Yeast as a model to understand the interaction between genotype and the response to calorie restriction

Abstract

Calorie restriction is reported to enhance survival and delay the onset of age-related decline in many different species. Several proteins have been proposed to play a role in mediating the response to calorie restriction, including the target of rapamycin kinase, sirtuins, and AMP kinase. An enhanced mechanistic understanding of calorie restriction has popularized the concept of "calorie restriction mimetics", drugs that mimic the beneficial effects of caloire restriction without requiring a reduction in nutrient intake. In theory, such drugs should delay the onset and progression of multiple age-related diseases, similar to calorie restriction in mammals. Despite the potential benefits of such calorie restriction mimetics, however, relatively little is known about the interaction between genetic variation and individual response to calorie restriction. Limited evidence from model systems indicates that genotype plays a large role in determining both the magnitude and direction of effect that calorie restriction has on longevity. Here we present an overview of these data from the perspective of using yeast as a model to study aging and describe an approach we are taking to further characterize the molecular mechanisms underlying genotype-dependent responses to calorie restriction.

Figure 1. Reported effects of 40% calorie restriction in recombinant inbred mouse lines

Re-analysis of the data from Liao et al. [31] illustrating the percent change in life span in 41 mouse lines each subjected to 40% calorie restriction, relative to genetically matched ad libitum fed animals. Dark bars represent males and light bars represent females.

Figure 2. Theoretical and reported effects of calorie restriction on replicative life span

(A) Some possible replicative life span (RLS) effects across a range of calorie restriction (CR). Compared to a model wild-type life span response, represented by strain 1, experimental strains could show an enhanced response to CR with (strain 2) or without (not shown) an altered response maximum, no change in RLS at any level of restriction (strain 3), or a negative response to CR (strain4). Mitochondrial respiration becomes favored over fermentation as the glucose concentration drops. This metabolic shift is thought to occur near 0.5% glucose and is represented by the dashed line. (B) Representative published CR response profiles for a typical wild type laboratory strain (BY4742) [55], and isogenic sir2Δ fob1Δ [55] and lat1Δ [67] mutants.