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1996). Raising the adults on food which contained only 33% of the nutrients found in the standard food allowed a ~34-day increase in the median life span and a ~31-day increase in the maximum life span (Pletcher et al., 2002). Analysis of the age-specific mortality rates for this experiment showed that they did not begin to increase from the minimal values observed in the young until ~15 days in the control animals and about ~45 days in the CR animals. If this increase in the age-specific mortality is taken as indicating the age of onset of senescence, then the ~30-day delay in the age of onset of senescence in the CR animal essentially accounts for all the extra longevity noted in the survival curves. From a demographic point of view, the population enters what appears to be a period of stasis in which the age-specific mortality rate does not increase, and so this results in an extension of the young and healthy portion of the life span, as suggested in Figure 25.1A.

Gene expression analysis of the ad libitum (AL) and CR animals showed that >1% of the assayed genes showed a significant change in their expression. The genome is normally quite stable, and so our interest is focused on those few genes that do change. As a general rule, these changes occur more slowly in the CR set than in the control set. Those genes that increase with age in both sets comprise mostly genes involved with innate immunity and detoxification, enzyme inhibitors, and all sorts of genes involved in the response to various stresses. These data suggest that aging animals—regardless of their diet or chronological age—are under increasing stress from pathogens. It appears as if the proximate cause of death in old flies is infection (Tower et al., 2004). An upstream cause of these proximate stresses may well be a loss of mitochondrial function, and the 458 gene probes down-regulated with age are consistent with this idea. The loss of energy production associated with decreased mitochondrial function is a major factor in the loss of function characteristic of aging. Most interesting is the CR-induced down-regulation of at least one gene (methuselah (mth), see below) known to significantly extend longevity when mutated. Its down-regulation under CR conditions suggests that the wild-type mth might act as a negative regulator of extended longevity. There is no obvious reduction in reproductive activities in the CR animals, and so it cannot be attributed only to a shift of energy from reproduction to somatic maintenance (Mair et al., 2004). CR appears to extend longevity in the fly by ameliorating many of the normal transcriptional changes that occur with age. A model for the mechanisms involved in the onset of senescence is presented below and by Arking (2005b).

As was noted with CR in the mouse, different strains or mutants may have different sensitivity spectrums to CR. The chico mutant expresses its maximum life span at a higher food concentration than does the wild-type control (Clancy et al., 2002). Other mutants show similar changes in their optimal food concentration. Thus the amount of food needed to trigger the CR response is not fixed in a species but is itself the outcome of the organism's genotype and nutritional environment. It is known that the organism actually has several pathways that sense its nutritional state. The TOR signaling pathway (see Figure 25.3) senses the amino acid levels so as to modulate growth or longevity.

There may well be other specific nutrient-sensing pathways. Their variable interactions with the nutritional environment and with each other may well account for the existence of different sensitivity spectrums to CR noted above.

The preceding discussion describes what CR does to a fly. But how does it do it? What gene pathways are involved? The evidence here is less detailed but still informative. Two different histone deacetylases are involved in mediating the CR response. Flies carrying a mutant rpd3 deacetylase gene and raised on normal media have a mean and median life span about 40% longer than that of their wild-type controls (Rogina et al., 2002). But rpd3 mutants raised on low caloric food have a life span identical to that obtained if they are raised on normal food. The fact that the CR treatment has no effect on these mutants implies that the wild-type allele of the rpd3 gene plays a role in the CR response. Even more interesting is the response of the Drosophila Sir2 gene to CR and to rpd3. Wild-type animals subjected to CR show an approximate doubling in the level of Sir2 gene expression, while rpd3 mutants raised on normal food also show an approximate doubling in the level of Sir2 gene expression. Thus the normal allele of rpd3 seems to inhibit the Sir2 gene expression that is necessary for the CR effect. In another series of experiments, it was shown that if the Sir-2 histone deacetylase gene of Drosophila is up-regulated by feeding the animal a known sirtuin activator such as resveratrol (the longevity extending component of red wine), then life span is significantly extended even though the animals are fed AL (Wood et al., 2004). Conversely, flies lacking a functional Sir-2 gene failed to extend their longevity when fed resveratrol. Thus activation of Sir-2 seems to be essential for the expression of CR-dependent extended longevity. It is reasonable to conclude that both these genes are components of the genetic pathway mediating CR expression, related perhaps in the manner suggested in Figure 25.3. It should be noted that there is much disagreement over the details of this interaction, and this is now an active area of investigation.

Another gene possibly involved in CR is the indy gene which encodes a metabolite transporter protein responsible for the uptake and transport of Krebs and citric acid cycle intermediates through the gut epithelium and into the appropriate organs (Knauf et al., 2002). Homologous genes exist in nematodes and mammals. Flies carrying a mutation in this gene display a 90% increase in their mean life span and a 50% increase in their maximum life span (Rogina et al., 2000). In flies, the indy gene is normally expressed primarily in the midgut, fat body (liver equivalent) and oenocytes, which are the main sites of intermediary metabolism. It is not unreasonable to assume that the mutant-induced down-regulation in the activity of this metabolite co-transporter protein brings about a lower effective concentration of essential metabolites in the cell, thus creating a metabolic state similar to that induced by CR. One possible interpretation of its role in the CR pathway is shown in Figure 25.3.

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