The fly's innate immune response clearly has an effect on ageing rates; the constitutive induction of the Imd signalling pathway reduces the lifespan of male flies. Induction was initiated through the drug-induced over-expression of the receptor peptidoglycan-recognition protein long chain C (PGRP-LC) (Peng et al., 2005). The effects of both the immune induction and ageing could be blocked by mutating genes downstream in the pathway. Ageing rates can be increased by reactive oxygen damage and thus it is possible that it is the reactive oxygen produced during the immune response that alters the ageing rate.
Ageing has several effects on the immune response. As microarrays became available, several groups rushed to determine the difference between young and old flies. Old flies tend to express more AMPs. One explanation for this increased level of AMPs comes from the work of Zerofsky and colleagues (2005). They found that young and old flies expressed similar levels of AMPs when they were initially induced; however, the old flies were slower at turning the AMPs off. Immune senesence in ageing may involve the alteration of pathways that can downregulate an immune response.
There are a variety of molecular signalling events required for the negative regulation of immune responses and these might be altered during ageing (Schneider, 2007). Alternatively, the flies may be less able to clear the infecting bacteria, which persist and continue to stimulate the host. There is some evidence that this might be the cause of immune senescence in these experiments as the injection of dead bacteria, which should act merely as immune elicitors, produces a smaller induction of AMPs in old flies than it does in young flies, the opposite result of what is seen with live bacteria.
Most of the connections between ageing and immunity have focused on this induction of AMPs in old flies and thus pursue the changes in AMP-dependent resistance that might result in ageing flies. One study, using a unique injection model, implicates the senescence of tolerance as an important change in ageing flies. Ramsden and colleagues (2008) injected flies with a rather large dose of E. coli, on the order of 500 000 bacteria per fly. This is approximately 100-500 times more than is typically used in Drosophila experiments. High doses like this are lethal, whereas when low doses of E. coli (1000 colony-forming units) are injected into the fly it is non-pathogenic in wild-type flies. The authors found that old flies were as effective as young flies at clearing these high doses of bacteria, which rules out resistance as something that is affected by ageing in this model; instead, these results suggest that tolerance suffers from ageing senescence.
It may be possible to link ageing to immunity and some of the other physiological systems discussed above by examining dietary restriction. Dietary restriction in flies, as in many animals, will reduce ageing rates. Evolutionary arguments about diet restriction suggest that it represents a method for animals to find a broader optimum for diet and fitness. Given large amounts of food animals will produce a lot of offspring and die rapidly but when given lower amounts they will live longer and space out their offspring production. Dietary restriction functions in part through a reduction in insulin signalling although the effector mechanisms involved in this process remain a mystery.
Given that sick insects can become anorexic, we propose that this provides another regulatory feedback loop, this time between immune-induced changes in feeding and ageing. Anorexia induced by infections might be expected to shift flies into a diet-restriction state that may help broaden the optimum for survival and fecundity. Sick flies show reduced egg-laying but the life extension derived from reduced eating could possiblyrestore some fitness to these insects.
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