Gross energy metabolism in mice under late onset, short term caloric restriction

Abstract

Late onset, short-term moderate caloric restriction (CR) may have beneficial health effects. A 26% CR regime induced at 14 months of age for 70 days in male C57Bl/6 (ICRFa) mice resulted in a reduction in body mass of 17%. A decrease in daily energy expenditure was associated with decreased body mass in CR mice. There was no difference in total levels of physical activity between the CR and ad libitum (AL) groups; however, activity patterns were different. We developed a Bayesian model to dissect the impact of food anticipation activity (FAA) and feeding on physical activity. FAA was stronger in CR mice and remaining basal activity was higher in AL mice, but CR mice displayed larger diurnal variations as well as a phase shift in their diurnal activity. CR mice displayed lower body temperature, especially late during the dark phase. This was due to lower basal (activity-independent) temperature at all times of the day, coupled to a phase shift in the diurnal rhythm. The correlation between body temperature and physical activity was independent of feeding regimen and light/dark cycles. Reduction of body mass and basal temperature were major compensatory mechanisms to reduced food availability during late-onset, short-term CR.

Introduction

Caloric restriction (CR), whereby total caloric intake is reduced but adequate nutrition is maintained, results in an extension of lifespan (Weindruch and Walford, 1982). Additionally, CR has been shown to delay the onset and severity of cancer and other diseases associated with ageing. Since the initial reports of McCay et al. (1935), these effects have been consistently shown in the laboratory, and in a wide variety of model organisms including yeast, worms, flies and mice (Weindruch and Walford, 1988). The effect CR has on lifespan has generally, although not always, been shown to be robust (Liao et al., 2010). However, the mechanisms underlying the effect have not been wholly characterised (Masoro, 2005). In mammals, CR initiated in young age has the most dramatic effect on lifespan. However, there are also beneficial effects of starting CR in adulthood (Weindruch and Walford, 1982, Spindler, 2005, Yu et al., 1985). When CR is implemented in older animals, in general the observed increase in lifespan is not as great as if CR had been initiated from a young age (Lipman et al., 1995). However, many factors influence the effect of CR such as the genotype (Liao et al., 2010, Forster et al., 2003), duration of CR (Beauchene et al., 1986), severity of the restriction (Weindruch et al., 1982, Speakman and Hambly, 2007) and age of initiation (Forster et al., 2003, Lipman et al., 1998, Speakman and Hambly, 2007).

The present literature on late onset CR has been mainly focussed on the impact on lifespan (Spindler, 2005) and cancer incidence (Pugh et al., 1999, Volk et al., 1994, Weindruch and Walford, 1982, Dhahbi et al., 2004, Spindler, 2005). There are also data linking late onset CR to improvements to the immune response (Kubo et al., 1984, Weindruch et al., 1982) and cognitive function (Means et al., 1993). By far the majority of the current research in rodents has principally shown improvements in cellular and biochemical ageing during late onset CR (Lee et al., 2002, Lee et al., 2004, Cao et al., 2001, Dhahbi et al., 2004, Goto et al., 2007).

However, there are currently very few studies examining gross energy metabolism in response to late onset CR. Evidence so far suggests that metabolic changes may mirror some of the changes seen during early onset CR. For example Rhesus monkeys (Macaca mulatta) undergoing adult onset CR have shown improved insulin sensitivity, reduced central adiposity and reduced serum triglycerides (Edwards et al., 1998, Lane et al., 2000, Anderson et al., 2009). Also, mice subjected to late onset (at 22 months) CR for 3 months showed improved lipid metabolism (Araki and Goto, 2003). It is not clear which of a multitude of potential mechanisms, including reduced daily energy expenditure, physical activity, body temperature and organ mass or increased digestive efficiency, are most important for rodents to metabolically compensate for reduced food availability when exposed to late onset CR. In the current study we aimed to explore the responses of mice to late onset short term CR lasting 70 days. We found that energy loss in faeces was reduced, and digestive efficiency was maintained, possibly mediated by increased relative mass of the small intestine. Reduced daily energy expenditure during CR was positively associated with a decrease in body mass. There was no change in overall physical activity between the groups, but diurnal activity patterns were significantly different. Restricted feeding led to a decrease in basal, activity-independent body temperature but did not modify the changes in body temperature driven by physical activity. Reductions of body mass and basal body temperature were the major compensatory mechanisms for reduced food availability during late-onset, short-term CR in mice.