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 resemble 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. Here we show the chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice. On the other side, treatment with metformin failed influence blood estradiol concentration and spontaneous tumor incidence in female SHR mice. Thus, antidiabetic biguanide metformin dramatically extends life span, even without cancer prevention in this model.

Hyperglycemia and hyperinsulinemia accelerate both aging and cancer. Antidiabetic biguanides such as metformin decrease glucose, insulin and IGF-1 level. Metformin increases lifespan and prevents cancer in mice, although its effects vary, depending on mice strain and gender. Here we showed that chronic treatment of female outbred SHR mice with metformin started at the age of 3, 9 or 15 months decreased body temperature and postponed age-related switch-off of estrous function. Surprisingly, metformin did not affect levels of serum cholesterol, triglycerides, glucose and insulin. Treatment with metformin started at the age of 3 months increased mean life span by 14% and maximum life span by 1 month. The treatment started at the age of 9 months insignificantly increased mean life span by only 6%, whereas the treatment started at the age of 15 months failed to increase life span. The mean life span of tumor-free mice was increased by 21% in ‘the youngest group’, by 7% in ‘middle-aged group’ and in contrast was reduced by 13% in ‘the oldest group’. When started at the age of 3 and 9 months, metformin delayed the first tumor detection by 22% and 25%, correspondingly. Thus, in female SHR mice, metformin increased life span and postponed tumors when started at the young and middle but not at the old age. In contrast, metformin improves reproductive function when started at any age.

Aging is associated with obesity and cancer. Calorie restriction both slows down aging and delays cancer. Evidence has emerged that the nutrient-sensing mammalian target of rapamycin (mTOR) pathway is involved in cellular and organismal aging. Here we show that the mTOR inhibitor rapamycin prevents age-related weight gain, decreases rate of aging, increases lifespan, and suppresses carcinogenesis in transgenic HER-2/neu cancer-prone mice. Rapamycin dramatically delayed tumor onset as well as decreased the number of tumors per animal and tumor size. We suggest that, by slowing down organismal aging, rapamycin delays cancer.

(2010) Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo, Cell Cycle, 9:1,[188][189][190][191][192][193][194][195][196][197]

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.

The effect of the mitochondria-targeted, plastoquinone-containing antioxidant SkQ1 on the lifespan of outbred mice and of three strains of inbred mice was studied. To this end, low pathogen (LP) or specific pathogen free (SPF) vivaria in St. Petersburg, Moscow, and Stockholm were used. For comparison, we also studied mole-voles and dwarf hamsters, two wild species of small rodents kept under simulated natural conditions. It was found that substitution of a LP vivarium for a conventional (non-LP) one doubled the lifespan of female outbred mice, just as SkQ1 did in a non-LP vivarium. SkQ1 prevented age-dependent disappearance of estrous cycles of outbred mice in both LP and non-LP vivaria. In the SPF vivarium in Moscow, male BALB/c mice had shorter lifespan than females, and SkQ1 increased their lifespan to the values of the females. In the females, SkQ1 retarded development of such trait of aging as heart mass increase. Male C57Bl/6 mice housed individually in the SPF vivarium in Stockholm lived as long as females. SkQ1 increased the male lifespan, the longevity of the females being unchanged. SkQ1 did not change food intake by these mice. Dwarf hamsters and mole-voles kept in outdoor cages or under simulated natural conditions lived longer if treated with SkQ1. The effect of SkQ1 on longevity of females is assumed to mainly be due to retardation of the age-linked decline of the immune system. For males under LP or SPF conditions, SkQ1 increased the lifespan, affecting also some other system(s) responsible for aging.

Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosyl)ation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosyl)ation and PARP-1 may also play an important role in aging. Here we show that PARP-1−/− mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP-1−/− mice. The incidence of spontaneous tumors in both PARP-1−/− and PARP-1+/+ groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP-1−/− mice than PARP-1+/+ mice (72% and 49%, resp.; P < .05). In addition, spontaneous tumors appear earlier in PARP-1−/− mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.