Experiment
Dietary restriction (DR), one of the most robust life-extending manipulations, is usually associated with reduced adiposity. This reduction is hypothesized to be important in the life-extending effect of DR, because excess adiposity is associated with metabolic and age-related disease. Previously, the authors described remarkable variation in the lifespan response of 41 recombinant inbred (RI) strains of mice to DR, ranging from life extension to life shortening. Here, the authors used this variation to determine the relationship of lifespan modulation under DR to fat loss.
The whole-body-composition analysis was conducted using quantitative magnetic resonance (QMR) machine (Echo Medical System, Houston, TX, USA) (Tinsley et al., 2004). Across 41 ILSXISS RI strains, DR life extension correlated inversely with fat reduction, measured at midlife (males, r = -0.41, P < 0.05, n = 38 strains; females, r = -0.63, P < 0.001, n = 33 strains) and later ages. Thus, strains with the least reduction in fat were more likely to show life extension, and those with the greatest reduction were more likely to have shortened lifespan.
The DR strain means for fat mass, lean mass, and lifespan were regressed on their respective AL means (Rikke et al., 2010). The phenotypic data (the mean of each strain and group) were subjected to a QTL mapping using Map Manager QTXb20 (http://www.mapmanager.org/mmQTX.html) (Manly et al., 2001). The program uses marker regression and an additive regression model to detect genetic loci influencing complex traits. The strain distribution pattern of 330 simple sequence length polymorphism (SSLP) markers was used in the QTL analysis. The positions of these microsatellite markers were updated using the Mouse Genome Database (http://www.informatics.jax.org/) as of January 2010).
In males, the authors identified two significant QTL affecting DR fat mass (genome coordinates relative to NCBI37/mm9):
Fdr1 (fat response to DR, QTL 1) maps to Chr 7: 16.5 - 39.7 cM with a peak LOD score of 3.4 at 28.1 cM (D7Mit91). The ISS allele was associated with greater fat mass at Fdr1.
Fdr2 (fat response to DR, QTL 2) maps to Chr 8 with a peak LOD score of 3.3 at 58 cM (D8Mit200). The ISS allele was associated with lower fat mass at Fdr2.
For AL (ad libitum) mice, the authors identified a significant QTL affecting female lifespan:
Ls3 (lifespan 3) maps to Chr 1: 56.8 - 62.7 cM with an effect size of ~18%).
Several suggestive QTL were identified and are listed in Table 2 of the manuscript.
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