Do Women Age Differently Than Men? Research Looks at Key Differences in Autophagy, Intestinal Health, and Lifespan

Across countries and cultures, it’s well-documented that women live longer than men. In the United States, the average female lifespan is about five years longer than men; worldwide data shows a seven-year increase for women. However, women tend to suffer more often from age-related diseases, although that doesn’t seem to affect life expectancy. So, what causes these discrepancies? 

There are some valid theories—like that men tend to be bigger risk-takers, leading to often-fatal situations, or that they are more likely to have dangerous jobs and skip out on annual physical checkups. However, researchers have also wondered if there are biological reasons, on a cellular level, for these gender-specific differences. 

In a recent study published in Nature Aging, researchers primarily based out of the Max Planck Institute for Biology of Ageing in Cologne, Germany, aimed to get to the bottom of these divergences. As Yu-Xuan Lu, one of the study's leading authors, explains, “Our long-term goal is to make men live as long as women and women as healthy as men in late life. But for that, we need to understand where the differences come from.”

In this study, Lu and colleagues used the drug rapamycin on male and female fruit flies to test its anti-aging effects on the two sexes. They uncovered that rapamycin extended lifespan and slowed age-related intestinal pathologies in female flies but not in males—and changes in autophagy were often behind these variations. 

A Look at Autophagy and How Rapamycin Affects It

From the word "self-eating" in Greek, autophagy is a natural, regulated internal mechanism that removes unnecessary or damaged cells or cell parts. Without autophagy, dysfunctional or toxic cells and proteins accumulate and increase the risk of age-related bodily decline. With advancing age, our autophagic abilities drop progressively in all organs and tissues. 

Previous research has found that sex-specific variations in autophagy have been detected from early development to adulthood and may contribute to the more significant female vulnerability to certain age-related conditions. There are also variabilities in how males and females respond to drugs or treatments, including rapamycin—which is ​​currently the only pharmacological intervention that extends lifespan across all major models studied. 

Rapamycin works by inhibiting the mTOR complex 1 (mTORC1), a signaling pathway that ​​regulates vital cellular functions, including autophagy and cell growth, division, and death. However, scientists have also linked the overactivation of mTOR to various disease processes, including aging. Previous studies have shown that rapamycin extends lifespan substantially more in female fruit flies than males. Still, the effects of rapamycin on aging pathologies in male fruit flies haven’t been well explored. 

Rapamycin Lengthens Lifespan and Augments Autophagy in Females 

In this research, Lu and colleagues gave varying doses of rapamycin to female and male fruit flies. At all doses, females responded much more favorably to rapamycin than males, with females living about ten days longer than males (approximately 78 versus 88 days in males and females, respectively). 

One of the reasons for these variations may be that rapamycin increased autophagy in the females' intestinal cells. In contrast, the males’ intestinal cells already had higher baseline autophagy activity, which rapamycin treatment could not further increase. Lu explains, “Previous studies found that females had greater responses to rapamycin on lifespan extension than did males in mice; we now uncover an underlying mechanism of these differences using flies.”

Autophagy in intestinal cells was a crucial player in these processes, as genetically suppressing autophagy led to decreased lifespan. There were other effects of rapamycin on the gut, including that the females had better intestinal barrier function and reductions in age-related gut pathologies after taking the anti-aging drug. The authors of this study reported on the importance of this link, stating, “Intestinal barrier function maintenance is a key determinant of fruit fly lifespan.” 

So, while males may have shorter lifespans, they have healthier autophagic processes that lead to better intestinal function and fewer age-related conditions. On the other hand, females pay a cost for their longer lifespans: lower autophagy and higher rates of cell growth, leading to pathological conditions and dysplasia—abnormal cells that precede disease—at older ages.

A Step Closer to Understanding Sex-Specific Longevity

While this study provides more knowledge about sex-specific variations in lifespan, autophagy, and response to certain drugs in fruit flies, we are far from knowing if these changes would be the same in humans. We also can’t extrapolate how life expectancy and rapamycin research would translate to transgender people or those elsewhere on the sex-gender spectrum. 

Overall, understanding how sex influences the development of age-related diseases and responses to drugs will be essential for anti-aging and longevity-focused therapies. As Linda Partridge, a British geneticist at the University College London and the study's senior author, concludes, “Sex can be a decisive factor for the effectiveness of anti-ageing drugs. Understanding the processes that are sex-specific and determine response to therapeutics will improve the development of personalised treatments.”

References: 

Bjedov I, Toivonen JM, Kerr F, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 2010;11(1):35-46. doi:10.1016/j.cmet.2009.11.010

Papadopoli D, Boulay K, Kazak L, et al. mTOR as a central regulator of lifespan and aging. F1000Res. 2019;8:F1000 Faculty Rev-998. Published 2019 Jul 2. doi:10.12688/f1000research.17196.1

Regan JC, Lu YX, Ureña E., et al. Sexual identity of enterocytes regulates autophagy to determine intestinal health, lifespan, and responses to rapamycin. Nature Aging. 2022;1145-1158. https://doi.org/10.1038/s43587-022-00308-7