title: Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin.
abstract: The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone--IGF-1--insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (+20%, P < 0.05) and slightly increased the maximum life span (+3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (-9.1% and -13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice.
authors.affiliation: a N.N. Petrov Research Institute of Oncology ; St. Petersburg , Russia.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Anisimov
authors.forename: Irina G
authors.initials: IG
authors.lastname: Popovich
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zabezhinski
authors.forename: Peter A
authors.initials: PA
authors.lastname: Egormin
authors.forename: Maria N
authors.initials: MN
authors.lastname: Yurova
authors.forename: Anna V
authors.initials: AV
authors.lastname: Semenchenko
authors.forename: Margarita L
authors.initials: ML
authors.lastname: Tyndyk
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Panchenko
authors.forename: Alexandr P
authors.initials: AP
authors.lastname: Trashkov
authors.forename: Andrey G
authors.initials: AG
authors.lastname: Vasiliev
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Khaitsev
mesh_terms: D000375:Aging / Q000187:drug effects*; D000818:Animals; D000831:Animals, Newborn; D001831:Body Temperature; D001835:Body Weight / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008136:Longevity / Q000187:drug effects*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D057507:Mice, 129 Strain; D011247:Pregnancy; D016016:Proportional Hazards Models; D012737:Sex Factors; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D058570:TOR Serine-Threonine Kinases
keywords: biomarkers of aging; carcinogenesis; gender; life extension; metformin; mice; neonatal