Why Do Women Live Longer Than Men?

Long ago, researchers have observed that in humans and mammals, but also in insects (like the much-studied fruit fly Drosophila melanogaster) or other invertebrates (like octopuses) females tend to live longer than men.

Now, molecular biologist John Tower of the University of Southern California has proposed a new provocative model trying to solve this puzzle after genetic studies made on fruit flies revealed that genes which increase longevity always affect males and females differently.

His team found that genetic effects on longevity were highly sex-specific. His team found previously that a gene for the antioxidant enzyme Cu/Zn-superoxide dismutase (SOD) induces a longer life span in male flies, but had a slight impact in females and the p53 gene, which encodes a protein that suppresses cancerous growth but also shortens life span, also acted differently in both genders.

Scientists were surprised as they had assumed that aging was biologically identical in males and females.

Thus, based on the work of his team and on extensive meta-analysis of other researches, and investigating organisms ranging from alga to mice, Tower made a new model linking aging and sex, predicting which genes are most likely to regulate the life span of an organism.

"It's quite remarkable that women tend to survive better than men. It's not only hormones. The differences are present at birth [in humans], with boys more vulnerable to infant mortality up to age 1. There's something really different about how we [males and females] are built from the very beginning. And it's something that is still not well understood", said USC's Caleb Finch, a University Professor and the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging.

"With this model, Tower has made a significant contribution by suggesting new avenues to probe the biological basis of sex differences in aging," said Finch, a professor of gerontology, biological sciences and psychology. "The two sexes represent completely different environments for expression of genes affecting life span", said Trudy Mackay, a distinguished fruit fly geneticist at North Carolina State University.

Tower's studies on aging have focused on increasing life span by inducing changes in genes encoding the superoxidase dismutase (SOD) enzymes, the most powerful and ancient antioxidants. Antioxidants fight against free radicals, byproducts of the oxidations occurring inside the organism while the cells produce energy, harmful to DNA, protein and the other molecules.

The "oxidative stress" theory of aging states that age-related diseases like arthritis, dementia (Alzheimer), cancer, Parkinson's and others are the result of free radicals accumulation. At the basics, "oxidative stress" depends on the mitochondria, the powerhouses of the cell where all oxidations occur.

The mitochondria evolved from free-living bacteria which possess their own DNA, completely distinct from the cell's nuclear genome (DNA from nucleus).

Nuclear DNA is transmitted from both parents, but the mitochondrial DNA is received only from the female. Tower depicts a kind of Darwinian battle of the sexes played out on the DNA level called sexual antagonistic pleiotropy. As the mitochondrial DNA is inherited from the mother, evolution could have chosen versions better suited for the female body, explaining the longevity differences observed between the two sexes.

Tower's model comes with a new way of explaining how this could happen. Mitochondria regulates the programmed cell death (apoptosis), employed during normal embryonic development and sexual differentiation, molding the body by destroying unwanted cells.

Apoptosis, in which the p53 has a main role, seems to malfunction more frequently over an organism's lifetime, being a main player in aging and aging-related diseases. "This might happen more often or differently in males, leading to a shorter life span", said Tower.

He is very interested in the human Xist gene, which controls sex determination and could be extremely involved in determining human life span. His team will work on the analogue gene found in the fruit fly, called Sxl (sex lethal gene), to see how it influences Drosophila life span. "If my model is correct, Sxl in Drosophila and Xist genes in humans should be involved in sending a signal to the mitochondria that will make them viable longer and thereby make the organism live longer".

"This mechanism may inadvertently result in the molecular processes of aging", said Tower. "[The model] has enough to keep a small army of graduate students busy for many years," said George Martin, an expert in genetics of longevity at the University of Washington School of Medicine in Seattle. "Some [predictions] should be quickly amenable to testing, such as the prediction that female life span may be more limited by the insulin-like signaling pathway and dietary restriction, while male life span may be more limited by stresses such as oxidative stress. Some [other predictions]� already are supported by preliminary data."