Senior Researcher, Department of Carcinogenesis and Oncogerontology N.N. Petrov Research Institute of Oncology Pesochny-2, St.Petersburg, Russia

2016 - Metformin and rapamycin as geroprotectors and anti-carcinogens

V.N. Anisimov, I.G. Popovich, M.L.Tyndyk, P.A. Egormin, M.N. Yurova, V.V. Bekusova Department of Carcinogenesis and Oncogerontology, N.N.Petrov Research Institute of Oncology, Pesochny-2, St.Petersburg 197748, Russia

In a number of experiments we studied the effects of antidiabetic biguanides and rapamycin on biomarkers of aging, life span, spontaneous and chemically-induced carcinogenesis in outbred, inbred and transgenic HER-2/neu mice and in rats. The mTOR inhibitor rapamycin prevents age-related weight gain, decreases rate of aging, increases life span and decreases carcinogenesis in transgenic HER-2/neu cancer-prone mice. Rapamycin dramatically delayed tumors onset, decreased a number of tumors per animal and tumor size. Lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 years. Importantly, rapamycin was administrated intermittently (every other 2 weeks) starting from the age of 2 months. Rapamycin inhibited age-related weight gain, decreased aging rate, increased lifespan and delayed spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group. Treatment of female outbred SHR mice with metformin started at the age of 3 months increased mean life span by 14% and maximum life span by 1 month. Same treatment started at the age of 9 months insignificantly increased mean life span by 6%, whereas treatment started at the age of 15 months failed to increase life span. Thus, in female SHR mice, metformin slowed down aging and somewhat postponed appearance of tumors when started at the young and middle but not at the old age. Yet, metformin improved reproductive function when started at any age. The chronic treatment of inbred 129/Sv mice with metformin 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 sligtly increased the mean life span of female mice. The treatment with metformin failed influence spontaneous tumor incidence in male 129/Sv mice and decreased by 3.5 times the incidence of malignant neoplasms in female mice. Metformin increased mean life span by 8% and mammary adenocarcinoma (MAC) latency by 13.2% (p<0.05) in transgenic HER2/neu mice. We also have shown that phenformin or metformin inhibits 1,2-dimethylhydrazine-induced colon carcinogenesis in rats, X-rays, N-nitrosomethylurea- or 7,12-dimethylbenz(a)anthracene-benzo(a)pyrene-induced mammary carcinomas in rats, cervicovaginal, skin and soft tissue tumorigenesis in mice. These results suggest that both metformin and rapamycin may be useful in prevention of cancer and extension of lifespan when used in rational and appropriate ages, doses and schedules.