There is no shortage of theorizing as to the root cause of the difference between male and female life expectancy in humans. Is it genetic, the influence of hormones on known longevity genes, or dietary (such as via a lower calorie intake in women on average). Or perhaps it is related to other lifestyle choices that differ in the aggregate between genders, such as risky behavior or smoking? Does this difference in longevity involve modification of any of the known mechanisms that contribute to differing rates of biological aging between individuals, or is it something else?
It's all up in the air and still open for some researcher to make his or her name by developing a definitive answer. This, of course, remains true for so much of human biology - there is a lot of work left to do. But here is a theory on gender-based longevity differences that accompanies an intriguing method to engineer extended longevity in mice:
mice created from two female genomes (bi-maternal (BM) mice) lived an average of 186 days longer than control mice created from the normal combination of a male and female genome. The average lifespan for the type of mice used in the study is between about 600-700 days, meaning that the BM mice lived approximately a third longer than normal.
The researchers checked the weight of the mice at 49 days and 600 days (around 20 months after birth) and found that the BM mice were significantly lighter and smaller than the control mice. The BM mice also seemed to have better immune systems, with a significant increase in one type of white blood cell, eosinophil.
We believe that the most likely reason for the differences in longevity relates to the repression of a gene called Rasgrf1 in the BM mice. This gene normally expresses from the paternally inherited chromosome and is an imprinted gene on chromosome 9 associated with post-natal growth. Thus far, it's not clear whether Rasgrf1 is definitively associated with mouse longevity, but it is one of the strong candidates for a responsible gene.
Our results are consistent with models based on sex-specific selection of reproductive strategies, e.g. male individuals maximizing fitness by an intense investment in reproduction by way of a larger body size in order to achieve more breeding opportunities, resulting in shorter longevity…. In contrast, female individuals usually do not engage in such costly male behaviours and instead tend to optimize their reproductive output by conserving energy for delivery, providing for offspring, foraging and predator avoidance. Our results further suggested sex differences in longevity originating at the genome level, implying that the sperm genome has a detrimental effect on longevity in mammals.
That last paragraph is the bullet point on male-female longevity differences: it's the genes, evolution did it, and the biochemistry is just an implementation detail. At which point we'll drop that line of thinking for the moment to focus on the fact that here is demonstrated a previously unknown 30% life extension mechanism in mice that - at first glance at least - appears to be unrelated to calorie restriction. There aren't too many of those yet.