The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
chosen the informal alternative of presenting such material explicitly as my opinions; I
apologize in advance to any readers who disagree with my rationale.
I have also adopted a relatively informal style with regard to technical vocabulary. Since
aging is a feature of life for everyone, I have tried to make the book accessible to a wide
audience. With regard to subject matter, this has entailed the inclusion of introductory
material with which professional biologists will be familiar, but by and large that appears
only in the sections on the structure and function of mitochondria. In order to keep such
material out of other sections, I have attempted to minimize the use of jargon that is standard
to biologists but unfamiliar to others. I hope I have done so without introducing irritating
verbosity.
1.3. Why Suspect Mitochondria or Free Radicals?
The history of the mitochondrial free radical theory has been a bumpy one. Harman
realized in 1954 2 that toxic free radicals might be formed in the body and might cause aging;
it was not until 15 years later that their toxicity was robustly supported by McCord and
Fridovich’s discovery 3 of an enzyme that destroys such a radical. The mitochondrial free
radical theory of aging, hereafter usually abbreviated MiFRA, was truly born in 1972, when
Harman suggested 4 that mitochondria had the right characteristics to be both the sources
and the direct victims of toxic free radicals. Then the tide of opinion turned. The idea that
mitochondrial damage could contribute to aging was powerfully challenged by Comfort,
who pointed out 5 that damaged mitochondria would naturally be destroyed and replaced
by the cell; it came under further pressure in the early 1990s as numerous laboratories reported
that only very small quantities of mutant mtDNA were present even in very elderly
individuals. Then the tide turned again: Comfort’s objection was overturned with the
discovery by Müller-Höcker 6,7 that mutant mitochondria not only survive but are clonally
amplified when they arise, and Barja and others identified interspecies differences that
compellingly correlated free radical damage to mitochondria with lifespan. 8,9 This story is
told in Chapter 6.
One of the most powerful factors which have perpetually held back research into aging
is that it is phenomenologically so complex. This has resulted in a paralysing imbalance
between data and theory: there is so much information to absorb that no simple synthesis
can possibly be made, but the frequent reaction to this is to gather yet more data in the vain
hope that it will bring sudden illumination. The sad result has been that both theory and
experiment in gerontology have gained a widespread reputation for, if not mediocrity, then
at least paucity of top-quality work. While this reputation is to my mind undeserved by the
experimentalists, it is perhaps partly deserved by the theoreticians. Chapter 7 discusses these
issues in more detail.
The next two chapters cover two recent refinements of the mitochondrial free radical
theory. Chapter 8 presents a mechanism to explain the age-related accumulation of
mitochondrial DNA mutations; Chapter 9 a mechanism for intercellular transmission of
oxidative stress which may make those mutations disproportionately harmful. Chapter 10
deals with a wide range of potential challenges to aspects of the whole theory (particularly
to these recent refinements), and Chapter 11 with one more, whose refutation is complex
enough to be chapter-sized.
1.4. Tests, Interventions and Consequences
With Chapter 12 the book begins to look to the future. Although each step in the
mechanism set out here is already well supported by experimental evidence, there are still
several clear weaknesses in this support, which translate into possible tests of components
of the hypothesis.