant Defenses",
    Cold Spring Harbor Press.
2.  Muller-Hocker, J. (1989). Cytochrome-c-oxidase deficient cardiomyocytes
    in the human heart - an age-related phenomenon.  A histochemical
    ultracytochemical study. Am. J. Pathol. 134, 1167-1173.
3.  Yoneda, M. et al. (1992). Marked replicative advantage of human mtDNA
    carrying a point mutation that causes the MELAS encephalomyopathy. Proc.
    Natl. Acad. Sci. USA 89, 11164-11168.
4.  Munscher, C. et al. (1993). Human aging is associated with various point
    mutations in tRNA genes of mitochondrial DNA. Biol. Chem. Hoppe Seyler
    374, 1099-1104.
5.  Muller Hocker, J. et al. (1996). Defects of the respiratory chain in
    various tissues of old monkeys: a cytochoemical-immunocytochemical study.
    Mech. Ageing Dev. 86, 197-213.
6.  Kadenbach, B. et al. (1995). Human aging is associated with stochastic
    somatic mutations of mitochondrial DNA. Mutat. Res. 338, 161-172.
7.  de Grey, A.D.N.J. (1997). A proposed refinement of the mitochondrial free
    radical theory of aging. BioEssays 19, 161-166.  See also correspondence
    in BioEssays 19(6): 533-534.
8.  Larm, J.A. et al. (1994). Up-regulation of the plasma membrane
    oxidoreductase as a prerequisite for the viability of human Namalwa
    rho-0 cells. J. Biol. Chem. 269, 30097-30100.
9.  Lander, E.S. and H. Lodish (1990). Mitochondrial diseases: Gene mapping
    and gene therapy. Cell 61, 925-926.
10. Hoeben, P. (1993). Possible reversal of ageing and other mitochondrial
    deficiencies through retroviral transfection of mitochondrially encoded
    proteins to the nucleus. Med. Hypotheses 41, 131-133.
11. Chrzanowska-Lightowlers, Z.M.A. et al. (1995). Gene therapy for
    mitochondrial DNA defects: is it possible? Gene Therapy 2, 311-316.
12. Seibel, P. et al. (1995). Transfection of mitochondria: strategy towards
    a gene therapy of mitochondrial DNA diseases. Nucl. Acids Res. 23, 10-17.
13. Linnane, A.W. et al. (1989). Mitochondrial DNA mutations as an important
    contributor to ageing and degenerative diseases. Lancet 1(8639), 642-645.
14. Nagley, P. et al. (1988). Assembly of functional proton-translocating
    ATPase complex in yeast mitochondria with cytoplasmically synthesised
    subunit 8, a polypeptide normally encoded within the organelle. Proc.
    Natl. Acad. Sci. USA 85: 2091-2095.
15. Holliday, R. (1995). Understanding ageing. Cambridge: Cambridge
    University Press.

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