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 (C20%, P < 0.05) and slightly increased the maximum life span (C3.5%). 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.

Metformin: A Hopeful Promise in Aging Research

“…Although female mice were initially found to show a better response to metformin supplementation, recent results from our laboratory indicated no gender or stain differences in the actions of metformin (Martin-Montalvo et al 2013). Therefore, to establish the molecular mechanisms and pathways of aging, it is imperative to investigate potential hormone-metformin interactions in male and female animals of varying ages, as the age of starting metformin treatment determines whether an increase in mean and maximum life span occurs (Menendez et al 2011;Anisimov et al 2015). There are not enough studies to conclude whether there are epigenetic/genetic differences in metformin effect on aging, life span, and tumorigenesis.…”

“…Subcutaneous administration of metformin (100 mg/kg body weight) in 3-, 5-, and 7-dold 129/Sv mouse pups caused an inversion of the gender response to the prolongevity effects of the drug (Anisimov et al 2015). These investigators reported an increase in mean life span (þ20%) and a slight maximum life span extension (þ3.5%) in males who received metformin neonatally, while a decrease in mean and median life span (29.1% and 213.8%, respectively) without significant differences in maximum life span was observed when female mouse pups were treated with metformin, as compared with control animals.…”

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

“…In order to know if the Fus1 knockout female mice display the behavioral and biochemical alterations characteristic for sAD at early stages, we implemented a battery of behavioral tests comparing KO mice with the age- gender- and strain- matched WT mice. We used 4–5 months old mice, the age in which the control mice are considered mature adults but not yet affected by senescence (86% survival at age of 500 days, Anisimov et al, 2015). …”

Metformin — today’s panacea?

“…The endpoint of the study was reaching the age of 800 days, and almost half male of the control group and nearly 75% of the research group lived till that time. Slightly more than 50% of female mice of the control group and only 1/3 of the research group lived till that time [38]. The results of the research carried out by the Research Team from the National Institute on Ageing, Baltimore (USA) present the correlation of the applied metformin dose on the size of the effect prolonging life.…”