The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
such that the discs of rhodopsin which form the light-sensitive part of rod and cone cells are
recycled more than once a week. 30 The lysosomes in the pigmented epithelium, the cell layer
behind the rods which does the recycling, eventually become so full of lipofuscin that they
cease to function and the cells begin to lose integrity, leading to gradual loss of vision, technically
termed macular degeneration. This process is exacerbated by light-induced rupture
of these lysosomes. 31
But what determines the rate of accumulation of lipofuscin in other cell types? An
answer is suggested by the description of its composition given above. Oxidative damage
increases the incidence of damaged protein and lipid in cells, and that translates directly
into more lipofuscin. And indeed, the cells elsewhere than the eye which accumulate the
most lipofuscin are those which are non-dividing, so cannot dilute it away, and among
non-dividing cells the worst affected are those (such as cardiomyocytes) which use the most
energy, so create the most LECs and suffer the most oxidative damage.
5.5. Other Macroscopic Changes
The preceding sections have summarised only a selection of the major symptoms of
aging, though they have covered most classes. Many other cell types diminish in number
with aging; these include ones that are incapable of regeneration by division, such as neurons,
glomeruli, and the sensory hair cells of the inner ear, as well as ones which can divide but
generally do not. Various hormones diminish in concentration with age, for this reason and
others. A similar process happens to the immune system: this becomes progressively less
robust with age due to loss of cells in the thymus. 32 Another major change that more indirectly
involves loss of a specific cellular function is bone loss, leading to osteoporosis; this is thought
to be a response to a general failure of calcium regulation in many cell types, something
which can be detected histochemically as excessive calcium uptake.
5.6. Feedback, Turnover and Oxidative Stress
5.6.1. Negative Feedback
We would certainly not live as long as we do if not for our ability to react to, and recover
from, adverse physiological conditions. At the subcellular level, this response comprises rapid
regulation of all our systems for biological homeostasis, including our antioxidant systems.
This may seem vacuous, but in fact a remarkable deduction can be made from it. It tells
us that, despite (as discussed in the preceding sections) being pro-oxidant in nature, the processes
which drive aging are simply not challenged by our antioxidant defences—otherwise,
aging would not progress inexorably as it does. They proceed, slowly but surely, impervious to
antioxidants. This is further confirmed by the repeated failure of antioxidant therapy to increase
maximum lifespan of mammals, 33,34 an observation which will be discussed further in later
chapters.
This is a useful point because, on closer analysis, it dramatically narrows the field of
choices for the driving force behind aging. As we get older, there is a steady increase in the
levels of proteins which have suffered oxidative damage but not been recycled. Some such
proteins are themselves pro-oxidant, so they are part of the problem. But they cannot be a
driving part, because recycling is tunable: all other things being equal, the recycling machinery
would simply be up-regulated to match the increased levels of damaged proteins, thereby
lowering them again. This is the sort of negative feedback that maintains stability in the
body and in the cell in the face of exogenous challenges, such as disease. The same logic
applies to any component of cells—or of the extracellular space—that is recycled, whatever
the rate of that recycling (unless that rate is so slow as to be comparable with our lifetime).