The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki
68 Fig. 6.1. The vicious cycle theory (with emphasis on its instability). The Mitochondrial Free Radical Theory of Aging 6.5. Comparisons with Other Species The past decade has seen a series of advances in understanding aging of lower organisms. The three that have been studied most are the ones one would expect—the fruit fly Drosophila melanogaster, the nematode Caenorhabditis elegans and the yeast Saccharomyces cerevisiae—and they have been attractive for the usual reasons that their husbandry is convenient, their generation time short and their genetics and molecular biology very well characterised over many years. However, they feature only occasionally in this book. The phenotype of aging in a single-celled organism is a rather contentious concept in the first place, as exemplified by yeast: in Saccharomyces cerevisiae aging is defined in terms of the number of times a cell can “bud off” a daughter cell, but in other yeasts which divide by symmetrical fission there is no such definition, so there is deemed to be no aging! In multicellular organisms with a clear distinction between germ line and soma there is no difficulty of definition, but there is good reason to suspect that the processes of
History of the Mitochondrial Free Radical Theory of Aging, 1954-1995 macromolecular degradation which determine lifespan are not the same as in warm-blooded animals (see Section 10.5). Nonetheless, it is undeniable that comparing and contrasting the details of a process in multiple different species is a hugely useful approach in biology. Its role is very similar to that of mutational analysis, where the ultimate effects of a genetic alteration—that is, a comparison of a mutant organism with a wild-type one—can be used to demonstrate, for example, that the product of gene X stimulates or inhibits the expression of gene Y. Comparisons between vertebrate (and very long-lived invertebrate) species have been used extensively, especially in recent years, in an attempt to gain insight into what controls the rate of aging. Several relationships have emerged as being of particular importance, and they will be discussed in turn here. 6.5.1. Longevity and Specific Metabolic Rate An extremely obvious inter-species correlation with regard to longevity is that bigger animals tend to live longer. Unfortunately this is not (on the face of it) a very valuable insight, since not only does it fail to suggest any mechanisms, but also it is a necessary consequence of the fact that growth—cell division, in particular—entails a complex and intricate series of chemical reactions, and therefore takes time. If an animal is capable of reproduction when it is only a few millimetres long, it can tolerate living only a few days; if it cannot reproduce until it is a few metres long, it needs to live a lot longer. One can, however, make more progress if one examines the relationship of these two variables with a third: body temperature. This differs very greatly between warm-blooded animals (homeotherms) and cold-blooded animals (poikilotherms). All homeotherms maintain about the same body temperature, and doing so obviously requires the conversion of nutrients into heat, which consumes oxygen. An animal’s oxygen consumption (which is easy to measure, unlike, for example, its heat output) is thus a measure of the rate at which it is then using nutrients—its metabolic rate. An animal’s metabolic rate varies—it increases when the animal is physically active, and decreases during sleep—so it is usual to measure standard metabolic rate, which is defined to be that when the animal is awake but at rest. From that one establishes the animal’s specific metabolic rate by dividing its standard metabolic rate by its mass. This is the interesting number, because it is a measure of how hard the average cell is having to work to keep the animal warm. Since smaller animals have a higher ratio of surface area to volume, and hence of surface area to body mass, they end up needing a higher specific metabolic rate in order to maintain the same body temperature.* So the question is: is there a correlation between specific metabolic rate and longevity? Do animals of similar sizes but different specific metabolic rates have different longevity? Indeed they do. A poikilotherm of a given size generally lives much longer than a homeotherm of the same size. 25 Unlike the early observation that lifespan varies with size, this need not necessarily be so. Furthermore, the same relationship applies to poikilotherms kept at different temperatures: fruit flies live only about half as long at a given temperature as at 10˚ C cooler (within their range of good viability, of course). 26 This is also a measure of specific metabolic rate, since for poikilotherms specific metabolic rate varies with temperature just like any chemical reaction. * Intriguingly, the relationship between mass and specific metabolic rate that is seen is not precisely the obvious one. One would naturally predict that the rates of animals whose body temperatures were the same would vary as the inverse 2/3 power of their mass, since our surface is two-dimensional and our bodies are three-dimensional. In fact it is almost exactly the inverse 3/4 power. 24 This may not sound like much of a difference, but it has kept eminent comparative biologists in business for many years. 69
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68<br />
Fig. 6.1. <strong>The</strong> vicious cycle theory (with emphasis on its instability).<br />
<strong>The</strong> <strong>Mitochondrial</strong> <strong>Free</strong> <strong>Radical</strong> <strong>The</strong>ory <strong>of</strong> <strong>Aging</strong><br />
6.5. Comparisons with Other Species<br />
<strong>The</strong> past decade has seen a series <strong>of</strong> advances in understanding aging <strong>of</strong> lower organisms.<br />
<strong>The</strong> three that have been studied most are the ones one would expect—the fruit fly<br />
Drosophila melanogaster, the nematode Caenorhabditis elegans and the yeast Saccharomyces<br />
cerevisiae—and they have been attractive for the usual reasons that their husbandry is<br />
convenient, their generation time short and their genetics and molecular biology very well<br />
characterised over many years. However, they feature only occasionally in this book. <strong>The</strong><br />
phenotype <strong>of</strong> aging in a single-celled organism is a rather contentious concept in the first<br />
place, as exemplified by yeast: in Saccharomyces cerevisiae aging is defined in terms <strong>of</strong> the<br />
number <strong>of</strong> times a cell can “bud <strong>of</strong>f” a daughter cell, but in other yeasts which divide by<br />
symmetrical fission there is no such definition, so there is deemed to be no aging! In<br />
multicellular organisms with a clear distinction between germ line and soma there<br />
is no difficulty <strong>of</strong> definition, but there is good reason to suspect that the processes <strong>of</strong>
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