The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
cholesterol supply) that are unoxidized, but which are not receptive to them once they have
become significantly oxidized. 8 Thus this is a defence mechanism that prevents the build-up
of oxidized LDL in the blood, as noted in Section 4.3. Initially, and ideally, macrophages
ingest oxidized LDL and rapidly break it down.
However, especially in people with a high-fat diet, this mechanism is saturable.
Macrophages eventually become unable to cope with the rate of incoming LDL and cease to
function properly. Macrophages that have reached this point are called foam cells. Once
foam cells begin to accumulate in a region of arterial wall, things go from bad to worse: a
fibrous cap forms over the foam cells, probably in an attempt to contain it and stop it from
injuring the endothelial cells nearby. 9 A feature of this stage that is often overlooked, though
it has been repeatedly confirmed, 10,11 is that the growth of this lesion is then further
accelerated by hyperplasia: advanced lesions are found to be clonal, indicating that mutations
in cell-cycle control genes (probably caused, in large part, by the high levels of oxidized,
reactive lipids within the lesion) have caused it to become precancerous. Eventually
the lesion becomes so big that it impedes blood flow, and in the end it begins to fragment,
releasing material into the blood stream. They may become stuck elsewhere, actually arresting
the flow of blood to, for example, a region of the heart or brain.
Thus, the central cause of heart attacks and strokes is oxidation of LDL in the blood.
Moreover, a low-cholesterol diet does not have a greatly inhibitory effect on the rate of
progress of atherosclerosis, because plasma LDL levels are not much altered; 12a presumably
the liver makes up the deficit from the gut. This is no surprise, because ultimately we need to
supply our cells with cholesterol, a vital component of membranes which most cells do not
make in sufficient quantity for their needs (see Section 4.2). Only the liver and gut can
supply it fast enough; it is thus necessary to have it (as LDL) in the blood in order to make it
available elsewhere. In line with this, the genetic and environmental risk factors which cause
a wide variation in different people's susceptibility to atherosclerosis are largely related to
the later, hyperplastic stages of lesion formation: 12b foam cells are apparent at about the
same (early) age in all individuals. 12c
If we try to move one more step back in the chain of events, however, we hit a problem.
Only if and when some plasma LDL becomes oxidized are monocytes induced to attach to
the artery wall. The source of this oxidation, and in particular the reason why it becomes
more severe with age, is unknown; 7 indeed, the fact that it happens at all is highly paradoxical
(see Section 4.3). Somehow or other, though, it must be mediated by the preponderance of
LECs, since LECs are the chemicals which perform oxidation in vivo.
5.2. Cancer
Cancers—malignant tumors—form from the unregulated division of cells that
are only supposed to divide rarely. They do the most harm when they start to
fragment—metastasize—and malignant cells are carried away in the blood, eventually
attaching and forming new tumors all around the body. (The ability to metastasise is what
distinguishes a cancer from a benign tumor.) They occur as a result of spontaneous mutations
in multiple genes, particularly cell-cycle regulatory genes, of a single cell. Mutations are
happening all the time in all our cells, and if both copies of a gene in a given cell are mutated
the result can be the failure of specific functions in that cell; but such “double hits” are
extremely rare, so almost all cells remain capable of all their vital functions throughout life.
Furthermore, the few cells that do lose their function by this means are not a serious problem,
because other cells can stand in. With cancer, however, the body does not have the latter
safeguard: just a single cell going cancerous is enough to give rise to a potentially fatal tumor.
Therefore, cancer is probably by far the most serious pathological consequence of
spontaneous nuclear mutations.