No abstract

Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which mimetic effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. Antidiabetic biguanides are most promising among them. The chronic treatment of inbred 129/Sv mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but failed to influence the dynamics of body weight, decreased by 13.4% the mean life span of male mice and slightly increased the mean life span of female mice (by 4.4%). The treatment with metformin failed influence spontaneous tumor incidence in male 129/Sv mice, decreased by 3.5 times the incidence of malignant neoplasms in female mice while somewhat stimulated formation of benign vascular tumors in the latter.

SummaryA new abnormal, variant, plasminogen Chicago III has been isolated from a patient with recurring deep vein thrombosis. Studies on the plasma fibrinolytic system of four family members showed no inheritance pattern. Kinetics of activation parameters of Chicago III plasminogen with different activators showed lowered catalytic rate constants from 159fold with urokinase, to 3fold with light (B) chain ‧ streptokinase complex, to 1.3fold with streptokinase. The Michaelis constants of activation of Chicago III plasminogen were 16fold higher with streptokinase, 6fold higher with light (B) chain ‧ streptokinase complex, and similar with urokinase. Each of the three activators exhibited different interaction characteristics with this variant zymogen, as they did with variant Chicago I and Chicago II plasminogens (previously reported). However, the latter variants were characterized by having normal catalytic rate constants of activation, with higher than normal apparent Michaelis constants of activation. Chicago III plasminogen, as well as Chicago I and II plasminogens, has a homogeneous population of molecules; the interpretation of the kinetic data was possible only in terms of a single population of molecules. The plasmins derived from Chicago I plasminogen, and also Chicago II and Chicago III plasminogens, have 100% active sites with normal amidase parameters. Basically, a single population of normal isoelectric forms were found in the Chicago III plasma, with three minor forms, about 11% of the total.The kinetic parameters have permitted us to classify the four known plasminogen variants into three different classes. The Class A homozygote (Tochigi) has both an active center defect and a charge mutation difference with normal cleavage of the Arg560-Val peptide bond; the Class B homozygote (Chicago I and Chicago II) has a Km of activation defect with impaired activator binding and normal cleavage of the Arg560-Val peptide bond; and, the Class C homozygote (Chicago III) has both a Km of activation defect with impaired activator binding and a kcat of activation defect, and impaired Arg560-Val peptide bond cleavage.

No abstract

There have been some observations that low body weight and a low level of some hormones (e.g. IGF-1) during the first half of life are predictors of longer life in mice. However, contradictions in the available data on the biomarkers of aging and predictors of longevity have shown that the research in these fields has become a controversial pursuit. In our study we addressed the following questions: (i) Can particular physiological parameters (body weight, food intake, estrus function, body temperature, incidence of chromosome aberrations in bone marrow cells) measured at the age of 3 and 12 months be a predictor of longevity and the rate of tumor development in five strains of mice? (ii) Can a heavy body weight at the age of 3 and 12 months be a predictor of longevity and high tumor risk in five strains of mice? Mice of five strains-CBA, SHR, SAMR, SAMP and transgenic HER-2/neu (FVB/N)-were under observation from the age of 2 -3 months until natural death. Body weight and temperature, food consumption, and estrous cycle were longitudinally studied in all animals. Tumors discovered at autopsy were studied morphologically. We calculated the life span's parameters (mean, maximum, mortality rate, mortality rate doubling time) as well as their correlation with other parameters studied. The longest living CBA mice have the lowest body weight at the ages of 3 and 12 months, the lowest food consumption, body temperature, incidence of chromosome aberrations and spontaneous tumor incidence. In comparison with all other mouse strains they also have the latest disturbances in estrus function and highest body weight gain. The shortest living transgenic HER-2/neu mice have the lowest weight at the ages of 12 months, the lowest body weight gain, maximal body temperature, the most rapid disturbances in estrus function and the highest incidence of chromosome aberrations and tumor incidence in comparison to all other mouse strains. Our findings have shown that heavier body weight at the age of 12 months is a predictor of longevity in female CBA and SAMP mice but not in SHR, SAMR and HER-2/neu mice. Excessive body weight at the ages of 3 or 12 months is not a predictor of increased tumor risk in the strains studied. In general, the existence and direction of a significant correlation between body weight and life span depends upon the animals' age and genotype. q