The first substantive biological theory of aging, the rate of living theory, was developed from studies on Drosophila. The early work of Loeb and Northorp (1917) demonstrated that temperature was negatively associated with lifespan in Drosophila. Raymond Pearl, a biostatis-tician who worked on population genetics, put forward this phenomenon as the ''rate of living theory.'' He found that the coefficient relating lifespan to ambient temperature in flies had a magnitude between two and three, which was similar to that of chemical reactions; he interpreted this as signifying that all the biochemical reactions for living processes occurred faster at higher temperatures in flies.
Thus, increased lifespan in flies at lower temperatures was originally thought to be due to slowing down of all biochemical processes. However, the interpretation of effects of temperature may not be so simple because not all enzyme activities are affected by temperature to the same degree. Concentration of a molecule "X" depends on its production and consumption, and if the activities of the producer and the consumer have different Q10 values (thus differently affected by temperature) the concentration of molecule ''X'' could go up or down, depending on the balance. Furthermore, there are certain physiological responses to cold (temperature compensation) that are independent of metabolic rate, such as changes in membrane fatty acid composition, that can affect susceptibility to oxidative damage (unpublished observation). It is not known how circadian rhythms, which are known to control various physiological functions, are affected by temperature, although a constant 12:12 hour light:dark cycle in laboratory culture conditions can force them to follow this circadian cycle. Nevertheless, the demographic study of mortality trajectories has shown that lowering temperature changes the slope, suggesting the rate of aging was slowed down (Mair et al., 2003).
The rate of living theory stated that the metabolic rate of an organism is directly and causally linked to its longevity; that is, "live fast, die young.'' A mechanistic explanation of the rate of living theory was provided by the oxidative damage theory. Originally proposed by Harman (1956), its modified and refined version states that reactive oxygen species produced as byproducts by mitochondria during normal aerobic respiration can attack and damage surrounding molecules, and accumulation of such damage causes aging (Harman, 1972; Sohal and Weindruch, 1996; Beckman and Ames, 1998). It is thought that the phenomenon of increased physical activity in flies shortening lifespan is due to a higher metabolic cost in these flies, which in turn increases mito-chondrial reactive oxygen species production. However, this concept is confusing because mitochondrial reactive oxygen species production will be lower, rather than higher, under state 3 respiration (active respiration state, such as during exercise, producing ATP in the presence of ADP) compared with state 4 respiration (resting state, no production of ATP). This is because mitochondrial reactive oxygen species production correlates with membrane potential, and membrane potential is lower in state 3 than state 4. Furthermore, in mammals, elevated metabolic rate by wheel running exercise (Holloszy, 1997) or cold exposure (Holloszy and Smith, 1986) in rats does not shorten lifespan, and mice with higher metabolic rates (with lower membrane potential due to more mitochon-drial uncoupling) were reported to live longer than those with lower metabolic rates (Speakman et al., 2004), demonstrating a dissociation of increased metabolic rate and longevity. Similarly, it has been shown that extended lifespan in Drosophila was not accompanied by lowered metabolic rate (van Voorhies et al., 2003; Hulbert et al., 2004; Khazaeli et al., 2005).
Nonetheless, the elevation of respiration rates between rest and flight in Drosophila is much larger (~100 fold) than that seen in mammalian models, so intense oxygen uptake in flies might indeed have detrimental effects. Further investigations exploring effects of flight activity on longevity in flies are of great interest.
In addition, many Drosophila-based studies have tested the oxidative damage hypothesis; a popular approach has been to reduce the level of oxidative stress and see if lifespan can be extended. For example, using the candidate gene approach, attempts have been made to lower levels of oxidative stress either by overexpress-ing antioxidant enzymes or by lowering mitochondrial reactive oxygen species production through elevating proton conductance (Miwa et al., 2004; Fridell et al., 2005). Dietary antioxidant supplementation has also been performed (reviewed in Le Bourg, 2001).
However, not all studies support the hypothesis. Initial studies genetically inducing increased antioxidant defenses had technical problems: use of short-lived flies, different sized inserts between control and experimental groups, and uncontrolled position effects in transgene constructs (Tower, 2000; Partridge and Pletcher, 2003). Later work found that overexpression of Cu,Zn-SOD,
Mn-SOD, or both with the FLP/FRT system increased lifespan (Sun et al., 2002; Sun et al., 2004; Sun and Tower, 1999), Cu,Zn-SOD overexpression in motorneurons extended lifespan (Parkes et al., 1998), but overexpression of various combinations of Cu,Zn-SOD, Mn-SOD, catalase and thioredoxin reductase did not extend lifespan (Orr et al., 2003). In addition, most studies involving altering antioxidant status did not check whether damage was actually reduced.
The effects of lowered mitochondrial reactive oxygen species on lifespan have been examined using transgenic flies that have higher proton conductance. Expression of human uncoupling protein 2 (hUCP2) in nervous tissue lowered reactive oxygen species production and extended lifespan but not when it was expressed in muscles (Fridell et al., 2005). Overexpression of adenine nucleotide translocase in whole fly also lowered mitochondrial membrane potential and reactive oxygen species production, but lifespan was shortened (Miwa et al., 2004). Although such negative results are difficult to interpret due to potential unknown side effects, there could be tissue-specific effects of this type of manipulation on lifespan. Alternatively, it is possible that hUCP2 induction in neurons in flies extended lifespan through mechanisms which are not related to oxidative stress, for example, by impairing insulin signaling. Further examination of this issue will be enlightening.
Other studies—some of them on houseflies—have aimed to establish correlational evidence of the oxida-tive damage theory, as has been done in mammalian systems. Oxidative damage was found to increase with age (Sohal et al., 1993; Yan et al., 1997; Yan and Sohal, 1998). Mitochondrial reactive oxygen species production was found to increase with age (Sohal and Sohal, 1991; Sohal, 1993; Ross, 2000), and it was lower in long-lived lines of flies than controls (Farmer and Sohal, 1989). However, no such correlation was found when lifespan was extended by dietary restriction (Miwa et al., 2004).
Although there is much correlative evidence to support it, confirmation of the oxidative damage theory still requires establishment of (a) which specific forms of damage (DNA, proteins or lipids) are important; (b) how the balance between ROS formation, ROS removal, and damage repair is regulated; and (c) which tissues or cell types are most critically affected. Then the appropriate direct tests should be performed accordingly. The Drosophila model will be a major player in this ongoing research area.
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