The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

Frequently-Asked Questions
of electrons were being released into the plasma in an even distribution, we should indeed
expect that the antioxidants present in vivo should suffice to absorb them before they can
form superoxide or other LECs. But because their release is so focal, it is inevitable that the
local concentrations of antioxidants will be saturated. This will result in the annexation of
electrons by lower-affinity receptors—particularly by oxygen, which the PMOR does not
very readily reduce 59,60 but which is present in much greater concentrations than any
antioxidant. The amount of superoxide generated, therefore, will be far greater in the situation
described by MiFRA than if the same number of electrons were being released in total but at
a uniform rate by all arterial cells.
10.14. Why Doesn’t Low Plasma LDL Retard Aging?
The numerous studies of atherogenesis, which have led to a detailed understanding of
its mechanisms, were discussed in Section 5.1. A central feature is that macrophages, once
attached to the artery wall, express a receptor for LDL particles which is non-specific, whereas
the receptor expressed by other cells has an affinity dependent on the particle’s degree of
oxidation, such that highly oxidized particles are not imported. Atherosclerosis begins when
macrophages become engulfed by proliferating smooth muscle cells.
This causative role for LDL oxidation in atherogenesis is now widely accepted, 61 but
there is reason to doubt its direct relevance to aging. Atherosclerosis is undoubtedly a major
age-related disease, involved in the etiology of both heart attack and stroke. However, its
rates of onset and progression are highly dependent on diet, and moreover are far more
variable between individuals than are the rates of many other biomarkers of aging. One
may therefore wonder whether MiFRA can be held to underlie those other phenotypes of
aging. The explanation concerns the degree of LDL oxidation.
It was noted above that the standard LDL receptor does not bind oxidized LDL. However,
there is a threshold level of oxidation below which LDL is still readily imported by all cells.
In a young individual, almost all LDL in plasma is far below this level of oxidation. If the
average oxidation of LDL were to double, then the amount that exceeded the threshold for
import would rise by a larger factor. But it would still be a small minority of total circulating
LDL; the remainder, which was still below the threshold, would nonetheless have an average
oxidation level nearly twice the original. Only when average oxidation levels reached a far
higher—indeed, unphysiological—value could the average oxidation of sub-threshold LDL
slightly diminish, as depicted in Figure 10.3. This means that the blood LDL level does not
affect the rate of import of oxidized LDL as it affects atherogenesis: the quantity of LDL
imported by a given cell is set purely by its cholesterol requirements, so the average oxidation,
not the quantity in transit at one time, determines the amount of oxidized material that is
imported. Thus, a role for oxidized LDL in transmission of oxidative stress is consistent
with the observation that a diet which promotes low blood LDL levels is a powerful defense
against atherosclerosis but does little to retard aging. Rising LDL oxidation will, despite the
efforts of arterial macrophages, translate into rising import of oxidized LDL material.
10.15. Isn’t This “Reductive Hotspot” Business All Rather
Far-Fetched?
Yes. But in my view, to paraphrase Churchill’s opinion of democracy, it is the worst
theory of aging devised by the wit of man—except for all the others.
This book is not the place to enter into a detailed comparison of the competing claims
of the various proposed mechanisms of human aging, so I have restricted such discussion to
a summary of my own views at the time I entered biogerontology (see Section 7.4) and this
survey of a few items of recent data which I find especially persuasive that MiFRA (in the
form presented in Chapters 8 and 9) is on the right track.
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