Table 251

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Summary comparison of main longevity pathways in Drosophila melanogaster

Process

Major genes or pathway Effect

Metabolic control via CR

-ia ISP

via Nuclear-mito interactions

Stress resistance

Genetic stability Reproductive effects

Patterns of senescence indy, rpd3, Sir2

InR, chico, forkhead

CuZnSOD, MnSOD, catalase, Gpx, hsp, others

CR slows rate of gene expression change relative to WT. Downregulates synthesis, turnover, & reproduction. No consistent up-regulation pattern. CR effect is relatively rapid.

ISP affects hormones which indirectly affect longevity by altering stress resistance levels. See ''Repro Effects'' below. Forkhead is key transcription factor which increases stress resistances.

Cybrids show longevity intermediate between nuclear & mitochondrial donors.

Up-regulation of different ADS genes by various techniques usually leads to increased oxidative/other stress resistance. Likely basis of extended longevity; QTL confirmation of ADS basis in one strain. Tissue-specific protective effects. Genome appears to be highly stable in normal flies. No evidence for regional or overall genomic dysregulation.

ISP induces JH synthesis which induces egg production and 20HE synthesis. At high levels, 20HE represses resistance to various stressors, & reduces life span. At moderate levels, longevity & stress resistance significantly increase.

Various sensory & locomotor abilities do not age in unison. Long-lived mutants do not delay the senescence of all their functions but retain some & lose others as do normal-lived animals.

The second longevity phenotype (Type 2), shown in Figure 25.1B, is an increased early survival that leads to a significant increase in mean but not in maximum life span. The third longevity phenotype (Type 3), shown in Figure 25.1C, is an increased later survival, which leads to a change in the maximum (LT90) but not in the mean life spans.

Analysis of the mortality data supports these statements. The Type 1 phenotype yields a Gompertz curve which is significantly different from that of the control strain (Figure 25.2A).

Analysis of the data suggests that the Type 1 phenotype involves a ~50% reduction in the mortality rate doubling time (MRDT) of the long-lived strain (8.8 days) relative to the normal-lived strain (5.8 days). Although not a direct measure, the MRDT is a commonly used proxy indicator of comparative aging rates. However neither the Type 2 long-lived populations (Figure 25.2B) nor the Type 3 long-lived populations (Figure 25.2C) show any sustained alteration in aging rates relative to their controls, but rather show only a transient decrease in either early or late life but not both.

Moreover, it should be pointed out that the same phenotype may be induced by multiple different stimuli. For example, the Type 1 delayed onset of senescence phenotype may be induced in flies by (a) caloric restriction (Pletcher et al., 2002), (b) by the down-regulation of the insulin-like signaling pathway (Tatar, Partridge refs), (c) by up-regulation of the antioxidant defense system (ADS) plus altered mitochondrial properties (Arking et al., 2002), (d) by drugs which inhibit histone deacetylases (Kang et al., 1999), and by other mechanisms as discussed below. What is it that unites all these varied stimuli and mechanisms into bringing about a Type 1 phenotype? What is it that distinguishes them from the stimuli which yield only the Type 2 or 3 phenotypes? The remainder of this chapter will attempt to answer these questions.

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