Gender differences in free radical homeostasis during aging: shorter-lived female C57BL6 mice have increased oxidative stress

Summary Gender is a profound determinant of aging and lifespan,but little is known about gender differences in free radicalhomeostasis. Free radicals are proposed as key elementsin the multifactorial process of aging and it is predictedthat the longer-lived gender should have lower levels ofoxidative stress. While the majority of studies on aginghave included a single gender, recent studies in rats com-pared genders and found that females, the longer-livedsex, had lower oxidative stress and mitochondrial dys-function than males. We explored the associationbetween oxidative stress and gender-specific aging inC57BL6 mice, in which females are the shorter-lived gender.Reactive oxygen species (ROS) were measured in youngand old mice by confocal imaging of dihydroethidium(DHE) oxidation in the brain, and by electron para-magnetic resonance (EPR) spectrometry of isolated brainmitochondria. Both genders exhibited significant age-dependent increases in ROS. However, females had agreater increase with age than males in DHE oxidation butnot mitochondrial EPR. Superoxide dismutase 1 (Sod1)and glutathione peroxidase 1 (GPx1) protein levels werelower in old females. To determine whether enhancingantioxidant defenses would eliminate gender differencesin lifespan, mice were treated chronically with a superoxidedismutase mimetic. Treatment blocked the age-dependentincrease in ROS, with a greater effect in females on DHEoxidation, but not mitochondrial EPR. Treatment alsoincreased lifespan to a greater degree in females. Ourresults indicate that differences in ROS homeostasis con-tribute to gender divergence in survival, but also suggestthat mitochondrial superoxide production may not beprimarily responsible for gender differences in lifespan.Key words: aging; free radicals; gender; mitochondria;oxidative stress.