Reproductive Effects

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The antagonistic interaction between the soma and germ line cells first observed in the nematode also is found in the fly. In fact, there is much more information available in Drosophila on the several hormones involved and their various inhibitory and stimulatory effects on longevity (Tatar et al., 2002, 2003; Hwangbo et al., 2004)).

Cells of the CNS, the par intercerebralis, secrete insulin-like peptides (ILPs), which are directed to certain target cells as well as being released systemically. These insulin-like peptides (particularly dILP2) directly or indirectly stimulate certain neuroendocrine cells such as the corpora allata to produce one of the two key hormones in the insect, juvenile hormone (JH). dILP2 acts so as to activate the ISP and thus inactivate dFOXO and the stress resistance/somatic maintenance pathways. The ISP likely operates in the cells of the CNS as well as in the peripheral tissues. In the fly, the fat body cells in the head play a particularly important role, since these cells appear to regulate dFOXO, and thus control the aging of the organism, when activated (Hwangbo et al., 2004). The ISP operating in the gonad-somatic cell axis can activate or inhibit the synthesis of juvenile hormone (JH). Thus the longevity-extending effects of mutants affecting the ISP presumably arise out of interference with the operation of the ISP portion of the process. Longevity arises from the interaction of control centers in the gonads, central nervous system, and head fat body cells with the various peripheral somatic tissues.

JH is essential for reproduction. It is known to promote vitellogenesis and reproduction in insects, and to inhibit adult diapause (a nonreproductive long-lived somatic state characteristic of, for example, overwintering adults). In the gonad, JH stimulates egg development and also stimulates the synthesis of the active form of the second key insect hormone involved in our story, 20-hydroxy-ecdysone (20HE). This steroid hormone is well known for its effects on development, and the molecular details of its action within the cell have been worked out—particularly the fact that the 20HE must bind with a bipartite receptor protein in the nucleus if it is to specifically activate its target genes (Riddiford et al., 2000; Tatar, 2003). What is particularly interesting in the current context is that the known inhibitory effect of JH on the stress resistance of the adult may well be mediated through 20HE. The relationships of these two hormones are quite complex, and the interested reader should refer to Pu et al. (2005) for details.

Simon et al. (2003) have shown that animals bearing heterozygous mutations in the ecdysone receptor (EcR) protein, one component of the nuclear receptor protein complex, exhibit increased longevity relative to control animals. This locus is the probable site of a QTL known to be involved in longevity (Curtsinger et al., 1998). The animals have a higher metabolic rate coupled with a lower rate of spontaneous activity. More interestingly, they are also significantly more resistant to oxidative stress, heat, and starvation than are normal animals. This implies that the increased life span and the increased stress resistance both are the result of a decrease in the effective concentration of the 20HE in the cells. Interestingly enough, female age-specific fecundity was increased in these heterozygous mutants relative to normal animals, suggesting that moderate levels of 20HE are compatible with both an extended longevity and an enhanced fecundity. A comparable increase (~42%) in life span was obtained in a separate experiment by use of a temperature-sensitive mutant (DTS-3) that affects ecdy-sone synthesis in females. Because this gene product is inactivated at high temperatures, then one can effectively turn it on or off simply by transferring the fly from a permissive temperature (20oC) to a restrictive temperature (29oC). Doing such shifts at different times indicates that the greatest effect of the decreased hormone levels on longevity takes place within the first two or three weeks of adult life. Finally, feeding 20HE to these mutant female flies abolished that extended longevity in a dose-sensitive manner and also reversed their resistance to the stress of starvation. As little as 10"3 M 20HE added to the food allowed the females to have a normal life span.

Absence of ecdysone is lethal. But these three experiments taken together clearly show that high levels of 20HE have a negative effect on longevity and on stress resistance. Thus the JH stimulation of the gonads to synthesize and secrete the high levels of 20HE leads to a shorter (i.e., normal) life span. This decreased life span may well arise from the concomitant repression of stress resistance observed in these experiments. Using mutants to reduce the level of 20HE to a moderate (~50%) level brings about an extended longevity and an enhanced fecundity, as do experiments in which the effective level of the receptor protein is manipulated. Note that the Type 1 phenotype obtained with either manipulation yields a ~45% increase in mean life span in both sexes and is about equal to the increase in life span obtained with selection, caloric restriction, or ISP mutants.

There is another aspect to the topic of reproductive effects on longevity. Reproduction requires the female fly to expend a considerable amount of energy. Individuals in which the energy demands of the reproductive system are not synchronized with the energy production ability of the somatic cells are likely to die when the demands exceed the supply. A formal analysis of the interplay between the age-related energy demand and supply led to a hypothesis about a mechanism which predicts two critical periods in the life history of an individual fly (Novoseltsev et al., 2003). The first crisis occurs at early ages when the increased energy demand becomes greater than the available energy supply. This would often result in a ''premature'' or nonsenescent death and would presumably involve females in which their intrinsic rate of egg production is greater than can be supported by their intrinsic mitochondrial energy production. In other words, the weaker flies would preferentially die at this first stressful period in their lives. The stronger and surviving flies lay eggs at some more or less constant rate while their available energy supply is gradually decreased by various senescent processes. Eventually, they do not produce enough energy to simultaneously maintain their reproductive activities and to resist the various environmental stresses associated with living. The initially strong flies perferentially die late in life from a senescent-caused death precipitated by their inability to meet the cumulative energy demands placed upon them.

The reader will observe that these two mechanisms of reproductive effects on longevity—the hormonal mechanisms and the energy demands—are not contradictory but are really the same process as described on the one hand from the cell and tissue level of the geneticist, and on the other hand from the organismic level of life history theory.

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