Figure 25.3 summarizes the known activation and/or inhibition signals generated by each of the several longevity-extending mechanisms known to be operative in flies, which we have discussed above. The schematic is somewhat speculative in detail, but its tying together of the several known methods of inducing stress resistance with the expression of extended longevity as described in the foregoing text is most likely correct in concept. The important point to note is that all the interventions listed are known to induce the Type 1 longevity phenotype (i.e., delayed onset of senescence) (see Figure 25.1A). The ISS pathway, certainly, and the JNK pathway, probably, are involved in producing this phenotype. The details of the CR pathway are still being worked out. Even given our incomplete knowledge, it seems as if all inducers of the Type 1 phenotype work by effecting some common regulatory nexus, probably the dFOXO3 transcription factor that is known to activate or repress various stress resistance genes.
The interesting thing about the Type 1 phenotype is that delaying the onset of senescence means that the inflection point characteristic of such survival and mortality curves is shifted to some later time (see Figures 25.1A, 25.2A). What happens at that inflection point, regardless of its chronological value, that shifts the population from a state of health into a state of senescence? Senescence is the stochastic and nonpro-grammed loss of function which becomes obvious as the reproductive period ends. This is a time-independent process, occurring at about two years in a mouse but at about fifty-five years in a human. What triggers its onset? In the fly, it has been shown that the repression of the ISP results in the activation of the dFOXO gene, and in the activation or repression of a whole suite of downstream genes under its singular or joint control (Murphy et al., 2003). These downstream genes include a variety of stress resistance genes, including a number of molecular chaperones (hsp genes). Mutational inactivation of these downstream hsp genes reverses the extended longevity brought about by ISP repression. This leads to the emerging view that the beneficial effects of the ISP are mediated in part via these downstream hsps, which protect the cells in various ways against the accumulation of unrepaired damage to the cell's proteome (Marsh and Thompson, 2004) as well as the deleterious effects of ROS on the mitochondria and other cell structures. Up-regulation of the ISP, possibly via the increased production of the ILPs or growth factors such as IGF-1 under the control of the fly's glucoregulatory system, represses the expression of these downstream hsps and presumably of various antioxidant defense genes as well. This results in the down-regulation of damage control systems, the accumulation of unrepaired damage, and the gradual onset of senescence as various critical thresholds within the cell are exceeded. The individual nature of aging may be explained by individual and environmental variations in gene product levels, damage rates, repair levels, and so forth; all of which may be the outcome of various gene epistatic effects. A more extensive description of this model may be found in Chapter 9 of Arking (2005a).
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