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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online April 8, 2003 as doi:10.1096/fj.02-0819fje. |
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Department of Pathology and Gerontology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki City 852-8523, Japan
2Correspondence: Department of Pathology & Gerontology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki City 852-8523, Japan. E-mail: shimo{at}net.nagasaki-u.ac.jp
SPECIFIC AIMS
Reduction of growth hormone (GH) insulin-like growth factor 1 (IGF-1) axis and caloric restriction (CR) may produce a similar milieu that promotes survival in mammals. This study was conducted to elucidate whether the reduced GH-IGF-1 axis and CR affect life span and pathologies by similar or different mechanisms in a transgenic rat model in which the GH-IGF-1 axis was selectively suppressed by overexpression of the antisense GH transgene (tg).
PRINCIPAL FINDINGS
1. Rats heterozygous for the transgene had a dwarf phenotype comparable to that of control CR rats
Transgenic offspring expressed the rat GH anti-sense RNA in the pituitary gland, spleen, and thymus but not in the lung, liver, heart, kidney, or testis. In the present study, heterozygous (tg/-) male rats for the transgene, which had a longer life span, and control nontransgenic male Wistar (-/-) rats were used; homozygous (tg/tg) rats were not included due to their premature death from neoplastic diseases. Heterozygous (tg/-) rats and control nontransgenic (-/-) rats were subjected to CR (30% restriction of mean food intake in each rat group fed ad libitum (AL)) from 6 wk of age or fed AL throughout life.
Long-lived heterozygous rats fed AL [tg/-(AL)] manifested a dwarf phenotype comparable to that of control rats subjected to CR [-/-(CR)]. The amount of food intake, body weight, and plasma concentrations of IGF-1, insulin, and glucose in tg/- (AL) rats were similar, though not completely equivalent, to those in -/- (CR) rats. CR further decreased plasma concentration of IGF-1, food intake, and body weight in tg/- rats, but not the plasma concentration of insulin or glucose.
2. Transgenic rats had a life span similar to that of control CR rats, but CR exhibited not only a greater effect in life span extension but also an additive effect on life span in the transgenic rats
Life span was extended in tg/- (AL) rats by 10.0% at 25th and 10th percentile survival points and 10.7% and 17.8% in -/- (CR) rats compared with those in -/- (AL) rats. The survival curve in tg/- (AL) rats did not statistically differ from that in -/- (CR) rats by a log-rank test. However, multivariate analysis with Cox proportional hazards models estimated that the hazard ratios for mortality were 0.40 (95% confidence interval (CI), 0.27 to 0.59; P<0.0001) for CR and 0.59 (CI, 0.40 to 0.85; P<0.005) for the transgene, indicating a greater life-prolonging effect of CR. Life span was extended in tg/- (CR) rats by 20.7% and 29.5% at 25th and 10th percentile survival points compared with those in -/- (AL) rats, indicating the life-prolonging effect of CR in tg/- (AL) rats was simply additive.
3. The preventive effect of CR on diseases was greater than that in transgenic rats
Pathologic data were accumulated by autopsy in the longevity group of rats. Results were presented only for pituitary adenoma, chronic nephropathy, and cardiac thrombus (Fig. 1
), because these were potentially lethal and prevalent in aged rats.
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The prevalence of selected diseases was decreased by CR, although statistically insignificant in pituitary adenoma (P=0.0912). There was no reduction in the prevalence of pituitary adenoma in tg/- (AL) rats vs. that in -/- (AL) rats; the prevalence was decreased in -/- (CR) rats compared with tg/- (AL) rats. The preventive effect of CR on nephropathy and cardiac thrombus seemed to be greater than that of the reduced GH-IGF-1 axis. CR in tg/- rats significantly reduced the prevalence of those diseases.
CONCLUSIONS AND SIGNIFICANCE
Genetic mutations in mice that reduce the plasma concentration of IGF-1 and result in a dwarf phenotype are associated with a longer life span. We extended the paradigm using a transgenic rat model in which the GH-IGF-1 axis was selectively suppressed by overexpression of antisense GH gene. Long-term caloric restriction, which extends life span in laboratory animals, reduces the plasma concentration of IGF-1 and results in a dwarf phenotype. We therefore tested the hypothesis that CR extends the life span in animals by suppression of the GH-IGF-1 axis by comparing some biomarkers of aging, life span, and pathologies in CR rats with those in the transgenic rats.
The present findings of food intake, body weight, and plasma IGF-1 indicated that the transgenic rats manifested a dwarf phenotype similar, although not completely equivalent, to that of CR rats. The present findings of life span and pathologies, however, indicated that the effect of CR was slightly greater than that of the reduced GH-IGF-1 axis and that there was an simply additive effect on life span extension when long-lived tg/- rats were subjected to CR. The present pathologic analyses support this notion. These imply that CR affects aging and longevity by mechanisms other than suppression of the GH-IGF-1 axis, although CR might exhibit its effect partly through the reduced GH-IGF-1 axis.
To date, only one study has reported that the effect of CR on life span in Ames dwarf mice in which pituitary GH, prolactin, and thyroid-stimulating hormone are nearly absent due to mutation of the prop-1 gene. Although a decrease in plasma GH and IGF-1 are thought to be more important for life span extension, deficiency of PRL, TSH, or both might affect the life span. The present study is the first report testing the effect of CR on a mammalian model in which the GH-IGF-1 axis is selectively suppressed by the transgene. The present data on a reduction in plasma glucose and insulin in the transgenic rats suggest a similarity between daf-2 and age-1 mutants in nematodes for the insulin signaling pathway. In this sense, the present transgenic rat model can be used to elucidate a role for insulin or IGF-1 or their overlapping signaling pathways in the modulation of longevity in mammals.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-0819fje; to cite this article, use FASEB J. (April 8, 2003) 10.1096/fj.02-0819fje 
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