Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels

Abstract

To better characterize aging in mice, the Jackson Aging Center carried out a lifespan study of 31 genetically-diverse inbred mouse strains housed in a specific pathogen-free facility. Clinical assessments were carried out every 6 months, measuring multiple age-related phenotypes including neuromuscular, kidney and heart function, body composition, bone density, hematology, hormonal levels, and immune system parameters. In a concurrent cross-sectional study of the same 31 strains at 6, 12, and 20 months, more invasive measurements were carried out followed by necropsy to assess apoptosis, DNA repair, chromosome fragility, and histopathology. In this report, which is the initial paper of a series, the study design, median lifespans, and circulating insulin-like growth factor 1 (IGF1) levels at 6, 12, and 18 months are described for the first cohort of 32 females and 32 males of each strain. Survival curves varied dramatically among strains with the median lifespans ranging from 251 to 964 days. Plasma IGF1 levels, which also varied considerably at each time point, showed an inverse correlation with a median lifespan at 6 months (R = -0.33, P = 0.01). This correlation became stronger if the short-lived strains with a median lifespan < 600 days were removed from the analysis (R = -0.53, P < 0.01). These results support the hypothesis that the IGF1 pathway plays a key role in regulating longevity in mice and indicates that common genetic mechanisms may exist for regulating IGF1 levels and lifespan.

Figure 1

Strain selection. The mouse family tree was generated by Petkov et al. (2004). Strains involved in this study are framed. † NOD/LtJ (NOD) is susceptible to diabetes so we substituted the diabetes-resistant strain NOD.B10Sn-H2^b/J (NOD.B10), which was generated by transferring the diabetes-resistant major histocompatibility locus H2^b haplotype from the C57BL/10J (B10) to the NOD strain. Δ We used the PWD/PhJ (PWD) instead of the related PWK/PhJ strain; both were inbred from wild M. m. musculus pairs caught in the central Czech Republic.

Figure 2

Survival curves.

Figure 3

A. Correlation of female and male median lifespans. B. Correlation of female and male IGF1 levels. IGF1 was measured at 6 (circles), 12 (squares) and 18 (rectangles) months; closed symbols indicate the IGF1 levels that were significantly different between female and male mice of the same strain.

Figure 4

Correlation of median lifespans with IGF1 levels. IGF1 was measured at 6-(A), 12- (B), or 18-(C) months. Females and males are indicated by circles and rectangles. Solid symbols are strains with median lifespans less than 600 days; open symbols are strains with median lifespan greater than 600 days. Correlations are given for all strains (solid line), strains with median lifespan less than 600 days (dashed line), or strains with lifespan greater than 600 days (dotted line).