Caloric restriction and aging: studies in mice and monkeys

Abstract

It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies, and laboratory rodents. The mechanism underlying this phenomenon is still unknown. We have hypothesized that a reprogramming of energy metabolism is a key event in the mechanism of CR (Anderson and Weindruch 2007). Data will be presented from studies of mice on CR, the results of which lend support to this hypothesis. Effects of long-term CR (but not short-term CR) on gene expression in white adipose tissue (WAT) are overt. In mice and monkeys, a chronic 30% reduction in energy intake yields a decrease in adiposity of approximately 70%. In mouse epididymal WAT, long-term CR causes overt shifts in the gene expression profile: CR increases the expression of genes involved in energy metabolism (Higami et al. 2004), and it down-regulates the expression of more than 50 pro-inflammatory genes (Higami et al. 2006). Whether aging retardation occurs in primates on CR is unknown. We have been investigating this issue in rhesus monkeys subjected to CR since 1989 and will discuss the current status of this project. A new finding from this project is that CR reduces the rate of age-associated muscle loss (sarcopenia) in monkeys (Colman et al. 2008).

Figure 1. Inverse linear relationship between caloric intake and lifespan in mice

C3B10F₁ females were individually housed and placed on controlled diets (115kcal/wk, 85kcal/wk, 50 kcal/wk and 40kcal/wk) from weaning (n =49, 57, 71, 60 respectively). Animals with the highest caloric intake died earliest and survival improved with increased caloric restriction.

Figure 2. CR induced reprogramming of energy metabolism through activation of master regulators

This metabolic reprogramming results in an altered metabolic state that positively influences tissue-specific effectors of longevity pathways, leading to a reduced rate of aging. Master regulators may include the transcriptional co-activator PGC-1α and members of the nuclear receptor family.

Figure 3. Alterations in PGC-1α activity and stability through SIRT1 and GSK3β

In response to acute stress, activation of SIRT1 and GSK3β causes activation and subsequent degradation of PGC-1α, resulting in a rapid and transient effect on mitochondrial energy metabolism. In response to CR, a chronic stress, SIRT1 is activated and GSK3β is inhibited, causing increased PGC-1a activity and stability, resulting in a prolonged effect on mitochondrial energy metabolism.