Overactivity in growth and its effects on rates of ageing

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Caloric restriction (CR), which is the reduction of nutrient intake without change in nutrient composition or malnutrition, is one of the few known treatments that delay ageing in a wide variety of animals, from yeast to mammals. The down-regulation of nutrient-sensing genetic pathways, such as the highly conserved TOR kinase and insulin pathways, are thought to mediate the effects of CR. How exactly the activity of nutrient-sensing pathways leads to faster ageing is not known. A popular theory suggests that high metabolism results in the production of free radicals, which causes molecular damage. However, there is some evidence that contradicts the oxidative damage theory as the cause of ageing. This research will address the mechanisms of ageing using an alternative theoretical framework. According to a theory developed recently, ageing is the result of an unintended hyperfunction of a developmental program. Thus, growth that continues later in life could lead to pathology and eventual death. This theory can explain many of the paradoxes reported for the oxidative damage theory, as well as explain why CR delays ageing. Making an analogy with a car, instead of ageing due to "rusting", this new theory proposes that ageing is like a car that drives without any brakes and driver. We propose to study a species of nematode (roundworm) that produces genetically identical siblings, but that show different lifespan; hermaphrodites of this nematode consistently live a third longer than females. The absence of genetic differences between genders will facilitate proper control experiments for the cause of differences in lifespan. Nematodes are ideal for studying ageing because they have a relatively short lifespan, and are easy to culture and to manipulate in the laboratory. We hypothesize that females of hermaphrodites of our nematode model are ageing at different rates because they accumulate age-related pathologies that are the result of hyperfunction at different times during adulthood. We will test this hypothesis by manipulating the ageing rates using gender-modifying treatments, gene expression and gene knock-out analysis. Our model species provides a powerful system to study the mechanisms underlying ageing, because we can culture them at large numbers and genetically manipulate their genomes as well as genders. Recent research showed that nematodes, insects and mammals share some of the same mechanisms of ageing. Therefore, we anticipate that the results of this proposal will be applicable to other organisms.