Murine weight loss exhibits significant genetic variation during dietary restriction.

We present genetic analyses of murine weight loss during dietary restriction (DR) for females eating 60% ad libitum (AL). We examined 5 cohorts across 81 different strains (22 strains tested twice) that included the LXS and LSXSS recombinant inbred strains, the LXS parental strains ILS and ISS, and the classical inbreds 129S6, A, BALB/c, C57BL/6, C3H, and DBA. Weight loss exhibited highly significant genetic variation, with DR body weights ranging from approximately 60 to approximately 85% of AL body weight. This variation was not explained by the strain differences in absolute food intake, feces calorie content, motor activity, or AL body fat. Heritability was 40-50%, and several provisional quantitative trait loci were mapped. This variation can be used to test whether weight loss correlates with the health benefits of DR, independently of the reduction in calories. The genetic variation also implies the existence of genes that would be novel therapeutic targets, distinct from genes affecting AL body weight or body fat, for enhancing (or mitigating) weight loss during food restriction.

Quantitative trait Loci specifying the response of body temperature to dietary restriction.

Dietary restriction (DR) retards aging and mortality across a variety of taxa. In homeotherms, one of the hallmarks of DR is lower mean body temperature (T(b)), which might be directly responsible for some aspects of DR-mediated life extension. We conducted a quantitative trait locus (QTL) analysis of the response of T(b) to DR in mice using a panel of 22 LSXSS recombinant inbred strains, tested in two cohorts. T(b) in response to DR had a significant genetic component, explaining approximately 35% of the phenotypic variation. We mapped a statistically significant QTL to chromosome 9 and a provisional QTL to chromosome 17, which together accounted for about two thirds of the genetic variation. Such QTLs could be used to critically test whether the response of T(b) to DR also affects the response of life extension. In addition, this study demonstrates the feasibility of trying to map QTLs that affect other physiological responses to DR, including the life extension response. Importantly, the genes underlying such QTLs would be causal factors affecting these responses and could be identified by positional cloning.

Strain variation in the response of body temperature to dietary restriction.

Dietary restriction (DR, also referred to as calorie restriction, energy restriction, and food restriction) retards senescence and increases longevity in mammals. DR also lowers mean body temperature (T(b)), and thus mean T(b) might be useful as a covariate of DR-induced life extension. Indeed, lower T(b) could itself underlie some of the beneficial life-extension effects that occur during DR. To assess the relationship between lower T(b) during DR and life extension, we asked whether significant strain variation exists in the T(b) response of mice being fed 60% ad libitum (AL). Individually-housed, female mice from 28 strains, representing a genealogically diverse sample of the classical inbred strains, were directly compared. The mean T(b)s in response to DR exhibited highly significant strain variation, ranging from 1.5 degrees C below normal to a phenomenal 5 degrees C below normal. This variation was not explained by differences in loss of thermoregulation, AL adiposity, sensitivity to a nonadaptive hypothermia, motor activity, thermal arousal, absolute food intake, or efficacy of nutrient extraction. The variation in strain mean T(b) was also present in the absence of torpor. This strain variation could be used to critically test whether lower T(b) is a covariate of life extension during DR.