Women tend to live longer than men, a difference that seems to apply to female vs male individuals across the animal kingdom. Why is this the case?

Genetically, most women have two X chromosomes, and most men have one X and one Y chromosome.

X chromosomes contain hundreds of protein-encoding genes, while Y chromosomes, although poorer in genetic material, carry the gene that determines male traits, such as the development of testes. This gene is called "SRY."

Existing research has shown that, on average, women tend to live longer than men, and many mammals show this same pattern, with females outliving males.

No one is yet sure exactly why this is the case, but a new study by researchers from the University of California, San Francisco (UCSF) may now offer an explanation.

Their findings, which feature in the journal Aging Cell and are available to read online, reveal that the XX chromosomal pairing comprises genetic material that can extend lifespan, but only in the presence of corresponding female hormones, which the ovaries secrete.

"We've long wondered what causes female longevity," says senior author Dr. Dena Dubal, an associate professor of neurology at UCSF.

"One can imagine nature has driven females to evolve this way. When you're living longer, you can really ensure the well-being of your offspring and maybe even their offspring."

—Dr. Dena Dubal

Not just about the genes

In the new study, the research team used a mouse model to try to understand what might give females an advantage in terms of lifespan.

The researchers genetically engineered mice so that they would belong to one of four categories. Thus, some of the mice had XX chromosomes and developed ovaries, and some had XY chromosomes and developed testes, which is what would usually happen in nature. The remaining mice had either XX chromosomes and testes or XY chromosomes and ovaries.

Dr. Dubal and team were able to achieve this by moving the SRY gene from the Y chromosome to another chromosome that does not determine sex. This meant that mice would be able to inherit it whether or not they inherited the Y chromosome.

The researchers found that all the mice with the XX chromosomal pairing tended to survive longer than those with XY chromosomes, regardless of whether they had ovaries or testes.

However, when it came to enjoying a truly prolonged lifespan, only the mice who had both XX chromosomes and ovaries experienced extended life. This implies that both genetic makeup and hormonal profile played an important role in ensuring longevity.

"This suggests that the hormones produced by female gonads increase lifespan in mice with two X chromosomes, either by influencing how the mouse develops or by activating certain biological pathways during their lives," explains Dr. Dubal.

Having 2 X chromosomes is an advantage

In contrasting the characteristics of the two sets of genetically female mice, which had identical chromosomal pairings but different sets of gonads, the investigators noticed that the XX mice that had grown ovaries lived longer than their counterparts with testes. They measured this from the 21-month mark, which is as long as mice typically live.

"For an expanded lifespan, the mice needed to have ovaries working with XX," says study co-author Iryna Lobach, PhD.

"But, in terms of living a normal lifespan," she adds, "it didn't matter if they had ovaries or testes. As long as they had XX, they escaped early death during aging."

Still, Dubal notes, "We don't yet understand how the second X chromosome decreases mortality in aging."

However, some mechanisms that researchers have previously studied may offer some clues. For example, in female individuals, one X chromosome in every cell is randomly deactivated.

This ensures that, if the active X chromosome becomes damaged, the inactive X can step in and take over. While researchers need to investigate this line of inquiry and others more closely, Dr. Dubal stresses that individuals with two X chromosomes appear to be the winners of the genetic lottery.

"When things go wrong in aging, having more of the X chromosome, along with its diversity of expression, could be really beneficial," Dr. Dubal explains.