In the late fall of 1846, 87 California-bound pioneers found themselves stranded in the deepening snows of the Sierra Nevada mountains with little food and inept leadership, and with winter coming on fast. It would be months before rescue —if at all — was likely. This was the Donner Party, now infamous because some ultimately resorted to murder and cannibalism for survival.

Although the psychological pressures that led to the cannibalism (even of children) are fascinating 173 years later, what interests me most about this well-documented catastrophe is who died and who survived. Of the 87 original members (89 if you count two Native American men who joined them late and were eventually murdered), 47 members of the Donner Party survived. More than half of the men died of starvation or disease, but more than 70% of the women survived.

The Donner party is not an isolated case. Women always survive better than men. To take another striking case, in Iceland during the 19th century, life expectancy rose as high as 57 years during good times and plunged to as low as 18 years during famine or disease epidemics. But regardless of whether life expectancy was low or high, women lived longer than men in every single year.

That is still true today: Women live longer in all countries with reliable record-keeping. They survive better as infants, adolescents, adults and in old age.

Why do females survive longer?

One thing we know it isn’t is greater resistance to any single health problem. At similar ages, men in the U.S. are 60% more likely to die of heart disease, 40% more likely to die of cancer, more than twice as likely to die from accidents and 20% more likely to die of chronic lung disease. These are the top four causes of death in modern America. In fact, of the top 10 causes of death, women die more frequently of only one: Alzheimer’s disease.

To what is this greater female hardiness due? To tell the truth, we simply don’t know. Suspicion has fallen on hormones, of course. Could it be some kind of toxic effect of testosterone? In the first year of life, boy babies do have a spike in testosterone that then goes away again until puberty, when it roars back. Interestingly, a three-century-long study in Korea found that eunuchs, or castrated men, in royal court society lived about 20 years longer than the “intact” men.

Today, recent research suggests that sex chromosomes affect longevity more than hormones.

Dr. Dena Dubal, of the University of California San Francisco and a three-time grantee of the American Federation for Aging Research, has explored sex differences in longevity using mice that had been genetically engineered to have male reproductive organs (and hormones), regardless of whether they had the normal male complement of one X and one Y chromosome or instead had two X chromosomes like females normally do.

Similarly, other mice in Dubal’s study were engineered to develop female reproductive parts whether they had the normal two X chromosomes or an X and a Y pair like normal males. The surprising result was that having two X chromosomes led to longer mouse life, regardless of whether their reproductive sex was male or female. At this point, it isn’t clear whether the survival advantage is due to having two Xs or lacking the Y chromosome. In either case, this brings us closer to understanding the basis for male-female longevity differences.

Knowing more informs longevity drug development

Understanding sex differences and aging also has implications for the future of drug interventions to extend health as we grow older. Six drugs have been shown by multiple research labs to make mice live and stay healthy longer. Five of these drugs either have this effect only in males or have a much bigger effect in males than females. Conversely, the sixth drug, rapamycin, has a bigger effect in females.

AFAR-supported investigator Dr. Dudley Lamming, an assistant professor at the University of Wisconsin-Madison, for example, has studied how a gene called “RICTOR” may be responsible for the differential effects of the drug rapamycin in males and females. The gene is involved in many bodily functions, including growth and development, as well as diseases such as diabetes and cancer.

Inactivating RICTOR in the liver alone has no effect on female longevity, but shortens the lives of male mice. Dr. Lamming is testing whether sex hormones, such as estrogen and testosterone, affect what RICTOR does in the liver, and whether these hormones are important regulators of mouse longevity. So, the more we understand sex differences and aging, the better we can understand which of these health-extending medications might be more beneficial to men versus women, or vice versa.

From hormones to chromosomes, biological differences between men and women reveal fascinating paths to better understanding of longevity at any age.