エネルギー制限食によるマウスの老化遅延と腫瘍発生の抑制の機序に関する研究

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Although it has long been known that energy restriction (ER) inhibits tumors and retards aging in rats and mice, its mode of action remains unknown. In rodents, ER alters the rate of age-related changes in physiological indices. Thus, it affects a broad array of age-sensitive parameters. However, present evidence does not indicate which parameters are primary contributors to the deceleration of aging.Compared to fasting or short-term underfeeding, little is known about the metabolic effects of long-term, life-prolonging ER. We thus investigated the effects of ER on hepatic enzyme activities, including drug-metabolizing enzymes and antioxidant enzymes such as superoxide dismutase and catalase. The catalase activity was found to be higher in ER mice than in control mice both at 12 and 24 months of age. In accord with the high catalase activity, lipid peroxidation in liver was much less in ER mice than in age matched control mice. β-Naphthoflavone, known to induce P-450 related enzymes and xanthine oxidase, was given (ip) to increase lipid peroxidation. The ER was found to inhibit lipid peroxidation after β-naphthoflavone treatment. It was, therefore, concluded that long-term life-prolonging ER increases antioxidant defence, supporting indirectly the free radical theory of aging.It is well known that ER delays puberty in rodents and has a profound influence on serum hormone levels, including those of prolactin (PRL) and thyroid hormones. However, it remains unknown how these effects are produced by ER. We therefore investigated the effects of ER on the islets of Langerhans in the pancreas and on the pituitary-ovarian axis. In the islets of Langerhans, ER was found to increase the density of α-cells significantly both in 11-and 67-week-old mice. In the pituitary gland in ER mice, the cellular density of PRL-producing cells diminished significantly while that of growth-hormone-producing cells did not. One of the modes of action of ER on the endocrine system is thus concluded to be mediated by changing cellular prpulation.Since ER decreased PRL-producing cells and PRL plays a key role in mammary tumorigenesis, we investigated whether ER decreased the gene expression of mouse mammary tumor virus (MMTV) in SHN/C3H mice. The SHN strain, which was found to have a new MMTV provirus locus, mtv-4, was used in the study. All of the control mice (n=32) died by 28 months of age and 69 percent of the mice had developed mammary tumors, while 87 percent of the ER mice (n=33) survived and none had developed mammary tumors by that time. mRNA levels of MMTV, both in mammary glands and in uteri, were found to be much lower in the ER mice than in the control mice. Thus, it was concluded that ER suppressed the gene expression of MMTV.In conclusion, ER was demonstrated to have diverse physiological effects, indicating that ER creates a new steady state, which results in the deceleration of aging (the steady-state hypothesis). Three aspects-effects of ER on growth factors, research on energy-responsive regulatory elements and roles of retroviruses in aging-appear worth investigating in the future.
日本衛生学会の論文

エネルギー制限食によるマウスの老化遅延と腫瘍発生の抑制の機序に関する研究

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