The systems biology of caloric restriction
Caloric restriction (CR) is one of the only environmental manipulations known to extend both mean and maximal lifespan. CR animals also have improvements in the susceptibility to a wide range of pathological conditions including insulin resistance, type 2 diabetes and cancer. CR is therefore an important intervention modulating healthspan as well as lifespan. CR has been shown to be effective in a wide range of different species, however, its effects are not universal. It was recently shown for example that different recombinant inbred mouse strains (ILSXISS) vary enormously in their responses to CR (Liao et al 2010). Despite this recent work suggests that it may be effective in reducing mortality (Colman et al 2009: Fig 1) and age related disease risk (Fig 1) of non-human primates raising the hope that it may also be effective in humans.
Fig 1: (left panel): age related mortality and (right panel): age related disease risk in rhesus macaques (Colman et al 2009) under CR or ad libitum feeding. CR reduces age-related mortality and age related disease risk relative to controls.
Supporting this view a randomised controlled trial of CR called the CALERIE project is providing evidence that some of the metabolic responses in humans to CR are similar to those observed in animals. Details of the CALERIE (Comprehensive Assessment of the Long-term Effects of Reduction of Intake of Energy) project can be found here. John Speakman is a member of the data safety and monitoring board for CALERIE.
A key problem with CR is that despite many years of intensive research effort it remains unclear what the defining mechanisms are that mediate the specific health and longevity effects. In rodents it has been established that the extension of lifespan is directly and linearly related to the extent of restriction (Speakman and Hambly, 2007: Fig 2). With funding from the UK BBSRC we are using this fact to explore the causal mechanisms that underpin the CR effect.
Figure 2: the relationship between severity of restriction and extension of lifespan both relative to ad lib fed controls in studies of CR in rodents (from Speakman and Hambly, 2007).
The project involves exposing cohorts of C57Bl/6 mice to graded levels of CR from 0 to 40% restriction. All of the mice, including the control animals at 0% restriction are only fed during the hours of darkness. We also have two additional groups being fed medium (45% calories from fat) and high fat (60% calories from fat) diets. This provides us with cohorts of animals that range from chronic over- to chronic undersupply of calories. Adult mice are exposed to the CR for a period of 12 weeks before their responses are characterised.
Figure three – body mass changes of mice in the graded CR experiment #1 over 2 weeks of bseline and 12 weeks of restriction. The codes refer to exposure to high fat (HF) diets comprising 45 and 60% fat, Ad lib feeding for 24h and 12h per day and caloric restriction between 10 and 40% of baseline. Body mass measured daily for entire experiment.
Our group is part of the wider systems biology group at the University of Aberdeen