Research on aging treatments keeps turning up profound variations in how male and female subjects respond.
There’s a drug that makes mice live 8 percent longer — but only if they’re male. Female mice get roughly that amount of benefit from a totally different treatment, which does nothing for males.
These aren’t just one-off quirks in longevity research. A growing body of scientific research suggests that getting older plays out very differently in males and females. To make significant progress in fighting the diseases associated with aging, researchers will have to better understand and address these sex disparities.
“Males and females are more different organisms than we had originally appreciated, especially when it comes to longevity,” says David Sinclair, a geneticist and co-director of the Paul F. Glenn Center for the Biological Mechanisms of Aging at Harvard Medical School.
Life expectancy for women is generally longer than for men. In the United States, a girl born in 2014 could expect to live past age 81, while a boy was likely to survive five years less, to 76.5. The same is true in other higher-order primates, including monkeys and apes, research shows, although the pattern is not consistent across other mammal species.
But early anti-aging research, like most scientific investigations, focused just on male animals. Even when their experiments were in Petri dishes, scientists generally used cells from males.
“For years, people just didn’t really think there was going to be any difference,” says Derek Huffman, an associate professor of molecular pharmacology and medicine at the Albert Einstein College of Medicine in New York. “I think we’re finding out that that is a very dangerous assumption to make.”
In the early 1990s, the U.S. National Institutes of Health began requiring sex balance in the clinical trials it funded. But in 2014, the institutes realized that basic research was still largely biased toward male animals. Francis Collins, the head of the NIH, demanded more balance. “We’re now at a point where you can’t do a serious study without including females,” says Sinclair, who adds that this has essentially doubled the cost of research.
Once they began looking, longevity researchers realized that male and female animals responded very differently to medications intended to promote healthy aging. For instance, male mice live about 8 percent longer if given the equivalent of a low-dose aspirin a day; female mice see no such benefit. Likewise, a weak form of estrogen called 17α-Estradiol has been shown to extend the life span of male mice and do nothing for females.
“There doesn’t seem to be any rhyme or reason to it.”
Female mice, on the other hand, live 14 percent longer than expected when given rapamycin, which is used to prevent organ rejection after kidney transplants, while males get a 9 percent boost. And in a study published in June in Nature Communications, Huffman showed that the growth hormone IGF-1 extends the healthy life span of female mice by 9 percent, while doing little for male mice.
“There doesn’t seem to be any rhyme or reason to it,” Sinclair says.
The disparities seem to exist in people, too, says Brian Kennedy, director of the center for healthy aging at the National University of Singapore and a professor at the Buck Institute for Research on Aging in Novato, California. “My guess is there will be correspondence between what we see in mice and humans,” he says.
There’s a lot of speculation about why this is so, but no hard evidence.
The immediate assumption is that the difference has to do with hormones. Males are exposed to a lifetime of testosterone; females to estrogen. Studies show that men who have been castrated live longer than men who haven’t been, suggesting that testosterone may shorten life span.
The immune system also seems to play a crucial — and sex-dependent — role in aging. Male immune systems apparently weaken faster than their female counterparts, says Huffman. And drugs that address inflammation seem to provide more longevity benefit to males than females — at least in mice.
“We’re now at a point where you can’t do a serious study without including females.”
One particularly odd thing in humans is that though women live longer, they are nonetheless more prone to miserable but non-deadly ailments such as arthritis, Huffman says. Lethal illnesses such as heart disease and cancer strike men more often. (Although Alzheimer’s strikes women more than men, for unknown reasons.)
There’s no clear explanation for this paradox, Huffman says. “That’s a story still to be told.”
Ultra-personalized longevity
To complicate this picture further, the gender differences don’t always crop up. In a study published Monday in Nature Medicine, mice of both sexes got the same increase in healthy life span from drugs that cleared out so-called “senescent cells” — ones that are too old or damaged to reproduce.
Why might that be? James Kirkland, the paper’s senior author and director of the Robert and Arlene Kogod Center on Aging at the Mayo Clinic, says it’s possibly because senescence is such a fundamental biological process that it affects both sexes equally. But he really doesn’t know. (Kirkland says he wouldn’t recommend that people take “senolytic” drugs to clear out these senescent cells because the side effects remain largely unexplored.)
Kennedy has been wondering whether sex differences in aging can be explained by the activity of genes on the Y chromosome. (Men have an X and a Y chromosome; women have two X’s). He’s now tinkering with the sex chromosome of mice — making some males with XX, for instance, to see if the difference disappears.
Sex differences should also serve as a reminder, Kennedy says, that researchers need to be looking at variations by ethnicity and other factors, too. If he’s right, treating aging will be just like most areas of medicine: it will have to be personalized by many things. Longevity won’t be as easy to achieve as simply handing everyone the same pill.
This story was updated on July 16 to correct the description of Kirkland’s reason for caution about senolytic drugs.
