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Edison Biotechnology Institute (K.T.C., L.L.B., J.J.K.), Ohio University, Athens, Ohio 45701; Division of Endocrinology and Metabolism (D.C.), Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7170; Molecular and Cellular Biology Program, Ohio University (L.L.B., J.J.K.), Athens, Ohio 45701; and Department of Biomedical Sciences (J.J.K.), College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701
Address all correspondence and requests for reprints to: Dr. John J. Kopchick, Edison Biotechnology Institute, Ohio University, 101 Konneker Research Laboratories, The Ridges, Athens, Ohio 45701. E-mail: kopchick{at}ohio.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Protein and RNA transcripts for receptors of GH (GHR) have been detected in many of the tissues influenced by the hormone (4, 5, 6, 7). It was determined that a single molecule of GH binds sequentially to two receptor molecules, forming an active complex (8). This complex, in turn, signals stimulation of other genes, including insulin-like growth factor I (IGF-I). IGF-I, produced and secreted by the liver and other target tissues, mediates some of the indirect effects of GH on growth and development (9, 10). Other intracellular events occurring after the GH/GHR interaction include activation of tyrosine kinases such as Janus kinase 2 (Jak-2), which leads to phosphorylation and activation of other proteins including signal transducer and activator of transcription 5A (STAT 5A) and mitogen activated protein (MAP) kinase that, in turn, activate other proteins and genes (2, 11).
The cDNA encoding the GHR has been cloned from many species (5, 6). The receptor consists of an extracellular hormone-binding region (exons 2–7), a single membrane spanning region (exon 8), and an intracellular region (exons 9–10) (12). GHR has no intrinsic kinase domain, but the intracellular region plays a major role in the signal transduction process (13). A truncated form of the receptor, known as GH binding protein (GHBP), lacks the transmembrane and intracellular regions of GHR and is secreted into the serum (14). The truncated protein is produced by one of two different processes, depending on the animal species. In mice and rats, alternative splicing of GHR precursor messenger RNA replaces the transmembrane and intracellular regions with a very short hydrophilic tail (encoded by exon 8A; 15, 16). In humans, cows, and pigs (among others), no alternative RNA splicing is apparent but instead the GHBP is produced by proteolysis of the GHR (17). The function of the binding protein is not clear, but it appears to modulate the level of circulating GH (18).
In an attempt to understand the actions of GH, an animal that is resistant to GH action would be of value. Previously, we generated GH resistant animals by expression of a GH antagonist gene in transgenic mice (19, 20, 21, 22). These mice are smaller than control mice, with reduced levels of IGF-I. They also are resistant to diabetes-induced end organ damage (23). In an alternative approach, we disrupted the mouse GHR/BP gene, mimicking the primary defect causing Laron syndrome in humans (24). Mice homozygous for the gene disruption are smaller in size with reduced levels of IGF-I but increased levels of GH. We have recently demonstrated that these mice are also resistant to diabetes-induced end organ damage (25).
One question that has remained controversial is the role of GH in aging. It has been reported that dwarf mice deficient in GH have longer life expectancies (26). However, the mice used in those studies also had other hormonal deficiencies. We have extended our initial investigations to assess the combined effects of the GHR/BP gene disruption and advancing age on weight gain, IGF-I and IGF binding protein (IGFBP) levels, and longevity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Weight gain profiles
Progeny of multiple +/- x +/- matings were
weighed at weekly intervals starting at weaning (four weeks of age).
Mean weights for each mouse were calculated at 4-week intervals (termed
weighing intervals) for statistical analysis. Thus, mice averaged 5.5
weeks of age for weighing interval 1, 9.5 weeks of age for weighing
interval 2, etc. Means of the weighing interval means were determined
and plotted for each gender (male and female) and genotype (+/+, +/-,
-/-). One -/- male was excluded from the final analysis since his
weight differed from the mean by greater than 2 standard deviations
(SD) from the age of 5 weeks onward.
Plasma IGF-I measurements
Blood was collected into heparinized tubes from the tails of
five mice of each gender (male and female), genotype (+/+, +/-, and
-/-), and age (averaging 1, 10 and 23 months). After centrifugation,
the plasma was transferred to a new tube and stored at -20 C. IGFBPs
were removed from duplicate samples using an acid-ethanol extraction
kit essentially as described by the manufacturer (Nichols Institute Diagnostics, San Juan Capistrano, CA) except that
extractions were scaled down 20-fold and the total dilution for samples
from -/- mice was only 25-fold, whereas the total dilution for
samples from +/+ and +/- mice was the standard 225-fold. These
changes were necessary due to the reduced body size and, thus, reduced
blood volume of the -/- mice as well as due to the extremely low
levels of IGF-I in the -/- mice. Tests were performed to ensure that
the results were not altered by the changes. IGF-I levels were measured
using a human IGF-I RIA kit with human IGF-I standards (Nichols Institute Diagnostics, San Juan Capistrano, CA). Values between
assays were normalized by use of two control plasma samples included in
each assay. Means were determined for each gender, genotype and
age.
Plasma IGFBP analysis
Blood was collected into heparinized tubes from the tails of
60-day-old male and female +/+, +/- and -/- mice. After
centrifugation, the plasma was transferred to a new tube and stored at
-20 C. IGFBP levels were assessed by ligand blotting (28) and
quantified by scanning densitometry (29).
Longevity analysis
An average lifespan was calculated for +/+, +/- and -/- male
and female mice using mice born between July and December of 1996 that
had spontaneously died.
Statistical analyses
Weights at specific time points or as differences between two
time points, as well as lifespans, initially were analyzed by two-way
(genotype x gender) ANOVA using Quick Statistica for Macintosh
(StatSoft; Tulsa, OK). IGF-I levels initially were analyzed by
three-way (genotype x gender x age) ANOVA. As no
statistically significant interactions (P < 0.05) were
observed, significant main effects of independent variables were
analyzed by one-way ANOVA followed by posthoc comparisons using
Tukey’s HSD test, collapsing across the other independent variable(s)
when it was not differing significantly or separately when it was
differing significantly. Student’s t test for nonpaired
samples was used to assess age of attainment of final weight and also
IGFBP-3 levels.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2). At 4 weeks of age, which was when the
pups were weaned and this study initiated, weights did not differ
significantly between genders or between +/+ and +/- mice, but
-/- mice weighed significantly less than +/+ mice (
45% less;
P < 0.0002).
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). Significant differences were seen between
male and female +/+ mice (P < 0.004) and male and
female +/- mice (P < 0.02), but not between male
and female -/- mice, indicating a loss of gender difference in the
-/- mice. For both genders, the rates of growth for +/+ and +/-
mice did not differ, but the -/- mice grew significantly slower
(P < 0.0002).
Although they have a slower rate of growth, it might be expected that
the -/- mice eventually attain a final weight similar to +/+ mice but
that it just takes longer. However, this was not observed. In fact,
-/- mice reached their maximum weight at an earlier age than did the
+/+ and +/- mice (Fig. 2). Male -/- mice reached their maximum
weight at weighing interval 3 (an average age of 14 weeks), whereas
male +/+ mice reached their maximum weight 28 weeks later (weighing
interval 10). Female -/- mice reached their maximum weight at
weighing interval 8 (an average age of 34 weeks), whereas female +/+
mice reached their maximum weight 12 weeks later (weighing interval
11). Heterozygous mice reached plateaus at weighing interval 8 for
males and weighing interval 11 for females. The maximally attained
weights, analyzed at weighing interval 20, did not differ significantly
between genders or between +/+ and +/- mice, but -/- mice were
significantly smaller (P < 0.0002), attaining a final
weight that was approximately 40% that of +/+ mice.
IGF-I levels remain significantly lower in GHR/BP -/- mice than
in +/+ and +/- mice
As indicated by the decrease in body size, GHR/BP
gene-disrupted -/- mice of both genders have severely reduced levels
of plasma IGF-I, measured at less than 10% the levels found in +/+
mice (Fig. 3). A small but significant
difference between +/+ and +/- mice was also observed
(P < 0.005), mainly driven by the difference in levels
at 10 months of age. There were no significant differences seen between
genders or with age, although there was a slight tendency for +/+
levels to decrease and -/- levels to increase at the 23-month time
point.
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and Table 1). As no significant changes in IGF-I
levels were seen at different ages for the gene-disrupted mice, the
IGFBP profile was examined at a single age of 60 days. Ligand blotting
using radiolabeled IGF-I revealed no changes in plasma levels of
IGFBP-1, IGFBP-2, and IGFBP-4 in 60-day-old mice, but a severe
reduction in IGFBP-3 levels was detected in male and female -/-
mice (Fig. 4). Scanning densitometry of the IGFBP profiles indicated an
approximately 20-fold decrease in IGFBP-3 levels in -/- mice in
comparison to +/+ mice (P < 0.001; Table 1). Levels of
IGFBPs, including IGFBP-3, in +/- mice were similar to +/+ mice
and thus were not extensively analyzed.
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). Statistical analysis
indicated that males and females had similar lifespans. There were also
no differences in lifespans of +/+ and +/- mice, but a
significant increase in lifespan of nearly a year was observed for
-/- mice (P < 0.0002). Thus, loss of one GHR/BP
allele had no effect on lifespan but loss of both GHR/BP alleles
resulted in a significant extension of lifespan, regardless of
gender.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Even though in previous experiments we had shown little difference between GHR/BP +/+ and +/- mice (24), we included the +/- mice in our present study to characterize them more extensively. Once again, in all the parameters tested, there was little difference between +/+ and +/- mice. This further supports the observation that only one functional GHR/BP allele is necessary for full GHR/BP activity.
An area of study that has received limited attention in isolated GH-deficient animal models is an assessment of longevity. Alterations in longevity, or life expectancy, cannot easily be assessed in humans, but this is not the case in mice. We show here that the lifespan of -/- mice is significantly increased in comparison to +/+ and +/- mice. This analysis is the first documented study of life expectancy in animals or humans with mutations that cause isolated GH deficiency or altered/disrupted GH signaling. These results are in agreement with the increased longevity seen in hypophysectomized rats that were provided replacement therapy with glucocorticoids or thyroxine and seen in Ames and Snell dwarf mice as well as humans that are deficient in GH, PRL, and TSH (reviewed in Refs. 26, 31). The results implicate GH deficiency as the major factor in increased longevity and suggest use of a cautionary approach to the therapeutic administration of GH, especially as an anti-aging agent, until more studies can be completed.
Although the GHR/BP -/- mice appear to have a longer life expectancy, it is not clear whether they have a prolonged senescence or whether their entire development proceeds more slowly. We had previously observed that the first conception was somewhat delayed in matings between GHR/BP -/- males and females (24). Danilovich et al. (32) further examined the GHR/BP -/- females and found that their sexual maturity was delayed by approximately one week. These results suggest that the GHR/BP -/- mice may age more slowly than their +/+ counterparts, but this hypothesis needs to be further tested.
While the mechanism of aging remains elusive, one aging theory purports that exposure to growth factors and the rate of decline in reserve capacity influence lifespan (33). Support of this comes from caloric restriction studies in mammals, which result in decreased exposure to growth stimulus (e.g. GH, IGF-I, and insulin) and an increase in lifespan (33). At the molecular level, in addition to the GHR/BP gene disruption results presented here, two other genes have been identified that suggest involvement of the GH signaling pathway in determination of lifespan. daf-2, an insulin receptor-like gene from Caenorhabditis elegans, controls growth in a manner that may be homologous to the mammalian IGF-I receptor that acts downstream of GHR in the GH signaling pathway (34). Mutation of daf-2 results in a marked increase in longevity (34). To distinguish direct effects of GH from effects of IGF-I, it would be interesting to add back IGF-I to the GHR/BP -/- mice, either genetically or by IGF-I administration, and assess the effect on aging. In another report, gene disruption of the p66shc gene in mice results in an increased lifespan (35). It also enhances resistance to environmental stresses such as UV light and reactive oxygen species (35). The authors cite an expanding list of references that suggest a correlation between enhanced resistance to environmental stresses and an extended lifespan. It is of interest to note that GH regulates the phosphorylation status of two other SHC proteins, p52shc and p46shc (36). If disruption of either of these genes also resulted in enhanced resistance to environmental stresses, the same could hold true for disruption of the GHR/BP gene and GH signaling. Testing the resistance of the GHR/BP gene-disrupted mice to environmental stress would support or refute this idea.
In summary, disruption of the gene for GHR/BP results in -/- mice that are significantly smaller than their +/+ and +/- littermates. This difference, as assessed by weight gain, as well as their IGF-I levels, remains constant well into old age. IGFBP-3 levels are also significantly reduced in the GHR/BP -/- mice. Despite, or perhaps as a result of, their decreased growth, GHR/BP -/- mice have a longer life expectancy. Further experiments are in progress to elucidate the role of GH in aging.
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Acknowledgments |
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Footnotes |
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Received February 14, 2000.
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