The major aim of this study was to examine the pathological profile of GHR/BP KO mice to find possible explanations for their extended longevity. Because our previous report demonstrated that Ames dwarf mice show delayed occurrences of fatal neoplastic diseases with little change in the incidence of neoplastic diseases compared with their WT littermates (16
), it is of interest to compare the pathological profiles of animals with primary hormonal change due to GH/IGF-1 deficiency. Our results demonstrated that the types of pathological changes were similar for both GHR/BP KO mice and their WT littermates in both sexes, that is, no extraordinary pathological changes were evident in the GHR/BP KO mice compared with their WT littermates. The major neoplastic lesions seen in GHR/BP KO mice and their WT littermates were lymphoma, adenocarcinoma in lung, hepatocellular carcinoma, and hemangioma in liver or spleen. The major nonneoplastic lesion found was glomerulonephritis, which develops as an animal ages. The percentage of tumor-bearing mice (the percentage of mice having neoplastic lesions in each group) was 22% lower for the GHR/BP KO mice than for their WT littermates. Also, the tumor burden (the number of different tumors found in a mouse) was significantly less (47.5% less) in GHR/BP KO mice compared with their WT littermates. GHR/BP KO mice also showed a significantly lower incidence of fatal neoplastic lesions compared with the WT littermates. In addition to the reduced incidence of total neoplastic lesions, incidences of fatal lymphoma and fatal adenocarcinoma in lung were significantly lower than in the WT littermates, which could indicate that tumorigenesis of lymphoma and pulmonary adenocarcinoma are GH/IGF-1 dependent. Thus, these data indicated that GHR/BP KO mice showed an overall suppressed occurrence of tumor development compared with their WT littermates. The changes found in the neoplastic lesions in GHR/BP KO mice were more similar to the effects of calorie restriction (CR) (17
) than to the results from studies of Ames dwarf mice, which showed little influences on the percentage of tumor-bearing mice, tumor burden, and incidence of fatal neoplasms (16
). In addition to the suppressed occurrence of neoplastic lesions, fatal neoplastic disease was shown to occur later in life in GHR/BP KO mice, and the severity of adenocarcinoma in these mice was significantly less compared with their WT littermates, indicating that the lack of GH action in GHR/BP KO mice seemed to delay the progression of fatal neoplastic disease.
GHR/BP KO mice also showed a delayed progression of nonneoplastic lesions. The severity of glomerulonephritis was significantly less in GHR/BP KO mice compared with their WT littermates, which also indicated that the progression of glomerulonephritis in GHR/BP KO mice is delayed, similar to that in Ames dwarf mice (16
). Furthermore, compared with their WT littermates, GHR/BP KO mice showed a significantly lower disease burden and a slower age-related accumulation of various pathological changes, suggesting that GHR/BP KO mice maintained organ and whole-body integrity during aging. This implication is also supported by evidence showing that approximately 47% of GHR/BP KO mice had no obvious evidence of lethal pathology at death, which we commonly see in Ames and Snell dwarf mice (16
) and CR C57BL/6 mice (23
The pathological profile of the GHR/BP KO mice in this study showed more similarities to the effects of CR than to the pathological profile of Ames dwarf mice. Although Ames dwarf mice show the delayed occurrence of fatal neoplastic lesions, the incidence of neoplastic disease is affected little in these mice, which is different from the effects of CR in C57BL/6J mice (17
) and from the GHR/BP KO mice studies here. The data obtained from studies of these three long-lived animals may provide us with an opportunity to dissect the possible common underlying anticancer and antiaging mechanism(s) of these animal models.
The common endocrine change among GHR/BP KO, Ames dwarf, and CR mice is suppressed levels of peripheral IGF-1 due to GH resistance or insensitivity (GHR/BP KO mice), lack of GH (Ames dwarf mice), or reduced plasma GH levels (CR mice, at least initially). The change in GH action, which is associated with reduced levels of peripheral IGF-1, seem to play important roles in the delayed occurrence of fatal neoplastic lesions as well as their retarded somatic growth and smaller adult body size (7
) because IGF-1 is known for its potent mitogenic and antiapoptotic effects (24
). This idea also could be supported by some epidemiological studies that indicate possible correlations between plasma IGF-1 levels and some tumors (25
) and increased incidence and mortality from cancer by GH treatment during childhood (27
Some nonneoplastic diseases seem to be affected by changes in GH levels or action, as was shown by the lessened severity of glomerulonephritis in both the GHR/BP KO and the Ames dwarf mice (16
). Although studies of GH transgenic mice, which have pathologically high levels of GH, showed that the early death of these animals appears to be related primarily to pathological changes in the kidney [glomerulonephritis and glomerulosclerosis (24
)], IGF-1 transgenic mice did not exhibit as severe pathological changes as the GH transgenic mice (29
), indicating the important roles of GH in kidney pathology. Evidence also supports that CR rats have reduced GH levels (at least initially) (30
) and that CR F344 rats show significantly reduced severity of kidney pathology compared with their ad libitum counterparts (31
). Therefore, the reduced actions of GH/IGF-1 axis seem to play very important roles in the delayed progression of various age-related diseases and reduced disease burden in the body, which could be major contributing factors leading to the extended life span observed in these animals, including the GHR/BP KO mice.
GHR/BP KO mice showed significantly lower incidence of fatal neoplastic lesions compared with their WT littermates. This is similar to the effects of CR in mice (17
) but different from Ames dwarf mice, which showed similar incidence of fatal neoplasms compared with their WT littermates (16
). The reason(s) behind these interesting differences between GHR/BP KO, CR, and Ames dwarf mice remains to be identified. One possible explanation for these differences could be that primary changes in three major hormonal systems (somatotoropic, thyrotoropic, and lactotoropic axis), that is, the absence of three major pituitary hormones, in Ames dwarf mice may cause negative effects that counteract the anticancer actions commonly seen in long-lived animals. For example, GH and PRL have been shown to play important roles in intrathymic T-cell differentiation (32
), and earlier studies show that the immune functions of Ames dwarf mice are at subnormal levels (33
). Snell dwarf mice, another long-lived dwarf mouse due to hypopituitarism, also show suppressed B-cell development (34
). Contrary to these two dwarf mice, GHR/BP KO mice show increased plasma PRL levels (10
), which could be a compensatory mechanism because PRL and GH have some common actions. Thus, this elevated PRL level could play an important role in some of the immune functions in GHR/BP KO mice. Because cell-mediated cytotoxicity by natural killer cells is known for its destructive function of cancers cells, possible changes in immune functions could be the reason for the differences observed in the incidence of neoplastic diseases among the three long-lived animal models. Further studies are necessary to uncover the possible underlying mechanisms that could explain the differences in pathology of these animal models.
We concluded the following from this study: (i) GHR/BP KO mice had less overall incidence of neoplastic disease; (ii) GHR/BP KO mice had a significantly lower incidence of fatal neoplastic lesions, fatal lymphoma, and fatal pulmonary adenocarcinoma; (iii) GHR/BP KO mice exhibited a delayed occurrence of fatal neoplastic diseases; (iv) GHR/BP KO mice showed less severe lesions (both neoplastic and nonneoplastic) compared with their WT littermates at the time of death; (v) GHR/BP KO mice showed a reduced disease burden compared with their WT littermates at the time of death; and (vi) the pathological profiles of GHR/BP KO mice are very similar to those showing the effects of CR on age-related pathology.
We suggest that the reduced action of GH/IGF-1 axis and the subsequent pathophysiological changes could be a major underlying mechanism of life extension in long-lived animals, including GHR/BP KO, Ames dwarf, Snell dwarf, and CR mice.