Liver-derived IGF-I regulates mean life span in mice - PubMed (original) (raw)

Liver-derived IGF-I regulates mean life span in mice

Johan Svensson et al. PLoS One. 2011.

Abstract

Background: Transgenic mice with low levels of global insulin-like growth factor-I (IGF-I) throughout their life span, including pre- and postnatal development, have increased longevity. This study investigated whether specific deficiency of liver-derived, endocrine IGF-I is of importance for life span.

Methods and findings: Serum IGF-I was reduced by approximately 80% in mice with adult, liver-specific IGF-I inactivation (LI-IGF-I(-/-) mice), and body weight decreased due to reduced body fat. The mean life span of LI-IGF-I(-/-) mice (n = 84) increased 10% vs. control mice (n = 137) (Cox's test, p<0.01), mainly due to increased life span (16%) of female mice [LI-IGF-I(-/-) mice (n = 31): 26.7±1.1 vs. control (n = 67): 23.0±0.7 months, p<0.001]. Male LI-IGF-I(-/-) mice showed only a tendency for increased longevity (p = 0.10). Energy expenditure, measured as oxygen consumption during and after submaximal exercise, was increased in the LI-IGF-I(-/-) mice. Moreover, microarray and RT-PCR analyses showed consistent regulation of three genes (heat shock protein 1A and 1B and connective tissue growth factor) in several body organs in the LI-IGF-I(-/-) mice.

Conclusions: Adult inactivation of liver-derived, endocrine IGF-I resulted in moderately increased mean life span. Body weight and body fat decreased in LI-IGF-I(-/-) mice, possibly due to increased energy expenditure during exercise. Genes earlier reported to modulate stress response and collagen aging showed consistent regulation, providing mechanisms that could underlie the increased mean life span in the LI-IGF-I(-/-) mice.

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Conflict of interest statement

Competing Interests: Olle Isaksson was co-founder of Tercica Inc. that produced IGF-I for use in children of short stature. Tercica Inc. was acquired by Ipsen June 2008. Olle Isaksson has no current ownership of stocks or options in Tercica or Ipsen. None of the other authors has any conflict of interest. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1

Figure 1. Reduced body weight in LI-IGF-I-/- mice.

Body weight in A) female and B) male mice. Body weight was determined every third month during 3-30 months of age. Between 3 and 27 months of age, body weight was significantly lower in LI-IGF-I-/- compared with control mice in the total number of mice and also in the male and female subgroups (all analyses p<0.001). The vertical bars indicate the SE for the mean values shown.

Figure 2

Figure 2. Increased mean life span of female LI-IGF-I-/- mice.

A) Female LI-IGF-I-/- mice live 16% longer than female control mice (26.7 ± 1.1 vs. 23.0 ± 0.7 months, p<0.01 using unpaired _t_-test; Kaplan-Meyer analysis p<0.001, Cox's test). B) Although not statistically significant, male LI-IGF-I-/- mice live 6% longer than male control mice (23.5 ± 0.8 vs. 22.1 ± 0.7 months, p = 0.17 using unpaired t-test; Kaplan-Meyer analysis: p = 0.10, Cox's test).

Figure 3

Figure 3. Normal fertility in female LI-IGF-I-/- mice.

A) The percentage of pregnant female mice in relation to the total number of female mice in each group. B) Litter size when female LI-IGF-I-/- mice were mated with age-matched male control mice at 5 and 8 months of age (n = 12-14 in each group). The experiments showed normal fertility in female LI-IGF-I-/- mice. In Figure 3B, the error bars indicate the standard error for the mean values shown.

Figure 4

Figure 4. Increased oxygen consumption during submaximal exercise and post-exercise in LI-IGF-I-/- mice.

A) The volume of O2 consumed (VO2) and B) respiratory exchange ratio (RER) during submaximal exercise (30 min) and post-exercise (20 min) in 18-month-old female control (n = 7) and LI-IGF-I-/- (n = 7) mice. The vertical bars indicate the SE for the mean values shown. ** p<0.01 vs. control mice

Figure 5

Figure 5. Decreased mRNA levels of Hspa1a, Hspa1b, and Ctgf in LI-IGF-I-/- mice.

To confirm the microarray findings, RT-PCR analyses were performed on skeletal muscle (triceps) samples from individual mice. The RT-PCR analyses showed reduced mRNA levels of A) heat shock protein 1A (Hspa1a), B) heat shock protein 1B (Hspa1b), and C) connective tissue growth factor (Ctgf). D) IGF-I receptor mRNA level was unchanged. The mRNA levels in LI-IGF-I-/- mice (n = 7) are expressed as percent of that in control mice (n = 6). The vertical bars indicate the SE for the mean values shown.* p<0.05 ** p<0.01 vs. control mice.

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