Genetic modulation of hormone levels and life span in hybrids between laboratory and wild-derived mice

Abstract

Previously we showed that mouse stocks derived from wild-caught progenitors are long-lived relative to genetically heterogeneous mice derived from laboratory-adapted strains. Here we replicate this life-span effect, and show that F2 hybrids between wild-derived and laboratory-derived stocks have intermediate survival patterns. Moreover, wild-derived mice are small, lean, and slow to mature, and have low serum insulin-like growth factor-I (IGF-I) relative to genetically heterogeneous mice. These traits, too, were at intermediate levels in the F2 hybrids. Furthermore, serum IGF-I at 6 months was a significant predictor of life span in two different populations of F2 hybrid mice. Pooling across stocks, life span was negatively correlated with body weight and serum IGF-I levels, and positively correlated with age at vaginal patency and serum leptin levels. Overall, these finding suggest that wild-derived mice harbor alleles that increase longevity, perhaps through effects on growth, maturation, and early-life hormone levels.

Figure 1

Kaplan–Meier survival curves for each of the six mouse stocks. For clarity, North-Central Idaho (Id) and South Pacific Island of Majuro (Ma) mice and their hybrids have been plotted separately. Each point represents a single mouse. See Table 1 for summary statistics.

Figure 2

Weight as a function of age in each of the six stocks of mice. Each point represents the mean (± standard deviation) for each stock. N = 40–50 mice at 1 month, but due to natural deaths sample size decreased with time such that N = 17–26 at 28 months dependent upon stock. * Significant difference at p < .02 for the DC mice relative to the other stocks.

Figure 3

Life span as a function of: age at vaginal patency (top left); 2 month body weight (top right); serum insulin-like growth factor-I (IGF-I) at 6 months (bottom left); and leptin at 14 months (bottom right). See Table 5 for regression summary. Data for individual mouse stocks are as indicated in the legend in the top left panel. Each point represents an individual mouse. Regression lines were calculated by least-squares regression for all mouse stocks combined.

Figure 4

The association between life span and body weight declines with increasing age. Values on the y-axis are absolute partial correlation coefficients for body weight as a predictor of life span generated by bivariate linear regression as described. *Body weight is a statistically significant predictor of life span at each of the indicated ages (p < .03).

Figure 5

Life span as a function of serum insulin-like growth factor-I (IGF-I) at 14 months. Data for individual mouse stocks are as indicated in Figure 3. Regression lines were calculated for each stock separately by least squares regression. Dashed regression lines indicate a negative association between IGF-I and life span in DC, IdB6F2, Ma, and MaB6F2 mice. Solid regression lines indicate a positive association between IGF-I and life span in Id and IdDCF2 mice. See text for details.

Figure 6

Life span as a function of the 6-month insulin-like growth factor-I (IGF-I) level in two segregating F2 hybrid mouse stocks. Each point represents a single mouse.

Figure 7

Residuals of life span as a function of serum insulin-like growth factor-I (IGF-I) and leptin levels after adjustment for the effect of body weight at 6 months (6-month measures) or 14 months (14-month measures). Each point represents a single mouse. Each relationship is statistically significant as indicated.