Calorie restriction is the most studied of methods to slow aging and extend healthy life in laboratory species. Most of the diverse life extending interventions tested in these species are in fact ways to trigger some of the same mechanisms observed to be involved in calorie restriction. Cellular responses to stress, such as low levels of nutrients or heat, converge on mechanisms such as upregulation of the maintenance processes of autophagy, leading to better cell and tissue function. In short-lived species this can have quite large effects on life span, but that effect size diminishes greatly for longer-lived species such as our own. Mice live 40% longer when on a calorie restricted diet, but while we humans exhibit similar short-term health benefits, we only live a few additional years at most when practicing calorie restriction.
Epistasis analyses using mutant strains in lower organisms such as Caenorhabditis elegans (C. elegans) have revealed genes required for the effects of calorie restriction (CR), referred to here as CR genes, and the signal pathways mediating the effects of CR. In C. elegans, a number of genes such as aak-2, daf-16, skn-1, clk-1, and pha-4 have been reported to be associated with the life-prolonging effect of CR. Some of these genes also mediate the effects of CR in mice. Previous studies also reported that mutations of single genes (referred to here as longevity genes) can extend lifespan even in ad libitum feeding animals.
Many of these genes can be functionally categorized into genes associated with nutrient sensing or metabolic responses. Among these gene mutations, reduction- or loss-of-function mutations of genes in the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) signaling consistently extend lifespan in a range of organisms. Since CR is known to decrease the plasma concentration of GH and IGF-1, the GH-IGF-1 pathway is considered an evolutionary conserved pathway for longevity and a main aspect of the mechanism of CR.
Thus far, a total of 112 CR genes in yeast, 62 in nematode, 27 in drosophila, and seven in mice have been identified . Among these genes, forkhead box protein O 3 (Foxo3) and sirtuin 1 (Sirt1) genes are common in mice, nematodes, and flies. CR and longevity gene models have elucidated signal pathways for the extension of lifespan, although the signal pathways are context dependent.